* 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.
Stage #1: With potassium hydroxide In methanol; water for 3 h;
To a stirring solution of 1 (19.4 g, 100 mmol) in methanol (100 mL) and water (400 mL) was added 5N KOH solution (200mL). The reaction mixture was heated to refluxing and stirred for 3 h. Cooled to room temperature, the mixture was adjusted to pH 3 with 5N HCl, and then filtered. The precipitate was washed with water and dried in vacuo to give the title compound 2 (15.5 g, 94 percent) as an yellowish brown solid.
93%
Stage #1: With potassium hydroxide; water In methanol for 3 h; Heating / reflux Stage #2: With hydrogenchloride In methanol; water
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid which formed was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6)δ: 12.09 (s, br, 2N, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
93%
With potassium hydroxide; water In methanol for 3 h; Heating / reflux
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3),2.40 (s, 3H, CH3).
93%
Stage #1: With potassium hydroxide; water In methanol for 3 h; Heating / reflux Stage #2: With hydrogenchloride In methanol; water at 20℃;
[0168] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
93.5%
Stage #1: With water; potassium hydroxide In methanol at 60 - 70℃; for 4 - 6 h; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃;
Step (iv): Preparation of 5-formyl-2,4-dimethyI-lH-pyrrole-3-carboxylic acid (V):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition runnel and reflux condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70° C and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with cone. HCl. The resulting solution was stirred over night at 25-30° C. The product was filtered and washed with water. The product was dried at 60° C. Dry Weight: 0.483 Kg Yield: 93.5percent HPLC purity: 99.8percent
93.5%
With water; potassium hydroxide In methanol at 60 - 70℃; for 4 - 6 h;
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70oC. and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with conc. HCl. The resulting solution was stirred over night at 25-30oC. The product was filtered and washed with water. The product was dried at 60oC. Dry Weight: 0.483 Kg Yield: 93.5percent HPLC purity: 99.8percent
92%
With sodium hydroxide In methanol; water for 4 h; Reflux
24,4-dimethyl-5-formyl -1H- pyrrole-3-carboxylate (0.9g, 4.6mmol) in methanol (5ml) was added sodium hydroxide (1.0g) in water (8ml) solution of was heated at reflux for 4h, cooled to room temperature, poured into ice water (16ml) was added methylene chloride (10ml), standing layer was collected and the aqueous layer was adjusted with 10percent hydrochloric acid, pH3, and the filter cake was washed with cold water, and dried to give a pale yellow solid 11 (0.71g, 92percent).
91%
With water; sodium hydroxide In methanol at 82 - 83℃; for 4.5 h; Inert atmosphere
To a three-necked flask equipped with a thermometer, ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate (9, 1.17 g, 6.0 mmol) and methanol (6.0 mL) were added with stirring, to which was added solution of sodium hydroxide (1.20 g) in water (10 mL). The reaction mixture was kept under reflux at 82-83 °C for 4.5 h under nitrogen atmosphere. The mixture was then cooled down to r.t. before being added into ice-water (20 mL). The obtained mixture was extracted with dichloromethane (12 mL). The organic layer was then washed with water (15 mL 9 3) until there was no absorption under ultraviolet (UV) light. The aqueous layers were combined before being acidified with hydrochloride (2.0 mol/L) to pH 2 until many precipitates appeared from the mixture. The yellowish solids were obtained via filtrating under vacuum, washing with water, and drying under vacuum to provide 3 (0.91 g, 91 percent), m.p. >250 °C (sublimes and decomposes) (lit. 275-277° C [13]), yield 90.0 percent (lit. [13]). Rf = 0.28 (eluent: chloroform/methanol, v/v = 10:1 or petroleum ether/ethylacetate, v/v = 10:1). Electrospray ionization (EI) mass spectroscopy (MS) m/z (percent): 167.1 ([M]+, 100), 138.1 (20), 121.1 (60). 1H NMR (DMSO-d6) δ: 1.35 (t, 3H, J = 7.3 Hz, CH3), 2.53 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.29 (q, 2H,J = 7.3 Hz, CH2), 7.24 (s, 1H, pyrrole-1-NH), 9.97 (s, 1H, CHO).
89%
Stage #1: Heating / reflux
Step If. 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (compound 108) <n="58"/>A solution of KOH (6.2 g, 11 lmmol) in water (400 mL) was added to a solution of compound 507 (7.2 g, 37mmol) in ethanol (60 mL). The mixture was refluxed until the reaction was completed. The mixture was cooled to room temperature and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified to pH=2 with IN HCl. The precipitate was collected by filtration, washed with water and dried to give yellow solid product 108 (5.5 g, 89percent). LCMS: m/z 168(M+1), 1H NMR(DMSO-^6) δ2.40 (s, 3H), 2.43 (s, 3H), 9.24 (s,lH), 12.14 (bs, 2H).
89%
Stage #1: With potassium hydroxide; water In ethanolHeating / reflux Stage #2: With hydrogenchloride In ethanol; water
A solution of KOH (6.2 g, 11 lmmol) in water (400 mL) was added to a solution of compound 507 (7.2 g, 37mmol) in ethanol (60 mL). The mixture was refluxed until the reaction was completed. The mixture was cooled to room temperature and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified to pH=2 with IN HCl. The precipitate was collected by filtration, washed with water and dried to give yellow solid product 108 (5.5 g, 89percent). LCMS: m/z 168(M+1), 1H NMR(DMSO-J6) δ2.40 (s, 3H), 2.43 (s, 3H), 9.24 (s,lH), 12.14 (bs, 2H).
81%
Stage #1: With water; potassium hydroxide In ethanol at 120℃; for 1.5 h; Inert atmosphere Stage #2: With hydrogenchloride In ethanol; water
2-formyl-3,5-dimethylpyrrole-4-carboxylic acid4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxylic acid tert-Bu-ester 16.35g was dissolved in neat trifluoroacetic acid 85 mL and the solution was stirred at room temperature for 30 min (the mix turned Burgundy red with gas evolution), then cooled to +5 °C on ice/water bath. Neat triethyl orthoformate 16.5 mL (1.6 eq.) was added and the mix was stirred at +5 °C for 35 min, then concentrated on rotovap from ambient water bath to a small volume. The residue was diluted gradually with water addition, 300mL, the resulting slurry was shaken for 5 min and the precipitated ethyl ester intermediate was collected by filtration, washed thoroughly with water and dried by suction.This ethyl ester intermediate was suspended in ethanol 150 mL, placed on a120 °C oil bath and stirred to complete dissolution. A solution of KOH 20g (pellets, 85percent) in water 200mL was then added to the mix, the flask was equipped with a short- path distillation adaptor and the reaction mixture was distilled under a stream of nitrogen gas on a 120 °C oil bath for 90 min. (Only water distilled at this point and the ethyl ester hydrolysis was complete by HPLC). The reaction mixture was cooled, charcoal (5 spoons) was added and the reaction mix was then stirred on ambient water bath for 30 min, and filtered (the charcoal was thoroughly washed with water). The combined filtrates were acidified with addition of 6M HC1, the precipitated product was collected by filtration on a large Buchner funnel, washed with water and semi- dried by suction. The crude product was dissolved in EtOH (900mL) at reflux, the solution was allowed to crystallize at ambient temperature overnight (14 hours). The product was collected by filtration, washed with EtOH, dried by suction and on highvac. Concentrating the supernatants to a small volume, diluting the slurry with ethanol lOOmL and refluxing the mix for 30 min, then letting the mix to crystallize at RT overnight provided a second crop of a pure product. The combined yield was 8.32g (81percent overall) of a light-tan crystalline solid. 1H-NMR (d6-DMSO, 400MHz): 12.12(s, 1H), 12.10(very br s, 1H), 9.61(s, 1H), 2.46(s, 3H), 2.42(s, 3H)
93%
With potassium hydroxide In methanol; water
Step 3 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 103691 1H NMR (300 MHz, DMSO-d6) 5 12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3). MS m/z 167 (M+).
93%
With potassium hydroxide In methanol; water
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3). MS m/z 167 ((M+)).
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 248 - 262
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 139 - 146
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2782 - 2787
[5] Journal of Medicinal Chemistry, 2003, vol. 46, # 7, p. 1116 - 1119
[6] Patent: US6878733, 2005, B1, . Location in patent: Page/Page column 182
[7] Patent: US2004/204407, 2004, A1, . Location in patent: Page/Page column 14-15
[8] Patent: US2004/266843, 2004, A1, . Location in patent: Page 10; 11
[9] Patent: WO2009/157011, 2009, A1, . Location in patent: Page/Page column 29
[10] Patent: US2011/92717, 2011, A1, . Location in patent: Page/Page column 14-15
[11] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1723 - 1729
[12] Patent: CN102898402, 2016, B, . Location in patent: Sheet 0307-0309
[13] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[14] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[15] Patent: WO2008/33743, 2008, A1, . Location in patent: Page/Page column 53; 56-57
[16] Patent: WO2008/33747, 2008, A2, . Location in patent: Page/Page column 201
[17] Journal of Labelled Compounds and Radiopharmaceuticals, 2009, vol. 52, # 9, p. 360 - 365
[18] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[19] Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 2018, vol. 1092, p. 515 - 523
[20] Patent: WO2011/119777, 2011, A2, . Location in patent: Page/Page column 32-33
[21] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 807 - 812
[22] Chemische Berichte, 1923, vol. 56, p. 526
[23] Patent: US2003/69297, 2003, A1,
[24] Patent: US2003/125370, 2003, A1,
[25] Patent: WO2012/59941, 2012, A1, . Location in patent: Page/Page column 16
[26] Journal of the American Chemical Society, 2018, vol. 140, # 18, p. 5882 - 5885
[27] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2391 - 2398
2
[ 2199-59-9 ]
[ 253870-02-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium hydroxide In methanol; water
Step 2 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.6 g, 93percent). 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
93%
With potassium hydroxide In methanol; water
Step 2 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.6 g, 93percent). 1H NMR (300 MHz, DMSO-d6) δ12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
93%
With potassium hydroxide In methanol; water
Step 2 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.6 g, 93percent). 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH and COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
Reference：
[1] Synlett, 2010, # 17, p. 2561 - 2564
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 23, p. 3834 - 3845
4
[ 86770-31-2 ]
[ 253870-02-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 7, p. 1116 - 1119
[2] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[3] Patent: US2011/92717, 2011, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[5] Patent: WO2011/119777, 2011, A2,
[6] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1723 - 1729
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[8] Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 2018, vol. 1092, p. 515 - 523
5
[ 2199-51-1 ]
[ 253870-02-9 ]
Reference：
[1] Patent: US2011/92717, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2009, vol. 52, # 9, p. 360 - 365
[4] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1723 - 1729
[5] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[6] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[7] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 807 - 812
[8] Patent: CN102898402, 2016, B,
[9] Journal of the American Chemical Society, 2018, vol. 140, # 18, p. 5882 - 5885
6
[ 89909-48-8 ]
[ 253870-02-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 23, p. 3834 - 3845
7
[ 37059-10-2 ]
[ 253870-02-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 23, p. 3834 - 3845
8
[ 2436-79-5 ]
[ 253870-02-9 ]
Reference：
[1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[2] Patent: CN102898402, 2016, B,
9
[ 5442-91-1 ]
[ 253870-02-9 ]
Reference：
[1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
[2] Patent: CN102898402, 2016, B,
10
[ 253870-02-9 ]
[ 2199-59-9 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 85, p. 268 - 288
11
[ 253870-02-9 ]
[ 616-40-0 ]
[ 356068-86-5 ]
Yield
Reaction Conditions
Operation in experiment
86.3%
With dmap; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 59 h;
To a three-necked flask equipped with a thermometer, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3, 5.50 g, 32.7 mmol) and anhydrous DMF (13.1 mL) were added while being cooled down to 0 °C with an ice-salt bath. To the above mixture was added dropwise a solution of dicyclohexylcarbodiimide (DCC, 10.13 g, 49.0 mmol) in dichloromethane (78.4 mL) under stirring while keeping the reaction temperature between 0 and 2 °C, to which were then added at r.t. 4-dimethylaminopyridine (DMAP, 1.65 g) and N1,N1-diethylethane-1,2-diamine (4, 5.03 mL, 35.9 mmol). The reaction mixture was then allowed to react at r.t. for 59 h with TLC monitoring (eluent: chloroform/methanol, v/v = 5:1). The filtrate obtained from filtration was added with water, which was extracted with dichloromethane (15 mL x 3). The organic layers were combined, washed withsaturated brine (65.7 mL), then dried over anhydrous sodium sulfate. The filtrate was concentrated to give some solids, which were dissolved in a small amount of dichloromethane (5.0 mL). The obtained organic phase was washed with aqueous citric acid solution (5.0 percent, 330 mL x 3) until there was no product in the organic layer (as monitored by TLC). The reason was that the weak basic product 10 could form a water-soluble salt with citric acid. The aqueous phase was then basified with saturated aqueous sodium hydroxide solution and a large amount of aqueous sodium bicarbonate solution to pH 8, which was then extracted with dichloromethane (330 mL 9 3). The combined organic layers were combined and concentrated to provide brownish-red oily liquid. Further purification could be achieved with stepwise column chromatography with petroleum ether/ethyl acetate eluent (v/v = 3:1 to 1:1) to provide 10 as yellowish solid (8.11 g, 86.3 percent), m.p. 153-154 °C (lit. 177-181 °C [13]), yield 42.5 percent (lit. [13]). Rf = 0.60 (eluent: chloroform/methanol, v/v = 5:1). 1H NMR (400 MHz, DMSO-d6) δ: 11.85 (s, 1H, NH), 9.54 (s, 1H, CHO), 7.36-7.38 (t, 1H, CONH), 3.24-3.29 (m, 2H, NHCH2), 2.50-2.56 (m,6H, 3 x (N-CH2)), 2.32 (s, 3H, 4-CH3), 2.37 (s, 3H, 2-CH3), 0.95-0.99 (t, 6H, 2 x (CH3)).
Reference：
[1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8941 - 8954
12
[ 253870-02-9 ]
[ 2592-95-2 ]
[ 100-36-7 ]
[ 356068-86-5 ]
Yield
Reaction Conditions
Operation in experiment
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (819 g, 43 percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine In <i>N</i>-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10percent methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34° C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43percent yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 °C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66percent and 84percent respectively.
53%
Stage #1: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5 h; Stage #2: With triethylamine In tetrahydrofuran at 25 - 30℃; for 16 h;
Step (v): Preparation of 5-formyI-2,4-dimethyl-lH-pyrrole-3-carboxyIic acid(2-diethylaminoethyl)-amide (VII):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran(3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1 -hydroxy benzotriazole (0.306 Kg)and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30° C. After addition, the reaction mixture was stirred for 16 hours at 25-30° C and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCψ3, saturated solution of NaCl and DM water. Organic layer was separated and 3/4th of the solvent distilled under diminished pressure. The product was cooled to 0- <n="31"/>50 C and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60° C.Dry Weight: 210.2 g Yield: 53.0percent HPLC purity: 99.95percent
53%
Stage #1: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5 h; Stage #2: With triethylamine In tetrahydrofuran at 25 - 30℃; for 16 h;
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30oC. After addition, the reaction mixture was stirred for 16 hours at 25-30oC. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO3, saturated solution of NaCl and DM water. Dry Weight: 210.2 g Yield: 53.0percent HPLC purity: 99.95percent
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 21, p. 4829 - 4841
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 12, p. 5970 - 5977
[3] Patent: WO2009/157011, 2009, A1, . Location in patent: Page/Page column 29-30
[4] Patent: US2011/92717, 2011, A1, . Location in patent: Page/Page column 15
[5] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 16, p. 2153 - 2157
[6] Patent: US2003/125370, 2003, A1,
[7] Patent: WO2011/33472, 2011, A1, . Location in patent: Page/Page column 7
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3062 - 3065
[9] Patent: WO2011/110199, 2011, A1, . Location in patent: Page/Page column 14
[10] Patent: WO2012/59941, 2012, A1, . Location in patent: Page/Page column 16-17
[11] European Journal of Medicinal Chemistry, 2014, vol. 85, p. 268 - 288
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2782 - 2787
[13] Nature Chemistry, 2017, vol. 9, # 6, p. 571 - 577
14
[ 253870-02-9 ]
[ 356068-86-5 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 7, p. 2565 - 2568
15
[ 253870-02-9 ]
[ 100-36-7 ]
[ 356068-86-5 ]
Reference：
[1] Patent: US2003/69297, 2003, A1,
16
[ 253870-02-9 ]
[ 56341-41-4 ]
[ 356068-93-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: for 5 h; Reflux
(NH4)2SO4 (0.09 g, 0.67 mmol) was added into a stirred mixture of 8 (1.0 g, 6.61 mmol) in HMDS (20 mL, 20 P) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, 14 (1.1 g, 3.77 mmol) and TMSOTf (0.29 g, 1.32 mmol) were added. Then the mixture was stirred, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (6 mL, 6 P.) and MeCN (30 mL). The mixture was filtrated and the filtrate cake was washed with MeCN (20 mL) and EtOH (5 mL), then it was dried under vacuum at 40° C. overnight to give the goal product 15 (1.92 g, 97percent yield) as a yellow to brown powder with about 82.1percent HPLC purity.
96%
for 3 h; Heating / reflux
A mixture of 5-fluoro-1 , 3-dihydroindol-2-one (1.62 g, 10.2 mmol), 5- formyl^λ-dimethyl-IH-pyrrole-S-carboxylic acid (1.96 g, 10.7 mmol), pyrrolidine (12 drops) and absolute ethanol was heated to reflux for 3 hours. The mixture was cooled to 25 0C and the solids were collected by filtration. The solids were stirred with ethanol (30 mL) at 72 °C for 30min. The mixture was cooled to 25 0C and the solids were collected again by filtration, washed with ethanol (6 mL), and dried under vacuum overnight to give an orange solid (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3.094 g, 96percent). LC-ESIMS observed [M+H]+ 301 (calculated for Ci6Hi3FN2O3 300.09).
96%
With pyrrolidine In ethanol for 3 h; Heating / reflux
Exemplary Chiral Species; A general scheme for synthesizing chiral species of the invention is outline below:; Step 1 :; A mixture of 5-fluoro-1 , 3-dihydroindol-2-one (1.62 g, 10.2 mmol), 5- formyl^^-dimethyl-I H-pyrrole-S-carboxylic acid (1.96 g, 10.7 mmol), pyrrolidine (12 drops) and absolute ethanol was heated to reflux for 3 hours. The mixture was cooled to 25 0C and the solids were collected by filtration. The solids were stirred with ethanol (30 ml.) at 72 0C for 30min. The mixture was cooled to 25 0C and the solids were collected again by filtration, washed with ethanol (6 ml_), and dried under vacuum overnight to give an orange solid (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1 H-pyrrole-3- carboxylic acid (3.094 g, 96percent). LC-ESIMS observed [M+H]+ 300.95 (calculated for Ci6Hi3FN2O3 300.09).
93%
With pyrrolidine In ethanol for 3 h; Heating / reflux
Step 1 : A mixture of 5-fluoro-l,3-dihydroindol-2-one (A2) (2Og, 132mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (Al) (21. Ig, 126mmol), pyrrolidine (5ml) and absolute ethanol (40OmL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (10OmL). The solid was stirred in ethanol (350ml) at reflux for 0.5h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-lH-pyrrole-3- carboxylic acid (A3) (35.3g, 93percent) as orange solid. LC-MS observed [M-H]+: 299.2.
93%
With pyrrolidine In ethanol for 3 h; Heating / reflux
EXAMPLES The general procedure for the preparation of many examples is shown below: Step 1: A mixture of 5-fluoro-1,3-dihydroindol-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (A1) (21.1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 mL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL). The solid was stirred in ethanol (350 ml) at reflux for 0.5 h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93percent) as orange solid. LC-MS observed [M-H+: 299.2.
91%
Stage #1: With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile for 5 h; Reflux Stage #2: With 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 45℃; for 0.25 h; Stage #3: With trimethylsilyl trifluoromethanesulfonate In acetonitrile
(NH4)2SO4 (0.05 g, 0.38 mmol) was added into a stirred mixture of 8 (0.57 g, 3.77 mmol) in HMDS (7.1 mL, 12.5 P.) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, the reaction was distilled to remove about half of HMDS to give 20 of about 90percent GC purity. To the solution of 20 in HMDS (about 3.5 mL, 6.25 P.) at 45° C. was added MeCN (30 mL, 52.6 P.). After stirring for 15 minutes, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (14; 0.63 g, 3.77 mmol) and TMSOTf (0.16 g, 0.72 mmol) were added. Then the mixture was stirred for more than 4 hours, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (3 mL, 5 P.). The mixture was filtered and the filtrate cake was washed with Ethanol (5 mL), then it was dried under vacuum at 40° C. overnight to give the goal product 15 (1.03 g, 91percent yield) as a yellow to brown powder with about 85percent HPLC purity. 1H NMR (300 MHz, d6-DMSO): δ 2.48 (m, 6H, H-20, 21), 6.83 (m, 1H, H-6), 6.85 (m, 1H, H-4), 7.71 (m, 1H, H-12), 7.73 (m, 1H, H-1), 10.98 (s, 1H, H-7), 13.95 (s, 1H, H-14). API-ESI (NEG): m/z 299.0
79%
Stage #1: With pyrrolidine In ethanol for 4.5 h; Heating / reflux Stage #2: With acetic acid In ethanol for 0.5 h; Heating / reflux Stage #3: With hydrogenchloride In water; acetone for 2.16667 h;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 ml) and pyrrolidine (32 ml) were refluxed for 4.5 hours. Acetic acid (24 ml) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40 percent acetone in water (400 ml) containing 12 N hydrochloric acid (6.5 ml). The solids were collected by vacuum filtration and washed twice with 40 percent acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79 percent yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.48, 2.50 (2xs, 6H, 2xCH3), 6.80, 6.88, 7.68, 7.72 (4xm, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
Stage #1: With pyrrolidine In ethanol for 4.5 h; Heating / reflux Stage #2: With acetic acid In ethanol for 0.5 h; Heating / reflux
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (61 g), 5-fluoro-l,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40percent acetone in water (400 mL) containing 12 N hydrochloric acid (6.5mL). The solids were collected by vacuum filtration and washed twice with 40percent acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo- 1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl- lH-pyrrole-3- carboxylic acid (86 g, 79percent yield) as an orange solid.
77%
With pyrrolidine In ethanol at 78℃; for 6 h;
Step Ig. 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-N-hydroxy-2,4-dimethyl- lH-pyrrole-3-carboxamide (compound 1)A mixture of compound 108 (4.0 g. 24 mmol), 102 (3.6 g 24 mmol) and pyrrolidine (2 mL) in ethanol (200 mL) was stirred and heated at 78°C for 6h. The mixture was filtered to give yellow solid, dried to yield product 1 (5.5g, 77percent). LCMS: m/z 301(M+l), 1H NMR(DMSO-^6) δ2.39 (s, 3H), 2.42 (s, 3H), 6.82 ( m, 2H), 7.77 (s, IH), 7.80 (m, IH), 10.93 (s, IH), 12.23 (s, IH), 13.86 (s, IH).
77%
at 78℃; for 6 h;
A mixture of compound 108 (4.0 g. 24 mmol), 102 (3.6 g 24 mmol) and pyrrolidine (2 mL) in ethanol (200 mL) was stirred and heated at 780C for 6h. The mixture was filtered to give yellow solid, dried to yield product 1 (5.5g, 77percent). LCMS: m/z 301(M+l), 1H NMR(DMSO-J6) δ2.39 (s, 3H), 2.42 (s, 3H), 6.82 ( m, 2H), 7.77 (s, IH), 7.80 (m, IH), 10.93 (s, IH), 12.23 (s, IH), 13.86 (s, IH).
Reference：
[1] Patent: US2013/190512, 2013, A1, . Location in patent: Paragraph 0088
[2] Patent: WO2007/81560, 2007, A2, . Location in patent: Page/Page column 6
[3] Patent: WO2006/127961, 2006, A1, . Location in patent: Page/Page column 15-16
[4] Patent: WO2008/33562, 2008, A2, . Location in patent: Page/Page column 34
[5] Patent: US2009/76005, 2009, A1, . Location in patent: Page/Page column 12; 13
[6] Patent: US2013/190512, 2013, A1, . Location in patent: Paragraph 0086
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 248 - 262
[8] Patent: WO2004/76410, 2004, A2, . Location in patent: Page 11-12
[9] Patent: WO2007/34272, 2007, A1, . Location in patent: Page/Page column 17
[10] Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 2018, vol. 1092, p. 515 - 523
[11] Patent: WO2008/33743, 2008, A1, . Location in patent: Page/Page column 53; 57
[12] Patent: WO2008/33747, 2008, A2, . Location in patent: Page/Page column 202
[13] Journal of Medicinal Chemistry, 2003, vol. 46, # 7, p. 1116 - 1119
[14] Patent: WO2011/110199, 2011, A1, . Location in patent: Page/Page column 15
[15] Patent: WO2012/58780, 2012, A1, . Location in patent: Page/Page column 33-34
17
[ 123-75-1 ]
[ 253870-02-9 ]
[ 56341-41-4 ]
[ 356068-93-4 ]
Yield
Reaction Conditions
Operation in experiment
79%
With hydrogenchloride; acetic acid In ethanol; water; acetone
Scale-Up Procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40percent acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40percent acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79percent yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
With hydrogenchloride; acetic acid In ethanol; water; acetone
Scale-Up Procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40percent acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40percent acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79percent yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
With hydrogenchloride; acetic acid In ethanol; water; acetone
Scale-up procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40percent acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40percent acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79percent yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
Stage #1: With 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile for 0.25 h;
To a solution of 20 (prepared as in Example 16 from 5 g of 8) in HMDS (about 75 mL, 15 P) at r.t. was added MeCN (50 mL, 10 P). After stirring for 15 minutes, 14 (5.55 g, 33.1 mmol) and TfOH (0.5 g, 3.3 mmol) were added. Then the mixture was stirred for 24 hours, the reaction was heated to 65° C. for another 24 hours, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (3 mL). The mixture was filtrated and the filtrate cake was dried under vacuum at 40° C. overnight to give the goal product 15 (9.7 g, 97percent yield) as a yellow to brown powder with about 88.9percent HPLC purity.
To a stirring solution of 1 (19.4 g, 100 mmol) in methanol (100 mL) and water (400 mL) was added 5N KOH solution (200mL). The reaction mixture was heated to refluxing and stirred for 3 h. Cooled to room temperature, the mixture was adjusted to pH 3 with 5N HCl, and then filtered. The precipitate was washed with water and dried in vacuo to give the title compound 2 (15.5 g, 94 %) as an yellowish brown solid.
93%
With potassium hydroxide; water; In methanol; for 3h;Heating / reflux;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) delta 12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3),2.40 (s, 3H, CH3).
93%
[0168] 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) delta 12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
93.5%
Step (iv): Preparation of 5-formyl-2,4-dimethyI-lH-pyrrole-3-carboxylic acid (V):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition runnel and reflux condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70 C and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with cone. HCl. The resulting solution was stirred over night at 25-30 C. The product was filtered and washed with water. The product was dried at 60 C. Dry Weight: 0.483 Kg Yield: 93.5% HPLC purity: 99.8%
93.5%
With water; potassium hydroxide; In methanol; at 60 - 70℃; for 4 - 6h;
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70oC. and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with conc. HCl. The resulting solution was stirred over night at 25-30oC. The product was filtered and washed with water. The product was dried at 60oC. Dry Weight: 0.483 Kg Yield: 93.5% HPLC purity: 99.8%
93%
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid which formed was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6)delta: 12.09 (s, br, 2N, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
92%
With sodium hydroxide; In methanol; water; for 4h;Reflux;
24,4-dimethyl-5-formyl -1H- pyrrole-3-carboxylate (0.9g, 4.6mmol) in methanol (5ml) was added sodium hydroxide (1.0g) in water (8ml) solution of was heated at reflux for 4h, cooled to room temperature, poured into ice water (16ml) was added methylene chloride (10ml), standing layer was collected and the aqueous layer was adjusted with 10% hydrochloric acid, pH3, and the filter cake was washed with cold water, and dried to give a pale yellow solid 11 (0.71g, 92%).
91%
With water; sodium hydroxide; In methanol; at 82 - 83℃; for 4.5h;Inert atmosphere;
To a three-necked flask equipped with a thermometer, ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate (9, 1.17 g, 6.0 mmol) and methanol (6.0 mL) were added with stirring, to which was added solution of sodium hydroxide (1.20 g) in water (10 mL). The reaction mixture was kept under reflux at 82-83 C for 4.5 h under nitrogen atmosphere. The mixture was then cooled down to r.t. before being added into ice-water (20 mL). The obtained mixture was extracted with dichloromethane (12 mL). The organic layer was then washed with water (15 mL 9 3) until there was no absorption under ultraviolet (UV) light. The aqueous layers were combined before being acidified with hydrochloride (2.0 mol/L) to pH 2 until many precipitates appeared from the mixture. The yellowish solids were obtained via filtrating under vacuum, washing with water, and drying under vacuum to provide 3 (0.91 g, 91 %), m.p. >250 C (sublimes and decomposes) (lit. 275-277 C [13]), yield 90.0 % (lit. [13]). Rf = 0.28 (eluent: chloroform/methanol, v/v = 10:1 or petroleum ether/ethylacetate, v/v = 10:1). Electrospray ionization (EI) mass spectroscopy (MS) m/z (%): 167.1 ([M]+, 100), 138.1 (20), 121.1 (60). 1H NMR (DMSO-d6) delta: 1.35 (t, 3H, J = 7.3 Hz, CH3), 2.53 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.29 (q, 2H,J = 7.3 Hz, CH2), 7.24 (s, 1H, pyrrole-1-NH), 9.97 (s, 1H, CHO).
91%
With sodium hydroxide; In methanol; water; for 4.5h;Reflux; Inert atmosphere;
To a 100 mL three-necked flask equipped with a thermometer and a magnet, 6.0 mmol of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid ethyl ester and 6 mL of methanol were added. After dissolution, an aqueous solution of sodium hydroxide containing 1.2 g of sodium hydroxide and a concentration of 3 mol / L was added, followed by a reflux reaction for 4.5 h under the protection of nitrogen. After the reaction was completed, 20 mL of ice water was poured into the obtained reaction solution, and then formed. The ice-water solution was transferred into a separatory funnel, and 12 mL of dichloromethane was added to it for the first extraction. The organic phase obtained from the first extraction was collected, and the organic phase was extracted until the organic phase had no ultraviolet absorption. Combine the extractions. The aqueous phase obtained from the organic phase was adjusted to pH 2 with 2 mol / L hydrochloric acid, followed by suction filtration, the filter cake was washed with water and dried under vacuum to obtain 0.91 g of a yellow solid 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid, yield 91%, m.p.> 220 C.
89%
Step If. 5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (compound 108) <n="58"/>A solution of KOH (6.2 g, 11 lmmol) in water (400 mL) was added to a solution of compound 507 (7.2 g, 37mmol) in ethanol (60 mL). The mixture was refluxed until the reaction was completed. The mixture was cooled to room temperature and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified to pH=2 with IN HCl. The precipitate was collected by filtration, washed with water and dried to give yellow solid product 108 (5.5 g, 89%). LCMS: m/z 168(M+1), 1H NMR(DMSO-^6) delta2.40 (s, 3H), 2.43 (s, 3H), 9.24 (s,lH), 12.14 (bs, 2H).
89%
A solution of KOH (6.2 g, 11 lmmol) in water (400 mL) was added to a solution of compound 507 (7.2 g, 37mmol) in ethanol (60 mL). The mixture was refluxed until the reaction was completed. The mixture was cooled to room temperature and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified to pH=2 with IN HCl. The precipitate was collected by filtration, washed with water and dried to give yellow solid product 108 (5.5 g, 89%). LCMS: m/z 168(M+1), 1H NMR(DMSO-J6) delta2.40 (s, 3H), 2.43 (s, 3H), 9.24 (s,lH), 12.14 (bs, 2H).
81%
2-formyl-3,5-dimethylpyrrole-4-carboxylic acid4-ethoxycarbonyl-3,5-dimethylpyrrole-2-carboxylic acid tert-Bu-ester 16.35g was dissolved in neat trifluoroacetic acid 85 mL and the solution was stirred at room temperature for 30 min (the mix turned Burgundy red with gas evolution), then cooled to +5 C on ice/water bath. Neat triethyl orthoformate 16.5 mL (1.6 eq.) was added and the mix was stirred at +5 C for 35 min, then concentrated on rotovap from ambient water bath to a small volume. The residue was diluted gradually with water addition, 300mL, the resulting slurry was shaken for 5 min and the precipitated ethyl ester intermediate was collected by filtration, washed thoroughly with water and dried by suction.This ethyl ester intermediate was suspended in ethanol 150 mL, placed on a120 C oil bath and stirred to complete dissolution. A solution of KOH 20g (pellets, 85%) in water 200mL was then added to the mix, the flask was equipped with a short- path distillation adaptor and the reaction mixture was distilled under a stream of nitrogen gas on a 120 C oil bath for 90 min. (Only water distilled at this point and the ethyl ester hydrolysis was complete by HPLC). The reaction mixture was cooled, charcoal (5 spoons) was added and the reaction mix was then stirred on ambient water bath for 30 min, and filtered (the charcoal was thoroughly washed with water). The combined filtrates were acidified with addition of 6M HC1, the precipitated product was collected by filtration on a large Buchner funnel, washed with water and semi- dried by suction. The crude product was dissolved in EtOH (900mL) at reflux, the solution was allowed to crystallize at ambient temperature overnight (14 hours). The product was collected by filtration, washed with EtOH, dried by suction and on highvac. Concentrating the supernatants to a small volume, diluting the slurry with ethanol lOOmL and refluxing the mix for 30 min, then letting the mix to crystallize at RT overnight provided a second crop of a pure product. The combined yield was 8.32g (81% overall) of a light-tan crystalline solid. 1H-NMR (d6-DMSO, 400MHz): 12.12(s, 1H), 12.10(very br s, 1H), 9.61(s, 1H), 2.46(s, 3H), 2.42(s, 3H)
1.6 g (93%)
With potassium hydroxide; In methanol; water;
Step 3 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 103691 1H NMR (300 MHz, DMSO-d6) 5 12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3). MS m/z 167 (M+).
1.6 g (93%)
With potassium hydroxide; In methanol; water;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) delta 12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3). MS m/z 167 ((M+)).
To a stirred suspension of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester (1.0 kg, 5.122 mol) in aqueous methanol (5.8 L containing 5.0L water & 0.8L methanol), potassium hydroxide (1.15 kg, 20.5 mol) was added at ambience, and the reaction mixture was heated to 75-85 C for 6 hours. After completion of reaction, reaction mixture was cooled to ambient temperature and washed with ethyl acetate (2 x 2.5 L) followed by layer separation. Aqueous layer was cooled to 0-5 C and quenched with 2 N hydrochloric acid till pH 4-5. The resulting solid was filtered, washed with demineralized water (2 x 2.5 L) and suck dried. Demineralized water (5 L) was added to the obtained solid and mixture was cooled to 0-5 C followed by addition of potassium hydroxide (1.5 kg, 26.75 mol) to obtain clear solution. Activated carbon (0.15 kg) was added to the solution at 0-5 C and then mixture was heated to 25-30 C. Mixture was stirred for 30 minutes, filtered through celite, washed with demineralized water (0.5 L). All aqueous filtrates were combined, cooled to 0-5 C and quenched with 2N hydrochloric acid (4 L). The solid, thus formed, was filtered, washed with demineralized water (2 x 2.5 L) and dried in vacuum to give 0.788 kg of title compound having purity of 99.4 % by HPLC.
1.14 g
With potassium hydroxide; for 5h;Reflux;
DMF (0.80 g, 11.0 mmol) and phosphorus oxychloride (V) (1.69 g, 11.0 mmol) were added to 10 mL of CH2Cl2.After cooling to 4 C, 2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester was added dropwise.The reaction mixture was stirred for 15 minutes and heated for 1 h.Add 10 C hydrochloric acid solution (5 mL, 10 M),Stir vigorously,Let stand layering.Extract with 20 mL of hydrochloric acid and 20 mL of CH 2 Cl 2Add NaOH (25 mL, 10 M) to give a yellow solid (1. 4 g, 8.0 mmol).Add 90% KOH (20 mL),Reflux for 5 h.After cooling to room temperature,30 mL of water was added to the solution and washed with 40 mL of CH 2 Cl 2 .Adjust the pH of the solution to 4 with dilute hydrochloric acid.The yellow product was obtained (1.14 g, 6.82 mmol).
30 g
With water; potassium hydroxide; In methanol; for 3h;Reflux;
In this embodiment, as a modification of the present invention, in the fifth step, the ethyl 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylate obtained in the fourth step is 40 g (0.15). Mol) was dissolved in a mixed solution of 114 g of methanol and 680 g of water, added with 42 g of K0H, heated under reflux for 3 h, added with activated carbon 6 g, filtered while hot, the obtained liquid was extracted twice with dichloromethane, and the aqueous phase was adjusted to pH 4 with hydrochloric acid. 5, filtered and washed with water to obtain a solid dried 30 g of 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid, which is the finished sunitinib intermediate.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 59h;
To a 250 mL three-neck flask equipped with a thermometer and a magnet, 32.7 mmol of <strong>[253870-02-9]2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid</strong> and 13.1 mL of anhydrous DMF were added, and then cooled to 0 with an ice-salt bath. , followed by the dropwise addition of 49.0mmol of dichloromethane solution of cyclohexylcarbodiimide under stirring and controlling the reaction temperature at 0 C. After the addition was completed, 1.65g of 4-dimethylaminopyridine and 35.9mmol of N, N-di Ethylethylenediamine was reacted at room temperature, and the reaction process was detected to be complete by TLC. The developing solvent used for TLC monitoring was a mixed solvent of chloroform and methanol with a volume ratio of 5: 1. After 59 hours of reaction, TLC monitoring found that the reaction was complete. After the reaction was completed, the obtained reaction solution was suction-filtered, and water and dichloromethane were added to the filtrate for the first extraction (3 times). The organic phase of the first extraction was collected and washed with 65.7 mL of saturated brine, and anhydrous sodium sulfate Dried and then filtered with suction, the resulting filtrate was concentrated to remove the solvent to form a solid, the solid was dissolved with a small amount of dichloromethane, and then subjected to a second extraction (3 times) with 1000 mL of a 5% citric acid aqueous solution, as shown by TLC The organic phase contains no product and the reason for analysis is N- (2-diethyl Ethyl) -2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide is weakly basic, reacts with citric acid to form a salt and enters the aqueous phase, so the water for the second extraction is collected Phase, and then neutralize it with a large amount of a saturated solution of sodium bicarbonate and a saturated solution of sodium hydroxide, and adjust the pH to pH = 8, and then extract the above aqueous solution for a third time with a large amount of dichloromethane and collect The third extracted organic phase, the third extracted organic phase was concentrated to a reddish brown oily liquid, and finally the column Chromatography gave N- (2-diethylaminoethyl) -2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide (8.11 g) as a yellow solid. The eluent system used is in the order of elution: a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3: 1, and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1: 1. Yield 86.3%,
79%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (11, 0.500 g, 2.99 mmol) was dissolved in dry DMF (10 mL), to which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (635 mL, 3.59 mmol), 1-hydroxybenzotriazole (HOBt) (0.485 g, 3.59 mmol) and N,N-diethylethylenediamine (505 mL, 3.59 mmol) were added. The reaction mixture was stirred at RT for 16 h, before the solvent was removed in vacuo and the residuewas partitioned between sat. NaHCO3 solution (50 mL) and EtOAc (50 mL), and the aqueous phase was extracted with further EtOAc (50 mL). The combined organic extracts were washed with brine (50 mL) before being concentrated in vacuo and the residue triturated with 3:1 hexanes:Et2O (30 mL) and the suspension stirred for 30 min. The mixture was filtered and the filtrand was dried under air to give the desired product as a beige solid (0.627 g, 2.36 mmol, 79%). M.p.135-138 C; IR (cm-1) 1533, 1621, 2138, 2187, 2807, 2925, 2965,3251; 1H NMR (400 MHz, DMSO-d6) 0.97 (6H, t, J 7.0 Hz,N(CH2CH3)2), 2.32 (3H, s, pyrrole-CH3), 2.37 (3H, s, pyrrole-CH3),2.47-2.54 (6H, m, N(CH2CH3)2 and NHCH2CH2NEt2), 3.26 (2H, dt,J 6.6, 6.2 Hz, NHCH2CH2NEt2), 7.33 (1H, t, J 6.2 Hz,NHCH2CH2NEt2), 9.54 (1H, s, CHO), 11.83 (1H, s, pyrrole-NH); 13CNMR (100 MHz, DMSO-d6) 10.1 (pyrrole-CH3), 12.3 (N(CH2CH3)2),12.9 (pyrrole-CH3), 37.4 (NHCH2CH2NEt2), 47.0 (N(CH2CH3)2), 52.1(NHCH2CH2NEt2), 119.9 (Ar-C), 128.2 (Ar-C), 138.3 (Ar-C), 164.8(CO), 177.7 (CO); HRMS calcd. for C14H24N3O2 (ES+) m/z266.186852 [M+H]+, found 266.183829.
66%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.
53%
Step (v): Preparation of 5-formyI-2,4-dimethyl-lH-pyrrole-3-carboxyIic acid(2-diethylaminoethyl)-amide (VII):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4- dimethyl- lH-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran(3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1 -hydroxy benzotriazole (0.306 Kg)and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30 C. After addition, the reaction mixture was stirred for 16 hours at 25-30 C and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCtheta3, saturated solution of NaCl and DM water. Organic layer was separated and 3/4th of the solvent distilled under diminished pressure. The product was cooled to 0- <n="31"/>50 C and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60 C.Dry Weight: 210.2 g Yield: 53.0% HPLC purity: 99.95%
53%
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30oC. After addition, the reaction mixture was stirred for 16 hours at 25-30oC. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO3, saturated solution of NaCl and DM water. Dry Weight: 210.2 g Yield: 53.0% HPLC purity: 99.95%
Step-1: Preparation of N- [2- (diethyl amino) ethyl-5-formyl-2, 4 dimethyl-lH pyrrole- 3-carboxamideA mixture of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (100 g) in dimethylformamide (900 ml) was stirred for 15 minutes. l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (171.8 g), 1-hydroxybenzotriazole (121.2 g) and triethylamine (169.4 g) were added to the reaction mixture and stirred at 20C to 25C for 10 minutes. N,N-Diethylethylenediamine (104.2 g) was slowly added to the reaction mixture and stirred at 20C to 25C for 20 hours. The reaction mixture was diluted with water (350 ml), brine (250 ml) and saturated sodium bicarbonate solution (350 ml) followed by the addition of 10% v/v methanol in dichloromethane (1500 ml). The reaction mixture was stirred for 30 minutes and allowed to settle for 30 minutes. The organic layer was separated and washed with a saturated sodium bicarbonate solution (1500 ml). The organic layer was separated, dried over sodium sulfate and concentrated to obtain a residue. Toluene (300 ml) was added to the residue and evaporated to dryness. Ethyl acetate (600 ml) was added to the residue and washed with brine (400 ml). The organic layer was separated, dried over sodium sulfate and concentrated under vacuum to obtain a sticky solid. The solid so obtained was triturated with hexane: diethyl ether (3:1; 500 ml), stirred for 15 minutes, filtered under vacuum and dried under vacuum at 55C for 16 hours to obtain the title compound.Yield: 44 g
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 20℃;Product distribution / selectivity;
Example 1 - Conversion of (2a) to (la)To a solution of acid derivative (2a) (835 mg, ~5mmol) in N-diethylethylene-diamine (10 ml), with stirring at room temperature, propane phosphoric acid anhydride (T3P) (10 ml, 50% EtOAc solution) was added dropwise and completed in 1.5 hours. The resulting reaction mixture was stirred further over night. Water (25 ml) and dichloromethane (25 ml) were added, and the mixture was stirred for 25 minutes. The dichloromethane layer was separated and concentrated in vacuo to give an oily material. The oil was mixed with ethyl acetate (50 ml) and sodium carbonate solution (4%, 25 ml), and stirred at 70C for 30 minutes. After cooling, the ethyl acetate layer was separated and washed with water (10 ml), dried ( a2S04) and concentrated to give a yellow solid (la) (1.35 g).
To a stirred slurry of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (1.0 kg, 5.98 mol), hydroxybenzotriazole (0.969 kg,), l -ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.6 kg, 8.34 mol) in tetrahydrofuran (15L) at 25-30 C, triethylamine (1.162 kg, 1 1.48 mol) was added and mixture was stirred for 30 minutes. Nu,Nu-diethyl ethylenediamine (1.902 kg, 16.37 mol) was added to resulting mixture at 25-30 C and stirred for 5-6 hours at 25-30 C. After completion of reaction, reaction mixture was cooled to ambient followed by addition of saturated 15 % sodium bicarbonate solution (10 L ) till pH = 9-10. Resulting product was extracted with a mixture of dichloromethane- methanol (5% methanol, 3 x 10 L). The organic layers were combined, washed with demineralized water (2 x 5L). Solvent was distilled off from resulting organic layer. Methyl tert-butyl ether (5 L) was added to resulting product and stirred at 45-50 C for 30 minutes. Mixture was cooled to ambient temperature and resulting product was filtered. Filtered solid was washed with methyl tert- butyl ether (5L) and dried. Water (10 L) was added to thus obtained solid followed by addition of sodium bicarbonate (568 g), and a mixture of dichloromethane-methanol (10% methanol, 10 L). Resulting mixture was stirred at ambient temperature for 1 hour. The organic layer was separated, washed with demineralised water (2 x 5 L) and distilled off. Cyclohexane ( 5 L) was added to the crude mass, stirred for 30 minutes, filtered and dried in vacuum oven at 75-80 C for 24 hours to give 0.524 kg of title compound having purity 99.83 % by HPLC.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.92mmol), hydroxybenzotriazole hydrate (1.92mmol), triethylamine (1.85mL, 13.26mmol) and the appropriate amine (1.60mmol) were added into a stirred solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (5) or (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid (6) (1.28mmol) in DMF (5mL). The mixtures were stirred at room temperature for 12h and then diluted with water (5mL). The resultant mixture was adjusted to pH 10 with 10N NaOH and extracted with 10% (v/v) methanol in CH2Cl2. The organic extracts were dried over MgSO4, filtered through Celite, and evaporated to give the 5-formylpyrrole-carboxamides 9-15, which were used for the aldol condensations without purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
In a 20 L reactor, 4 L of acetonitrile and 1.8 kg of Compound II (10.8 mol) were added in that order.1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride 2.5 kg (12.9 mol),1.75 kg (12.9 mol) of 1-hydroxybenzotriazole, stirred well, and reacted at 35 C for 2 hours.At the end of the reaction, 1.9 kg (16.2 mol) of N,N diethylethylenediamine was added, and the reaction was carried out at 35 C for 2 hours. The reaction was completed, and 1.6-kg (10.8 mol) of 5-fluoroindol-2-one and 3 kg of triethylamine were added. ,The temperature was raised to 60 C for 2 hours, the reaction was completed, and the temperature was lowered to below 40 C.4L of methanol and 5kg (37.7mol) of L-malic acid were added, and the mixture was heated to 60 C for 1 hour.The reaction was completed, and it was cooled to room temperature, and filtered to give an orange-yellow solid, 5.1 kg.That is, compound I sunitinib malate, the yield was 88%, and the HPLC purity was 99.8%.
(NH4)2SO4 (0.09 g, 0.67 mmol) was added into a stirred mixture of 8 (1.0 g, 6.61 mmol) in HMDS (20 mL, 20 P) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, 14 (1.1 g, 3.77 mmol) and TMSOTf (0.29 g, 1.32 mmol) were added. Then the mixture was stirred, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (6 mL, 6 P.) and MeCN (30 mL). The mixture was filtrated and the filtrate cake was washed with MeCN (20 mL) and EtOH (5 mL), then it was dried under vacuum at 40 C. overnight to give the goal product 15 (1.92 g, 97% yield) as a yellow to brown powder with about 82.1% HPLC purity.
96%
pyrrolidine; In ethanol; for 3h;Heating / reflux;
A mixture of 5-fluoro-1 , 3-dihydroindol-2-one (1.62 g, 10.2 mmol), 5- formyl^lambda-dimethyl-IH-pyrrole-S-carboxylic acid (1.96 g, 10.7 mmol), pyrrolidine (12 drops) and absolute ethanol was heated to reflux for 3 hours. The mixture was cooled to 25 0C and the solids were collected by filtration. The solids were stirred with ethanol (30 mL) at 72 C for 30min. The mixture was cooled to 25 0C and the solids were collected again by filtration, washed with ethanol (6 mL), and dried under vacuum overnight to give an orange solid (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3- carboxylic acid (3.094 g, 96%). LC-ESIMS observed [M+H]+ 301 (calculated for Ci6Hi3FN2O3 300.09).
96%
With pyrrolidine; In ethanol; for 3h;Heating / reflux;
Exemplary Chiral Species; A general scheme for synthesizing chiral species of the invention is outline below:; Step 1 :; A mixture of 5-fluoro-1 , 3-dihydroindol-2-one (1.62 g, 10.2 mmol), 5- formyl^^-dimethyl-I H-pyrrole-S-carboxylic acid (1.96 g, 10.7 mmol), pyrrolidine (12 drops) and absolute ethanol was heated to reflux for 3 hours. The mixture was cooled to 25 0C and the solids were collected by filtration. The solids were stirred with ethanol (30 ml.) at 72 0C for 30min. The mixture was cooled to 25 0C and the solids were collected again by filtration, washed with ethanol (6 ml_), and dried under vacuum overnight to give an orange solid (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1 H-pyrrole-3- carboxylic acid (3.094 g, 96%). LC-ESIMS observed [M+H]+ 300.95 (calculated for Ci6Hi3FN2O3 300.09).
93%
With pyrrolidine; In ethanol; for 3h;Heating / reflux;
Step 1 : A mixture of 5-fluoro-l,3-dihydroindol-2-one (A2) (2Og, 132mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (Al) (21. Ig, 126mmol), pyrrolidine (5ml) and absolute ethanol (40OmL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (10OmL). The solid was stirred in ethanol (350ml) at reflux for 0.5h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-lH-pyrrole-3- carboxylic acid (A3) (35.3g, 93%) as orange solid. LC-MS observed [M-H]+: 299.2.
93%
With pyrrolidine; In ethanol; for 3h;Heating / reflux;
EXAMPLES The general procedure for the preparation of many examples is shown below: Step 1: A mixture of 5-fluoro-1,3-dihydroindol-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrole-3-carboxylic acid (A1) (21.1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 mL) were heated to reflux for 3 hours. Then the mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 mL). The solid was stirred in ethanol (350 ml) at reflux for 0.5 h again. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 ml) and dried under vacuum overnight to give (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93%) as orange solid. LC-MS observed [M-H+: 299.2.
91%
(NH4)2SO4 (0.05 g, 0.38 mmol) was added into a stirred mixture of 8 (0.57 g, 3.77 mmol) in HMDS (7.1 mL, 12.5 P.) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, the reaction was distilled to remove about half of HMDS to give 20 of about 90% GC purity. To the solution of 20 in HMDS (about 3.5 mL, 6.25 P.) at 45 C. was added MeCN (30 mL, 52.6 P.). After stirring for 15 minutes, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (14; 0.63 g, 3.77 mmol) and TMSOTf (0.16 g, 0.72 mmol) were added. Then the mixture was stirred for more than 4 hours, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (3 mL, 5 P.). The mixture was filtered and the filtrate cake was washed with Ethanol (5 mL), then it was dried under vacuum at 40 C. overnight to give the goal product 15 (1.03 g, 91% yield) as a yellow to brown powder with about 85% HPLC purity. 1H NMR (300 MHz, d6-DMSO): delta 2.48 (m, 6H, H-20, 21), 6.83 (m, 1H, H-6), 6.85 (m, 1H, H-4), 7.71 (m, 1H, H-12), 7.73 (m, 1H, H-1), 10.98 (s, 1H, H-7), 13.95 (s, 1H, H-14). API-ESI (NEG): m/z 299.0
79%
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 ml) and pyrrolidine (32 ml) were refluxed for 4.5 hours. Acetic acid (24 ml) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40 % acetone in water (400 ml) containing 12 N hydrochloric acid (6.5 ml). The solids were collected by vacuum filtration and washed twice with 40 % acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79 % yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) delta 2.48, 2.50 (2xs, 6H, 2xCH3), 6.80, 6.88, 7.68, 7.72 (4xm, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (61 g), 5-fluoro-l,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo- 1 ,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl- lH-pyrrole-3- carboxylic acid (86 g, 79% yield) as an orange solid.
77%
With pyrrolidine; In ethanol; at 78℃; for 6h;
Step Ig. 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-N-hydroxy-2,4-dimethyl- lH-pyrrole-3-carboxamide (compound 1)A mixture of compound 108 (4.0 g. 24 mmol), 102 (3.6 g 24 mmol) and pyrrolidine (2 mL) in ethanol (200 mL) was stirred and heated at 78C for 6h. The mixture was filtered to give yellow solid, dried to yield product 1 (5.5g, 77%). LCMS: m/z 301(M+l), 1H NMR(DMSO-^6) delta2.39 (s, 3H), 2.42 (s, 3H), 6.82 ( m, 2H), 7.77 (s, IH), 7.80 (m, IH), 10.93 (s, IH), 12.23 (s, IH), 13.86 (s, IH).
77%
In pyrrolidine; ethanol; at 78℃; for 6h;
A mixture of compound 108 (4.0 g. 24 mmol), 102 (3.6 g 24 mmol) and pyrrolidine (2 mL) in ethanol (200 mL) was stirred and heated at 780C for 6h. The mixture was filtered to give yellow solid, dried to yield product 1 (5.5g, 77%). LCMS: m/z 301(M+l), 1H NMR(DMSO-J6) delta2.39 (s, 3H), 2.42 (s, 3H), 6.82 ( m, 2H), 7.77 (s, IH), 7.80 (m, IH), 10.93 (s, IH), 12.23 (s, IH), 13.86 (s, IH).
With piperidine; In ethanol; at 60℃;
Example 4 - Conversion of (2a) to (2b)To a mixture of 200 mg of 5-fluoro oxindole (5) and 266 mg of aldehyde (2a) in 6 ml of ethanol, -0.5 ml of piperidine (10 drops) was added and the mixture was heated to 60 C over night. After cooling to RT the solid was filtered off and washed twice with 5 ml of 1 M HCL solution. The solid was dried over night at 40 C under vacuum. 390 mg desired product (2b) was obtained.
(NH4)2S0 (0.09 g, 0.67 mmol) was added into a stirred mixture of 8 (1.0 g, 6.61 mmol) in HMDS (20 mL, 20 P) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, 14 (1.1 g, 3.77 mmol) and TMSOTf (0.29g, 1.32 mmol) were added. Then the mixture was stirred, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (6 mL, 6 P.) and MeCN (30 mL). The mixture was filtrated and the filtrate cake was washed with MeCN (20 mL) and EtOH (5 mL), then it was dried under vacuum at 40 C overnight to give the goal product 15 (1.92 g, 97% yield) as a yellow to brown powder with about 82.1 % HPLC purity.
Step 4 The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60 C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M-1]+·, 100).
In ethanol;
Step 4 The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60 C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M+1]+, 100).
Step 4 The reaction mixture of5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60 C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M-1]+, 100).
With hydrogenchloride; acetic acid; In ethanol; water; acetone;
Scale-Up Procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) delta 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
With hydrogenchloride; acetic acid; In ethanol; water; acetone;
Scale-Up Procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) delta 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
79%
With hydrogenchloride; acetic acid; In ethanol; water; acetone;
Scale-up procedure: 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid. 1H-NMR (dimethylsulfoxide-d6) delta 2.48, 2.50 (2*s, 6H, 2*CH3), 6.80, 6.88, 7.68, 7.72 (4*m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrrole NH). MS m/z 299 [M-1].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.
40%
3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carboxaldehyde To a mixture of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (1.67 g, 10 mmol) in dimethylformamide (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 6 g, 13.5 mmol) followed by 3 mL of diisopropylethylamine. After stirring for 5 minutes, 2 mL of 1-methylpiperazine was added and the mixture was stirred at room temperature for 24 hours. To the reaction was then added 25 mL of 1N sodium hydroxide and 25 mL of brine. After stirring for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted (3*200 mL) with 10% of methanol in dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The residue which remained was purified by chromatography(silica gel column, 5%-10% of methanol in dichloromethane) to give 1 g (40%) of 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carboxaldehyde. 1H NMR (360 MHz, DMSO-d6)delta: 11.82 (s, 1H, NH), 9.50 (s, 1H, CHO), 3.14 (br m, 4H, 2*CH2), 2.29 (br m, 4H, 2*CH2), 2.19 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS EI 249 [M]+.
38%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
General procedure: To a solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (8.35g, 50mmol) in DMF (100ml) were addedN-hydroxybenzotriazole (HOBt) (10.1g, 75mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI) (16.9g, 88mmol), triethylamine (30ml) and 1-methylpiperazine (8ml). The mixture was stirred for 24h at room temperature and diluted with 300ml of water and 100ml of brine. After adjusting the pH to >10 with 10N sodium hydroxide solutions, the mixture was extracted with 10% methanol in dichloromethane (500ml×3) and the organic layers were combined, dried (Na2SO4) and evaporated to dryness. The residue was triturated and stirred in 300ml of hexane and ethyl acetate (3:1) for 2h. The solid was collected by filtration, and washed with ethyl acetate and dried under vacuum for 16h to give 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (4.73g, 38% yield).
5.3g (72%)
Example B-1 3,5-Dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 29.9 mmol) reacted with N-methylpiperazine (4.0 mL) to give 5.3g (72%) of 3,5-imethyl-4-(4-piperazine- 1 -carbonyl)- 1 H-pyrrole-2-carbaldehyde. 1H NMR (360 MHz, DMSO-d6) delta 11.82 (s, 1H, NH), 9.50 (s, 1H, CHO), 3,14 (br m, 4H, 2*CH2), 2.29 (br m, 4H, 2*CH2), 2.19 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS m/z 249 [M]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.92mmol), hydroxybenzotriazole hydrate (1.92mmol), triethylamine (1.85mL, 13.26mmol) and the appropriate amine (1.60mmol) were added into a stirred solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (5) or (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid (6) (1.28mmol) in DMF (5mL). The mixtures were stirred at room temperature for 12h and then diluted with water (5mL). The resultant mixture was adjusted to pH 10 with 10N NaOH and extracted with 10% (v/v) methanol in CH2Cl2. The organic extracts were dried over MgSO4, filtered through Celite, and evaporated to give the 5-formylpyrrole-carboxamides 9-15, which were used for the aldol condensations without purification.
1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride[ No CAS ]
[ 2592-95-2 ]
[ 100-36-7 ]
[ 356068-86-5 ]
Yield
Reaction Conditions
Operation in experiment
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid(2-diethylamino-ethyl)-amide (819 g, 43 % yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
43%
With sodium hydroxide; triethylamine; In N-methyl-acetamide; methanol; dichloromethane; water; ethyl acetate; toluene;
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1204 g) and 6020 mL of dimethylformamide were stirred at room temperature while 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (2071 g), hydroxybenzotriazole (1460 g), triethylamine (2016 mL) and diethylethylenediamine (1215 mL) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 3000 mL of water, 2000 mL of brine and 3000 mL of saturated sodium bicarbonate solution and the pH adjusted to greater than 10 with 10 N sodium hydroxide. The mixture was extracted twice with 5000 mL each time of 10% methanol in dichloromethane and the extracts combined, dried over anhydrous magnesium sulfate and rotary evaporated to dryness. The mixture was with diluted with 1950 mL of toluene and rotary evaporated again to dryness. The residue was triturated with 3:1 hexane:diethyl ether (4000 mL). The solids were collected by vacuum filtration, washed twice with 400 mL of ethyl acetate and dried under vacuum at 34 C. for 21 hours to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (819 g, 43% yield) as a light brown solid. 1H-NMR (dimethylsulfoxide-d6) delta 0.96 (t, 6H, 2*CH3), 2.31, 2.38 (2*s, 2*CH3), 2.51 (m, 6H 3*CH2), 3.28 (m, 2H, CH2), 7.34 (m, 1H, amide NH), 9.56 (s, 1H, CHO), 11.86 (s, 1H, pyrrole NH). MS m/z 266 [M+1].
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.
59%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;
2,4-dimethyl-5-aldehyde-1H- pyrrole-3-carboxylic acid(167 mg, 1 mmol),1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride(230 mg, 1.2 mmol),1-hydroxybenzotriazole(162 mg, 1.2 mmol)And N, N-dimethylformamide(15 mL) was stirred at 0-4 C for 20 min,N, N-dimethylethylenediamine (0.26 mL, 2 mmol) was added,The reaction temperature was 30min after stirring at room temperature for 12h.Add distilled water and dilute it with saturated sodium carbonate solution to adjust pH = 9, extract 15mLx3 times with dichloromethane containing 10% methanol, wash once with water, once with saturated saline, and dry over anhydrous sodium sulfate.Suction filtration, the filtrate was concentrated under reduced pressure to give a red oily liquid (yield 59%).
42%
5-Formyl-2,4-diomethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl) amide To a mixture of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (1.67 g, 10 mmol) in dimethylformamide (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 6 g, 13.5 mmol) followed by 3 mL diisopropylethylamine. After stirring for 5 minutes, 1 mL of N,N-dimethylethylendiamine was added and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 25 mL of 1N sodium hydroxide and 25 mL of brine. After stirring for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted (3*200 mL) with 10% of methanol in dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated using a rotary evaporator. The residue which remained was purified by chromatography (silica gel column, 5%-10% methanol in dichloromethane) to give 1 g (42%) of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (2-dimethylamino-ethyl)-amide. 1H NMR (360 MHz, DMSO-d6) delta: 11.77 (s, 1H, NH), 9.53 (s, 1H, CHO), 7.34 (t, J=5.6 Hz, 1H, CONH), 3.27 (m, 2H, CONC2CH2), 2.37 (t, J=6.8 Hz, 2H, CONCH2C2), 2.35 (s, 3H, CH3), 2.3 (s, 3H, CH3), 2.17 (s, 6H, 2*CH3). MS m/z 238.3 [M+1]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In water; N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.92mmol), hydroxybenzotriazole hydrate (1.92mmol), triethylamine (1.85mL, 13.26mmol) and the appropriate amine (1.60mmol) were added into a stirred solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (5) or (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propanoic acid (6) (1.28mmol) in DMF (5mL). The mixtures were stirred at room temperature for 12h and then diluted with water (5mL). The resultant mixture was adjusted to pH 10 with 10N NaOH and extracted with 10% (v/v) methanol in CH2Cl2. The organic extracts were dried over MgSO4, filtered through Celite, and evaporated to give the 5-formylpyrrole-carboxamides 9-15, which were used for the aldol condensations without purification.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20 min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
Example 9. Synthesis of N-(pyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were added to DMF (500mL) with stirring at about 0C and stirred for 1.5 hrs, then pyrrolidine-3-amine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mL*3), the combined organic phase was washed with saturated salt water (300mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 159.8g (680mmol) of N-(pyrrolidin-3-yl)-5-formyl-2, 4-dimethyl-1H- pyrrole-3-formamide as an off-white solid. Yield 68.0%.
Example 13. Synthesis of N-[4-(dimethylamino) phenyl]-5-formyl-2,4-dimethyl -1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3- formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, then N,N-dimethyl-p-phenylenediamine (1.09g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (25mLx3), the combined organic phase was washed with saturated salt water (30mLx3), dried over anhydrous Na2SO4 and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol:ethyl acetate = 1:2) to give 0.682g (2.4mmol) of N-[4-(dimethylamino) phenyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide. Yield 59.9%. 1HNMR (DMSO-d6) delta 10.92 (s, br, 1H, NH), 9.64 (s, 1H), 9.34 (s, br, 1H, NH), 7.54-7.52 (d, 2H), 6.77-6.74 (d, 2H), 3.38-2.58 (s, 6H), 2.58-2.56 (m, 3H),2.55-2.41), (m, 3H).
Example 7. Synthesis of N-[(piperidin-4-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were added to DMF (500mL) with stirring at about 0C and stirred for 1.5 hrs, then piperidin-4-yl-methylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mLx3), the combined organic phase was washed with saturated salt water (300mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 158.3g (602mmol) of N-[(piperidin-4-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 60.2%.
Example 3. Synthesis of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4 -dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were sequentially added to DMF (500mL) with stirring at about 0C, and stirred for 1.5 hrs, then (1-methylpyrrolidin-2-yl) ethylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mLx3), the combined organic phase was washed with saturated salt water (300mL*3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 139.1g (502mmol) of N-[(1-methylpyrrolidin-2-yl)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 50.2%, m.p. 143-149C.
Example 1. Synthesis of N-[(1-ethylpyrrolidin-2-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4 mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were added to DMF (500mL) with stirring at about 0C and allowed to stir for 1.5 hrs, and then (1-ethylpyrrolidin-2-yl) methylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mL*3). The combined organic phase was washed with saturated salt water (300mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to afford 131.86g (476mmol) of N-[(1-ethylpyrrolidin-2-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 47.6%, m.p.166-169C.
Example 11. Synthesis of N-(1-benzylpyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were added to DMF (500mL) with stirring at about 0C and stirred for 1.5 hrs, then 1-benzylpyrrolidine-3-amine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mLx3), the combined organic phase was washed with saturated salt water (300mL*3), dried over anhydrous Na2SO4 and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 170.3g (524mmol) of N-(1-benzylpyrrolidin-3-yl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 52.4%.
Example 5. Synthesis of N-[(piperidin-2-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1g, 1.4mol), triethylamine (280.0mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0g, 1.0mol) and 1-hydroxybenzotriazole (189.2g, 1.4mol) were sequentially added to DMF (500mL) with stirring at about 0C and stirred for 1.5 hrs, then piperidin-2-yl-methylamine (1.2mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (300mL*3), the combined organic phase was washed with saturated salt water (300mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate = 1/1) to give 117.8g (448mmol) of N-[(piperidin-2-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 44.8%, m.p. 107-115C.
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3 -formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, and the oily residue obtained in the above step (1.66g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with organic solvents (10% methanol/ dichloromethane) (25mLx3), the combined organic phase was washed with saturated salt water (25mLx3), dried over anhydrous Na2SO4 and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol: ethyl acetate = 1:2) to give 0.786g (2.21mmol) of N-{1-[4-(dimethylamino)anilino]-1-oxoprop-2-yl} -5-formyl-2,4-dimethyl-1H-pyrrale-3-formamide, yield 55.2%. 1HNMR (DMSO-d6) delta 10.83 (s, br, 1H, NH), 9.67 (s, 1H), 9.34 (s, br, 1H, NH), 7.65 (m, br, 1H, CONHCH2), 7.54-7.52 (d, 2H), 6.77-6.74 (d, 2H), 4.71 (m, 1H), 3.38-2.58 (s, 6H), 2.58-2.56 (m, 3H), 2.55-2.41 (m, 3H), 1.48-1.41 (d, 3H).
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3- formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were sequentially added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, and the oily residue obtained in the above step (1.48g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with organic solfents (10% methanol/dichloromethane) (25mLx3), the combined organic phase was washed with saturated salt water (25mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol: ethyl acetate = 1:2) to give 0.786g (2.35mmol) of N-{2-[(1-ethylpyrralidin-2-yl)methylamino]-2-oxoethyl}-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide. Yield 58.8%. 1HNMR (DMSO-d6) 610.83 (s, br, H, NH), 9.75 (s, 1H), 7.74 (m, br, 1H, CONHCH2), 7.51 (m, br, 1H, CONHCH2), 3.85-3.83 (d, 2H), 3.07-3.03 (m, 2H), 2.85 (m, 1H), 2.49-2.46 (m, 2H), 2.32-2.30 (m, 2H), 2.37-2.33 (m, 3H), 2.14-2.10 (m, 3H), 1.68-1.64 (m, 2H), 1.56-1.54 (m, 2H), 1.06- 1.01 (m, 3H).
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole -3-formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, and the oily residue obtained in the above step (1.48g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with organic solvent (10% methanol/ dichloromethane) (25mL×3), the combined organic phase was washed with saturated salt water (25mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol: ethyl acetate = 1:2) to give 0.783g (2.34mmol) of N-{2-[2-(1-methylpyrrolidin-2-yl)ethylamino]-5-formyl -2,4-dimethyl-2-oxoethyl}-1H-pyrrole-3-formamide. Yield 58.6%. 1HNMR (DMSO-d6) delta 10.83 (s, br, 1H, NH), 9.75 (s, 1H), 7.65 (m, br, 1H, CONHCH2), 7.64 (m, br, 1H, CONHCH2), 3.81-3.73 (d, 2H), 3.12-3.10 (m, 2H), 2.86 (m, 1H), 2.37 -2.31 (m, 3H), 2.30-2.22 (m, 2H), 2.26-2.20 (s, 3H), 2.12-2.08 (m, 3H), 1.68-1.64 (m, 2H), 1.61-1.53 (m, 2H), 1.56 -1.54 (m, 2H).
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3- formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, and the compound obtained in the above step (1.59g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (25mLx3), the combined organic phase was washed with saturated salt water (25mLx3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol:ethyl acetate = 1:2) to give 0.768g (2.21mmol) of N-{1-[2-{1-methylpyrrolidin-2-yl)ethylamino]-1-oxaprop-2-yl} -5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide. Yield 55.2%. 1HNMR (DMSO-d6) delta 10.83 (s, br, 1H, NH), 9.75 (s, 1H), 7.78 (m, br, 1H, CONHCH2), 7.77 (m, br, 1H, CONHCH2), 4.71 (m, 1H), 3.12-3.10 (m, 2H), 2.86 (m, 1H), 2.37 -2.31 (m, 3H), 2.30-2.22 (m, 2H), 2.26-2.20 (s, 3H), 2.12-2.08 (m, 3H), 1.68-1.64 (m, 2H), 1.61-1.53 (m, 2H), 1.56- 1.54 (m, 2H), 1.48-1.41 (d, 3H).
Example 31. Synthesis of N-{2-[(piperidin-2-yl)methylamino]-2-oxoethyl}-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide 2-Chloroacetic chloride (4.5g, 40mmol) was added dropwise to a solution of 2-aminomethylpiperidine (4.56g, 40mmol) in dichloromethane (50mL) with stirring at about 0C. Afterwards, the reaction was warmed to room temperature and stirred until completion was indicated by thin layer chromatography (TLC). The solvent was distilled off to give 7.02g (36.96mmol) of an oily residue. Yield 92.4%. The oily residue obtained in the above step and aqueous ammonia (300mL) were added to methanol solution (300mL) and stirred at about 45C until thin layer chromatography (TLC). The solvent was distilled off to give 5.37g (31.42mmol) of an oily residue. Yield 85.0%. 1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.074g, 5.6mmol), triethylamine (1.12mL, 8mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3- formic acid (0.668g, 4mmol) and 1-hydroxybenzotriazole (0.756g, 5.6mmol) were added to DMF (10mL) with stirring at about 0C and stirred for 1.5 hrs, and the compound obtained in the above step (1.37g, 8mmol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 1.2 mL of water and 1 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/ dichloromethane (25mL*3), the combined organic phase was washed with saturated salt water (25mL*3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed (silica gel column chromatography, eluent: methanol: ethyl acetate = 1:2) to give 7.99g (2.50mmol) of N-{2-[(piperidin-2-yl)methylamino]-2-oxoethyl}-5-formyl -2,4-dimethyl-1H-pyrrole-3-formamide. Yield 62.4%. 1HNMR (DMSO-d6) delta10.82 (s, br, 1H, NH), 7.71 (s, 1H), 7.67(m, br, 1H, CONHCH2), 7.49 (t, br, 1H, NH), 4.40 (s, br, 1H, NH), 3.81-3.73 (d, 2H), 3.39-3.43 (m, 1H), 3.16-3.18 (m, 2H), 2.50 (s, 3H), 2.60 (s, 3H), 2.08-2.11 (m, 2H), 1.82-1.86 (m, 2H), 1.58-1.64 (m, 2H), 1.39-1.44 (m, 2H).
Into a 500 mL four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, a nitrogen bubbler, and a reflux condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (V) (10.0 g; 0.06 mole), 1-Hydroxy benzotriazole (12.0 g), dicyclohexylcarbodiimide (17.2 g) and tetrahydrofuran (150 mL). To this stirred solution, a solution of triethyl amine (16.8 mL) in 65 mL tetrahydrofuran followed by N,N-diethylaminoethyl amine (10 mL; 0.07 mole) in 65 mL tetrahydrofuran were added through addition funnel and stirred for 20 hours. The progress of the reaction was monitored by TLC. After completion of reaction, the urea derivative was filtered off and the filtrate was re-charged into a fresh 500 mL round-bottomed flask equipped with a mechanical stirrer, thermometer pocket, a nitrogen bubbler, and a reflux condenser. To this stirred solution L(-)-malic acid (8.9 g; 0.06 mole) was charged and further maintained for 4-6 hours. To the resulting solution, 5-fluoro-2-oxindole (8.99 g; 0.06 mole) was charged and continued at reflux temperature for 4-6 hours. The yellow crystalline precipitate was filtered off and wet cake was washed with tetrahydrofuran (50 mL). The product was again triturated in tetrahydrofuran (70 mL) at reflux temperature for 1 hour and filtered. The product was dried at 80-85oC.Dry Weight: 21.5 g Yield: 67.0% HPLC Purity: >99.5%
Multi-step reaction with 3 steps
1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h
1.2: 16 h / 25 - 30 °C
2.1: pyrrolidine / methanol / 5 - 7 h / Reflux
3.1: ethanol / 2 - 4 h / Reflux
Multi-step reaction with 2 steps
1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h
1.2: 16 h / 25 - 30 °C
2.1: ethanol / 8 - 10 °C / Reflux
2.2: 4 - 6 h / Reflux
Multi-step reaction with 4 steps
1.1: 1,1,1,3,3,3-hexamethyl-disilazane / ammonium sulfate / 5 h / Reflux
2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h
2.2: 25 °C
3.1: N,N-dimethyl-formamide / 25 °C
4.1: methanol / 8 h / 25 °C / Inert atmosphere
Multi-step reaction with 4 steps
1.1: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane / 5 h / Reflux
2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C
2.2: 1 h / 40 °C
3.1: acetonitrile; N,N-dimethyl-formamide / 1 h / 25 °C
4.1: methanol / 0.5 h / 20 °C / Inert atmosphere
4.2: 25 °C
Multi-step reaction with 3 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 2 h / 35 °C / Large scale
1.2: 2 h / 35 °C / Large scale
2.1: triethylamine / 2 h / 60 °C / Large scale
3.1: methanol / 1 h / 40 °C / Large scale
5-fluoroanthracene-2-one (1.51 g, 10.0 mmol),2,4-Dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid (1.67 g, 10.0 mmol)And refluxing with tetrahydropyrrole (1.42 g, 1.66 mL, 20.0 mmol) in 120 mL of ethanol for 3 hours.After cooling to room temperature,Add 36mL of 1M hydrochloric acid solution, stir for a while, then filter.The filter cake was washed successively with 20 mL of ethanol and 20 mL of petroleum ether.The filter cake is dried to give a yellow powdery solid.Namely Intermediate 4 (2.95 g, 98.2%).
2.34 g
In ethanol; for 3h;Reflux;
Take compound 1 (8.8 mmol, 1.33 g),2 (8.8 mmol, 1.47 g),Tetrahydropyrrole (18.0 mmol, 1.5 mL)Heat under reflux in 120 mL of ethanol for 3 h.Cool to room temperature,Add 15 mL of dilute hydrochloric acid, filter,The yellow product (2.34 g, 7.80 mmol) was obtained eluting with 20 mL of ethyl ether and petroleum ether.
With piperidine; In ethanol; at 60℃;
Step 1), 5-fluoroindol-2-one (compound 5, 13 g, 1.1 eq.) and2,4-Dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid (compound 3, 13 g, 1.0 eq.) andEthanol (39mL)Add to the 100L reaction bottle,Stirring to 60 C,Piperidine (19.7 g, 0.3 eq.) was added to the reaction flask until the reaction was completed.Filtration and drying gave Compound 12.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.
General procedure: A mixture of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (17, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (4.5 mmol) and HOBt (4.5 mmol) inN,N-Dimethylformamide (10 mL) was stirred for 0.5 h at room temperature. Then compounds5-7, 14-16 or 18-20 (4.5 mmol) and DIEA (6.6 mmol) were added. The reaction mixture was stirred for12-24 h and later water was added. The aqueous layer was extracted with dichloromethane/methanol(10:1, 30 mL x 2) and the combined organic layer was concentrated under reduced pressure. A solutionof the residue and 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (22, 3.0 mmol) in ethanol(10 mL) was stirred at temperature for 8-16 h. The precipitate was filtered, purified via silica gelcolumn chromatography (methanol/dichloromethane 40:1) and recrystallized from ethanol to affordthe title compounds 23a-q (26%-33%, two steps) as yellow solids.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;
A solution of <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (1b, 230mg, 1mmol) dissolved in DMF (10mL) was stirred at room temperature while N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (192mg, 1mmol), hydroxybenzotriazole hydrate (153mg, 1mmol), triethylamine (101mg, 1mmol), and N-(2-aminoethyl)morpholine (130mg, 1mmol) were added. The reaction mixture was stirred at room temperature for 12h [43]. The <strong>[253870-02-9]5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid</strong> (2-morpholin-4-yl-ethyl)-amide (1a) was filtered, washed with DMF and then dried in air. Yield 82%. Anal. Calc. for C14H21N3O3: C, 60.20; H, 7.58; N, 15.04. Found: C, 60.11; H, 7.47; N, 14.99%. 1H NMR (400MHz, DMSO-d6), delta(ppm): 11.85 (s, 1H, NH-pyrrole), 9.54 (s, 1H, CH), 7.40-7.43 (t, 1H, NH), 3.56-3.58 (t, 4H, 2CH2), 3.30-3.33 (q, 2H, CH2), 2.39-2.44 (m, 6H, 3CH2), 2.33 (s, 3H, CH3), 2.38 (s, 3H, CH3). ESI-MS: m/z=280.1720 for [M+H]+.
66%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 5 - 20℃;
General procedure: The substituted acid (5a or 6a, 1.0 mmol), EDC (229 mg, 1.2 mmol) and HOBt (160 mg, 1.2 mmol) were dissolved in DMF (25 mL). After cooling to 5 C, the substituted amine was added to the mixture and was stirred at room temperature overnight followed by evaporation under reduced pressure to remove DMF. The residue was purified by column chromatography (pet. ether/EtOAc 7:1 to 2:1) to afford 5 and 6 with the yields of 66% and 84% respectively.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
To a solution of 20 (prepared as in Example 16 from 5 g of 8) in HMDS (about 75 mL, 15 P) at r.t. was added MeCN (50 mL, 10 P). After stirring for 15 minutes, 14 (5.55 g, 33.1 mmol) and TfOH (0.5 g, 3.3 mmol) were added. Then the mixture was stirred for 24 hours, the reaction was heated to 65 C. for another 24 hours, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (3 mL). The mixture was filtrated and the filtrate cake was dried under vacuum at 40 C. overnight to give the goal product 15 (9.7 g, 97% yield) as a yellow to brown powder with about 88.9% HPLC purity.
With 1,1,1,3,3,3-hexamethyl-disilazane;trifluorormethanesulfonic acid; In acetonitrile; at 20 - 65℃; for 48h;Product distribution / selectivity;
To a solution of 20 (prepared as in Example 16 from 5 g of 8) in HMDS (about 75 mL, 15 P) at r.t. was added MeCN (50mL, 10 P). After stirring for 15 minutes, 14 (5.55 g, 33.1 mmol) and TfOH (0.5g, 3.3 mmol) were added. Then the mixture was stirred for 24 hours, the reaction was heated to 65 C for another 24 hours, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (3 mL). The mixture was filtrated and the filtrate cake was dried under vacuum at 40 C overnight to give the goal product 15 (9.7g, 97% yield) as a yellow to brown powder with about 88.9% HPLC purity.
Stage #1: 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: N-ethylethane-1,2-diamine In N,N-dimethyl-formamide
Stage #1: 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: N-ethylethane-1,2-diamine In N,N-dimethyl-formamide
1 Preparation of N-[2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole- 3-carboxyamide (4)
5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2.0 g, 11.96 mmol) was added to the solution of 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU, 4.23 g, 13.16 mmol) and N-hydroxybenzotriazole (HOBt, 2.01 g, 13.16 mmol) in N,N-dimethylformamide (10 mL). Next, N,N- diisopropylethylamine (DIPEA, 4.5 mL, 26 mmol) was added and the mixture was stirred at room temperature for 30 min. After addition of N-ethyl-ethylenediamine (2.78 mL, 26 mmol) the solution became brown-red, it was stirred overnight. 1M HC1 (10 mL) was added to this mixture, which was stirred for 1 h, after completion of the reaction water (10 mL) and methylene dichloride (150 mL) were added. The organic phase was separated and water layer was diluted with saturated NaHC03 solution (30 mL), brine (30 ml) and 10 % NaOH to reach pH ~13. The obtained mixture was extracted with 10% methanolic solution in methylene dichloride (3 x 30 mL), the combined organic extracts were dried over anhydrous MgS04 and condensed to yield dark oily crude product. The crude material (4 g) was purified by column chromatography filled with silica gel (150 g), using methanol as the eluent. After combining appropriate fractions and removing the solvent, product 4 was obtained. HPLC 96,34%, ES-MS for (M+H)+ calc. 238.30, found 238.3. NMR (600 MHz, DMSOd6): δ 1.00 (t,3H,CH3, Ν-6 ι), 2.31(s,3H,C2-CH3), 2.36(s,3H,C4-CH3), 2.55(q,2H,CH2,N-e,hyi), 2.65 (t,2H,CH2-Nethyiene), 3.27(dt,2H,CH2-NHamide), 7.48 (t,lH,NHamide), 9.54 (s,lH,CHO), 11.8 (bs,lH,NHpyrr0,e) ; 13C NMR: δ 177.22(CH0f0rmyi), 164.55(C=Oamide), 137.72(C2), 130.57(C4), 127.68 (C5), 119.64(C3), 48.49(CH2-Nethy.ene), 43.11 (CH2,N-etKy.), 38.72CH2-NHamide), 12.40(C5-CH3), 15.08(CH3, N-ethyi), 9.55(C3-CH3).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;
General procedure: To a solution of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (8.35g, 50mmol) in DMF (100ml) were addedN-hydroxybenzotriazole (HOBt) (10.1g, 75mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI) (16.9g, 88mmol), triethylamine (30ml) and 1-methylpiperazine (8ml). The mixture was stirred for 24h at room temperature and diluted with 300ml of water and 100ml of brine. After adjusting the pH to >10 with 10N sodium hydroxide solutions, the mixture was extracted with 10% methanol in dichloromethane (500ml×3) and the organic layers were combined, dried (Na2SO4) and evaporated to dryness. The residue was triturated and stirred in 300ml of hexane and ethyl acetate (3:1) for 2h. The solid was collected by filtration, and washed with ethyl acetate and dried under vacuum for 16h to give 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (4.73g, 38% yield).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
General procedure: A solution of compound 2 (167 mg, 1 mmol), EDC·HCl (230mg, 1.2mmol) and HOBt (162mg, 1.2mmol) in DMF (15mL) was stirred at 0-4C under the atmosphere of nitrogen for 20 min. The substituted amine a-f (2 mmol) was added to the mixture and stirred at the same temperature for 30 min and then overnight at room temperature. The mixture was diluted with water and adjusted to pH 9 with saturated Na2CO3 solution and then extracted with dichloromethane and methanol (9:1, v/v). The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide crude product 3a-f (50-60%) as red oils.
With piperidine; In ethanol; at 20.0℃; for 3.0h;Inert atmosphere;
General procedure: A solution of 1-3, 7a,b, 11 (1mmol) and 12a-c (0.7mmol) in anhydrous ethanol (10mL) and piperidine (6 drops) was stirred at room temperature under atmosphere of nitrogen for 2-3 h. The yellow precipitate was collected by suction and washed with ethanol and then dried under vacuum to afford the targeted compounds 13a1-11, 13b1-8, 13c1-8 (50-70%) as yellow solids.
With piperidine; In ethanol; at 20℃; for 3h;Inert atmosphere;
General procedure: A solution of 1-3, 7a,b, 11 (1mmol) and 12a-c (0.7mmol) in anhydrous ethanol (10mL) and piperidine (6 drops) was stirred at room temperature under atmosphere of nitrogen for 2-3 h. The yellow precipitate was collected by suction and washed with ethanol and then dried under vacuum to afford the targeted compounds 13a1-11, 13b1-8, 13c1-8 (50-70%) as yellow solids.
General procedure: A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (17, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (4.5 mmol) and HOBt (4.5 mmol) inN,N-Dimethylformamide (10 mL) was stirred for 0.5 h at room temperature. Then compounds5-7, 14-16 or 18-20 (4.5 mmol) and DIEA (6.6 mmol) were added. The reaction mixture was stirred for12-24 h and later water was added. The aqueous layer was extracted with dichloromethane/methanol(10:1, 30 mL x 2) and the combined organic layer was concentrated under reduced pressure. A solutionof the residue and 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (22, 3.0 mmol) in ethanol(10 mL) was stirred at temperature for 8-16 h. The precipitate was filtered, purified via silica gelcolumn chromatography (methanol/dichloromethane 40:1) and recrystallized from ethanol to affordthe title compounds 23a-q (26%-33%, two steps) as yellow solids.
Stage #1: 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 4-piperidin-1-yl-butylamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
General procedure: A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (17, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (4.5 mmol) and HOBt (4.5 mmol) inN,N-Dimethylformamide (10 mL) was stirred for 0.5 h at room temperature. Then compounds5-7, 14-16 or 18-20 (4.5 mmol) and DIEA (6.6 mmol) were added. The reaction mixture was stirred for12-24 h and later water was added. The aqueous layer was extracted with dichloromethane/methanol(10:1, 30 mL x 2) and the combined organic layer was concentrated under reduced pressure. A solutionof the residue and 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (22, 3.0 mmol) in ethanol(10 mL) was stirred at temperature for 8-16 h. The precipitate was filtered, purified via silica gelcolumn chromatography (methanol/dichloromethane 40:1) and recrystallized from ethanol to affordthe title compounds 23a-q (26%-33%, two steps) as yellow solids.
General procedure: A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (17, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (4.5 mmol) and HOBt (4.5 mmol) inN,N-Dimethylformamide (10 mL) was stirred for 0.5 h at room temperature. Then compounds5?7, 14?16 or 18?20 (4.5 mmol) and DIEA (6.6 mmol) were added. The reaction mixture was stirred for12?24 h and later water was added. The aqueous layer was extracted with dichloromethane/methanol(10:1, 30 mL x 2) and the combined organic layer was concentrated under reduced pressure. A solutionof the residue and 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (22, 3.0 mmol) in ethanol(10 mL) was stirred at temperature for 8?16 h. The precipitate was filtered, purified via silica gelcolumn chromatography (methanol/dichloromethane 40:1) and recrystallized from ethanol to affordthe title compounds 23a?q (26percent?33percent, two steps) as yellow solids.
Stage #1: 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 3-(N-methylpiperazino)propylamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
General procedure: A mixture of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (17, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (4.5 mmol) and HOBt (4.5 mmol) inN,N-Dimethylformamide (10 mL) was stirred for 0.5 h at room temperature. Then compounds5-7, 14-16 or 18-20 (4.5 mmol) and DIEA (6.6 mmol) were added. The reaction mixture was stirred for12-24 h and later water was added. The aqueous layer was extracted with dichloromethane/methanol(10:1, 30 mL x 2) and the combined organic layer was concentrated under reduced pressure. A solutionof the residue and 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (22, 3.0 mmol) in ethanol(10 mL) was stirred at temperature for 8-16 h. The precipitate was filtered, purified via silica gelcolumn chromatography (methanol/dichloromethane 40:1) and recrystallized from ethanol to affordthe title compounds 23a-q (26%-33%, two steps) as yellow solids.
dimethyl N-[(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)carbonyl]-D-glutamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
General procedure: Compound 2 (2.0 g, 0.012 mol) and HBTU (5.0 g, 0.013 mol) was dissolved in dry DMSO (15 ml), in a 250 ml round bottom flask. DIPEA (6.5 ml, 0.037 mol) was added and the reaction mixtures were stirred for 30 min. L or D- phenylalanine methyl ester hydrochloride (3.0 g, 0.014 mol) or <strong>[13515-99-6]glutamic acid dimethyl ester hydrochloride</strong> (3.0 g 0.014 mol) was added and the reaction mixture was kept stirring overnight under ambient conditions. Reaction monitoring by TLC was performed on silica gel plates using CHCl3:MeOH 9:1 as eluent. Saturated NaHCO3 solution (150 ml) was added to the mixture and the precipitate was filtered, washed with saturated NaHCO3 solution and water. The crude product was purified by column chromatography CHCl3:MeOH (95:5) to give the product as white to off-white solid.
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