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[ CAS No. 866546-07-8 ] {[proInfo.proName]}

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Chemical Structure| 866546-07-8
Chemical Structure| 866546-07-8
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Product Details of [ 866546-07-8 ]

CAS No. :866546-07-8 MDL No. :MFCD06659676
Formula : C7H5ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :MFZQJIKENSPRSJ-UHFFFAOYSA-N
M.W : 152.58 Pubchem ID :24229213
Synonyms :
5-chloro-1H-pyrrolo[2,3-b]pyridine

Calculated chemistry of [ 866546-07-8 ]

Physicochemical Properties

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

Pharmacokinetics

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

Lipophilicity

Log Po/w (iLOGP) : 1.6
Log Po/w (XLOGP3) : 1.94
Log Po/w (WLOGP) : 2.22
Log Po/w (MLOGP) : 1.58
Log Po/w (SILICOS-IT) : 2.71
Consensus Log Po/w : 2.01

Druglikeness

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

Water Solubility

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

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.36

Safety of [ 866546-07-8 ]

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

Application In Synthesis of [ 866546-07-8 ]

* 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 [ 866546-07-8 ]
  • Downstream synthetic route of [ 866546-07-8 ]

[ 866546-07-8 ] Synthesis Path-Upstream   1~20

  • 1
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YieldReaction ConditionsOperation in experiment
71% With sodium hydroxide In 1-methyl-pyrrolidin-2-one; water at 75 - 81℃; Inert atmosphere Step 3: Synthesis of 5-chloro-7-azaindol (Ib); A 500 mL double-jacket reactor (under a nitrogen atmosphere) is charged with 25.0 g 4-(2-amino-5-chloro-pyridin-3-yl)-2-methyl-but-3-yn-2-ol, 120 mL N-methylpyrrolidone and 130 mL water. The mixture is heated to 75 to 80° C. (ca. 95° C. jacket temperature) 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 85 mL sodium hydroxide (28percent in water). The dropping funnel is rinsed with 5 mL water and the mixture stirred at 78 to 81° C. over night. During stirring the jacket temperature and the vacuum have to be adjusted such that a slight steadily distillate flow is guaranteed. In a typical lab experiment approx. 50 mL of water/acetone are distilled off in 2 hours. During the reaction, water is continuously added to keep the volume constant at approx. 270 mL. Upon complete conversion, the reaction mixture is cooled to 50 to 55° C. The mixture is treated at this temperature with 60 mL toluene. The biphasic mixture 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.50 mL with toluene. The combined toluene layers are washed at 50 to 55° C. with 5.x.40 mL with water. The toluene layer is concentrated to dryness. The residue (17.3 g) is crystallized from 90 mL toluene to afford 13.0 g (71percent) of 5 chloro-7-azaindol (Ib) as slightly yellow crystals with a purity of 96.7percent (area).
Reference: [1] Patent: US2011/28511, 2011, A1, . Location in patent: Page/Page column 14
  • 2
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YieldReaction ConditionsOperation in experiment
90% With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 5 h; Molecular sieve 3Å Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve (lOg of 3A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30percent EtOAc-70percent hexanes) to give 02.3 g (90percent) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reference: [1] Patent: WO2005/95400, 2005, A1, . Location in patent: Page/Page column 342; 343
  • 3
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YieldReaction ConditionsOperation in experiment
82.6% With manganese(IV) oxide In toluene at 60℃; for 3 h; (6) The 5-chloro-7-azaindoline obtained in step (5), manganese dioxide was added to toluene, 5-chloro-7-azaindoline,Manganese dioxide, toluene weight ratio of 17:45:80, heated to 60 ° C and refluxed for 3 hours, cooled to room temperature after the product was filtered,The filter cake was washed three times with trichloromethane. The combined filtrates were evaporated to dryness and recrystallized from methyl acetate to give 5-chloro-7-azaindole.
Reference: [1] Patent: CN106279156, 2017, A, . Location in patent: Paragraph 0031; 0039; 0047; 0055; 0063; 0071; 0073
  • 4
  • [ 866318-90-3 ]
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YieldReaction ConditionsOperation in experiment
85% With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 80℃; for 1 h; Inert atmosphere Third Step
Under a nitrogen atmosphere, to a solution of potassium tert-butoxide (4.0 g, 0.036 mol) in 1-methyl-2-pyrrolidone (8.0 mL) which stirred with heating at 80° C., a solution of 2-amino-5-chloro-3-[(trimethylsilyl)ethynyl]pyridine (4.0 g, 0.018 mol) in 1-methyl-2-pyrrolidone (22 mL) was added dropwise and the mixture was stirred for 1 h.
Cooled to ambient temperature, the reaction mixture was diluted with brine and stirred, then extracted with diethyl ether for 3 times.
The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 5-chloro-7-azaindole as solid (2.3 g, y. 85percent).
1H NMR (CDCl3) δ (ppm) 9.46 (s, 1H), 8.26 (s, 1H), 7.91 (d, 1H, J=1.12 Hz), 7.35 (s, 1H), 6.46 (s, 1H); LCMS (m/z): 153.2 [M+H]+.
41% With potassium <i>tert</i>-butylate In N-methylpyrrolidone (NMP) at 80℃; for 0.833333 h; A solution of potassium tert-butoxide (36g, 320mol) in N-methylpyrrolidone (70ml) was heated to 80°C under nitrogen. A solution of 5-chloro-3-(trimethyl-silanylethynyl)-pyridin-2-ylamine (2) (36g, 160mol) in NMP (200ml) was added dropwise via a dropping funnel. The reaction mixture was stirred at 80°C for a further fifty minutes. The reaction mixture was allowed to cool to room temperature. Brine (500ml) was added to the reaction mixture and extracted with diethyl ether (5 x 200mol). The combined organic were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography, using as eluent pentane/EtOAc 0percent to 40percent, and further recrystallised from cyclohexane to afford the title compound (10g, 41percent). 1H NMR (CDCl3) 6.5 (1H, s), 7.4 (1H, s), 8.0 (1H, s), 8.2 (1H, s), 10.4-10.6 (1H, brs). MS (ES+) 153.
40% With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 80℃; for 4 h; Inert atmosphere Into a 10000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of potassium t-butoxide (446.3 g, 3.98 mol, 2.00 equiv) in NMP (1300 mL). This was followed by the addition of a solution of 5-chloro-3-(2- (tratne lsilyl)em^ (446.3 g, 1.98 mol, 1.00 equiv) in NMP (2500 mL) dropwise with stirring at 80°C over 3 hours. After stirred for 60 min at 80°C in an oil bath, the reaction mixture was cooled to 40°C and diluted with 7500 mL of brine. The resulting solution was extracted with 5x3000 mL of ether. The organic layers were combined, washed with 2x3000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE to EtOAc:PE (1-30). This resulted in 120 g (40percent) of 5-chloro-1H-pyrrolo[2,3-b3pyridine as a yellow solid.
Reference: [1] Patent: US2014/18533, 2014, A1, . Location in patent: Paragraph 0078; 0079
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 307 - 315
[3] Patent: WO2005/95400, 2005, A1, . Location in patent: Page/Page column 345; 346-347
[4] Patent: WO2011/137022, 2011, A1, . Location in patent: Page/Page column 31
  • 5
  • [ 918523-59-8 ]
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Reference: [1] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 35
[2] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 105
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  • [ 866318-88-9 ]
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  • [ 1001014-88-5 ]
Reference: [1] Patent: WO2008/4117, 2008, A1, . Location in patent: Page/Page column 104
  • 7
  • [ 10592-27-5 ]
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Reference: [1] Patent: CN108101903, 2018, A, . Location in patent: Paragraph 0031; 0032; 0037-0044; 0047; 0048; 0055; 0056
  • 8
  • [ 1072-98-6 ]
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Reference: [1] Patent: WO2011/137022, 2011, A1,
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 307 - 315
[3] Patent: US2014/18533, 2014, A1,
  • 9
  • [ 211308-81-5 ]
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Reference: [1] Patent: WO2011/137022, 2011, A1,
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 307 - 315
[3] Patent: US2014/18533, 2014, A1,
  • 10
  • [ 1072-98-6 ]
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  • [ 1001014-88-5 ]
Reference: [1] Patent: WO2008/4117, 2008, A1,
  • 11
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  • [ 1001014-88-5 ]
Reference: [1] Patent: WO2008/4117, 2008, A1,
  • 12
  • [ 1603-40-3 ]
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Reference: [1] Patent: CN106279156, 2017, A,
  • 13
  • [ 138343-75-6 ]
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Reference: [1] Patent: CN106279156, 2017, A,
  • 14
  • [ 271-63-6 ]
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Reference: [1] Patent: CN106279156, 2017, A,
  • 15
  • [ 866318-90-3 ]
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  • [ 1001014-88-5 ]
Reference: [1] Patent: WO2008/4117, 2008, A1,
  • 16
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  • [ 76-09-5 ]
  • [ 121-43-7 ]
  • [ 754214-56-7 ]
YieldReaction ConditionsOperation in experiment
56.8%
Stage #1: With tert-butyldimethylsilyl chloride; triethylamine In dichloromethane at 0 - 20℃;
Stage #2: With sodium carbonate In tetrahydrofuran; dichloromethane at -5℃;
step one,A solution of 5-chloro-7-azaindole (3 g, 0.02 mol) in dichloromethane (50 ml)Triethylamine (0.20 mol) was added under stirring, and a solution of tert-butyldimethylchlorosilane (0.2 mol)The mixture was stirred at room temperature overnight until TLC showed complete reaction. After completion of the reaction, 50 ml of water and 10 ml of 0.1 mol / L dilute hydrochloric acid were added. After partitioning the methylene chloride phase was washed with 50 ml of water, 50 ml of saturated carbonic acid Sodium solution and 50ml of saturated sodium chloride, and then evaporated the solvent, and then washed three times with acetone and dried to obtain a yellow solid;Step two, the above yellow solid was dissolved in 50ml THF, keeping the temperature of the reaction system at -5 under the conditionsInto 0.005 mol sodium carbonate (0.53 g) and then slowly addedTrimethyl borate(4.6ml, 0.04mol), added after the riseWarmed to room temperature, the solvent was evaporated under reduced pressure to give a yellow oily substance;Step three, to the above-mentioned yellow oily substance was added 80ml of ethyl acetate and 0.02mol pinacol after refluxThe reaction was completed by TLC at night, the solvent was evaporated, the residue was added to 100ml of acetone, stirred and filtered, the filtrate was concentrated to dryness to give a colorless oil;Step four, to the above colorless oil was added 50ml ether and 30ml concentration of 0.1mol / L dilute hydrochloric acid, stirringAfter stirring overnight, the solvent was evaporated and the residue was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was further purified by a 1: 1 by volume chloroform- Crystallization (20ml) afforded a white solid. 2.78g of a white solid was obtained as 7-azaindole-5-boronic acid pinacol ester with HPLC purity of 99.8percent and overall yield of 56.8percent.
Reference: [1] Patent: CN104478909, 2017, B, . Location in patent: Paragraph 0016; 0017; 0018; 0019; 0020; 0021-0036
  • 17
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  • [ 866546-09-0 ]
YieldReaction ConditionsOperation in experiment
100% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 4 h; [0230] Step 1 : 3-Bromo-5-chloro-lH-pyrrolo[2,3-b]pyridine. N-Bromosuccinimide (1.08 g, 6.1 mmol) was added to a solution of 5-chloro-lH-pyrrolo[2,3-]pyridine (0.85 g, 5.5 mmol) in DMF (25 mL) and stirred for 4 h at it. Water (100 mL) was added the mixture extracted with EtOAc (3 x 50 mL), the organics combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (1.28 g, quant.). 1H NMR (400 MHz, DMSO-^) δ ppm 12.3 (br. s), 8.30 (d, 1 H), 7.93 (d, 1H), 7.84 (s, 1H)
92% With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2 h; To a stirred solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1) (50 g, 0.3289 mol) in DMF (200 mL) was added N-bromosuccinimide (70.26 g, 0.3947 mol) by portion wise at 0 °C and stirred for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was poured into ice cold water (600 mL) to form brown precipitate which was filtered and dried under air to afford 3- bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (2) (70 g, 0.3043mol, 92percent yield) as pale brown solid. TLC system: 20percent EtOAc in hexane Rf: 0.5 LCMS (ESI): m/z 230.8 [M+H]+
69% With bromine In chloroform at 0℃; for 1 h; Cooling with ice A solution of bromine (3.5mol) in chloroform (40mol) was added dropwise to an ice-cold solution of the 5-chloro-1H- pyrrolo[2,3-b]pyridine (3) (10g, 65mM) in chloroform (260mol). The reaction mixture was stirred for 60 minutes at 0°C. The reaction mixture was then hydrolyse with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration, and the. aqueous was extracted with dichloromethane. The organic was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (10.5g, 69percent). 1H NMR (DMSO-d6) 7.8 (1H, s), 7.9 (1H, s), 8.3 (1H, s)
52% With N-Bromosuccinimide; dibenzoyl peroxide In dichloromethane at 20℃; for 18 h; 0.30 g (1.97 mmol) of 5-chloro-lH-pyrrolo[2,3-b]pyridine was dissolved in 10 mL of methylene chloride to which 0.38 g (2.16 mmol) of N-bromosuccinimide and 0.52 g (2.16 mmol) of dibenzoyl peroxide were added, followed by stirring at room temperature for 18 hours. The precipitated crystals were filtered and then washed with methylene chloride to give 0.24 g (52.0percent yield) of 3-bromo-5-chloro-lH-pyrrolo[2,3-b] pyridine. 1H NMR (DMSO) δ : 12.32(br s, 1H), 8.28(m, 1H), 7.91 (m, 1H), 7.82(m, 1H)
48% at 90℃; for 3 h; Into a 3000-mL 3-necked round-bottom flask was placed a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (120 g, 784.31 mmol, 1.00 equiv) in AcOH (1200 mL). This was followed by the addition of a solution of B (139 g, 868.75 mmol, 1.10 equiv) in AcOH (600 mL) dropwise with stirring at 90°C over 80 min. The resulting solution was stirred for 1.5 h at 90°C in an oil bath. Then it was cooled and concentrated under vacuum. The residue was adjusted to pH 10 with sodium hydroxide solution (1M). The solid was collected by filtration, then washed with 3x500 ml of water and dried in an oven under reduced pressure. This resulted in 87.2 g (48percent) of 3-bromo-5-cWoro-1H-pyrrolo[2,3-b]pyridine as a yellow solid.

Reference: [1] Patent: WO2014/4863, 2014, A2, . Location in patent: Paragraph 0230
[2] Patent: WO2018/200425, 2018, A1, . Location in patent: Paragraph 00384
[3] Patent: WO2005/95400, 2005, A1, . Location in patent: Page/Page column 345; 347
[4] Patent: WO2016/129933, 2016, A2, . Location in patent: Page/Page column 45-46
[5] Patent: WO2011/137022, 2011, A1, . Location in patent: Page/Page column 31
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  • [ 916176-52-8 ]
Reference: [1] Patent: CN108570048, 2018, A,
[2] Patent: WO2018/169700, 2018, A1,
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  • [ 1029044-16-3 ]
Reference: [1] Patent: WO2016/179412, 2016, A1,
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  • [ 900514-08-1 ]
Reference: [1] Patent: US2011/263595, 2011, A1, . Location in patent: Page/Page column 78
[2] Patent: US9096593, 2015, B2, . Location in patent: Page/Page column 88
[3] Patent: WO2017/133664, 2017, A1, . Location in patent: Page/Page column 70
[4] Patent: WO2017/133667, 2017, A1, . Location in patent: Page/Page column 111
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