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Chemical Structure| 55052-28-3
Chemical Structure| 55052-28-3
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Product Details of [ 55052-28-3 ]

CAS No. :55052-28-3 MDL No. :MFCD08272232
Formula : C7H5ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :HNTZVGMWXCFCTA-UHFFFAOYSA-N
M.W : 152.58 Pubchem ID :11389493
Synonyms :

Calculated chemistry of [ 55052-28-3 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.1
TPSA : 28.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.85 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.54
Log Po/w (XLOGP3) : 1.94
Log Po/w (WLOGP) : 2.22
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 2.71
Consensus Log Po/w : 2.0

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.67
Solubility : 0.323 mg/ml ; 0.00212 mol/l
Class : Soluble
Log S (Ali) : -2.17
Solubility : 1.04 mg/ml ; 0.00681 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.51
Solubility : 0.0472 mg/ml ; 0.000309 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.27

Safety of [ 55052-28-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P280-P302+P352-P337+P313-P362+P364-P332+P313 UN#:N/A
Hazard Statements:H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 55052-28-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 55052-28-3 ]
  • Downstream synthetic route of [ 55052-28-3 ]

[ 55052-28-3 ] Synthesis Path-Upstream   1~38

  • 1
  • [ 55052-28-3 ]
  • [ 98549-88-3 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 11, p. 2317 - 2319
  • 2
  • [ 75-16-1 ]
  • [ 55052-28-3 ]
  • [ 824-24-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2018,
  • 3
  • [ 271-63-6 ]
  • [ 55052-28-3 ]
YieldReaction ConditionsOperation in experiment
85% With 3-chloro-benzenecarboperoxoic acid; trichlorophosphate In 1,2-dimethoxyethane; n-heptane at 20 - 85℃; for 18 h; 7-azaindole (3.6 g, 30 mmol) was dissolved in dimethoxyethane (17 ml) and heptane (33 ml), meta-chloroperoxybenzoic acid (mCPBA) (8.1 g, 77percent And the mixture is stirred at room temperature. The mixture was filtered through a filter paper using a solution of dimethoxyethane (34 ml) and heptane (64 ml), phosphorus oxychloride (POCl3) (22 ml, 0.24 mol) was added to the obtained compound,For 18 hours The mixture is heated under reflux at 80°C . The mixture is sufficiently cooled, diluted with water (150 ml), and adjusted to pH 10 with 6N sodium hydroxide (NaOH). The mixture was filtered on a filter paper using water to obtain a solid compound (1) having a pale orange color. (3.9 g, 85percent yield):
80%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In ethyl acetate at 0 - 20℃; for 4 h;
Stage #2: With potassium carbonate In water at 0 - 20℃; for 2 h;
Stage #3: With methanesulfonyl chloride; sodium hydroxide In N,N-dimethyl-formamide at 0 - 75℃;
A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0°C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0°C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30percent K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0°C for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58percent) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50°C, and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70°C. This reaction solution was stirred at 75°C for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0°C, followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60°C under reduced pressure to yield 2.7 g (80percent) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85°C for 12 hr and then cooled to room temperature, and 10percent Na2CO3 (28 mL) and 10percent NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28percent sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92percent). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (t, 1H, J = 3.1 Hz), 7.51 (d, 1H, J = 5.0 Hz), 6.27 (d, 1H, J = 3.4 Hz).
Reference: [1] Patent: KR101548492, 2015, B1, . Location in patent: Paragraph 0048; 0049
[2] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 3, p. 217 - 220
[3] Patent: EP2487180, 2012, A1, . Location in patent: Page/Page column 20
[4] Patent: WO2011/23081, 2011, A1,
[5] European Journal of Medicinal Chemistry, 2011, vol. 46, # 8, p. 3218 - 3226
[6] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1571 - 1576
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 1160 - 1170
[8] ChemMedChem, 2014, vol. 9, # 2, p. 277 - 281
[9] Archiv der Pharmazie, 2014, vol. 347, # 9, p. 635 - 641
[10] Patent: WO2014/151147, 2014, A1,
[11] Patent: US9295673, 2016, B2,
[12] Patent: US2014/336182, 2014, A1,
[13] Patent: US2015/30588, 2015, A1,
[14] Patent: US2015/218155, 2015, A1,
[15] Patent: EP2955181, 2015, A1,
[16] Patent: CN105777747, 2016, A,
[17] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4636 - 4656
[18] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4730 - 4734
[19] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1160 - 1166
[20] Patent: WO2006/46024, 2006, A1,
[21] Patent: WO2007/125321, 2007, A2,
[22] Patent: WO2007/125325, 2007, A1,
[23] Patent: WO2007/125320, 2007, A1,
[24] Patent: WO2008/5457, 2008, A2,
[25] Patent: WO2008/124083, 2008, A2,
[26] Patent: EP1921078, 2008, A1,
[27] Patent: WO2008/139161, 2008, A1, . Location in patent: Page/Page column 136-137
[28] Patent: WO2004/39796, 2004, A1,
[29] Patent: WO2004/39796, 2004, A1,
  • 4
  • [ 74420-18-1 ]
  • [ 55052-28-3 ]
YieldReaction ConditionsOperation in experiment
57% at 90℃; for 18 h; [00256] POCl3 (10 mL) was added to 7-hydroxy-lH-pyrrolo[2,3-b]pyridin-7-ium 3- chlorobenzoate (1.0 g, 3.4 mmol). The resulting mixture was heated to 900C for 18 hours. The mixture was then cooled to room temperature and concentrated. The resulting residue was diluted with acetonitrile ("ACN"; 3 mL) and water (3 mL). The pH was adjusted with 50percent NaOH to a pH of 9. The resulting solid was filtered and washed with water. The solid was then washed with DCM to give 4-chloro-lH-pyrrolo[2,3-b]pyridine (0.30 g, 57percent yield).
Reference: [1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1571 - 1576
[2] Archiv der Pharmazie, 2014, vol. 347, # 9, p. 635 - 641
[3] Patent: WO2009/89352, 2009, A1, . Location in patent: Page/Page column 53
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 8, p. 3218 - 3226
[5] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1160 - 1166
  • 5
  • [ 55052-24-9 ]
  • [ 55052-28-3 ]
YieldReaction ConditionsOperation in experiment
83% With methanesulfonyl chloride In N,N-dimethyl-formamide at 50 - 73℃; for 3 h; REFERENCE SYNTHETIC EXAMPLE 2
4-Chloro-1H-pyrrolo[2,3-b]pyridine
A solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (4.95 g, 36.9 mmol) in N,N-dimethylformamide (10 mL) was warmed to 50°C, and methanesulfonyl chloride (8.00 mL, 103 mmol) was added to it, and the mixture was stirred at 73°C for 3 hours.
Water (70 mL) was added to the iced reaction mixture, and the mixture was neutralized with sodium hydroxide, followed by stirring at ice bath temperature for 10 minutes.
The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound as a reddish brown solid (4.65 g, yield: 83percent).
82.2% With methanesulfonyl chloride In N,N-dimethyl-formamide at 50 - 73℃; for 2 h; To a 50 °C pink solution of lH-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in N,N-dimethylformamide (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol). The pink color changed to orange. The mixture was heated to 73 0C for 2 h, and cooled to 40 °C. Then 35 mL of water was added and the resulting suspension was cooled to 0 °C. NaOH was added to adjust the pH of the mixture to ~7. The mixture was filtered and washed with water (x3) to give 3.8 g of wet pale orange solid that was dried at 40 0C overnight to give 2.35 g (82.2percent yield).1H NMR (400 MHz, CDCl3): δ 10.8 (IH, br); 8.21 (IH, d); 7.41(1H, d); 7.18 (IH, d); 6.61 (IH, d). MS (M+H)+: 153.
81%
Stage #1: With methanesulfonyl chloride In N,N-dimethyl-formamide at 50 - 72℃;
Stage #2: With sodium hydroxide; water In N,N-dimethyl-formamide at 30℃; for 0.25 h;
1 OB. 4-Chloro-lH-pyrrolo[2.3-61pyridine; Methanesulphonyl chloride (5 mL, 64 mmol) was added dropwise to a solution of IH- pyrrolo[2,3-]pyridine 7-oxide (3.18 g, 24 mmol) in DMF (16 mL) and heated to 5O0C. The <n="137"/>resulting mixture was heated at 720C overnight. The reaction mixture was cooled to 3O0C and quenched with water (50 mL). The mixture was cooled in an ice bath and sufficient 1OM aqueous NaOH was added to raise the pH to 7. The resulting slurry was warmed to room temperature, stirred for 15 min, and then filtered to collect the product. The solid was washed with water and dried in vacuo to give 4-chloro-lH-pyrrolo[2,3-]pyridine (2.97g, 19.5 mmol, 81percent). LC-MS (LCTl) m/z 153.03 [M+η+], R1 5.77 min.
76% at 80℃; Part 1: [0193] 4-Chloro-1H-pyrrolo[2,3-b]pyridine: 1H-Pyrrolo[2,3-b]pyridine 7-oxide was added slowly to 200 mL POCl3 and the resulting mixture stirred at 80 C. overnight. The excess POCl3 was then removed in vacuo and the residue treated with 500 mL H2O and basified with saturated K2CO3 (aq), prior to extraction with EtOAc (2x300 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 76percent). MS (ES+): 153 [MH+].
76% With trichlorophosphate In water Part 1
4-Chloro-1H-pyrrolo[2,3-b]pyridine:
1H-Pyrrolo[2,3-b]pyridine 7-oxide was added slowly to 200 mL POCl3 and the resulting mixture stirred at 80° C. overnight.
The excess POCl3 was then removed in vacuo and the residue treated with 500 mL H2O and basified with saturated K2CO3 (aq), prior to extraction with EtOAc (2*300 mL).
The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 76percent). MS (ES+): 153 [MH+].
75% With methanesulfonyl chloride In N,N-dimethyl-formamide at 52 - 72℃; for 2 h; Synthesis of 3
32 ml of methanesulfonyl chloride are added dropwise to a solution of 18.5 g of intermediate 2 in 1 l of DMF at 52° C.
When the addition is complete, the batch is stirred at 72° C. for a further 2 h.
For work-up, the batch is poured onto crushed ice and neutralised using 5N NaOH.
The precipitate is filtered off and dried, giving 4-CI-7-azaindole in 75percent yield (16 g) as colourless solid;
LCMS: (method A) 153.0 (M+H), RT. 2.10 min, 93.4percent (max), 93.6percent (254 nm). (Method A—0.1percent of TFA in H2O, B—0.1percent of TFA in ACN: flow—2.0 ml/min. Column: X Bridge C8 (50×4.6 mm, 3.5 μm)+ve mode); 1H NMR 400 MHz, DMSO-d6: δ [ppm] 12.03 (s, H), 8.16 (d, J=5.12 Hz, H), 7.58 (t, J=3.00 Hz, H), 7.18 (d, J=5.16 Hz, H), 6.49 (dd, J=1.96, 3.44 Hz, H).
70%
Stage #1: With methanesulfonyl chloride In N,N-dimethyl-formamide at 70℃; for 1.5 h;
Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 0℃;
Preparation of 4-chloro-1H-pyrrolo[2,3-b]pyridine
7-Azaindole N-oxide (43.6 g, 325 mmol) was dissolved in anhydrous DMF (280 mL), and methanesulfonyl chloride (d = 1.477, 80 mL, 1.03 mol) was dropwise added thereto under an argon atmosphere.
The resulting mixture was stirred at 70°C for 90 minutes.
The reaction content was poured onto ice (1 kg) and was neutralized with a 5 N sodium hydroxide solution (400 mL).
The precipitated solid was collected by filtration under reduced pressure, washed with iced-water, and dried under reduced pressure using an oil pump to give 34.7 g of 4-chloro-1H-pyrrolo[2,3-b]pyridine (yield: 70percent).
1H-NMR (270MHz, CDCl3) δ (ppm): 6.63 (1H, d, J=2.4Hz), 7.16 (1H, d, J=5.9Hz), 7.41 (1H, d, J=1.9Hz), 8.22 (1H, d, J=5.4Hz), 10.90 (1H, br.s)
ESI (LC-MS positive mode) m/z 153, 155 (M+H).
51% With methanesulfonyl chloride In tetrahydrofuran at 50 - 55℃; for 1.5 h; 5L reaction flask was added 250g, 1.87mol, 1. Oeq. N_ oxo_7_ azaindole and 2.1L of tetrahydrofuran, open stirring. While stirring, 369 g, 3.23 mol, 1.73 eq. Of methanesulfonyl chloride was added and the mixture was added over 0.5 hour. Methanesulfonyl chloride at the same time as a chlorination reagent and water removal reagents, cost savings, reduce operational difficulty, naturally exothermic heating to 50 ° C, then heated to 55 ° C insulation lh after the consumption of raw materials is completed. after the consumption of raw materials is cooled down to 10 ° C, the control temperature at 15 ° C dropping 750ml sodium hydroxide solution, liquid separationThe aqueous phase is separated and washed with 850 ml of water. The organic phase was desolventized to give 170 dark brown solid. beaten with 850ml of methylene chloride to give a pale yellow solid 145g. Dichloromethane excellent solvency, beating extractionOut of high purity products. Yield 51.0percent.
46%
Stage #1: at 0 - 80℃; for 16 h;
Step 4: C10 (18 g, 136 mm) was slowly added to a POCI3 solution (9OmL) solution at 0sC. The mixture was then slowly heated to 75-8O0C, stirred for 16 hr., and cooled to 253C. The reaction mixture was treated with petroleum ether (50 mL) and stirred for 15 min. The petroleum ether layer was decanted from the reaction mixture. The reaction mixture was treated again with petroleum ether (50 mL) and stirred as described above. The petroleum ether layer was decanted off and the resultant thick residue was slowly poured into ice. Solid K2C03was to achieve a pH of 8the mixture was 8 using solid K2CO3. The resultant solids were collected by filtration and dried under reduced pressure to provide 4-chloro-1 H-pyrrolo[2,3- b]pyridine (C11) as a pale pink solid. Yield: 12g, 46percent. 1HNMR(CDCI3) δ: 10.2 (b, 1 H), 8.2 (d, 1 H), 7.4 (d, 1 H), 7.0-7.09 (d, 1 H), 6.6 (d, 1 H). Mass:(M+1) 153 calculated for mol. form. C7H5CIN2.
36% for 6 h; Heating / reflux A mixture of lH-pyrrolo[2,3-]pyridine 7-oxide (1.35 g, 10 mmol) and phosphorous oxychloride (7.6 ml) was refluxed for 6 hours. After cooling down the reaction mixture to room temperature, ice (90 ml) was added and the mixture was basified to pΗ 9 with a saturated aqueous solution of potassium carbonate. The brownish solid was filtered, washed with water, hexane and diethyl ether (547 mg, 3.6 mmol, 36percent). LC/MS (LCT) R, 5.74 [M+Η]+ 153, 155.
36%
Stage #1: for 6 h; Heating / reflux
Stage #2: With potassium carbonate In water at 0℃;
13B. 4-Chloro-1 /-/-pyrrolor2.3-ib1pyridine <n="121"/>A mixture of 1H-pyrrolo[2,3-/)]pyridine 7-oxide (1.35 g, 10 mmol) and phosphorous oxychloride (7.6 ml) was refluxed for 6 hours. After cooling down the reaction mixture to room temperature, ice (90 ml) was added and the mixture was basified to pH 9 with a saturated aqueous solution of potassium carbonate. The brownish solid was filtered, washed with water, hexane and diethyl ether (547 mg, 3.6 mmol, 36percent). LC/MS (LCT) R1 5.74 [M+H]+ 153, 155.
22%
Stage #1: for 8 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In water
Stage 4(b):
4-Chloro-1H-pyrrolo[2,3-b]pyridine, 24
Azaindole 23 (3.18 g, 0.0237 mmol) is refluxed in POCl3 (50 mL) for 8 h, after which the POCl3 is eliminated from the reaction medium by vacuum distillation and the residue is treated with H2O and saturated NaHCO3.
The precipitate is collected by filtration and dried in air.
Purification by flash chromatography leads to 24 (0.84 g, 22percent) as a white crystalline solid: 1H NMR (CDCl3) δ 9.5 (s broad, 1H), 8.18 (d, 1H, J=5.4 Hz), 7.36 (dd, 1H, J=3.5, 2.3 Hz), 7.11 (d, 1H, J=5.1 Hz), 6.61 (dd, 1H, J=3.6, 1.8 Hz), TLC (EtOAc at 40percent/heptane) Rf=0.10, m/z obs.=152.86 (M+1), 154.86, 193.93 (M+Na).

Reference: [1] Patent: EP2955181, 2015, A1, . Location in patent: Paragraph 0147; 0148
[2] Patent: WO2006/69080, 2006, A2, . Location in patent: Page/Page column 35
[3] Patent: WO2007/125320, 2007, A1, . Location in patent: Page/Page column 134-135
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4730 - 4734
[5] Patent: US2004/186124, 2004, A1, . Location in patent: Page/Page column 14
[6] Patent: US2005/154014, 2005, A1,
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1934 - 1937
[8] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 1160 - 1170
[9] ChemMedChem, 2014, vol. 9, # 2, p. 277 - 281
[10] Patent: US2015/218155, 2015, A1, . Location in patent: Paragraph 0311-0315
[11] Patent: WO2004/39796, 2004, A1, . Location in patent: Page/Page column 67
[12] Patent: EP1921078, 2008, A1, . Location in patent: Page/Page column 29-30
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3216 - 3218
[14] Patent: CN107298680, 2017, A, . Location in patent: Paragraph 0009; 0012; 0015; 0016; 0017
[15] Patent: WO2008/12635, 2008, A2, . Location in patent: Page/Page column 80
[16] Patent: WO2006/46024, 2006, A1, . Location in patent: Page/Page column 120
[17] Patent: WO2007/125321, 2007, A2, . Location in patent: Page/Page column 117-118
[18] Patent: US2008/45561, 2008, A1, . Location in patent: Page/Page column 28; 23-24
[19] Journal of Physical Chemistry A, 2003, vol. 107, # 10, p. 1459 - 1471
[20] Journal of Medicinal Chemistry, 2007, vol. 50, # 18, p. 4351 - 4373
[21] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 154
[22] Patent: WO2005/82367, 2005, A1, . Location in patent: Page/Page column 42
[23] Patent: WO2006/12374, 2006, A1, . Location in patent: Page/Page column 214-215
[24] Patent: WO2007/84667, 2007, A2, . Location in patent: Page/Page column 93
[25] Patent: US2004/9983, 2004, A1, . Location in patent: Page/Page column 119
[26] Patent: US2003/225106, 2003, A1, . Location in patent: Page 95
[27] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[28] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0329
[29] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 76
[30] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 362
[31] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4636 - 4656
[32] Patent: WO2004/39796, 2004, A1,
  • 6
  • [ 124-63-0 ]
  • [ 55052-24-9 ]
  • [ 55052-28-3 ]
YieldReaction ConditionsOperation in experiment
81% at 50 - 72℃; lB. 4-Chloro-lH-pyrrolor2,3-61pyridineMethanesulphonyl chloride (5 niL, 64 mmol) was added dropwise to a solution of lH-ρyrrolo[2,3-]pyridine 7-oxide (3.18 g, 24 mmol) in DMF (16 mL) heated to 5O0C. The resulting mixture was heated at 720C overnight. The reaction mixture was cooled to 3O0C and quenched with water (50 mL). The mixture was cooled in an ice bath and sufficient 1OM aqueous NaOH was added to raise the pH to 7. The resulting slurry was warmed to room temperature, stirred for 15 min, and then filtered to collect the product. The solid was washed with water and dried in vacuo to give 4-chloro-lH-pyrrolo[2,3-δ]pyridine (2.97g, 19.5 mmol, 81percent). LC-MS (LCTl) m/z 153.03 [M+η+], Rt 5.77 min.
Reference: [1] Patent: WO2007/125325, 2007, A1, . Location in patent: Page/Page column 86
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  • [ 55052-24-9 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: US6878714, 2005, B2,
  • 8
  • [ 744209-63-0 ]
  • [ 55052-28-3 ]
Reference: [1] Synlett, 2010, # 10, p. 1481 - 1484
  • 9
  • [ 1033809-58-3 ]
  • [ 124-63-0 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 70
  • 10
  • [ 55052-24-9 ]
  • [ 346599-62-0 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: US2002/183319, 2002, A1,
  • 11
  • [ 74420-00-1 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: WO2004/39796, 2004, A1, . Location in patent: Page/Page column 66
  • 12
  • [ 74420-06-7 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: WO2004/39796, 2004, A1,
  • 13
  • [ 55052-28-3 ]
  • [ 5912-18-5 ]
Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 11, p. 2317 - 2319
  • 14
  • [ 55052-28-3 ]
  • [ 74-88-4 ]
  • [ 74420-05-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1934 - 1937
[2] Journal of Organic Chemistry, 1980, vol. 45, # 20, p. 4045 - 4048
[3] Patent: US2009/312366, 2009, A1, . Location in patent: Page/Page column 12; 77
  • 15
  • [ 55052-28-3 ]
  • [ 74420-00-1 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 26, p. 5023 - 5025
  • 16
  • [ 55052-28-3 ]
  • [ 74420-02-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 317 - 325
[2] Organic Letters, 2003, vol. 5, # 26, p. 5023 - 5025
  • 17
  • [ 55052-28-3 ]
  • [ 640735-23-5 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 9, p. 1527 - 1529
[2] Organic Letters, 2003, vol. 5, # 26, p. 5023 - 5025
  • 18
  • [ 557-21-1 ]
  • [ 55052-28-3 ]
  • [ 344327-11-3 ]
YieldReaction ConditionsOperation in experiment
78% With (diphenylphosphin)ferrocene; zinc In ISOPROPYLAMIDE at 120℃; for 18 h; Step 1: lH-pyrrolo [2,3-6] pyridine-4-carbonitrile (21)To degassed N,N-dimethylacetamide (200 mL), compound 12 (30.0 g, 196.7 mmol), zinc cyanide (23.1 g, 196.7 mmol), zinc powder (1.28 g, 19.67 mmol), tris(dibenzylideneaceton)- dipalladium (3.6 g, 3.93 mmol) and diphenylphosphinoferrocene (4.36 g, 7.86 mmol) were added and the mixture was heated at 120 °C for 18 h. After cooling to room temperature, reaction mixture was poured on crushed ice (1.5 kg) and resulting solid was filtered. Solid was taken in ethyl acetate (2 x 1500 mL) and stirred for 0.5 h and filtered. Filtrate was concentrated, residue was crystallized from ethyl acetate and filtered to afford 1H- pyrrolo[2,3-.pound.] pyridine-4-carbonitrile 22.0 g (78percent). 1HNMR (400MHZ, DMSO-dtf): δ 12.20 (br s, 1H), 8.41 (d, J= 4.8 Hz, 1H),7.84 (s, 1H), 7.56 (d, J= 4.8 Hz, 1H), 6.65 d, J= 1.6 Hz, 1H).
70% With zinc In ISOPROPYLAMIDE at 120℃; for 2 h; Inert atmosphere A suspension of 4-chloro-7-azaindole (Int-6, 18.2 g, 119 mmol) in dimethylacetamide (100 mL) was degassed and then filling with nitrogen. To this suspension was added zinc powder (720 mg, 11 mmol), diphenylphosphinoferrocene (2.1 g, 3.8 mmol), zinc cyanide (8.2 g, 69.8 mmol), and tris(dibenzylideneacetone) dipalladium (1.74 g, 1.9 mmol) at room temperature. The mixture was heated at 120 0C under nitrogen for 2 h. After cooled to room temperature, water (300 mL) was added, and the mixture was extracted with ethyl acetate, the organic layer was washed sequentially with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to provide Int-7 (12.3 g, yield: 70percent).MS (ESI+): m/z 144.1 [M+H]+.
Reference: [1] Patent: WO2012/127506, 2012, A1, . Location in patent: Page/Page column 64
[2] Patent: WO2011/23081, 2011, A1, . Location in patent: Page/Page column 52
  • 19
  • [ 55052-28-3 ]
  • [ 344327-11-3 ]
YieldReaction ConditionsOperation in experiment
91% With zinc In ISOPROPYLAMIDE at 120℃; for 1.5 h; Inert atmosphere [001218] (i) Production of lH-pyrrolo[2,3-b]pyridine-4-carbonitrile[001219] A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine (3.1 g, 20 mmol), zinc cyanide (1.4 g, 12 mmol), zinc (130 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (370 mg, 0.40 mmol), 1,1'- bis(diphenylphosphino)ferrocene (440 mg, 0.80 mmol) and N,N-dimethylacetamide (20 mL) was stirred at 1200C for 1.5 hr under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane=2O/8O->; 100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (2.60 g, 91percent) as a red-brown solid.[001220] 1H-NMR (DMSO-d6, 300 MHz) δ 6.65 (IH, dd, J = 1.7, 3.4 Hz), 7.56 (IH, d, J = 4.9 Hz), 7.81 - 7.87 (IH, m), 8.41 (IH, d, J = 4.9 Hz), 12.38 (IH, br s).
Reference: [1] Patent: WO2010/90716, 2010, A1, . Location in patent: Page/Page column 331
  • 20
  • [ 557-21-1 ]
  • [ 55052-28-3 ]
  • [ 344327-11-3 ]
Reference: [1] Patent: WO2007/48070, 2007, A2, . Location in patent: Page/Page column 135
  • 21
  • [ 75-86-5 ]
  • [ 55052-28-3 ]
  • [ 344327-11-3 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1540 - 1545
  • 22
  • [ 55052-28-3 ]
  • [ 344327-11-3 ]
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10035 - 10039[2] Angew. Chem., 2013, vol. 125, # 38, p. 10219 - 10223
  • 23
  • [ 55052-28-3 ]
  • [ 319474-34-5 ]
YieldReaction ConditionsOperation in experiment
48%
Stage #1: With acetyl chloride; sodium iodide In acetonitrile at 80℃; for 96 h;
Stage #2: With sodium hydroxide; water In tetrahydrofuran
Part 2: [0195] 4-Iodo-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80 C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10percent K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3x100 mL). The combined organic extracts were washed with 10percent sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48percent). MS (ES+): 245 [MH+].
39%
Stage #1: With acetyl chloride; sodium iodide In acetonitrile at 80℃; for 168 h; Inert atmosphere
Stage #2: With sodium hydroxide In tetrahydrofuran; water at 25℃; for 3 h;
Intermediate 1.1: 4-iodo-1H-pyrrolo[2,3-b]pyridine
Acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) was added dropwise to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL).
The resulting suspension was heated at 80° C. for 7 days.
After cooling to room temperature, the reaction mixture was concentrated under vacuo, and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue.
The mixture was then extracted with dichloromethane (3*50 mL), the combined organic phase was washed with a saturated solution of sodium bisulfite (2*50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuo.
The residue was dissolved in THF (25 mL) and added to an aqueous solution 1N of sodium hydroxide (15 mL).
The resulting solution was stirred at 25° C. for 3 h.
The reaction mixture was then concentrated under vacuo, and water (100 mL) was added to the residue.
The mixture was extracted with dichloromethane (3*50 mL), the combined organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated under vacuo.
The residue was purified by chromatography on a SP1 Biotage system, using hexanes and ethyl acetate as eluents to afford the title compound (1.26 g, 39percent) as a yellow solid (HPLC: 66percent, RT: 5.77 min) 1H NMR (CDCl3) δ=11.77 (br s, 1H), 7.94 (d, J=5.1 Hz, 1H), 7.51 (d, J=5.1 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 6.41 (d, J=3.3 Hz, 1H); MS (m/z) 245 [M+H]+ (127I).
39% With acetyl chloride; sodium iodide In acetonitrile at 80℃; for 168 h; Step 1 : To a solution of 4-chloro-1 H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL) was added dropwise acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) and the resulting suspension was heated at 80 °C for 7 days. After cooling the reaction mixture was concentrated under vacuo and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase washed with a saturated solution of sodium bisulfite (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. To a solution of the residue in THF (25 mL) was added an aqueous solution 1 N of sodium hydroxide (15 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under vacuo and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The residue was purified on silica gel column using column using hexane / ethyl acetate as eluent to give 4-iodo- H-pyrrolo[2,3- b]pyridine (1.26 g, 39percent) as a yellow solid; LCMS (ESI) 245 (M+H); HPLC 66percent, RT: 5.77 min; H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1 1.77 (br s, 1 H), 7.94 (d, J=5.1 Hz, 1 H), 7.51 (d, J=5.1 Hz, H), 7.44 (d, J=3.7 Hz, 1 H), 6.41 (d, J=3.3 Hz, 1 H).
Reference: [1] Journal of Medicinal Chemistry, 2018,
[2] Tetrahedron Letters, 2007, vol. 48, # 9, p. 1527 - 1529
[3] Patent: US2004/186124, 2004, A1, . Location in patent: Page/Page column 14
[4] Patent: US2011/282056, 2011, A1, . Location in patent: Page/Page column 16
[5] Patent: WO2014/121883, 2014, A1, . Location in patent: Page/Page column 54
[6] Patent: EP2487180, 2012, A1,
  • 24
  • [ 75-36-5 ]
  • [ 55052-28-3 ]
  • [ 319474-34-5 ]
  • [ 443729-67-7 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With sodium iodide In acetonitrile at 20 - 85℃; for 12 h;
Stage #2: With sodium carbonate; sodium hydrogensulfite In water at 20℃; for 0.25 h;
A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0°C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0°C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30percent K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0°C for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58percent) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50°C, and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70°C. This reaction solution was stirred at 75°C for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0°C, followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60°C under reduced pressure to yield 2.7 g (80percent) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85°C for 12 hr and then cooled to room temperature, and 10percent Na2CO3 (28 mL) and 10percent NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28percent sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92percent). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (t, 1H, J = 3.1 Hz), 7.51 (d, 1H, J = 5.0 Hz), 6.27 (d, 1H, J = 3.4 Hz).
Reference: [1] Patent: EP2487180, 2012, A1, . Location in patent: Page/Page column 20
  • 25
  • [ 75-36-5 ]
  • [ 55052-28-3 ]
  • [ 319474-34-5 ]
YieldReaction ConditionsOperation in experiment
48% With sodium hydroxide; sodium iodide In tetrahydrofuran; acetonitrile Part 2
4-Iodo-1H-pyrrolo[2,3-b]pyridine:
To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol).
The mixture was allowed to stir at 80° C. for 4 days, and then the excess acetonitrile was removed in vacuo.
300 mL of 10percent K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3*100 mL).
The combined organic extracts were washed with 10percent sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g).
To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL).
The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2.
The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo.
The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48percent). MS (ES+): 245 [MH+].
Reference: [1] Patent: US2005/154014, 2005, A1,
  • 26
  • [ 55052-28-3 ]
  • [ 346599-62-0 ]
Reference: [1] Patent: WO2014/713, 2014, A1,
[2] Patent: WO2017/59080, 2017, A1,
[3] Patent: WO2007/125325, 2007, A1,
[4] Patent: WO2007/125320, 2007, A1,
  • 27
  • [ 55052-24-9 ]
  • [ 346599-62-0 ]
  • [ 55052-28-3 ]
Reference: [1] Patent: US2002/183319, 2002, A1,
  • 28
  • [ 55052-28-3 ]
  • [ 885500-55-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 5, p. 341 - 353
  • 29
  • [ 55052-28-3 ]
  • [ 920966-03-6 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 5, p. 341 - 353
  • 30
  • [ 6831-82-9 ]
  • [ 55052-28-3 ]
  • [ 937797-32-5 ]
YieldReaction ConditionsOperation in experiment
21% With Celite In toluene for 24 h; Heating / reflux A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1.24 g, 8.13 mmol), K(i-Pr)O (3.2 g, 32.5 mmol) and celite (1.9 g) in toluene (150 mL) was refluxed for 24 h.
The reaction mixture was cooled to 80° C. and quenched by addition of water.
The suspension was cooled to RT, and celite was collected by filtration and triturated with DCM.
The filtrate was extracted with chloroform and the combined organic layers were dried onto silica and purified via flash chromatography (hexane/EtOAc), affording 4-Isopropoxy-1H-pyrrolo[2,3-b]pyridine (295 mg, 21percent yield).
Reference: [1] Patent: US2007/123535, 2007, A1, . Location in patent: Page/Page column 48
  • 31
  • [ 55052-28-3 ]
  • [ 876343-82-7 ]
Reference: [1] ChemMedChem, 2014, vol. 9, # 2, p. 277 - 281
[2] Patent: WO2018/191587, 2018, A1,
  • 32
  • [ 55052-28-3 ]
  • [ 940948-29-8 ]
Reference: [1] Patent: WO2011/75613, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4730 - 4734
  • 33
  • [ 55052-28-3 ]
  • [ 935466-69-6 ]
Reference: [1] Patent: KR101560536, 2015, B1,
  • 34
  • [ 73183-34-3 ]
  • [ 55052-28-3 ]
  • [ 942919-26-8 ]
YieldReaction ConditionsOperation in experiment
94% With potassium acetate In 1,4-dioxane at 100℃; for 5 h; 4-chloro-1 H-pyrrolo[2,3-b]pyridine (457mg, 3mmol), palladium acetate (13.2mg, 2percent), 2-(dicyclohexylphosphino)biphenyl (42mg, 4percent), bis(pinacolato) diborane (1.5g, 6mmol) and potassium acetate (590mg, 6mmol) were taken up in a degassed dioxane (1OmL) under an atmosphere of nitrogen. The resulting mixture was stirred at 1001C for 5 hours, cooled to room te mperature and filtered through a thin pad of Celite (eluting with ethyl acetate). The eluent was washed with water, brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography to give the product (690mg) with a yield of 94percent.
48% With potassium acetate; CyJohnPhos In 1,2-dimethoxyethane at 90℃; for 5 h; Inert atmosphere To a suspension of 4-chloro-lH-pyrrolo [2, 3-b] pyridine (1.00 g, 6.55 mraol), 4, 4,4' , 4' , 5,5, 5' , 5' -octamethyl-2,2' -bi- 1,3,2-dioxaborolane (2.16 g, 8.52 iranol) , biphenyl-2- yl (dicyclohexyl)phosphane (575 mg, 1.64 iranol) and potassium acetate (2.25 g, 22.9 iranol) in 1,2-dimethoxyethane (20 mL) was added tris (dibenzylideneacetone)dipalladium(O) (600 mg, 0.655 iranol). The mixture was degassed and stirred at 900C for 5 h under argon atmosphere. To the resulting mixture were added EtOAc (100 mL) and water (50 mL) . An insoluble material was removed by filtration and the layers of the filtrate were separated. The aqueous layer was extracted with EtOAc (10 mL) . The combined organic layers were washed with brine (10 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with EtOAc/hexane (1:1, 10 mL) to give pale yellow solid (442 mg, 28percent) . The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 60:40 hexane/EtOAc) to give the title compound (320 mg, 20percent, total yield = 762 mg, 48percent) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) 1.35 (12H, s), 6.66 (IH, dd, J = 3.2, 1.9 Hz), 7.28 (IH, d, J = 4.5 Hz), 7.51 (IH, t, J = 3.2 Hz), 8.21 (IH, d, J = 4.5 Hz), 11.63 (IH, br s) .
48% With potassium acetate In 1,4-dioxane for 3 h; Heating / reflux Step b - 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 l-l-pyrrolo[2,3-b]pyridine; A solution of 2-(dicyclohexylphosphino)biphenyl (0.287g, 0.819mmol), 6/s(pinacolato)diboron (0.915g, 3.60mmol), Acetic acid potassium salt (0.965g, 9.83mmol), fr7s(dibenzylideneacetone)dipalladium(0) (0.03Og, 0.032mmol) and 4-chloro- 1 H-pyrrolo[2,3-b]pyridine (0.50Og, 3.28mmol) in dioxane (10ml) was degassed, placed under a nitrogen atmosphere and heated under reflux for 3 hours. The solvent was removed in vacuo. The residue was taken up in MeOH and loaded onto a MP-TsOH cartridge (2500mg). The cartridge was washed with MeOH then with 2M ammonia in MeOH and the solvent reduced in vacuo to afford 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine (0.394g, 1.62mmol, 48percent) of a brown solid. LCMS (2) Rt: 1.39min; m/z (ES+) 245.
Reference: [1] Patent: WO2009/93981, 2009, A1, . Location in patent: Page/Page column 106
[2] Patent: WO2010/101302, 2010, A1, . Location in patent: Page/Page column 186
[3] Patent: WO2008/139161, 2008, A1, . Location in patent: Page/Page column 137
  • 35
  • [ 55052-28-3 ]
  • [ 1000340-39-5 ]
YieldReaction ConditionsOperation in experiment
96% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; General procedure: 1H-4-chloro-pyrrolo[2,3-b]pyridine (0.763g, 5.0mmol, 1 eq.) was dissolved in DMF (7.5mL, 1.5mL/mmol SM) and NCS (0.701g, 5.25mmol, 1.05 eq.) was added. The resulting mixture was stirred at ambient temperature overnight, protected from light. Then, ice-cold water (25mL, 5mL/mmol SM) was added and the resulting precipitate filtered. The solids were washed four additional times with ice-cold water (4×10mL, 2mL/mmol SM). The solid was collected and dried under high vacuum to give 60 (0.861g, 4.6mmol) as an off-white solid in 92percent yield. Melting point: 236°C (decomposed). 1H NMR (300MHz, DMSO‑d6) δ: 7.21 (d, J=4.2Hz, 1H, H-5), 7.77 (s, 1H, H-2), 8.20 (d, J=4.2Hz, 1H, H-6), 12.35 (br. s, 1H, NH). 13C NMR (75MHz, DMSO‑d6) δ: 101.1 (C-3), 113.7 (C-3a), 117.1 (C-5), 125.1 (C-2), 133.8 (C-4), 144.4 (C-6), 147.6 (7a). HRMS (ESI): calculated for C7H5Cl2N2 ([M+H]+): 186.9824, found: 186.9824.
90.9% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 6 h; A 50ml of flask was charged with 1.52 g of 4-chloro-lH-pyrrolo[2,3-b]pyridine (prepared according to Tetrahedron Letters (2007), 48(9), 1527-1529), 2.7 gNBS and 29ml DMF. The mixture was stirred at rt for 6h. The solvent was evaporated off and purified by chromatography to give the 2.11 g of product, yield: 90.9percent.
58% With N-Bromosuccinimide In acetone at 25℃; for 1 h; Step 1 : A solution of C11 (9 g, 59.016 mM) in acetone (60 mL) was slowly added to a solution of N-N-bromosuccinimide (NBS) (10.44 g, 59.01 mM) in acetone (100 mL) at 25°C, and the reaction mixture was stirred for 1 hr. at 250C. The solids were collected by filtration, washed with chilled acetone (5OmL), and dried under reduced pressure to provide 3-bromo-4- chloro-1 H-pyrrolo[2,3-b]pyridine (C38) as pale yellow solid. Yield: 7.5g, 58percent. 1HNMR(CDCI3) δ: 11.6-11.7 (b, 1 H), 8.1-8.2 (d, 1 H), 7.2-7.4 (s, 1 H), 7.0-7.01 (d, 1 H). Mass:(M+1) 231 calculated for mol. form. C7H4BrCIN2.
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 248 - 267
[2] Patent: WO2008/5457, 2008, A2, . Location in patent: Page/Page column 180
[3] Patent: WO2008/12635, 2008, A2, . Location in patent: Page/Page column 90
  • 36
  • [ 100-97-0 ]
  • [ 55052-28-3 ]
  • [ 918515-16-9 ]
Reference: [1] Patent: WO2009/23623, 2009, A1, . Location in patent: Page/Page column 70
[2] Patent: US2009/253679, 2009, A1, . Location in patent: Page/Page column 36
[3] Patent: US2015/218165, 2015, A1, . Location in patent: Paragraph 1319
[4] Patent: WO2009/108551, 2009, A2, . Location in patent: Page/Page column 59-60
  • 37
  • [ 55052-28-3 ]
  • [ 1015610-31-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 1160 - 1170
[2] Patent: US2015/218155, 2015, A1,
  • 38
  • [ 55052-28-3 ]
  • [ 951625-93-7 ]
Reference: [1] Patent: WO2016/123392, 2016, A2,
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[ 171879-99-5 ]

4-Chloro-6-methyl-7-azaindole

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Chemical Structure| 866546-07-8

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Chemical Structure| 688782-02-7

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4-Chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine

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4-Chloro-6-methyl-7-azaindole

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5-Chloro-1H-pyrrolo[2,3-b]pyridine

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