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Chemical Structure| 183208-35-7
Chemical Structure| 183208-35-7
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Product Details of [ 183208-35-7 ]

CAS No. :183208-35-7 MDL No. :MFCD06659677
Formula : C7H5BrN2 Boiling Point : -
Linear Structure Formula :- InChI Key :LPTVWZSQAIDCEB-UHFFFAOYSA-N
M.W :197.03 Pubchem ID :10307932
Synonyms :

Calculated chemistry of [ 183208-35-7 ]

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 : 43.79
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) : -6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 2.0
Log Po/w (WLOGP) : 2.33
Log Po/w (MLOGP) : 1.75
Log Po/w (SILICOS-IT) : 2.75
Consensus Log Po/w : 2.1

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.99
Solubility : 0.203 mg/ml ; 0.00103 mol/l
Class : Soluble
Log S (Ali) : -2.23
Solubility : 1.16 mg/ml ; 0.0059 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.77
Solubility : 0.0337 mg/ml ; 0.000171 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.47

Safety of [ 183208-35-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 183208-35-7 ]

* 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 [ 183208-35-7 ]
  • Downstream synthetic route of [ 183208-35-7 ]

[ 183208-35-7 ] Synthesis Path-Upstream   1~57

  • 1
  • [ 183208-35-7 ]
  • [ 98549-88-3 ]
Reference: [1] Patent: WO2018/29711, 2018, A2,
[2] Patent: CN107434807, 2017, A,
  • 2
  • [ 183208-35-7 ]
  • [ 100960-07-4 ]
YieldReaction ConditionsOperation in experiment
63% With ammonia; copper(II) sulfate In waterin a sealed tube; Heating / reflux [0250] 5-bromo-lH-pyrrolo[2,3-b]ρyridine (6.Og, 30.45mmol) in ammonium hydroxide (12OmL) was treated with copper sulphate pentahydrate (1.50g, 6.09mmol, 0.2 eq) and heated in a sealed tube overnight. The reaction was diluted with EtOAc and the insoluble black solid was filtered off. The filtrate was extracted (EtO Ac/Water) and the organic layer washed with saturated aqueous ammonium chloride, followed by water and brine. The organics were dried over magnesium sulphate, filtered and evaporated to dryness to give the product as a pale brown solid (2.57g, 63percent)
Reference: [1] Patent: WO2008/79346, 2008, A1, . Location in patent: Page/Page column 148
  • 3
  • [ 183208-35-7 ]
  • [ 183208-34-6 ]
Reference: [1] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
  • 4
  • [ 115170-40-6 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
100% With manganese(IV) oxide In dichloromethane for 72 h; To a stirred solution of azaindoline 5 (7.00 g, 35.2 mmol) in CH2C12 (664 ML) was added activated MnO2 (3.06 g, 35.2 MMOL), AND PROGRESS of the reaction was monitored BY LH EMR of reaction aliquots. After 3 days the mixture was filtered through A pad of silica, and the pad was washed with EtOAc. The filtrates were concentrated to afford the azaindole 27 (6. 98 g, 100 percent) as A brown solid. 1H NMR data as in Method 1.
90% With manganese(IV) oxide In toluene for 4 h; Reflux The 84.8 g of the 5-bromo-7-azaindoline product obtained in step 4 was dissolved in 400 mL of toluene,221.5 g of manganese dioxide was added,Heating reflux reaction 4h;Step 6) The reaction solution obtained in Step 5 was cooled to room temperature,filter,The filter cake was washed twice with dichloromethane,Combine organic phase,dry,Concentrated 5-bromo-7-azaindole crude product,The product was crystallized from a petroleum ether-ethyl acetate mixed solution of ΡΕ / ΕΑ = 10: 1 to give 75 g of 5-bromo-7-azaindole,Yield 90percent.
85.43% With activated carbon fiber catalyst In 5,5-dimethyl-1,3-cyclohexadiene at 100℃; for 8 h; a) 30g (0.151mol) of 5-bromo-7-azaporphyrin, 60g of activated carbon fiber catalyst, 264g of xylene into the reaction flask, stirring evenly, to obtain a reaction mixture G;b) The reaction mixture G at 100 °C, oxygen flow 200mL/min, reaction 8h, chromatographic monitoring of the disappearance of raw materials;c) Filtration, filter out activated carbon fiber catalyst, obtain organic layer H, recover solvent, get 5-bromo-7-azaindole crude product, recrystallize from methanol to obtain product 25.37g, yield 85.43percent, content ≥99percent .
82% at 80 - 90℃; for 2 h; Large scale To the autoclave was added 100 kg of dihydro-5-bromo-7-azaindole, 100 kg of manganese dioxide and 950 kg of glacial acetic acid,Control the temperature of 80-90 degrees Celsius, reaction 2h, then the reaction solution cooled to 20 degrees Celsius, filtered, washed with water, centrifuged for 0.5 hours, dried product 5 - bromo-7-azaindole 82kg.
75% With manganese(IV) oxide In toluene at 90℃; for 2 h; Step 3; To a stirred solution of 5-bromo- 2,3-dihydro- 1H-pyrrolo[2,3-b]pyridine (3.4 g, 17 mmole) in 30 ml of toluene was added activated MnO2 ( 9.5 g, 100 mmole) and the mixture was heated at 90°C for 2 hrs. Then the reaction mixture was filtered through a pad of celite and washed with dichloromethane. Purification was performed by flash chromatography using dichloromethane as eluent giving 2.5 g of 5-bromo- 1 H-pyrrolo[2,3-b]pyridine (3) (75percent yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 6.46 (dd, J=1.83 Hz , J=1.70 Hz, 1H) 7.55 (t, J=3.05 Hz , 1H) 8.21(d, J=2.32 Hz , 1 H) 8.27(d, J=2.90 Hz , 1 H) 11.87 (bs,1 H)
44% With 2,3-dicyano-5,6-dichloro-p-benzoquinone In toluene for 0.666667 h; Heating / reflux Preparation Example R-5.
5-Bromo-1H-pyrrolo[2,3-b]pyridine
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600mg, 3.01 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone described in Preparation Example R-4 (753mg, 3.31 mmol) was dissolved in toluene (15mL), and the solution was refluxed for 40 minutes under nitrogen atmosphere.
The reaction solution was cooled to room temperature, water and ethyl acetate were added thereto, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and the title compound (260mg, 1.32mmol, 44percent) was obtained as a white solid.
1H-NMR Spectrum (DMSO-d6) δ (ppm): 6.40-6.48 (1 H, m), 7.50-7.60 (1 H, m), 8.20 (1 H, s), 8.30 (1 H, s), 11.9 (1H, s).
44% With 2,3-dicyano-5,6-dichloro-p-benzoquinone In toluene for 0.666667 h; Heating / reflux 5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600mg, 3.01mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone described in Preparation Example R-4 (753mg, 3.31 mmol) was dissolved in toluene (15mL), and the solution was refluxed for 40 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added thereto, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 5 : 1), and the title compound (260mg, 1.32mmol, 44percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 6.40-6.48 (1 H, m), 7.50-7.60 (1 H, m), 8.20 (1 H, s), 8.30 (1 H, s), 11.9 (1 H, s).

Reference: [1] Patent: WO2004/78757, 2004, A2, . Location in patent: Page 65; 66-67
[2] Patent: CN105461718, 2016, A, . Location in patent: Paragraph 0016
[3] Patent: CN107987076, 2018, A, . Location in patent: Paragraph 0042; 0054-0057; 0070-0073; 0086-0089
[4] Patent: CN106188050, 2016, A, . Location in patent: Paragraph 0021
[5] Patent: EP2070928, 2009, A1, . Location in patent: Page/Page column 101
[6] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 63
[7] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 71
[8] Patent: CN105622605, 2016, A, . Location in patent: Paragraph 0140; 0141; 0149; 0150; 0151; 0152
[9] Patent: WO2007/135398, 2007, A1, . Location in patent: Page/Page column 81
  • 5
  • [ 183208-34-6 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
77.6%
Stage #1: With hydrogenchloride; tin In ethanol; water at 40℃; for 2 h;
Stage #2: With copper(ll) bromide In chloroform at 60℃; for 2 h;
In the 250 ml flask is sequentially added in 50 ml ethanol and 5 - bromo -1 - hydrogen pyrrolo [2,3 - the b] pyridine -2 - ketone (4.2g, 20 mmol), Sn powder (4.7 g, 40 mmol) and 5 mol/L hydrochloric acid (14 ml), 40 °C stirring for 2 hours, the reaction is completed, to remove the ethanol, add 50 ml of water residue is completely dissolved, saturatedNaHCO3solution and to PH=8, and filtering the resulting solid, after drying, dissolved in 50 ml chloroform, addingCuBr2(13.4 g, 60mmol), 60 °Cstirring for 2 hours, the reaction is completed, the end of the reaction, rotary evaporated to remove chloroform, adding 50 ml saturatedNaHCO3solution, ethyl acetate (3 × 100 ml), the combined organic phase with water (50 ml) for washing and then the saturated salt water (50 ml) washing, anhydrousNa2SO4drying, filtering, the filtrate is concentrated to obtain 5 - bromo - 1H - pyrrolo [2,3 - the b] pyridine the crude product, the crude product is chloroform: hexane=2:1 (volume ratio) mixed solution recrystallize to get 3.1 g of pale yellow 5 - bromo - 1H - pyrrolo [2,3 - the b] pyridine pure product, yield 77.6percent, melting point:176.8-177.3 °C,
Reference: [1] Patent: CN106045995, 2016, A, . Location in patent: Paragraph 0022
[2] Heterocycles, 2003, vol. 60, # 4, p. 865 - 877
[3] Journal of the American Chemical Society, 2006, vol. 128, # 45, p. 14426 - 14427
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 309 - 313
[5] Heterocycles, 1999, vol. 50, # 2, p. 1065 - 1080
  • 6
  • [ 1262985-25-0 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
75% With sodium hydroxide In 1-methyl-pyrrolidin-2-one; water at 75 - 81℃; Inert atmosphere b) Preparation of 5-bromo-7-azaindole from isolated 4-(2-Amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol; A 1000 mL double-jacket reactor (under a nitrogen atmosphere) is charged with 80.0 g 4-(2-amino-5-bromo-pyridin-3-yl)-2-methyl-but-3-yn-2-ol, 320 mL N-methylpyrrolidone and 330 mL water. The mixture is heated to 75 to 80° C. and a vacuum of ca 350 mbar is applied. The solution is then treated at 75 to 80° C. within 30 to 45 minutes with 181 mL sodium hydroxide (28percent in water). The dropping funnel is rinsed with 5 mL water and the mixture stirred at 78 to 81° C. for 15 to 20 hours. During stirring the jacket temperature and the vacuum have to be adjusted such that the internal temperature is 78 to 81° C. and a slight steadily distillate flow is guaranteed. When the volume in the reactor has reached approx. 800 mL water is continuously added to keep the volume constant for the rest of the reaction time. In-process control. Upon complete conversion, the reaction mixture is concentrated to a volume of approx. 700 mL and then cooled to 50 to 55° C. The mixture is treated at this temperature with 200 mL toluene. The biphasic mixture (ca. 900 mL) is stirred at 50 to 55° C. for 15 to 30 minutes and the layers are then allowed to separate for 15 to 30 minutes. The aqueous layer is separated and then extracted at 50 to 55° C. with 3.x.140 mL, totally with 420 mL toluene. The combined toluene layers are washed at 50 to 55° C. with 2.x.100 mL, totally with 200 mL water. The toluene layer is concentrated under reduced pressure at 45 to 55° C. until a residual volume of 450 to 500 mL is obtained. The residue is treated at 50 to 55° C. with 225 g ethyl acetate and the resulting solution is washed at 50 to 55° C. with 3.x.150 mL, totally with 450 mL water. From the organic layer, water and ethyl acetate are azeotropically distilled off with toluene under reduced pressure at 45 to 55° C. At the end of the distillation a volume of 600 to 700 mL is adjusted. The mixture is heated to 90 to 95° C. and stirred until a clear solution is obtained. The solution is treated with 2.0 g activated charcoal (Norit SX) and the resulting mixture stirred for 15 to 30 minutes at 90 to 95° C. The charcoal is removed by a hot filtration at 90 to 95° C. The first reactor, the filter and the transfer pipes are washed with 3.x.100 mL, totally with 300 mL toluene. The filtrate is concentrated under reduced pressure to a volume of approx. 400 mL. The resulting suspension is heated to 90 to 100° C. to obtain a clear solution. The solution is cooled to -5 to -10° C. within 7 to 10 hours and the resulting suspension stirred at this temperature for additional 3 to 5 hours. The crystals are filtered off and washed in two portions with 120 mL toluene (pre-cooled to <0° C.). The wet crystals are dried at 55 to 65° C./<30 mbar until constant weight. Yield: 46.5 g (75percent) of slightly yellow crystals with an assay of 100.1percent (m/m).
Reference: [1] Patent: US2011/28511, 2011, A1, . Location in patent: Page/Page column 12-13
  • 7
  • [ 754214-54-5 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogenchloride In methanol for 0.133333 h; To a stirred solution of the TBS derivative 26 (1.01 g, 3.3 mmol) in MeOH (10 mL) was added a 10percent solution of HCl in MeOH (7 mL). After 8 min the solvents were evaporated and the residue was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted with AcOEt (3x). The combined organic solutions were dried (MgSO4), concentrated and purified by PTLC with CH2CL2 : MeOH=95: 5 as eluent to afford the bromo derivative 27 (0.60 g, 94 percent). H NMR (400 MHz; CDCl3) 8 6.47 (dd, J = 2.0, 3.5 Hz, 1H), 7.37 (dd, J = 2.5, 3.5 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8. 36 (d, J = 2.0 Hz, 1H), 10.24 (br s, NH).
Reference: [1] Patent: WO2004/78757, 2004, A2, . Location in patent: Page 65; 66
[2] Patent: US2011/144105, 2011, A1, . Location in patent: Page/Page column 16
  • 8
  • [ 875639-46-6 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
67% With tetrabutyl ammonium fluoride In tetrahydrofuran for 15 h; Heating / reflux To a solution of N-(5-bromo-3-trimethylsilanylethynyl-pyridin-2-yl)-acetamide (4.75 g, 15.26 mmol) in THF (90 ml) was added dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (30.5 ml, 30.5 mmol). After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuo and water was added. The aqueous layer was extracted three times with dichloromethane with, and the combined extracts were directly adsorbed on silica gel. Purification by flash chromotography on silica gel with a gradient of ethyl acetate/hexanes afforded 2.29 g of a beige solid. Recrystallization from ethyl acetate/hexanes provided the title compound as light beige flakes (1.33 g). Further purification of the filtrate on silica gel with a gradient of ethyl acetate/hexanes afforded more of the title compound as a crystalline powder (675 mg) for a combined yield of 2.01 g; 67percent. 1H NMR (DMSO-d6): δ 11.89 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.53 (t, J=3.0 Hz, 1H), 6.42 (dd, J=1.0, 3.0 Hz, 1H); HPLC/MS m/z: 197 [MH]+.
67% With tetrabutyl ammonium fluoride In tetrahydrofuran for 15 h; Heating / reflux Step 3:
Synthesis of 5-bromo-1H-pyrrolo[2,3-b]pyridine.
To a solution of N-(5-bromo-3-trimethylsilanylethynyl-pyridin-2-yl)-acetamide (4.75 g, 15.26 mmol) in THF (90 ml) was added dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (30.5 ml, 30.5 mmol).
After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuo and water was added.
The aqueous layer was extracted three times with dichloromethane with, and the combined extracts were directly adsorbed on silica gel.
Purification by flash chromotography on silica gel with a gradient of ethyl acetate/hexanes afforded 2.29 g of a beige solid.
Recrystallization from ethyl acetate/hexanes provided the title compound as light beige flakes (1.33 g).
Further purification of the filtrate on silica gel with a gradient of ethyl acetate/hexanes afforded more of the title compound as a crystalline powder (675 mg) for a combined yield of 2.01 g; 67percent. 1H NMR (DMSO-d6): δ 11.89 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.53 (t, J=3.0 Hz, 1H), 6.42 (dd, J=1.0, 3.0 Hz, 1H); HPLC/MS m/z: 197 [MH]+.
Reference: [1] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 70-71
[2] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 75
  • 9
  • [ 905966-34-9 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 12 h; Heating / reflux
Stage #2: With hydrogenchloride In water; <i>tert</i>-butyl alcohol at 20℃; for 12 h; Heating / reflux
Stage #3: With sodium hydroxide In water; <i>tert</i>-butyl alcohol
A solution of 10a (440 g, 1.63 mol) in t-butanol (5 L) was treated with potassium t-butoxide (732 g, 6.54 mol). The reaction was heated at reflux for 12 hours. Progress of the reaction was monitored by HPLC. First, quick trimethylsilyl deprotection occurs, over time the t-butyl enol is noted in the HPLC. Once the HPLC indicates that all material is converted to the enol, the reaction is cooled to room temperature and concentrated hydrochloric acid (1 L) is added. The reaction is again brought to reflux and stirred for 12 hours. Once the reaction is determined to be complete by HPLC, the reaction is cooled to room temperature, poured into water (5 L) and filtered through a bed of Celite (diatomaceous earth). The aqueous solution is then diluted with water (5 L) and made basic by the addition of 50percent sodium hydroxide. The mixture is extracted with ethyl acetate (3.x.6 L). The organics are washed with water (4 L) and saturated sodium chloride (4 L), dried over sodium sulfate and solvent removed under reduced pressure to a thick slurry. The slurry is filtered and solids washed with 50percent methyl t-butyl ether/heptane (500 mL). The pale yellow solid 11a are dried in a vacuum oven to constant weight, 192 g (60percent); 1H NMR δ (300 MHz, CDCl3): δ 6.47 (m, 1 H); 7.38 (m, 1 H): 8.08 (d, 1 H); 8.37 (s. 1 H); 10.85 (bs. 1 H). 13 C NMR (300 MHz, CDCl3): δ 100.76. 111.50. 122.31, 126.88. 131.33. 143.26, 147.17.
53% With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 20 - 80℃; for 1 h; Example 85-bromo-7-azaindole (12, via Sonogashira reaction)SiMe.1112A solution of 2-Amino-3-iodo-5-bromopyridine (1 1 ) in toluene was degassed with argon and then treated with PdCI2(PPh3)2CI2 (0.17 eq.) and Cul (0.17 eq.) and degassed with argon again. To the suspension was added tetramethylguanidine (1 .4 eq.) and ethyltrimethylsilane (2 eq.) and stirred at 80 °C for 1 h. After cooling to roomtemperature, extractive work-up the intermediate was collected in 83percent yield as brown solid.A solution of the intermediate in 1 -methyl-2-pyrrolidinone (NMP) was treated at room temperature with potassium tert. butylate (2 eq.). The mixture was heated to 80 °C and stirred for 1 h. After cooling to room temperature, extractive work-up andchromatographic purification the title compound (12) was collected in non optimized 53percent yield.
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10093 - 10096[2] Angew. Chem., 2013, vol. 52, # 38, p. 10093 - 10096,4
[3] Patent: US2006/183758, 2006, A1, . Location in patent: Page/Page column 9
[4] Organometallics, 2010, vol. 29, # 4, p. 998 - 1003
[5] Patent: WO2012/10538, 2012, A2, . Location in patent: Page/Page column 30
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  • [ 1210838-82-6 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: US2011/28511, 2011, A1, . Location in patent: Page/Page column 12
  • 11
  • [ 183208-32-4 ]
  • [ 183208-35-7 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 45, p. 14426 - 14427
[2] Heterocycles, 2003, vol. 60, # 4, p. 865 - 877
[3] Heterocycles, 1999, vol. 50, # 2, p. 1065 - 1080
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 309 - 313
  • 12
  • [ 883052-76-4 ]
  • [ 183208-35-7 ]
YieldReaction ConditionsOperation in experiment
26%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -30℃;
Stage #2: With acetic acid In tetrahydrofuran
Example 2bSynthesis of 5-bromo-7-azaindole (1)150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30° C. Then 24.2 g (0.10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound (4) was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4.x.100 mL of hot toluene (40° C.). The organic phases were combined and THF was removed under vacuum at 45° C. The residual toluene solution was washed with 3.x.150 mL of water and 2.x.150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0° C. for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50° C. for 8 h to furnish 2.8 g of the title compound (I) with a HPLC purity of >99percent. All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10:1 as eluent to afford additional 2.2 g of the title compound (I) with a purity of >98.9percent (HPLC). In total 5.0 g (26percent) of 5-bromo-7-azaindole (1) were obtained.
26%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -30℃;
Stage #2: With acetic acid In tetrahydrofuran
Example 2b: Synthesis of 5-bromo-7-azaindole (1):150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30°C. Then 24.2 g (0.10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound 4 was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4x 100 mL of hot toluene (40°C). The organic phases were combined and THF was removed under vacuum at 45°C. The residual toluene solution was washed with 3x 150 mL of water and 2x 150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0°C for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50°C for 8 h to furnish 2.8 g of the title compound (1) with a HPLC purity of >99 percent. All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10: 1 as eluent to afford additional 2.2 g of the title compound (1) with a purity of >98.9 percent (HPLC). In total 5.0 g (26percent) of 5-bromo-7-azaindole (1) were obtained.
Reference: [1] Patent: US2011/224438, 2011, A1, . Location in patent: Page/Page column 3-4
[2] Patent: WO2011/110479, 2011, A1, . Location in patent: Page/Page column 7
  • 13
  • [ 1111638-00-6 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 72-73
  • 14
  • [ 1743-36-8 ]
  • [ 183208-35-7 ]
Reference: [1] Chemistry - A European Journal, 2016, vol. 22, # 42, p. 14826 - 14830
  • 15
  • [ 271-63-6 ]
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Reference: [1] Heterocycles, 2003, vol. 60, # 4, p. 865 - 877
[2] Heterocycles, 1999, vol. 50, # 2, p. 1065 - 1080
[3] Patent: WO2005/9958, 2005, A1, . Location in patent: Page 158-159
[4] Patent: US2011/144105, 2011, A1,
[5] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 309 - 313
[6] Patent: CN105622605, 2016, A,
[7] Patent: CN106045995, 2016, A,
[8] Patent: CN105461718, 2016, A,
[9] Patent: CN106188050, 2016, A,
[10] Patent: CN107987076, 2018, A,
[11] Patent: WO2007/135398, 2007, A1,
  • 16
  • [ 1356397-50-6 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: WO2012/10538, 2012, A2, . Location in patent: Page/Page column 29
[2] Patent: US2012/22258, 2012, A1, . Location in patent: Page/Page column 13
  • 17
  • [ 1072-97-5 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: WO2012/10538, 2012, A2,
[2] Patent: WO2012/10538, 2012, A2,
[3] Patent: US2012/22258, 2012, A1,
[4] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10093 - 10096[5] Angew. Chem., 2013, vol. 52, # 38, p. 10093 - 10096,4
  • 18
  • [ 381233-96-1 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: WO2012/10538, 2012, A2,
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10093 - 10096[3] Angew. Chem., 2013, vol. 52, # 38, p. 10093 - 10096,4
  • 19
  • [ 10592-27-5 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: US2011/144105, 2011, A1,
[2] Patent: WO2007/135398, 2007, A1,
  • 20
  • [ 3430-21-5 ]
  • [ 183208-35-7 ]
Reference: [1] Patent: CN108752341, 2018, A,
[2] Patent: CN109053727, 2018, A,
  • 21
  • [ 124-41-4 ]
  • [ 183208-35-7 ]
  • [ 183208-36-8 ]
YieldReaction ConditionsOperation in experiment
78% With copper(I) bromide In N,N-dimethyl-formamide at 140℃; 5-Methoxy-1H-pyrrolo[2,3-b]pyridine (30).
To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25percent (w/w) MeONa (48 mL, 210 mmol) followed by copper (I) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140 °C for 2.5.
It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL).
The mixture was extracted with AcOEt (3x), the combined organic extracts dried (MgSO4) and concentrated.
The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78percent); 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.45 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).
78% With copper(I) bromide In N,N-dimethyl-formamide at 140℃; for 2.5 h; 5-Methoxy-1H-pyrrolo[2,3-b]pyridine (30)
To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25percent (w/w) MeONa (48 mL, 210 mmol) followed by copper (1) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140° C. for 2.5.
It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL).
The mixture was extracted with AcOEt (3*), the combined organic extracts dried (MgSO4) and concentrated.
The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78percent); 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.45 (d, J=2.3 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).
45% With copper(I) bromide In methanol; N,N-dimethyl-formamide at 140℃; for 2.5 h; 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (38); [00424] To a solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (2.00 g, 10.2 mmol) inN,N-dimethylformamide (30 mL) was added a 25percent weight solution in methanol of sodium methoxide (46.4 mL, 203 mmol) followed by copper(I) bromide (2.91 g, 20.3 mmol). The reaction mixture was heated at 140 °C for 2.5 hours, after it was cooled to room temperature and concentrated to remove most of the NN-dimethylformamide. Water (100 mL) was added followed by saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography (Biotage) using using 0 to 50percent ethyl acetate in hexanes over 60 minutes to afford 5-methoxy-lH-pyrrolo[2,3-b]pyridine(0.680 g, 4.59 mmol, 45percentyield) as a green solid. NMR (400 MHz, CDC13) δ (ppm): 9.90 (br. s, 1H), 8.10 (m, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 6.44 (m, 1H), 3.89 (s, 3H).[00425] To a mixture of 5-methoxy-lH-pyrrolo[2,3-b]pyridine (670 mg, 4.52 mmol), and benzyltributylammonium bromide (70.5 mg, 0.226 mmol) in dichloromethane (20 mL) was added powdered sodium hydroxide (561 mg, 14.0 mmol). The reaction mixture was cooled to 0 °C, after which 4-methylbenzene-l-sulfonyl chloride (991 mg, 5.20 mmol) was added portionwise. The mixture was stirred at 0 °C for 15 min then warmed to room temperature where it was stirred for two hours, extracted with toluene (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. The crude product was triturated in ether and filtrated to afford the compound 5-methoxy-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.21 g, 4.01 mmol, 89percent yield) as a solid. 1H NMR (400 MHz, CDC13) δ (ppm): 8.15 (s, 1H), 8.05 (m, 2H), 7.66 (m, 1H), 7.25 - 7.30 (m, 3H), 6.51 (m, 1H), 3.83 (s, 3H), 2.35 (s, 3H).[00426] To a -60 °C solution of 5-methoxy-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.20 g, 3.97 mmol) in tetrahydrofuran (25 mL) was added 2M intetrahydrofuran/ethylbenzene/toluene solution of lithium diisopropyl amide (3.97 mL, 7.94 mmol). The reaction mixture was stirred at -60 °C for 30 minutes, after which iodomethane (0.298 mL, 4.76 mmol) was added, after which the reaction mixture was room temperature. Upon warming, the reaction was poured into ice water, extracted with ethyl acetate (3 x 50 mL), washed with water (3 x 50 mL), saturated sodium chloride solution (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (Biotage) using 0 to 50percent ethyl acetate in hexanes to afford 5-methoxy-2- methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine (0.550 g, 1.74 mmol, 44 percent yield). NMR (400 MHz, CDC13) δ (ppm): 8.08 (s, 1H), 7.96 (d, 2H), 7.26 (m, 2H), 7.16 (m, 1H), 6.20 (s, 1H), 3.83 (s, 3H), 2.69 (s, 3H), 2.35 (s, 3H).[00427] A solution of 5-methoxy-2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.14 g, 3.60 mmol) and sodium hydroxide (14.4 g, 360 mmol) in methanol (70 mL) and water (70 mL) was heated at 80 °C for 30 minutes, after which it was cooled to room temperature, poured into to ice water, extracted with ethyl acetate (3 x 50 mL), washed with saturated sodium chloride solution (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated to afford 5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridine (0.550 g, 3.39 mmol, 94 percent yield) as a solid. NMR (400 MHz, CDC13) δ (ppm): 9.48 (b, 1H), 7.97 (m,lH), 7.33 (m, 1H), 6.10 (m 1H), 3.89 (s, 3H) 2.49 (s, 3H). This material was used in the subsequent step without any purification.[00428] 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-N- (2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in 55percent yield starting from l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2,3-b]pyridin using general procedure D. NMR (400 MHz, CDC13) δ (ppm): 9.13 (br. s, 1H), 8.10 - 8.17 (m, 3H), 7.25 - 7.27 (m, 3H), 7.14 (d, 1H), 7.06 (m, 2H), 5.55 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.70 (s, 3H).[00429] 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[3,2-b]pyridin-3-yl)-N- (2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid starting from methoxy-2- methyl-lH-pyrrolo[3,2-b]pyridine using general route 2. NMR (400 MHz, CD3OD) δ (ppm): 8.02 (d, 1H), 7.69 (d, 1H), 7.33 (m, 3H), 7.21 - 7.23 (m, 1H), 7.06 (d, 2H), 6.56 (d, 1H), 5.51 (s, 2H), 3.90 (s, 3H), 3.52 (s, 3H), 2.81 (s, 3H).
28% at 120℃; To 5-bromo-7-azaindole (67, 500.0 mg, 2.53 mmol) in N,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120 0C under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (104, 140 mg, 28percent). MS(ESI)[M+H+]+ = 149.1.
15.6% at 100℃; for 3 h; In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (67, 2.3 g, 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100 °C under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride: ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30percent to 70percent ethyl acetate in hexanes to give a yellow solid (104, 0.27 g, 15.6percent). MS(ESI) [M + H+J+= 149.2.

Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 45, p. 14426 - 14427
[2] Patent: EP1749829, 2007, A1, . Location in patent: Page/Page column 52
[3] Patent: US2007/72896, 2007, A1, . Location in patent: Page/Page column 51
[4] Patent: WO2012/88469, 2012, A1, . Location in patent: Page/Page column 175-177
[5] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 122
[6] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 122
[7] European Journal of Medicinal Chemistry, 2004, vol. 39, # 6, p. 515 - 526
[8] Patent: WO2005/9958, 2005, A1, . Location in patent: Page 158-159
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  • [ 183208-36-8 ]
YieldReaction ConditionsOperation in experiment
77.3% With sodium; copper(I) bromide In N,N-dimethyl-formamide for 5 h; Inert atmosphere; Reflux To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 10 g, 50.8 mmol) in N,N-dimethylformamide (200 mL) and methanol (150 mL) at 25° C. was added sodium (100 g, 185.1 mmol) and copper(I) bromide (14.56 g, 101.5 mmol) under a nitrogen atmosphere. The mixture was then heated at reflux for 5 h. After cooling, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3.x.300 mL), and washed with a saturated aqueous ammonium chloride solution, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 5-methoxy-1H-pyrrolo[2,3-b]pyridine (5.8 g, 77.3percent) as a light yellow solid: LC/MS m/e calcd for C8H8N2O [M+H]+ 149.17, observed 149.3.
Reference: [1] Patent: US2011/144105, 2011, A1, . Location in patent: Page/Page column 20
[2] Heterocycles, 1999, vol. 50, # 2, p. 1065 - 1080
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  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 183208-35-7 ]
  • [ 183208-36-8 ]
YieldReaction ConditionsOperation in experiment
28% With copper(l) iodide In N,N-dimethyl-formamide at 120℃; Step 1-Preparation of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (17)To 5-bromo-7-azaindole (1, 500.0 mg, 2.53 mmol) in N,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (17, 140 mg, 28percent). MS (ESI)[M+H+]+=149.1. In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (1, 2.3 g, 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(1) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100° C. under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride:ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30percent to 70percent ethyl acetate in hexanes to give a yellow solid (17, 0.27 g, 15.6percent). MS (ESI) [M+H+]+=149.2.
28% With copper(l) iodide In N,N-dimethyl-formamide at 120℃; Example 11: Synthesis of 5-Methoxy-lH-pyrrolo[2,3-b]pyridine 2 and related compounds.[0147] 5-Methoxy-lH-pyrrolo[2,3-b]pyridine 2 was synthesized in one step from 5-bromo-lH- pyrrolo[2,3-b]pyridine 1 as described in Scheme 1.Scheme 1Step 1 - Preparation of5-Methoxy-lH-pyrrolo[2,3-b]pyridine (2):[0148] T 5 b 7 i d l (1 500 0 2 53 l) i N N di th lf mamide (8 mL) were <n="66"/>added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120 °C under an atmosphere of Argon, The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (2, 140 mg, 28percent). MS(ESI)[M+HT = 149.1.
15.6% With copper(I) bromide In N,N-dimethyl-formamide at 20 - 100℃; for 3 h; Step 1-Preparation of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (17)To 5-bromo-7-azaindole (1, 500.0 mg, 2.53 mmol) in N,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (17, 140 mg, 28percent). MS (ESI)[M+H+]+=149.1. In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (1, 2.3 g, 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(1) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100° C. under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride:ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30percent to 70percent ethyl acetate in hexanes to give a yellow solid (17, 0.27 g, 15.6percent). MS (ESI) [M+H+]+=149.2.
15.6% With copper(I) bromide In N,N-dimethyl-formamide at 20 - 100℃; for 3 h; In an alternative method, 2.3 g (1 1.7 mmol) 5-bromo-7-azaindole (1, 2.3 g. 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0,6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100 0C under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride: ammonium hydroxide (4: 1). The organic layer was extracted with ammonium chloride:ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30percent to 70percent ethyl acetate in hexanes to give a yellow solid (2, 0.27 g. ). MS(ESI) [M + H+]"= 149.2.
58 g With copper(l) iodide In N,N-dimethyl-formamide at 5 - 100℃; for 2 h; A mixture of 5-bromo-7-azaindole (100 g) and dimethyl formamide (800 mL)were cooled 5-10 Sodium methoxide (275 g), copper (I) iodide (194 g), and methanol (450 mL) were added and the temperature was raised to 95-100 °C and stirred for 2 hours. Aft er cooling to 35°C, ethyl acetate (1 L) and aqueous ammonium chloride solution (200 g of ammonium chloride was dissolved in 600 mL water) were added, the reaction mixture was stirred for 4hours and the reaction mass was filtered through a Celite bed. The filtrate was washed thrice with ethyl acetate (400 mL x 3). Ethyl acetate (800 mL) and 30 percent aqueous ammonium chloride solution (1600 mL) were added, the reaction mixture was stirred, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (400 mL) and the combined ethyl acetate layers were washed with 30percent aqueous ammonium chloride solution (200 mL)until the blue colour disappeared. The ethyl acetate layer was concentrated under vacuum at 50 Toluene (200 mL)was charged to the residue at 50°C and the reaction mass was stirred for 15 minutes. After cooling to 5-1 Ο°C, the reaction mixture was stirred for 2 hours then filtered. The obtained solid was washed with chilled toluene (50 mL) then dried under vacuum oven at 50°C for 4 hours (58 g, Yield: 0.29w/w).

Reference: [1] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 37
[2] Patent: WO2008/79909, 2008, A1, . Location in patent: Page/Page column 64-65
[3] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 37
[4] Patent: WO2008/79909, 2008, A1, . Location in patent: Page/Page column 65
[5] Patent: WO2018/29711, 2018, A2, . Location in patent: Page/Page column 31;32
[6] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 294 - 309
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  • [ 183208-35-7 ]
  • [ 74-88-4 ]
  • [ 183208-22-2 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;
Stage #2: at 20℃;
To a solution of 5-bromo-1H-pyrrolo[2,3-bjpyndine (1.5 g, 7.6 mmol) in DMF (10 mL) was addedNaH (365 mg, 9.1 mmol) at 0 °C. The mixture was stirred at rt for 1.5 hrs. Mel (1.4 g, 9.8 mmol) was added and stirred at rt overnight. The reaction was quenched with sat. NH4C1 solution (10 mL) and separated between water (20 mL) and EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4. The solvent was removed to give 5-bromo-1-methyl-1H-pyrrolo[2,3- bjpyndine (1.7 g, yield: quantitative) as pale yellow crystal. ‘HNMR (300 MHz, CDC13): = 8.34 (d, J= 2.1 Hz, 1H), 8.01 (d,J 2.4 Hz, 1H), 7.18 (d,J= 3.6 Hz, 1H), 6.39 (d,J= 3.3 Hz, 1H), 3.86 (s, 3H).
99%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 25℃; for 3 h; Inert atmosphere
Step 1 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (Compound 1-2) (0150) At 0° C., a solution of compound 5-bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.4 mmol, commercially available) in DMF was added to a solution of sodium hydride (4.32 g, 30.5 mmol) in 40 ml of DMF, and vigorously stirred at 0° C. for 0.5 h, and then methyl iodide (1.22 g, 30.5 mmol) was added, and stirred vigorously at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was poured into ice water. After the solids were completely precipitated, the solids were filtered and dissolved in dichloromethane and methanol (10:1), washed with water three times, and dried. The organic layer was separated, and concentrated under reduced pressure to give compound 1-2 (5.4 g, 99percent). The product was used directly in the next step. MS m/z (ESI): 211.0 [M+H]+.
97%
Stage #1: With sodium hydride In N,N-dimethyl acetamide; mineral oil at 20℃; for 0.5 h;
Stage #2: for 4 h;
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (96percent pure, 3.88 g, 14.6 mmol) in dimethylacetamide (70 mL) was carefully added sodium hydride (60percent suspension in oil, 0.76 g, 19.0 mmol). The mixture was stirred at rt for 30 min and methyl iodide (3.14 g, 22.1 mmol) was slowly added as a solution in dimethylacetamide (10 mL). After additional 4 h water (150 mL) was added and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic phases were washed with water, dried over MgSO4, and evaporated. Column chromatographic purification (SiO2, CH/EtOAc, 1:1) yielded a colorless solid [3.88 g, 97percent yield].Mp: 59 – 60 °C (CH/EtOAc).1H-NMR (300 MHz, CDCl3): δ = 3.86 (s, 3H, 11-CH3), 6.39 (d, 3JH,H = 3.5 Hz, 1H, 3-CH),7.18 (d, 3JH,H = 3.5 Hz, 1H, 2-CH), 8.01 (d, 4JH,H = 2.1 Hz, 1H, 4-CH), 8.34 (d, 4JH,H = 2.1 Hz,1H, 6-CH) ppm.13C-NMR (75 MHz, CDCl3): δ = 31.6 (q, C-11), 99.1 (d, C-3), 111.7 (s, C-5), 122.2 (s, C-9),130.7 (d, C-2), 130.9 (d, C-4), 143.5 (d, C-6), 146.4 (s, C-8) ppm.ESI(+)-MS: calcd. for C8H7BrN2 + H+, 210.9865/212.9845; found 210.9866/212.9906.
85%
Stage #1: With Tris(3,6-dioxaheptyl)amine; potassium <i>tert</i>-butylate In toluene at 0 - 20℃; for 3 h;
Stage #2: at 0 - 20℃; for 1 h;
General procedure: To a cold solution of appropriate pyrrolo-pyridines 8a,c,e (2.5 mmol) in anhydrous toluene (25 mL), t-BuOK (0.38 g, 3.4 mmol) and TDA-1 (1 or 2 drops) were added at 0 °C. The reaction mixture was stirred at room temperature for 3 h and then MeI (2.5 mmol, 0.2 mL) was added at 0 °C. TLC analysis (ethyl acetate) revealed that methylation was complete after 1 h. The solvent was evaporated under reduced pressure. The residue was treated with water, extracted with DCM (3 × 20 mL), dried (Na2SO4), evaporated and purified by column chromatography using DCM/ethyl acetate (9/1) as eluent to give derivatives 8b,d,f [42].
47%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 4 h;
[00357] Intermediate 23a: 5-bromo-1 -methyl-pyrrolo[2,3-b]pyridine[00358] 5-Bromo-1H-pyrrolo[2,3-b]pyridin (2.OOg, 10.l5mmol) and NaH (609mg, 15.23mmol) werestirred under N2 in DMF (4OmL) for 1 hour at room temperature. lodomethane (0.95mL, 15.23mmol)was added and left to stir for 4 hours. The reaction was quenched with 1 M NaOH (2OmL), then extracted with EtOAc (4 x 25mL), washed with brine (4 x 25mL) and dried over Na2SO4. The compound was purified via column chromatography using an eluent of 0-75percent EtOAc in petroleum etherto yield 5-bromo-1-methyl-pyrrolo[2,3-b]pyridine (1 .00mg, 4.76mmol, 47percent yield) as a yellowsolid.1H NMR (CDCI3, 400MHz) O/ppm: 8.36 (1H, d, J= 2.0Hz), 8.03 (1H, d, J= 2.0Hz), 7.21 (1H, d, J=3.6Hz), 6.41 (1H, d, J= 3.6Hz), 3.89 (3H, 5).MS Method 2: RT: 1.65 mi m/z210.9 [M+H], 212.9 [M+H]

Reference: [1] Patent: WO2016/123392, 2016, A2, . Location in patent: Paragraph 00786
[2] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0149; 0150
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5734 - 5739
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 309 - 313
[5] Marine Drugs, 2015, vol. 13, # 1, p. 460 - 492
[6] Journal of Organic Chemistry, 2016, vol. 81, # 13, p. 5636 - 5648
[7] Organic Letters, 2017, vol. 19, # 24, p. 6566 - 6569
[8] Heterocycles, 2003, vol. 60, # 4, p. 865 - 877
[9] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00356; 00357; 00358
[10] Patent: WO2010/135524, 2010, A1, . Location in patent: Page/Page column 221
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 12, p. 5115 - 5129
[12] Patent: WO2015/186056, 2015, A1, . Location in patent: Page/Page column 96
[13] Marine Drugs, 2016, vol. 14, # 12,
[14] Patent: WO2017/31325, 2017, A1, . Location in patent: Paragraph 0653
  • 25
  • [ 13154-24-0 ]
  • [ 183208-35-7 ]
  • [ 858116-66-2 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sodium hydride In 1,4-dioxane; N,N-dimethyl-formamide for 0.5 h;
Stage #2: at 20℃;
Step 4; To a stirred solution of 5-bromo- 1 H-pyrrolo[2,3-b]pyridine (1.5 g, 7.5 mmole) in 15 ml of dioxane and 5 ml of DMF, sodium hydride ( 345 mg, 9 mmole) was added portionwise and, after 0.5 hrs., TIPSCI (2.5 ml, 12.3 mmole); the reaction was stirred at r.t. overnight, then diluted with water and extracted with methylene chloride; a fast purification by silica gel chromatography with dichloromethane gave 2.6 g of 5-bromo-1-triisopropylsilanyl- 1H-pyrrolo[2,3-b]pyridine (4) (97percent yield). This product was used for the following reaction without any further purification.
94%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Schlenk technique; Inert atmosphere
Stage #2: at 0 - 20℃; Schlenk technique; Inert atmosphere
A Schlenk tube was charged with sodium hydride (95percent pure, 282 mg, 11.15 mmol) anddry THF (12 mL) under argon. The suspension was cooled to 0 °C in an ice bath and 5-bromo-1H-pyrrolo[2,3-b]pyridin2 (96 percent pure, 2.00 g, 9.74 mmol) was slowly added as aS 11solution in dry THF (20 mL). After 15 min, chloro-triisopropylsilane (95percent pure, 1.96 g,10.15 mmol) was added as a solution in dry THF (6 mL) at 0 °C and the ice bath wasremoved. At room temperature saturated aqueous solution of ammonium chloride (30 mL)was added and the resulting mixture was extracted with cyclohexane (2 × 100 mL). Thecombined organic phases were dried over MgSO4, and evaporated. Column chromatographicpurification (SiO2, CH/EtOAc, 19:1) yielded a colorless, crystalline solid [3.25 g, 94percent yield].MP: 59 – 60 °C (CH/EtOAc).1H-NMR (400 MHz, CDCl3): δ = 1.11 (d, 3JH,H = 7.6 Hz, 18H, 13-CH3), 1.83 (sep, 3JH,H = 7.6Hz, 3H, 12-CH), 6.49 (d, 3JH,H = 3.5 Hz, 1H, 3-CH), 7.30 (d, 3JH,H = 3.5 Hz, 1H, 2-CH), 7.98(d, 4JH,H = 2.2 Hz, 1H, 4-CH), 8.27 (d, 4JH,H = 2.2 Hz, 1H, 6-CH) ppm.13C-NMR (101 MHz, CDCl3): δ = 12.3 (d, C-12), 18.2 (q, C-13), 102.6 (d, C-3), 112.2 (s,C-5), 124.2 (s, C-9), 129.9 (d, C-2), 132.8 (d, C-4), 142.9 (d, C-6), 152.3 (s, C-8) ppm.ESI(+)-MS: calcd. for C16H25BrN2Si + H+, 353.1044/355.1023; found 353.1039/355.1017.
93.8% With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 5℃; At room temperature, 400 ml of N,N-dimethylformamide was added to a 1 L three-necked flask to start stirring. Add 5_bromo-7-azaindole (30g, 0.15mol) and potassium tert-butoxide (25·6g, 0 · 23mol) to the reaction flask. After stirring and clearing, cool the ice bath to wait for the internal temperature. At 0 °C, triisopropylsilyl chloride (43.3 g, 0.225 mol) diluted with 80 ml of tetrahydrofuran was initially added dropwise. After the addition is completed, the reaction is maintained at 0-5 °C for 10-20 minutes. TLC control, the reaction is over. 300 ml of water was added to the reaction flask, and the mixture was stirred for 15 minutes. The aqueous phase was extracted with methyl tert-butyl ether (200 ml*2). The organic phase was combined and the organic phase was washed with 500 ml of saturated aqueous sodium chloride solution once. After drying over anhydrous sodium sulfate, the solvent is concentrated to obtain an oil, and 50 ml of methanol is added to precipitate a solid. The solid is vacuum filtered and dried to obtain a compound of the formula. Yield: 50.5 g, yield: 93.8percent.
59% With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2 h; Step 1-Preparation of 5-bromo-1-triisopropylsitaoyl-1H-pyrrolo[2,3-b]pyridine (2)To 5-bromo-7-azaindole (1, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60percent in mineral oil, 0.27 g, 11.0 mmol) and trriisopropylsilyl chloride (2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10percent ethyl acetate in hexane to give the compound (2, 1.6 g, 59percent). MS (ESI)[M+H+]+=352.3.
59% With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2 h; To 5-bromo-7-azaindole (67, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60percent in mineral oil, 0.27 g, 11.0 mmol) and trriisopropylsilyl chloride ( 2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10 percent ethyl acetate in hexane to give the compound (68, 1.6 g, 59percent). MS(ESI)[M+H+]+ = 352.3.

Reference: [1] Patent: EP2070928, 2009, A1, . Location in patent: Page/Page column 101-102
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5734 - 5739
[3] Patent: CN107434807, 2017, A, . Location in patent: Paragraph 0050-0053; 0075-0078; 0095-0100
[4] Organic Letters, 2013, vol. 15, # 12, p. 2954 - 2957
[5] Patent: WO2017/133667, 2017, A1, . Location in patent: Page/Page column 106
[6] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 34
[7] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 101
[8] Patent: US2010/184766, 2010, A1, . Location in patent: Page/Page column 56
[9] Patent: US2010/305122, 2010, A1, . Location in patent: Page/Page column 119
[10] Patent: WO2011/150016, 2011, A1, . Location in patent: Page/Page column 79; 80
[11] Patent: WO2012/71336, 2012, A1, . Location in patent: Page/Page column 11
[12] Patent: US2014/275082, 2014, A1, . Location in patent: Paragraph 0226
[13] Patent: WO2016/24230, 2016, A1, . Location in patent: Paragraph 00744
  • 26
  • [ 557-21-1 ]
  • [ 183208-35-7 ]
  • [ 517918-95-5 ]
YieldReaction ConditionsOperation in experiment
83% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 80℃; for 36 h; Inert atmosphere 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile
A solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 25.0 mmol, 1.0 eq.), Zn(CN)2 (3.6 g, 20.0 mmol, 0.8 eq.) in dry DMF (65 mL) was deoxygenated with a stream of argon for 30 min and then Pd(Ph3P)4 (1.7 g, 1.5 mmol, 0.06 eq.) was added.
The reaction mixture was heated at 80° C. for 36 h then quenched with water and extracted with EtOAc.
The organic layer was dried over Na2SO4 and evaporated to dryness.
The residue was treated with small amount of CH2Cl2 and filtered.
The collected precipitate was rinsed with CH2Cl2 and dried on air to give 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (Intermediate 2a) as a white solid (3.0 g; yield: 83percent; UPLC purity: 100percent).
75% at 80℃; 1H-Pyrrolo [2,3-b]pyridine-5-carbonitrile (35) 24 35 A mixture of bromide 24 (10.0 g, 50.8 mmol), ZnCl2 (3.58 g, 30.5 mmol), and Pd (PPh3) 4 (3.52 g, 3.05 mmol) in DMF (110 mL) was heated at 80 C overnight. The solvent was evaporated and the residue separated by silicagel chromatography (100 g column) using hexane: ethyl acetate as eluent (gradient elution). The resulting solid was partitioned between water (200 ML)/CH2CL2 (100 mL) and the aqueous phase extracted with more CH2C12 (4 x 100 mL). The combined organic extracts were dried (MGSO4) and concentrated to give the product as a white solid (5. 48 g, 75percent), which was used for subsequent reactions without further purification.
73% at 110℃; for 4.5 h; Preparation Example R-6.
1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile
5-Bromo-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-5 (90mg, 0.46mmol), zinc cyanide (80mg, 0.69mmol) and tetrakis(triphenylphosphine)palladium(0) (53mg, 46μmol) were dissolved in N-methyl-2-pyrrolidinone (2mL), and the mixture was stirred for 4.5 hours at 110°C under nitrogen atmosphere.
The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and the title compound (48mg, 0.34mmol, 73percent) was obtained as a white solid.
1H-NMR Spectrum (DMSO-d6) δ (ppm) 6.55-6.68(1 H, m), 7.65-7.78 (1 H, m), 8.52 (1 H, s), 8.60 (1 H, s), 12.3 (1H, brs).
Reference: [1] Patent: US2018/179199, 2018, A1, . Location in patent: Paragraph 0451-0452
[2] Patent: WO2004/78756, 2004, A2, . Location in patent: Page 120-121
[3] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 63
[4] Patent: WO2014/73904, 2014, A1, . Location in patent: Paragraph 1425-1427
  • 27
  • [ 557-21-1 ]
  • [ 183208-35-7 ]
  • [ 517918-95-5 ]
YieldReaction ConditionsOperation in experiment
75% at 80℃; 1H-Pyrrolo [2, 3-b] pyridine-5-carbonitrile (2); A mixture of bromide 1 (10.0 g, 50.8 mmol), ZnCl2 (3.58 g, 30.5 mmol), and Pd (PPh3) 4 (3.52 g, 3.05 mmol) in DMF (110 mL) was heated at 80 °C overnight. The solvent was evaporated and the residue separated by silicagel chromatography (100 g column) using hexane: ethyl acetate as eluent (gradient elution). The resulting solid was partitioned between water (200 mL)/CH2Cl2 (100 mL) and the aqueous phase extracted with more CH2C12 (4 x 100 mL). The combined organic extracts were dried (MgSO4) and concentrated to give product 2 as a white solid (5.48 g, 75percent), which was used for subsequent reactions without further purification.
73% at 110℃; for 4.5 h; 5-Bromo-1H-pyrrolo[2,3-b]pyridine described in Preparation Example R-5 (90mg, 0.46mmol), zinc cyanide (80mg, 0.69mmol) and tetrakis(triphenylphosphine)palladium(0) (53mg, 46μmol) were dissolved in N-methyl-2-pyrrolidinone (2mL), and the mixture was stirred for 4.5 hours at 110°C under nitrogen atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 5 : 1), and the title compound (48mg, 0.34mmol, 73percent) was obtained as a white solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 6.55-6.68(1H, m), 7.65-7.78 (1 H, m), 8.52 (1 H, s), 8.60 (1 H, s), 12.3 (1 H, brs).
Reference: [1] Patent: WO2005/85244, 2005, A1, . Location in patent: Page/Page column 46-47
[2] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 71
  • 28
  • [ 143-33-9 ]
  • [ 183208-35-7 ]
  • [ 517918-95-5 ]
YieldReaction ConditionsOperation in experiment
67% at 125℃; for 48 h; To a solution of 5-Bromo-7-azaindole XXX (300 mg, 1.52 mmol) in DMF (10 ml), sodium cyanide (150 mg, 3.06 mmol), cuprous iodide (45 mg, 0.24 mmol), and Tetrakis (triphenylphosphine) palladium(0) (100 mg, 0087 mmol) were added. The reaction was placed under argon heated at 125° C. for 48 hours after which the reaction was allowed to cool to ambient temperature before diluting with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (2.x., 150 ml). The organic layers were then combined and washed with saturated bicarbonate solution (3.x., 100 ml), before drying over sodium sulfate and evaporate under reduced pressure. The crude material was purified by preparative TLC, eluting with a solution of 70percent hexane, 30percent ethyl acetate with triethylamine as an additive to yield the titled compound as an off-white solid. (150 mg, M-1=142.0)
Reference: [1] Patent: US2007/49615, 2007, A1, . Location in patent: Page/Page column 60-61
  • 29
  • [ 64-19-7 ]
  • [ 183208-35-7 ]
  • [ 757978-33-9 ]
YieldReaction ConditionsOperation in experiment
62% With hexamethylenetetramine In water at 120℃; Sealed tube (a) Step 1
5-Bromo-1H-pyrrolo[2,3-b]pyridine (0.087 g, 0.44 mmol) was successively added with acetic acid (0.2 mL), water (0.4 mL), and hexamethylenetetramine (0.087 g, 0.62 mmol), and then the mixture was stirred overnight at 120°C in a sealed tube.
The reaction mixture was added with water, and then the precipitated solid was collected by filtration to obtain 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.061 g, 62percent).
1H NMR (300 MHz, CDCl3) δ 8.46 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.54 (s, 1H), 9.93 (s, 1H).
33% at 100℃; for 6 h; Step A: 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1561) Hexamethylenetetramine (1.08 g, 7.61 mmol) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5 mol) in HOAc (6.34 mL). The mixture was heated at 100° Celsius for 6 hours. The reaction mixture was then cooled to rt and diluted with water. The mixture was extracted with EtOAc, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to provide the title compound (379 mg, 33percent). 1H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.77 (d, J=2.2, 1H), 8.48 (d, J=2.2, 1H), 7.99 (d, J=2.7, 1H).
Reference: [1] Patent: EP2565192, 2013, A1, . Location in patent: Paragraph 0304
[2] Patent: US2015/259357, 2015, A1, . Location in patent: Paragraph 1561
  • 30
  • [ 4885-02-3 ]
  • [ 183208-35-7 ]
  • [ 757978-33-9 ]
Reference: [1] Patent: US2009/253679, 2009, A1, . Location in patent: Page/Page column 40
  • 31
  • [ 183208-35-7 ]
  • [ 757978-33-9 ]
Reference: [1] Patent: WO2014/193647, 2014, A2,
[2] Patent: CN104119331, 2018, B,
[3] Patent: WO2004/101565, 2004, A2,
  • 32
  • [ 183208-35-7 ]
  • [ 757978-18-0 ]
YieldReaction ConditionsOperation in experiment
100% With N-iodo-succinimide In acetone at 20℃; for 0.333333 h; Preparation of 5-bromo-3-iodo-lH-pyrrolo [2,3-6] pyridine (Intermediate A)[0442] To a stirred solution of 5-bromo-lH-pyrrolo[2,3-.pound.]pyridine (10 g, 50.76 mmol) in 500 mL of acetone N-idodosuccinamide was added and the reaction mixture was stirred for 20 min at room temperature. The product was crashed out as white solid was filtered and washed with lOOmL acetone. Resulting solid was dried under vacuum to afford 5-bromo-3-iodo-lH- pyrrolo[2,3-6]pyridine (16.34 g, 100percent) as a light yellow powder. 1H NMR (DMSO-d , 300MHz) δ 8.51 (d, J= 2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J= 1.2 Hz, 1 H), 8.00 (d, J= 5.1 Hz, 2H), 7.44 (dd, J= 8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 322/324 (M+l)+, calc. 322.
100% With N-iodo-succinimide In acetone at 20℃; for 0.333333 h; To a stirred solution of 5-bromo-lH-pyrrolo[2,3-Z?]pyridine (10 g, 50.76 mmol) in 500 mL of acetone N-idodosuccinamide was added and the reaction mixture was stirred for 20 min at room temperature. The product was crashed out as white solid was filtered and washed with lOOmL acetone. Resulting solid was dried under vacuum to afford 5- bromo-3-iodo-lH-pyrrolo[2,3-Z?]pyridine (16.34 g, 100percent) as a light yellow powder. XH NMR (DMSO-i , 300MHz) δ 8.51 (d, J= 2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J= 1.2 Hz, 1 H), 8.00 (d, J= 5.1 Hz, 2H), 7.44 (dd, J= 8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 322/324 (M+l)+, calc. 322.
100%
Stage #1: With potassium hydroxide In dichloromethane at 20℃; for 0.5 h;
Stage #2: for 15 h;
To a solution of 5-bromo-1H-pyrrolo[2,3-b]-pyridine (commercial product, 1 g, 5.10 mmol) in 200 ml of CH2Cl2 is added KOH (145 mg, 2.55 mmol) at room temperature. After 30 minutes, N-iodosuccinimide (1.2 g, 5.10 mmol) is added and the solution is stirred for 15 hours, neutralized with saturated Na2S2O3 solution and extracted several times with CH2Cl2. The organic phases are combined, dried on MgSO4 and concentrated under reduced pressure. The expected product is obtained with a quantitative yield and used in the following step without additional purification.1H NMR (DMSO-d6, 300 MHz) δ 12.34 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.30 (s, 1H);13C NMR (DMSO-d6, 75 MHz) δ 146.5, 143.8, 132.5, 129.9, 123.8, 111.5, 53.6. HRMS (ESI+) calculated for C7H479BrIN2[M+H]+ 322.8681. found 322.8682, HRMS (ESI+) calculated for C7H481BrIN2[M+H]+ 324.8660. found 324.8670. IR (cm−1): v 3118, 2821, 1638.
97% With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 4 h; Cooling with ice To a solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (9.0 g, 0.046mol) and KOH (5.16 g, 0.092 mol) in DMF (90 mL) was added I2 (12.75 g, 0.050 mol) over an ice-water bath. The mixture was stirred at the room temperature for 4 hours, and TLC showed the reaction was complete. Saturated NaHS03 aqueous solution (50 mL) was added to quench the reaction. The precipitate that formed was collected by filtration, washed with water (50 mL), dried under vacuum to give the title compound 5-bromo-3-iodo-lH-pyrrolo[2,3-b]pyridine as a yellow solid (14.45 g, yield: 97percent).
95% With potassium hydroxide; iodine In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 3.5 h; To a solution of bromide 24 (10.00 g, 51 mmol) in DMF (330 mL) was added KOH (10.70 g, 191 mmol, pellets) and the reaction mixture was stirred for about 20 min. The mixture was then cooled in an ice-bath and iodine (11.55 g, 45.62 mmol) was added portionwise over 10 min. When the addition was complete the reaction mixture was stirred at room temperature for 3.5 h, diluted with EtOAc (500 mL) and washed with saturated brine solution (500 mL). The aqueous layer was extracted with EtOAc (4x 200 mL), The combined organic solutions were dried (MgS04) and concentrated to afford 45 as a pale yellow solid (15.62 g, 95percent) ; 1H NMR (400 MHz, DMSO) No. 7. 78 (s, 1H), 7.84 (D, J= 2. 2 Hz, 1H), 7.93 (bs, NH), 8. 29 (d, J= 2.0 Hz, 1H).
89% With N-iodo-succinimide In dichloromethane at 25℃; for 1 h; To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 25.38 mmol) in dichloromethane (400 mL) was added N-iodosuccinimide (6.28 g, 27.91 mmol). The mixture was stirred at 25°C for 1 h. The product precipitated as a white solid. The solid was isolated by filtration and washed with acetone (50 mL) to give 5-bromo-3-iodo-1H-pyrrolo[2,3- b]pyridine (7.3 g, 22.61 mmol, 89percent yield) as a white solid. LCMS (ESI) [M+H] = 322.9.
88% With N-iodo-succinimide In acetone at 25℃; for 1 h; Inert atmosphere To a solution of 5-Bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.2 mmol) in Acetone (20 mL) NIS (2.7 g, 12.0 mmol) was added at 25 °C and stirred for 1 h.
The mixture was concentrated and then extracted with EtOAc (30 mL * 2), the organic phase was washed with sat.
Sodium thiosulfate (Na2S2O3) solution (30 mL * 2), brine (30 mL * 2), dried over Na2SO4.
After filtering, the organic phase was concentrated to give compound 33 as an off-white solid (2.9 g, 88.0percent yield).
1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H, NH), 8.35 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.43 (s, 1H, Ar-H).
88% With N-iodo-succinimide In acetone at 20℃; for 1 h; The 5-bromo -1H-pyrrolo [2,3-b] pyridine (2.0g, 10 . 2mmol) adding 20 ml acetone, stirring to dissolve, then adding N-iodo succinimide (2.7g, 12 . 0mmol), stir at room temperature reaction 1h. After the reaction is ended, evaporating solvent under reduced pressure, ethyl acetate (20 ml) to dissolve, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated, that is, getting white solid (2.9g, 88.0percent).
88% With N-iodo-succinimide In acetone at 20℃; for 1 h; 6.28 g (27.9 mmol) of N-iodosuccinimide are added portionwise to a solution of 5 g (25.4 mmol) of 5-bromo-1H-pyrrolo[2,3-b]pyridine in 100 ml of acetone. The mixture is stirred for 1 hour at ambient temperature then cooled to0°C. The precipitate is filtered off, rinsed with a small amount of cold acetone and dried under vacuum for several hoursto give 7.18 g of a white solid. The compound is used in the next step without further purification. Yield: 88percent.1H NMR (DMSO-d6, 300 MHz): δ 12.34 (br s, 1H); 8.31 (d, J=2.1Hz, 1H); 7.86 (d, J=2.1Hz, 1H); 7.80 (d, J=2.6Hz, 1H).
86.1% With N-iodo-succinimide In acetone at 20℃; for 1.5 h; To a solution of 5-bromo-1H-pyrrolo [2, 3-b] pyridine (100 mg, 0.51 mmol) in acetone (10 mL) was added N-iodosuccinimide (125.6 mg, 0.56 mmol) . The mixture was stirred at rt for 1.5 h and filtered, the filter cake was washed with acetone to give a gray solid product (150 mg, 86.1) .[0784]MS (ESI, pos. ion) m/z: 322.9 [M+1]+.
78% With N-iodo-succinimide In dichloromethane at 20℃; for 2 h; To a solution of commercially available 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.60 g, 28.4 mmol) in CH2Cl2 (25 mL) was added N-iodosuccinimide (7.67 g, 34.1 mmol).
The reaction mixture was stirred at ambient temperature for 2 h.
The precipitate was filtered and washed with cold CH2Cl2 (2*5 mL) to provide the title compound as a light tan solid (7.17 g, 78percent yield) which was used as is in the next step without further purification: MS (ES) m/z 323 (M+H).
77% With N-iodo-succinimide In 1,2-dichloro-ethane at 95℃; A mixture of 5-Bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 252.5 mmol) and N-iodosuccinimide (13.6 g, 60.6 mmol) in dichloroethane (200 ml) was stirred at 95° C. overnight. The reaction was allowed to cool to room temperature and saturated Na2H2SO4 (200 ml) was added. The mixture was then extracted with ethyl acetate (400 ml.x.2). The combined organic layers were dried with Na2SO4, concentrated. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (62.8 g, 77percent yield).
75% With N-iodo-succinimide In acetone at 20℃; for 1 h; [0235] Step 1 : 5-Bromo-3-iodo-lH-pyrrolo[2,3-]pyridine: N-Iodosuccinimide (6.75 g, 30.0 mmol) was added to a solution of 5-bromo-lH-pyrrolo[2,3-]pyridine (5.39 g, 27.4 mmol) in acetone (130 mL) and stirred for 1 h at rt. The resulting solid was collected by vacuum filtration and washed with acetone to afford 6.65 g (75percent) of the desired product as an off-white to gray solid. 1H NMR (400 MHz, DMSO-^) δ ppm 12.4 (br. s, 1H), 8.32 (s, 1 H), 7.87 (s, 1H), 7.81 (s, 1H)
74% With N-iodo-succinimide In acetone at 20℃; for 1 h; Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12. 2 g (74percent) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ=12.35 (br.s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1 H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH+].
74% With N-iodo-succinimide In acetone at 20℃; for 1 h; Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2,3-b]ρyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12. 2 g (74percent) of the title compound as a tan powder. 1H-NMR (500 MHz, ^6-DMSO) J= 12.35 (br.s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1 H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH+].
67% With N-iodo-succinimide In acetone at 20℃; for 0.75 - 1 h; Synthesis of Compounds:; Method 1:; Step 1: Synthesis of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.; Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12.2 g (74percent) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ=12.35 (br.s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.0 Hz 1H), 7.79 (s, 1H); MS: m/z 322.8/324.8 [MH+].; Step 4:
Synthesis of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.52 mmol) in acetone (10 ml) was added N-iodosuccinimide (377 mg, 1.67 mmol) in one portion.
The reaction mixture was stirred at room temperature for 45 minutes.
The resulting precipitate was filtered off, washed with a minimal amount of acetone, and dried in vacuo to give the title compound as a cream-colored solid (329 mg, 67percent yield).
1H NMR (DMSO-d6): δ 12.36 (s, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H); HPLC/MS m/z: 323.
7.05 g With N-iodo-succinimide In acetone at 20℃; for 2 h; Inert atmosphere Step-1: 5-Bromo-3-iodo-lH-pyrrolor2,3-blpyridine 5-Bromo-lH-pyrrolo[2,3-b]pyridine (5 g, 25 mmol) was dissolved in anhydrous acetone (75 ml) and added N-Iodo succinimide (6.18 g, 27.5 mmol) under nitrogen atmosphere and stirred at RT for 2 h. The reaction was monitored by TLC (10percent Ethyl acetate in hexane). The reaction mixture was cooled to RT and filtered, washed with cold acetone (50 ml) and dried under vacuum to afford 7.05 g (87percent yield) of 5-bromo-3-iodo-lH-pyrrolo[2,3-b]pyridine. LCMS: m/z = 324.6 (M+l); HPLC: 91.11percent in method B.
3.15 g With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 2 h; Step 1: (0558) To a solution containing compound 6 (2.0 g, 10.15 mmol) dissolved in N,N-dimethylformamide (78.93 mL, 1015.05 mmol) was added 1-iodopyrrolidine-2,5-dione (2.28 g, 10.15 mmol) and the solution was allowed to stir at room temperature for 2 hours. Upon completion, the reaction mixture was poured into a saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give 3.15 grams of compound 7 in about 95percent purity.

Reference: [1] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 162
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9569 - 9585
[3] Patent: WO2014/85795, 2014, A1, . Location in patent: Paragraph 0400
[4] Patent: US2015/307492, 2015, A1, . Location in patent: Paragraph 0120-0125
[5] Patent: WO2016/26078, 2016, A1, . Location in patent: Paragraph 076
[6] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
[7] Patent: WO2004/78756, 2004, A2, . Location in patent: Page 125-126
[8] Patent: WO2018/167147, 2018, A1, . Location in patent: Paragraph 0183
[9] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8032 - 8048
[10] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[11] Patent: CN103613591, 2016, B, . Location in patent: Paragraph 0328-0330
[12] Patent: EP3170822, 2017, A1, . Location in patent: Paragraph 0085-0087
[13] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00483
[14] Patent: US2018/208594, 2018, A1, . Location in patent: Paragraph 0417; 0423; 0424
[15] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 137
[16] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7212 - 7215
[17] Patent: WO2014/4863, 2014, A2, . Location in patent: Paragraph 0235
[18] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 71
[19] Patent: WO2008/124849, 2008, A2, . Location in patent: Page/Page column 50
[20] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 24; 75
[21] Patent: WO2014/6554, 2014, A1, . Location in patent: Page/Page column 24
[22] Patent: WO2014/24077, 2014, A1, . Location in patent: Page/Page column 27
[23] Patent: US2015/183781, 2015, A1, . Location in patent: Paragraph 0135
[24] Patent: US2016/326162, 2016, A1, . Location in patent: Paragraph 0556; 0557; 0558
[25] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 2052 - 2070
  • 33
  • [ 73183-34-3 ]
  • [ 183208-35-7 ]
  • [ 754214-56-7 ]
YieldReaction ConditionsOperation in experiment
95.9% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere Example 9 7-(3 -((2.6-dichlorophenyl)ethynyl)- 1 H-pyrrolo [2.3 -blpyridin-5 -yl)- 1.2.3.4- tetrahydroisoquinoline Step 1) 5-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH-pyrrolo[2.3-blpyridine To a solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (19.7 g, 100 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (30.5 g, 120 mmol) in 1,4-dioxane (400 mL) was added CH3COOK (19.6 g, 200 mmol). The mixture was degassed and charged with nitrogen for three times. Then Pd(dppf)Cl2-CH2Ci2 (1.6 g, 2 mmol) was added. The mixture was stirred at 80 °C under nitrogen atmosphere for overnight, then cooled to rt, and concentrated in vacuo. The residue was diluted with EtOAc (500 mL) and washed with brine (300 mL x 3). The separated organic phase was dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the crude product, then the crude product was then recrystalhzed by PE/EtOAc (10/1 (v/v), 25 mL) to give the title compound as a white solid (23.4 g, 95.9percent). MS (ESI, pos. ion) m/z: 245.2 (M+l); FontWeight="Bold" FontSize="10" HNMR (400MHz, DMSO-i): δ 1.31 (s, 12H), 6.48 (d, J=3.4 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 8.22 (d, J=1.4 Hz, 1H), 8.44 (d, J=1.4 Hz, 1H), 11.75 (s, 1H).
95.9% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere The compound 5-bromo-1H-pyrrolo[2,3-b]pyridine (19.7 g, 100 mmol),Potassium diborate (30.5 g, 120 mmol) was dissolved in 1,4-dioxane (400 mL), and then potassium acetate (19.6 g, 200 mmol) was added to the reaction mixture.After the reaction liquid is exchanged for three times (nitrogen),Pd(dppf)Cl2.CH2Cl2 (1.6 g, 2 mmol) was added.The reaction solution was stirred at 80 ° C overnight under a nitrogen atmosphere, and then cooled to room temperature.Concentrate under reduced pressure, then ethyl acetate (500 mL) was added and the residue was dissolved.The resulting mixture was washed with brine (300 mL x 3).The organic phase obtained by liquid separation is dried with anhydrous Na2SO4.Concentrated under reduced pressure, and the residue was applied to silica gel column chromatography(PE/EtOAc (v/v) = 1/1)PE/EtOAc (10/1, 25 mL)The title compound was obtained as a white solid (23.4 g, 95.9percent).
94.2% With potassium acetate In 1,4-dioxane at 80℃; for 10 h; Example 15A
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine
5-Bromo-1H-pyrrolo[2,3-b]pyridine (Alfa Aesar. 1.00 g, 5.0 mmol) was coupled with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Aldrich. 1.52 g, 6.0 mmol) under the catalysis of {1,1'-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex PdCl2(dppf)-CH2Cl2 (Aldrich. 82 mg. 0.1 mmol) with KOAc (Aldrich, 0.98 g. 10.0 mmol) in dioxane (anhydrous, 20 mL) at 80° C. for 10 h.
It was then cooled down to ambient temperature, concentrated and diluted with EtOAc (100 mL).
The mixture was then washed with brine (2*10 mL).
The organic solution was concentrated and the residue was purified chromatography (SiO2. EtOAc/hexane, v. 50J50.
Rf=0.40) to give the title compound (1.15 g, yield. 94.2percent).
1H NMR (300 MHz, CD3OD) δ ppm 1.38 (s, 12H) 6.52 (d, J=3.39 Hz, 1H) 7.38 (d, J=3.39 Hz, 1H) 8.34 (d, J=1.70 Hz, 1H) 8.49 (d, J=1.36 Hz, 1H); MS (DCI/NH3) m/z 245 (M+1)+.
94.2% With potassium acetate In 1,4-dioxane at 80℃; for 10 h; Example 19S-IS-rfiJ^-β-methyl-S.β-diazabicvclorS^.Olheptan-S-yllpyridin-S-vU-lH- pyrrolo|"2,3-b]pyridine tosylateExample 19A5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolor2,3-blpyridine 5-Bromo-lH-pyrrolo[2,3-b]pyridine (Alfa Aesar, 1.00 g, 5.0 mmol) was coupled with 4,4,4>,4>,5,5,5',5'-octamethyl-2,2>-bi(l,3,2-dioxaborolane) (Aldrich, 1.52 g, 6.0 mmol) under the catalysis of {l,r-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex PdCl&2(dppf)-CH2Cl2 (Aldrich, 82 mg, 0.1 mmol) with KOAc (Aldrich, 0.98 g, 10.0 mmol) in dioxane (anhydrous, 20 mL) at 80 0C for 1O h. It was then cooled down to ambient temperature, concentrated and diluted with EtOAc (100 mL). The mixture was then washed with brine (2 x 10 mL). The organic solution was concentrated and the residue was purified using chromatography (SiO2, EtOAc/hexane, v. 50/50, Rf=0.40) to give the title compound (1.15 g, yield, 94.2percent). .1H NMR (300 MHz, CD3OD) δ ppm 1.38 (s, 12 H) 6.52 (d, J=3.39 Hz, 1 H) 7.38 (d, J=3.39 Hz, 1 H) 8.34 (d, J=I.70 Hz, 1 H) 8.49 (d, J=I.36 Hz, 1 H); MS (DCI/NH3) m/z 245 (M+l)+.

Reference: [1] Patent: WO2014/89280, 2014, A1, . Location in patent: Page/Page column 67-68
[2] Patent: CN103833753, 2017, B, . Location in patent: Paragraph 0527; 0529; 0530
[3] Patent: US2008/153860, 2008, A1, . Location in patent: Page/Page column 24
[4] Patent: WO2009/67586, 2009, A1, . Location in patent: Page/Page column 51
[5] Patent: WO2004/78757, 2004, A2, . Location in patent: Page 70
[6] Patent: WO2004/78757, 2004, A2, . Location in patent: Page 76-77
[7] Patent: WO2012/135631, 2012, A1, . Location in patent: Page/Page column 75
[8] Patent: CN107033142, 2017, A, . Location in patent: Paragraph 0016; 0031; 0034; 0037; 0040
[9] Patent: WO2007/135398, 2007, A1, . Location in patent: Page/Page column 81
[10] Patent: WO2008/138889, 2008, A2, . Location in patent: Page/Page column 201
  • 34
  • [ 1103234-56-5 ]
  • [ 183208-35-7 ]
  • [ 918504-27-5 ]
YieldReaction ConditionsOperation in experiment
77%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
Stage #2: With aluminum (III) chloride In dichloromethane at 20℃;
General procedure: The carboxylic acid (1.1 eq.) was suspended in dry DCM (0.5 m), oxalyl chloride (1 .05 eq.) and a few drops of DMF were added successively. After the gas formation stopped the resulting solution was added dropwise to a suspension of the azaindole (1 eq.) and AICI3(5 eq.) in dry DCM (0.5 m). The mixture was stirred at room temperature for 0.5 - 3h.Saturated, aqueous NH4CI solution was added to quench the reaction. The water phase was extracted with EtOAc (3x), the combined organic layers were dried over Na2S04and the solvent was evaporated under reduced pressure. The product was purified via flash chromatography (Si02, nHex/EtOAc 1 :1 or DCM/MeOH (content of MeOH increased in 0.5percent- steps from 0 to 3percent (v/v)) to yield the titled compound.
Reference: [1] Patent: WO2018/134254, 2018, A1, . Location in patent: Page/Page column 33; 35
[2] Patent: WO2014/159353, 2014, A1, . Location in patent: Paragraph 0055
  • 35
  • [ 1186194-32-0 ]
  • [ 183208-35-7 ]
  • [ 918504-27-5 ]
YieldReaction ConditionsOperation in experiment
31.4%
Stage #1: With aluminum (III) chloride In dichloromethane at 5℃; Inert atmosphere
Stage #2: at 5 - 20℃;
Stage #3: With water In dichloromethane
To aluminum trichloride (8.89 g, 66.7 mmol), 150 mL of dichloromethane was added under an atmosphere of nitrogen with the temperature maintained below 5 0C. To this, 5-bromo-l H-pyrτolo[2,3- bjpyiidine (8, 1.64 g, 8.34 mmol) in 20 ml, of dichloromethane was added. The reaction was stirred for 60 minutes and 2,6-diπuoro-3-(propane-l -sulfonyIamino)-benzoyl chloride (7. 3.50 g, 1 1.8 mmol) in 20 ml of dichlorυmethdne was added The reaction was stirred for 6 hours, then warmed to room temperature overnight. I he reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sul fate, filtered and the filtrate concentrated under vacuum. 1 he desired compound was isolated by silica gel column chromatography (dichloromethane/methanol 5percent) to give a white solid (9, 1.2 g, 31.4percent). MS(ESI) [MH-H+]" = 460.0, 462.0.
31.4%
Stage #1: With aluminum (III) chloride In dichloromethane at 5℃; for 1 h;
Stage #2: at 5 - 20℃;
To aluminum trichloride (8.89 g, 66.7 mmol) was added methylene chloride (150 mL) under an atmosphere of nitrogen below 5 0C. Into this, 5-bromo-7-azaindole (67, 1.64 g, 8.34 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 60.0 minutes and 2,6-difluoro-3- (propane-l-sulfonylamino)-benzoyl chloride (46, 3.50 g, 11.8 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 6 hours and warmed to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5percent) to give a white solid (P-0773, 1.2 g, 31.4percent). MS(ESI) [M+HT = 460.0, 462.0.
3.7 g With aluminum (III) chloride In dichloromethane at 0 - 25℃; Example 2 Preparation of propane-l-suifonic acid-{3-[5-lH-pyrrolo[23-b)pyridine-3-carbonyl]- phenyl}-amide (IV) Charge aluminum chloride (12.5gm, 0.093moles) was charged in to a reaction flask at 0-5°C containing dichloromethane (65ml) and stirred for 10-15 min. Prepared solution of 5-bromo- ljy-pyrrolo[2,3-b]pyridine (2.5gm, 0.012moles) in dichloromethane (50ml) was slowly added in to reaction mass at 0-5°C over a period of 45min to 1 hr. Reaction mass allowed to warm 5-10°C. Solution of 3-(Propane-l-sulfonylamino)-benzoyl chloride (in dichloromethane (50ml)) was added to reaction mass over a period of 45min to 1 hr at 5-10°C. Reaction mass stirred at 20-25°C for 14hrs to complete reaction. Reaction mass quenched in chilled water (500ml) slowly at below 15°C and stirred for 30min. The precipitated product was filtered and washed the wet cake with water. Wet cake was dissolved in mixture of ethyl acetate (100ml) and methanol (20ml) solvent and washed with water for twice. Organic layer was dried over sodium sulphate and distilled off solvent completely to get residue. To the obtained residue hexane was added and stirred for 45min. Precipitated product was filtered on Buchner funnel, washed with hexane and dried at 50-55°C to yield the title product. Yield: 3.7g; Chromatographic Purify (By HPLC): 99.28percent
3.7 g
Stage #1: With aluminum (III) chloride In dichloromethane at 0 - 5℃;
Stage #2: at 5 - 25℃;
Charge 9 aluminum chloride (12.5 gm, 0.093 moles) was charged in to a reaction flask at 0-5° C. containing 10 dichloromethane (65 ml) and stirred for 10-15 min. Prepared solution of 11 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.5 gm, 0.012 moles) in dichloromethane (50 ml) was slowly added in to reaction mass at 0-5° C. over a period of 45 min to 1 hr. Reaction mass allowed to warm 5-10° C. Solution of 4 3-(Propane-1-sulfonylamino)-benzoyl chloride (in dichloromethane (50 ml)) was added to reaction mass over a period of 45 min to 1 hr at 5-10° C. Reaction mass stirred at 20-25° C. for 14 hrs to complete reaction. Reaction mass quenched in chilled 12 water (500 ml) slowly at below 15° C. and stirred for 30 min. The precipitated product was filtered and washed the wet cake with water. Wet cake was dissolved in mixture of 13 ethyl acetate (100 ml) and 14 methanol (20 ml) solvent and washed with water for twice. Organic layer was dried over sodium sulphate and distilled off solvent completely to get residue. To the obtained residue 15 hexane was added and stirred for 45 min. Precipitated 16 product was filtered on Buchner funnel, washed with hexane and dried at 50-55° C. to yield the title product. (0125) Yield: 3.7 g; Chromatographic Purity (By HPLC): 99.28percent

Reference: [1] Patent: WO2010/104945, 2010, A1, . Location in patent: Page/Page column 34-35
[2] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 75
[3] Patent: US2011/28511, 2011, A1, . Location in patent: Page/Page column 9
[4] Patent: WO2016/83956, 2016, A1, . Location in patent: Page/Page column 23
[5] Patent: WO2010/129567, 2010, A1, . Location in patent: Page/Page column 81
[6] Patent: US2018/334457, 2018, A1, . Location in patent: Paragraph 0124-0125
  • 36
  • [ 183208-35-7 ]
  • [ 918504-27-5 ]
Reference: [1] Patent: WO2011/79133, 2011, A2,
  • 37
  • [ 183208-35-7 ]
  • [ 754214-42-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703
[2] Patent: US2018/179199, 2018, A1,
  • 38
  • [ 68-12-2 ]
  • [ 183208-35-7 ]
  • [ 849067-90-9 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
1H-Pyrrolo[2,3-b]pyridine-5-carbaldehyde
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.0 mmol, 1.0 eq.) in anhydrous THF (50 mL) at -78° C. under argon was slowly added a solution of 1.6 M n-butyl lithium in hexane (6.7 mL, 10.7 mmol, 2.1 eq.) and the reaction mixture was allowed to stir for next 40 min at -78° C.
To the resulting suspension 1 mL of dry DMF was added successively and the reaction mixture stirring was continued at rt overnight.
Then the reaction mixture was quenched with saturated solution of NH4Cl; the organic layer was separated and the aqueous phase was extracted with EtOAc.
The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to afford 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (Intermediate 3a) as an yellow solid (1.0 g; yield: 69percent; UPLC purity: 98percent).
Reference: [1] Patent: US2018/179199, 2018, A1, . Location in patent: Paragraph 0459-0460
[2] Patent: WO2016/114816, 2016, A1, . Location in patent: Paragraph 0300
  • 39
  • [ 107-31-3 ]
  • [ 183208-35-7 ]
  • [ 849067-90-9 ]
YieldReaction ConditionsOperation in experiment
33%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 1 h; Inert atmosphere
Stage #2: at -70 - 20℃; Inert atmosphere
step 1 : To a solution of 5-bromo-1H-pyrrolo[2,3-6]pyridine (2.0 g, 10 mmol) in anhydrous THF (50 mL) at -70 °C under nitrogen was added n-butyl lithium (2.5 M in hexane, 50 mmol) and the reaction mixture was stirred for 1 h at -70 °C. The resulting orange gel was quenched with methyl formate (10 mL) and the reaction mixture was slowly warmed to RT. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to afford 500 mg, (33percent) of 1H-pyrrolo[2,3-6]pyridine-5-carbaldehyde as yellow solid. MS (ESI) m/z: 147.2 [M+l] +.
Reference: [1] Patent: WO2013/92940, 2013, A1, . Location in patent: Page/Page column 40
  • 40
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 183208-35-7 ]
  • [ 849067-96-5 ]
YieldReaction ConditionsOperation in experiment
71% With palladium diacetate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl-formamide at 80℃; for 10 h; A solution of 91 (3.0 g, 15.2 mmol), Pd(OAc)2(342 mg, 1.52 mmol), Xantphos (881 mg, 1.52 mmol), and TEA (3.08 g, 30.5 mmol, 4.22 mL) in DMF (30 mL), and MeOH (15 mL) is stirred under CO (50 psi) at 80 °C for 10 hours. After iilteration and removal of MeOH, the mixture is diluted with EA (200 mL), washed with water (30 mL x 3) and brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 1 :5 to 1 :2) to give 92 as a yellow solid (2.7 g, 71 percent yield). (MS: | V | 177.1)
Reference: [1] Patent: WO2017/176812, 2017, A1, . Location in patent: Paragraph 0339
[2] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 111
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2692 - 2703
  • 41
  • [ 183208-35-7 ]
  • [ 13939-06-5 ]
  • [ 849067-96-5 ]
YieldReaction ConditionsOperation in experiment
30% With methanol; trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II); triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In tetrahydrofuran at 150℃; for 0.166667 h; Microwave irradiation To a mixture of 5-Bromo-lH-pyrrolo[2,3-b]pyridine 0.6g (3 mmol) , molybdenum hexacarbonate 0.4 g (1.5 mmol), Herrmann's catalyst 0.28g, 4,4-bis(diphenylphosphino)-9,9- dimethylxanthane and triethylamine 0.85 ml (6 mmol) in a 20 ml microwave reactor THF (10ml) and methanol (2ml) was added. The resulting suspension was heated at 150 °C on microwave for 10 minutes. The mixture was poured into sat NH4C1 (aq.) and extracted twice with EtOAC. The organic layers were combined, washed with sat NH4C1 (aq.), dried (MgS04) and the volatiles were removed in vacuo. The crude product was purified on silica to yield lH-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester 2 0.16 g as a brown solid (30 percent). 1H-NMR(CDC13, 300 MHz) δ 9.28 (d, IH, ArH), 8.86 (d, IH, ArH), 8.25 (s, IH, ArH), 4.02 (s, 3H, CH3) LC-MS: m/z 178 M + H+.
Reference: [1] Patent: WO2013/96496, 2013, A2, . Location in patent: Page/Page column 78
  • 42
  • [ 183208-35-7 ]
  • [ 849067-96-5 ]
Reference: [1] Patent: WO2014/73904, 2014, A1,
  • 43
  • [ 76-02-8 ]
  • [ 183208-35-7 ]
  • [ 849068-61-7 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 0.166667 h;
Stage #2: at 20℃;
5-Bromo-7-azaindole (10.00 g, 50.75 mmol)Was dissolved in dichloromethane (200 mL)Aluminum chloride (34.00 g, 254.99 mmol) was added,Stirred at room temperature for 10 minutes,Trichloroacetyl chloride (8.6 mL, 77 mmol) was added,Continue stirring at room temperature overnight,The reaction solution was poured into ice water,Filtration gave a white solid,The filtrate was extracted with ethyl acetate (200 mL x 3)Concentrate the filtered white solid,(250 mL) and water (125 mL) were added, triethylamine (50 mL) was added, stirred at room temperature for 24 h,The solvent was concentrated and evaporated to dryness, adjusted to pH 5-6 with 1.0 M dilute hydrochloric acid, filtered, dried at 50 ° C,The product was 8.20 g of an off-white solid,Yield: 67.0percent.
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 2052 - 2070
[2] Patent: CN106336413, 2017, A, . Location in patent: Paragraph 0557; 0558; 0559
  • 44
  • [ 75-36-5 ]
  • [ 183208-35-7 ]
  • [ 866545-96-2 ]
YieldReaction ConditionsOperation in experiment
93% at 20℃; for 6 h; Step 1:
Synthesis of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone.
To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrous CH2Cl2 (100 mL) under N2 was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.15 mmol).
The reaction solution was stirred for 1 hour at ambient temperature whereupon acetyl chloride (3.61 mL, 50.75 mmol) was added dropwise and the resulting solution was stirred for 5 more hours.
The reaction was cooled to 0° C. in an ice bath and quenched carefully by addition of MeOH until the solution became clear.
The reaction was concentrated under vacuum.
H2O was added and 1 N NaOH was added dropwise until the pH=4.
The product was extracted into ethyl acetate and the organic layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts.
The organic layer was dried over Na2SO4 and concentrated under vacuum.
The material was redissolved in ethyl acetate and filtered through a bed of silica gel.
The filtrate was concentrated to afford the title compound as an orange solid (2.25 g, 93percent yield).
1H NMR (500 MHz, d6-DMSO) δ 12.70 (br s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.55 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 2.46 (s, 3H). MS: m/z 238.9/240.9 (M+H+).
93%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h;
Stage #2: for 5 h;
To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrous CH2Cl2 (100 mL) under N2 was added 5-bromo-1H -pyrrolo[2,3-δ]pyridine (2.00 g, 10.15 mmol). The reaction solution was stirred for 1 hour at ambient temperature whereupon acetyl chloride (3.61 mL, 50.75 mmol) was added dropwise and the resulting solution was stirred for 5 more hours. The reaction was cooled to 0 °C in an ice bath and quenched carefully by addition of MeOH until the solution became clear. The reaction was concentrated under vacuum. H2O was added and 1 N NaOH was added dropwise until the pH = 4. The product was extracted into ethyl acetate and the organic layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts. The organic layer was dried over Na2SO* and concentrated under vacuum. The material was redissolved in ethyl acetate and filtered through a bed of silica gel. The filtrate was concentrated to afford the title compound as an orange <n="79"/>solid (2.25 g, 93percent yield). 1H NMR (500 MHz, ^-DMSO) δ 12.70 (br s, 1H), 8.56 (d, J = 2.5 Hz, 1H),8.55 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 2.46 (s, 3H). MS: m/z 238.9/240.9 (M + H+).
87%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h;
Stage #2: at 20℃;
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Acetyl chloride (9 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. Next day the reaction was cooled to 0° C. and quenched with methanol (500 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 4 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml.x.3). The combined organic layers were extracted with saturated sodium potassium tartrate and brine and dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-ethanone (5.2 g, 87percent yield). 1H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 8.41 (s, 1H), 8.57 (s, 1H), 8.58 (s, 1H). MS: m/z 241.0 (M+H+).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7212 - 7215
[2] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 61-62
[3] Patent: WO2008/124849, 2008, A2, . Location in patent: Page/Page column 77-78
[4] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 141-142
[5] Patent: US2011/82138, 2011, A1, . Location in patent: Page/Page column 65
[6] Patent: WO2014/111496, 2014, A1, . Location in patent: Page/Page column 100; 101
[7] Patent: WO2016/142310, 2016, A1, . Location in patent: Page/Page column 65-66
  • 45
  • [ 183208-35-7 ]
  • [ 866319-00-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6396 - 6400
  • 46
  • [ 1692-25-7 ]
  • [ 183208-35-7 ]
  • [ 918511-92-9 ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate In water; acetonitrile at 170℃; Step 1-Preparation of 5-pyridin-3-yl-1H-pyrrolo[1,3-b]pyridine (22)To 5-bromo-7-azaindole (1, 1.00 g, 5.08 mmol) in water (13.0 mL) and acetonitrile (36 mL) were added pyridine-3-boronic acid (21, 1.0 g, 8.1 mmol), potassium carbonate (1.79 g, 0.0130 mol) and Tetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under an atmosphere of nitrogen. The reaction mixture was heated to 170° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25percent ethyl acetate in hexane to provide a light yellow solid (22, 820 mg, 82percent). MS (ESI)[M+H+]+=196.1.
82% With potassium carbonate In water; acetonitrile at 170℃; Example 4: Synthesis of 5-Pyridin-3-yl-lH-pyrrolo[2,3-b] pyridine 20 and related compounds.[0137] 5-Pyndin-3-yl-l H-pyrrolo[2,3-b]pyπdine 20 was synthesized in one step from 5-bromo-lH- pyrrolo[2,3-b]pyridme 1 as described m Scheme 6Scheme 6Step 1 - Preparation of5-Pyndιn-3-yl-LH-ρyrrolo[2,3-b]pyndιne (20)[0138] To 5-bromo-7-azaindole (1, 1 00 g, 5 08 mmol) m water (13 0 mL) and acetonitnle (36 mL) were added pyridine-3-boronic acid (19, 1 0 g, 8 1 mmol), potassium carbonate (1 79 g, 0 0130 mol) and Tetrakis(tnphenylphosphine)palladmm(0) (50 0 mg, 0 043 mmol) under an atmosphere of nitrogen The reaction mixture was heated to 170 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate The organic layer was washed with brine, dried over sodium sulfate, and concentrated The residue was purified with silica gel column chromatography elutmg with 25percent ethyl acetate in hexane to provide a light yellow solid (20, 820 mg, 82percent) 1
82% With potassium carbonate In water; acetonitrile at 170℃; To 5-bromo-7-azaindole (67, 1.00 g, 5.08 mmol) in water (13.0 mL) and acetonitrile (36 niL) were added pyridine-3-boronic acid (609, 1.0 g, 8.1 mmol), potassium carbonate (1.79 g, 0.0130 mol) and Tetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under an atmosphere of nitrogen. The reaction mixture was heated to 170 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25percent ethyl acetate in hexane to provide a light yellow solid (89, 820 mg, 82percent). MS(ESI)[M+Hf]+ = 196.1.
Reference: [1] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 37-38
[2] Patent: WO2008/80001, 2008, A2, . Location in patent: Page/Page column 60
[3] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 123
[4] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 12, p. 1238 - 1243
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9470 - 9489
  • 47
  • [ 197958-29-5 ]
  • [ 183208-35-7 ]
  • [ 918511-92-9 ]
YieldReaction ConditionsOperation in experiment
72% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.166667 h; Microwave irradiation The compound of formula 10-1 (5-bromo-1H-pyrrolo[2,3-b]pyridine) (0.3 g, 1.52 mmol), pyridine-2-boronic acid (0.22 g, 1.84 mmol), Pd(dppf)C12 (0.12 g, 0.15 mmol) and potassium carbonate (0.63 g, 4.57 mmol) were added to 1,4-dioxane (20 mL) I water (10 mL), and heated by microwave irradiation at 120°C for 10 minutes, and then cooled to room temperature. After completion of the reaction, the reaction mixture was filtered through a celite pad to remove solids, and the filtrate was concentrated under reduced pressure to remove the solvent. The concentrate was purified by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = from 10percent to 40percent) to afford the desired compound of formula 10-2 (0.21 g, 72percent) as a pale brown solid.
Reference: [1] Patent: WO2015/87151, 2015, A1, . Location in patent: Paragraph 251; 252; 253
  • 48
  • [ 1679-18-1 ]
  • [ 183208-35-7 ]
  • [ 918516-27-5 ]
YieldReaction ConditionsOperation in experiment
92% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In Dimethyl ether; waterReflux General procedure: Procedure: 5-bromo-1 H-pyrrolo[2,3-b]pyridine (2 g, 10.2 mmol, 1.0 eq.) , K2C03(2.8 g, 20.3 mmol, 2 eq.) and (4-chlorphenyl)boronic acid (1.8 g, 1 1.2 mmol, 1.1 eq.) was suspended in DME/H20 (30 ml, 4:1 ) and degassed with argon. Pd(PPh3)4(587 mg,508 μηηοΙ, 0.05 eq.) was added and the reaction mixture was heated under reflux until complete consumption of the starting material. The resulting solution was passed through a Celite pad, diluted with EtOAc and washed with water. The combined organic layers were dried over Na2S04and the solvent was evaporated under reduced pressure. The crude product was purified via flash chromatography (Si02, nHex/EtOAc 6:4).Yield: 2.23 g, 9.4 mmol, 92percent (white solid).TLC: PE/EtOAc 1 :11H NMR (DMSO-de,200 MHz, ppm): δ 1 1.76 (s, 1 H), 8.51 (d, J = 2.1 Hz, 1 H), 8.20 (d, J = 1 .9 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 2H), 7.57 - 7.43 (m, 3H), 6.50 (dd, J = 3.2, 1.7 Hz, 1 H).;13C NMR (DMSO-d6, 50 Hz, ppm): δ 148.2, 141 .4, 138.0, 131.7, 128.9, 128.6, 127.1 , 126.9, 126.1 , 1 19.7, 100.2.
76% With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,2-dimethoxyethane at 130℃; for 0.5 h; Inert atmosphere; Microwave irradiation 5-Bromo-7-azaindole (6e) (1.0 g, 5.0 mmol) and (4-chlorophenyl)boronic acid (6f) (954 mg, 6.2 mmol) were dissolved in 1,2-dimethoxyethane (28 mL). A solution of potassium carbonate (844 mg, 6.2 mmol) in water (8.0 mL) was then added. The resulting mixture was purged with argon for 5 min, followed by addition of bis(triphenylphosphine)dichloropalladium(II) (356 mg, 0.5 mmol). The reaction mixture was then reacted at 130 °C for 30 min under microwave irradiation. The volatiles were then removed under reduced pressure and the crude residue diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over sodium sulphate, filtered, and the resulting filtrate evaporated in vacuo to give a crude solid that was purified using flash column chromatography to afford compound 6b (875 mg, 76percent) as a light-brown crystalline solid.
4.2 g With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 85 - 90℃; for 3 h; A 250 ml round bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer socket was charged 5-bromoazaindole (10gm) of Formula VII, 4- chlorophenyl boronic acid (7.1gm) of Formula VIII in 1,4-dioxane (lOOmi) at room temperature and stirred for I 0mm. To the reaction mass aqueous potassium carbonate(10.5gm dissolved in 40m1 water), Pd(PPh3)4 was charged and heated to 85°C to 90°C for 3hr. After completion of the reaction cooled the temperature to 55°C to 60°C and separated organic and aqueous layers and followed by cooling the organic layer to 0°C to 5°C and stirred for lhr to precipitate solid compound. The precipitated solid was isolated by filtration, washed with n-heptane (30m1) to get crude compound.Yield: 7.2 gmPurity by HPLC: 94.8percentFormula A by HPLC: 0:1percentPurification of Formula IX:A 250 ml round bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer socket was charged above obtained crude product (7.2gm) and tetrahydrofuran (1 lOmi) at room temperature and heated to 65°C for 1 1w, then distilled the tetrahydrofuran till the reaction mass volume 3 5-40 ml in the flask. Then the reaction mass temperature was cooled to room temperature and followed by 0°C to 5°C and allowed to stir for 1 hr. The precipitated solid was isolated by filtration, washed with n5 heptane (15m1) to get cream color solid. Same purification was repeated once again toobtaine pure compound of Formula IX.Yield: 4.2 gmPurity by HPLC: 99.9percentFormula A by HPLC: 0.02percent
Reference: [1] Patent: WO2018/134254, 2018, A1, . Location in patent: Page/Page column 35; 36; 79; 80
[2] Tetrahedron Letters, 2012, vol. 53, # 32, p. 4161 - 4165
[3] Patent: WO2015/75749, 2015, A1, . Location in patent: Page/Page column 43; 44
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9470 - 9489
  • 49
  • [ 195062-61-4 ]
  • [ 183208-35-7 ]
  • [ 918516-27-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 3, p. 963 - 969
  • 50
  • [ 183208-35-7 ]
  • [ 944059-24-9 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
  • 51
  • [ 98-09-9 ]
  • [ 183208-35-7 ]
  • [ 1001070-33-2 ]
YieldReaction ConditionsOperation in experiment
99.6%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 0.333333 h; Inert atmosphere
Stage #2: at 0 - 25℃; for 1 h; Inert atmosphere
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine 17 (5 g, 25 mmol) in N,N-Dimethylformamide (DMF, 40 mL) Sodium hydride (NaH, 0.91 g, 37 mmol) was added at 0 °C and stirred at 25 °C for 20 min.
To the mixture Benzenesulfonyl chloride (5.37 g, 30 mmol) was added dropwise at 0 °C and stirred at 25 °C for 1 h.
The mixture was quenched with Ammonium chloride (NH4Cl) solution, extracted with Bichloromethane (DCM, 50 mL * 2).
The organic phase was washed with water (50 mL * 2), brine (50 mL * 2), dried over Sodium sulfate (Na2SO4).
After filtering, the organic phase was concentrated to give compound 18 as a white solid (8.5 g, 99.6percent yield).
1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H, Ar-H), 8.18-8.16 (d, J = 7.8 Hz, 2H, Ar-H), 7.96 (s, 1H, Ar-H), 7.74-7.73 (m, J = 4.0 Hz, 1H, Ar-H), 7.59-7.50 (t, J = 7.4 Hz, 1H, Ar-H), 7.47-7.38 (t, 2H, Ar-H), 6.55-6.54 (d, J = 4.0 Hz, 1H, Ar-H).
95%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 2.5 h;
Stage #2: at 20℃;
A solution of 5-bromo- lH-pyrrolo[2,3-b]pyridine 8 (196 g, 994 mmol) in anhydrous tetrahydrofuran (2 L) was cooled to 0 °C and treated with sodium hydride (60percent in mineral oil, 49.3 g 1233 mmol) over 30 minutes. After two hours, benzenesulfonyl chloride 9 (153 mL, 1 193 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was quenched with brine (1 L). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 500 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure. The product was triturated with methyl tert-butyl ether to give compound 10 as a tan solid (319 g, 95percent). The data from the lH NMR spectrum were consistent with the structure of the compound.
94.3%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: at 5 - 20℃;
Preparation of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-7-4)B-7-3 B-7-4To a suspension of 5-bromo-1 H-pyrrolo[2,3-b]pyridine (B-7-3) (6.2 g, 0.031 mol) in THF (100 mL) was added NaH (1.51 g, 0.037 mol) under N2. BsCI (3.58 g, 0.035mol) was added 30 minutes later. The mixture was stirred at room temperature overnight. TLC (Petroleum ether: EtOAc = 5:1 ) showed that the reaction was complete. Water (200 mL) and EtOAc (50 mLχ3) were added into the mixture. The organic layer was separated and concentrated to give 5-bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine (B-7- 4) (10 g, 94.3percent) as a light yellow solid. 1HNMR (400 MHz, CDCI3): δ 8.465 (s, 1 H), 8.141-8.114 (d, 2H), 7.905 (s, 1 H), 7.679-7.669 (d, 1 H), 7.586-7.529 (m, 1 H), 7.430-7.351 (2, 1 H), 6.458-6.475 (d, 1 H). Example H-1 : 4-(3-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 -isopropyl-1 H-pyrazol-4-yl)pyridin-2- aminePreparation of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (H-1 -2)H-1-1 H-1 -2To a suspension of NaH (87 g, 2.18 mol, 60percent in oil) in dry THF (1 L) was added dropwise a solution of 5- bromo-1 H-pyrrolo[2,3-b]pyridine H-1-1 (120 g, 0.62 mol) in dry THF (1 L) at O0C. After addition, the mixture was stirred at O0C under N2 for 0.5 h. To the mixture was added dropwise BsCI (219.5 g, 1.24 mol) at 50C. After the addition, the mixture was stirred at room temperature overnight. TLC (Petroleum ether/EtOAc 5:1 ) showed the reaction was complete. The reaction mixture was poured slowly into ice-cold saturated NH4CI (500 mL). The mixture was extracted with EtOAc (600 mLχ2). The combined organic layers were washed with saturated aqueous NaCI (700 mL), dried over Na2SO4 and concentrated in vacuo. The residue was washed with Petroleum ether/EtOAc (15:1 , 1.5 L) to give compound H-1-2 (198 g, 94.8percent) as an off-white solid.
92.2% at 85℃; for 4 h; Compound numbers 1 to 7 recited in Example 4 apply only to Example 4. To a solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine(50 g, 0.254 mol) in pyridine (300 mL) was added benzene sulfonyl chloride (224 g, 1.27 mol). The resulted mixture was heated at 85 °C for 4 hours and then concentrated under vacuum. The residue was diluted with EtOAc (1500 mL). The pH of the solution was adjusted to 3 with 1M HC1, and the resulted mixture was washed with NaHC03 and water. The organic layer was washed with water and brine, dried (Na2S04) and concentrated. The residue was purified by a silica gel column to afford (85 g, 99.2 percent) of the title compound as a slightly yellow solid
76%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h;
Stage #2: at 20℃; for 16 h;
5-Bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine
To a well stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 50.7 mmol) in dry THF (100 mL) was added NaH (60percent oil suspension; 3.0 g, 75 mmol) at 0° C. and stirred for 30 min.
Phenylsulfonyl chloride (10.7 g, 60 mmol) was added slowly and the mixture was stirred at ambient temperature for 16 h (TLC monitoring: 60percent ethyl acetate in hexanes).
Solvent was removed under reduced pressure, water (25 mL) was added to the residue, and the mixture was extracted with dichloromethane (3*100 mL).
The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.
The residue thus obtained was crystallized from dichloromethane to yield the title compound (13.0 g, 76percent).
1H NMR (CDCl3, 300 MHz): δ=6.55 (d, J=4.2 Hz, 1H), 7.46-7.62 (m, 3H), 7.74 (d, J=4.0 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 8.15-8.18 (m, 2H), 8.44 (d, J=2.1 Hz, 1H).
75% With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 0℃; for 2 h; Preparation of Method A Intermediate 2: l-Benzenesulfonyl-5-bromo-lH-pyrrolo[2,3- b] pyridine[0425] 5-Bromoazaindole (1, 2.00 g, 10.1 mmol), tetrabutylammonium bromide (0.03 eq, 0.25 mmol, 82 mg) and powdered NaOH (3 eq, 30.45 mmol, 1.22 g) are combined in DCM (100 ml) and cooled to 0°C. Phenylsulfonyl chloride (1.25 eq, 12.69 mmol, 1.62 mL) is added dropwise. After the addition is completed the mixture is stirred for 2h at 0°C. The mixture is filtered, absorbed on Celite and purified by silica gel chromatography with a 40 to 60percent gradient of EtOAc in hexane. 2.58 g (7.65 mmol, 75percent yield) of 2 is obtained. 1H NMR (CDC13, 300 MHz): δ 8.45 (d, J= 1.8 Hz, 1H), 8.17 (m, 2 H), 7.98 (d, J= 2.1 Hz, 1H), 7.74 (d, J= 3.9 Hz, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 6.55 (d, J= 3.9 Hz, 1H). MS (m/z): 338 (M+H).
75% With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 0℃; for 2 h; 5-Bromoazaindole (1, 2.00 g, 10.1 mmol), tetrabutylammonium bromide (0.03 eq, 0.25 mmol, 82 mg) and powdered NaOH (3 eq, 30.45 mmol, 1.22 g) are combined in DCM (100 ml) and cooled to 0°C. Phenylsulfonyl chloride (1.25 eq, 12.69 mmol, 1.62 mL) is added dropwise. After the addition is completed the mixture is stirred for 2h at 0°C. The mixture is filtered, absorbed on Celite and purified by silica gel chromatography with a 40 to 60percent gradient of EtOAc in hexane. 2.58 g (7.65 mmol, 75percent yield) of 2 is obtained. XH NMR (CDC13, 300 MHz): δ 8.45 (d, J= 1.8 Hz, 1H), 8.17 (m, 2 H), 7.98 (d, J= 2.1 Hz, 1H), 7.74 (d, J= 3.9 Hz, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 6.55 (d, J= 3.9 Hz, 1H). MS (m/z): 338 (M+H).
55.46%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.166667 h;
Stage #2: at 20℃;
To a mixture of 5-bromo-7-azaindole (1.00 g, 5.08 mmol) and DMF (3 ml) was added 60percent NaH (0.13 g, 5.59 mmol). The mixture was stirred for 10 minutes, and, after addition of benzenesulfonyl chloride (0.71 ml, 5.59 mmol), was stirred again overnight at room temperature. The reaction was quenched with water and the mixture was extracted with ethyl acetate (30ml x 3). The organic layer was collected, dried over anhydrous MgS04, and concentrated in vacuo to yield a brown residue, which was purified by a flash column over silica gel (ethyl acetate: n-hexane = 1 : 1, Rf = 0.40) to afford 11a (0.95 g, 55.46percent) as a yellow solid. *H-NMR (500MHZ, CDCI3 ): δ 6.55 (d, /= 4.5 Hz, 1H), 7.50 (t, /= 8.0 Hz, 2H), 7.59(t, /= 7.5 Hz, 1H), 7.74 (d, /= 4.0 Hz, 1H), 7.97 (d, /= 2.0Hz, 1H), 8.17 (t, /= 8.0 Hz, 2H), 8.45 (d, /= 2.0Hz, 1H).

Reference: [1] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[2] Patent: WO2014/100620, 2014, A2, . Location in patent: Paragraph 0285
[3] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 73
[4] Patent: WO2016/210296, 2016, A1, . Location in patent: Page/Page column 164
[5] Patent: US2011/281888, 2011, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 151
[7] Patent: WO2014/85795, 2014, A1, . Location in patent: Paragraph 0392
[8] Patent: WO2015/157504, 2015, A1, . Location in patent: Page/Page column 75
[9] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 582 - 586
[10] Patent: WO2009/54941, 2009, A1, . Location in patent: Page/Page column 44-45
  • 52
  • [ 183208-35-7 ]
  • [ 1111637-68-3 ]
YieldReaction ConditionsOperation in experiment
13% With acetic acid; Selectfluor In acetonitrile at 80℃; Preparation of 3-fluoro-1 H-pyrrolo[2,3-b]pyridin-5-ylboronic acid (67)65 66 67To a solution of compound 65 (4 g, 20 mmol) in MeCN (500 mL) and AcOH (100 mL) was added Select-Fluor (10 g, 30 mmol), the resulting mixture was heated at 8O0C overnight. TLC (Petroleum ether/EtOAc 5:1 ) indicated the complete consumption of compound 1. The reaction mixture was concentrated in vacuo, the residue was purified via flash chromatography on silica gel (Petroleum ether/EtOAc 10:1 ) to yield 66 (0.64 g, 13percent) as an off-white solid. 1 H NMR: (400 MHz, CDCI3): δ 9.434 (brs, 1 H), 8.311-8.280 (m, 1 H), 8.056-8.023 (m, 1H), 7.191 (s, 1 H), 7.086-7.053 (m, 1 H).
Reference: [1] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 51
  • 53
  • [ 183208-35-7 ]
  • [ 1111638-02-8 ]
Reference: [1] Patent: WO2011/149950, 2011, A2,
[2] Patent: WO2014/85795, 2014, A1,
[3] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[4] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 582 - 586
  • 54
  • [ 183208-35-7 ]
  • [ 1235865-75-4 ]
Reference: [1] Patent: WO2011/150016, 2011, A1,
[2] Patent: WO2012/71336, 2012, A1,
[3] Patent: US2014/275082, 2014, A1,
[4] Patent: WO2016/24230, 2016, A1,
[5] Patent: WO2018/29711, 2018, A2,
[6] Patent: CN107445958, 2017, A,
  • 55
  • [ 183208-35-7 ]
  • [ 951626-91-8 ]
YieldReaction ConditionsOperation in experiment
85% With N-chloro-succinimide; dibenzoyl peroxide In N,N-dimethyl-formamide at 20℃; for 18 h; 0.50 g (2.54 mmol) of 5-bromo-lH-pyrrolo[2,3-b]pyridine was dissolved in 10 n L of Ν,Ν-dimethylformamide to which 0.37 g (2.79 mmol) of N-cMorosuccinimide and 0.38 g (2.79 mmol) of dibenzoyl peroxide were added, followed by stirring at room temperature for 18 hours. After extracting with ethyl acetate/distilled water, the organic layer was concentrated under reduced pressure. The residue was separated by column chromatography to give 0.50 g (85.0percent yield) of 5-bromo-3-chloro-lH-pyrrolo[2,3-b] pyridine. 1H NMR (DMSO) δ: 12.24 (br s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 8.03 (d, 1H), 7.81 (m, 1H), 7.77 (s, 1H), 7.64 (t, 1H)
Reference: [1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
[2] Patent: WO2016/129933, 2016, A2, . Location in patent: Page/Page column 48
  • 56
  • [ 183208-35-7 ]
  • [ 1220696-34-3 ]
Reference: [1] Patent: US2017/8889, 2017, A1,
  • 57
  • [ 183208-35-7 ]
  • [ 507462-26-2 ]
YieldReaction ConditionsOperation in experiment
84% at 0℃; for 0.5 h; 5-Bromo-1H-pyrrolo[2,3-b]pyridine (470mg, 2.39mmol) was added in portions to a stirring solution of fuming nitric acid (2.5ml) at 0°C. After addition the reaction was stirred at 0°C for 30 minutes and then carefully added to a mixture of ice/H20 (25ml) and stirred for 30 minutes. The solids were separated via filtration and the filter cake washed with copious amounts of H2O and then iso-hexane prior to drying in vacuo to afford the desired title compound, 484mg, 84percent.
84% With nitric acid In water at 0℃; for 0.5 h; 5-Bromo-1H-pyrrolo[2,3-b]pyridine (470 mg, 2.39 mmol) was added in portions to a stirring solution of fuming nitric acid (2.5 mL) at 0° C.
After addition the reaction was stirred at 0° C. for 30 minutes and then carefully added to a mixture of ice/H2O (25 mL) and stirred for 30 minutes.
The solids were separated via filtration and the filter cake washed with copious amounts of H2O and then iso-hexane prior to drying in vacuo to afford the desired title compound, 484 mg, 84percent.
Reference: [1] Patent: WO2013/114113, 2013, A1, . Location in patent: Page/Page column 23
[2] Patent: US2015/11533, 2015, A1, . Location in patent: Paragraph 0101
[3] Patent: WO2018/134254, 2018, A1, . Location in patent: Page/Page column 78; 79
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