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Chemical Structure| 1235865-77-6
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Product Details of [ 1235865-77-6 ]

CAS No. :1235865-77-6 MDL No. :MFCD28129979
Formula : C33H35ClN4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :DMRMYQUGHOAQFW-UHFFFAOYSA-N
M.W : 571.11 Pubchem ID :66713100
Synonyms :

Calculated chemistry of [ 1235865-77-6 ]

Physicochemical Properties

Num. heavy atoms : 41
Num. arom. heavy atoms : 21
Fraction Csp3 : 0.33
Num. rotatable bonds : 7
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 171.73
TPSA : 81.69 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.41
Log Po/w (XLOGP3) : 4.06
Log Po/w (WLOGP) : 6.73
Log Po/w (MLOGP) : 4.41
Log Po/w (SILICOS-IT) : 6.25
Consensus Log Po/w : 5.17

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -5.86
Solubility : 0.000796 mg/ml ; 0.00000139 mol/l
Class : Moderately soluble
Log S (Ali) : -5.48
Solubility : 0.00189 mg/ml ; 0.00000331 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -10.0
Solubility : 0.0000000574 mg/ml ; 0.0000000001 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.33

Safety of [ 1235865-77-6 ]

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

Application In Synthesis of [ 1235865-77-6 ]

* 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.

  • Downstream synthetic route of [ 1235865-77-6 ]

[ 1235865-77-6 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 1235865-76-5 ]
  • [ 1235865-77-6 ]
YieldReaction ConditionsOperation in experiment
96.9% With sodium hydroxide; In tetrahydrofuran; methanol; water; at 45℃; A solution of 2 - ((lH-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- 2-yl) methyl) piperazin-1-yl) benzoate (1.65 g, 2.82 mmol, 1.0 eq)Was added to THF (30 mL) and methanol (10 mL), sodium hydroxide (0.60 g, 15.0 mmol, 5.5 eq) and water (6 mL) were added and reacted at 45 C overnight. Point half analysis, the raw material has been completely responsive. After cooling, the mixture was poured into 100 mL of water, adjusted to pH = 2 with 2M hydrochloric acid and extracted with DCM (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, spin dried, and then 5 mL of DCM and 100 mL of PE were stirred for 10 min , Filtered to filter the white solid product 1.56g, the yield 96.9%.
93% With water; sodium hydroxide; In tetrahydrofuran; ethanol; at 20℃; 1.0 g of the compound (I) was added to a 10 ml single-necked flask,5 ml of water, 5 ml of ethanol, 5 ml of tetrahydrofuran,Sodium hydroxide 136 mg,The reaction solution was stirred at room temperature, and after completion of the reaction, TLC was added, followed by the addition of ethyl acetate,With 1N hydrochloric acid to adjust rhoEta4-5,Ethyl acetate was extracted three times, dried over anhydrous sodium sulfate and spin-dried to give 907 mg of compound (J) in a yield of 93%.
92% With water; sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 3h; Aqueous sodium hydroxide solution (70g in 200mLwater) was charged slowly to a mixture of formula 3 (100 g) in dimethyl sulfoxide (1000 mL) and stirred for 3 hours at room temperature. Water (200 mL) was charged to the reaction mixture followed by slow addition of a solution of concentrated HCI (150 mL) and water (450 mL).The reaction mixture was stirred for 2 hours at room temperature. The solution was filtered and the solid was washed with water (400 mL). The solid was dried under vacuum at 50C. (67 g, Yield = 92%)
85% With water; sodium hydroxide; In tetrahydrofuran; methanol; at 45℃; for 10h; Sodium hydroxide (0.20 g, 5.12 mmol), Water (2 ml) was added to a mixed solution of the compound 21 (0.6 g, 1.03 mmol) in tetrahydrofuran (10 ml) and methanol (3 ml), and the mixture was stirred at 45 C for 10 h. Cool to room temperature, remove most of the solvent, and adjust the residue to 2 with 2M hydrochloric acid. Extracted with dichloromethane (30 ml × 3), and the organic phases were combined.Dry over anhydrous sodium sulfate, The solvent was removed to give 0.45 g of a white solid. The yield was 85%.
Example 43E 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid EXAMPLE 43D (200 mg) in dioxane (10 mL) and 1M aqueous NaOH (6 mL) at 50 C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.
Example 3J 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid EXAMPLE 3I (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50 C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.
EXAMPLE II (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50 C was stirred for 24 hours. The reaction was cooled, added to aqueous NaH2P04 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the title product.
With sodium hydroxide; In 1,4-dioxane; at 50℃; for 24h; Compound J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50C was stirred for 24 hours. The reaction was cooled, added to NaH2P04 solution, and extracted thee times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.
With water; sodium hydroxide; In 1,4-dioxane; at 50℃; for 24h; Example 1J 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid EXAMPLE 1I (200 mg) in dioxane (10 mL) and 1M aqueous NaOH (6 mL) at 50 C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to afford the title compound.
With sodium hydroxide; In 1,4-dioxane; at 50℃; for 24h; Compound K, 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4- dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid, may be prepared as follows. Compound J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) at 50 C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.
10.2 g With water; lithium hydroxide; In tetrahydrofuran; at 32 - 65℃; for 64h; To a mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[ 1,1 '-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate ( 11.5 g)in tetrahydrofuran (115 mL), a solution of lithium hydroxide in water (8.2 g in 57 mL)was added at 32C. The reaction mixture was heated and stirred at 65C for 44 hours andat 40C for 20 hours. The solvent was evaporated under reduced pressure at 50C anddistilled the reaction mixture azeotropically with toluene (2 x 50 mL). Reaction mixturewas washed with ethyl acetate (2 x 200 mL) and neutralized with 10% sodium dihydrogenphosphate solution (200 mL). Reaction mixture was extracted the ethyl acetate (3 x 150mL) and the combined organic layer was washed with water (2 x 100 mL), brine solution(100 mL). The organic layer was dried over sodium sulfate and evaporated the solventunder reduced pressure to obtain the crude product as yellow solid. The crude product was recrystallized from mixture of 2-methyl tetrahydrofuran and heptane to obtain thetitle compound. Yield: 10.2 g; Purity by HPCL: 99.28%
42 g With water; sodium hydroxide; In 1,4-dioxane; at 55℃; for 18h; In round bottom flask equipped with mechanical stirrer and thermometer, intermediate (II) (R = CH3) (45 g), dioxane (450 ml) and aq. NaOH solution (9 g in 450 ml water) were stirred at 55 C for 18 hrs. The reaction was cooled to room temperature, and the reactionmass was concentrated and 6M HCI was added to residue till acidic. The obtained solid was filtered, washed with water, and dried to give the title compound (42 g)
With sodium hydroxide; In 1,4-dioxane; at 50℃; for 24h; (0086) Compound 3I (200 mg) in dioxane (10 ml) and 1M NaOH (6 ml) at 50 C. was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.

  • 2
  • [ 1235865-77-6 ]
  • [ 97-09-6 ]
  • [ 1257044-99-7 ]
YieldReaction ConditionsOperation in experiment
96.8% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 30℃; for 16h; Compound (II) (20.0 g, 35.0 mmol)Placed in 300 mL of dichloromethane (DCM),Add sequentially at room temperature3-nitro-4-chlorobenzenesulfonamide (9.1 g, 38.5 mmol),4-dimethylaminopyridine (DMAP) (6.4 g, 52.5 mmol),1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCL) (10.1 g, 52.5 mmol).The reaction was stirred at a temperature of 20 to 30 C for 16 hours.The TLC test showed that the reaction of the starting material was completed.After the reaction was completed, it was washed once by adding 100 mL of a 5% acetic acid aqueous solution.Then wash it again with 100 mL of water.The organic phase is dried with 20 g of sodium sulfate.Filter, spin dry,26.8 g of a chlorine-containing compound (III) was obtained, and the yield was 96.8%.Used directly for the next step.
  • 3
  • [ 1228779-96-1 ]
  • [ 1235865-77-6 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
91.4% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h; Compound IX 20.3 g (0.064 mol), 15.8 g (0.13 mol) DMAP, 20.9 g were added to a 2 L reaction flask.(0.11 mol) EDCI and 500 mL dichloromethane (DCM),The system was stirred at 20 C.A solution of 37.5 g (0.064 mol) of compound VIII and 23.7 g (0.23 mol) of triethylamine and 200 mL of dichloromethane prepared in advance was slowly added dropwise to the above system.After the completion of the dropwise addition, the mixture was stirred at 20 C for 3 hours, and then controlled by HPLC or TLC. The starting material was completely reacted.To the system was added 14.1 g of N,N'-dimethylethylenediamine.The system is heated to 35 C and stirring is continued.After the temperature is stable, add 200 mL of 12% acetic acid solution.After stirring for 10 min, the layers were separated, and the organic layer was washed with 5% sodium hydrogen carbonate solution (200 mL) and then washed with 5% sodium chloride solution (200 mL).The organic layer was dried, filtered, and evaporated to dryness.After the system is heated to 30 C, the methanol solution is added dropwise.After the system is clarified, start to cool down to 0-5 C, and stir for 1 h.After filtration, the cake was dried to give a white solid compound I about 50.8 g.The yield is 91.4%,
84% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; Solution preparation prior to reaction: 10% Acetic Acid:Acetic Acid (37 mL) in water (333 g); 5% NaHCO3:NaHCO3 (9 g) in water (176 g); 5% NaCl:NaCl (9 g) in water (176 g). Compound (N) (13.5 g), DMAP (10.5 g), EDAC (10.7 g) and dichloromethane (300 mL) were combined in a suitable reactor and agitated at 25 C. In a second suitable reactor was charged the Acid (Compound (L), 25 g), Et3N (8.7 g) and dichloromethane (120 mL). The resulting Acid (Compound (L)) solution was slowly charged to the initial suspension of Compound (N) and agitated until reaction completion. N,N-dimethylethylenediamine (9.4 g) was then charged to the reaction mixture with continued agitation. The reaction mixture was warmed to 35 C. and washed with 10% Acetic acid solution (185 mL) twice. The lower organic layer was diluted with more dichloromethane (75 mL) and methanol (12.5 mL). The organic, product layer was then washed with 5% NaHCO3 solution (185 mL) and then washed with 5% NaCl solution (185 mL) at 35 C. The lower, organic layer was separated and then concentrated to 8 vol (256 mL) diluted with methanol (26 mL) and warmed to 38 C. Ethyl Acetate (230 mL) was slowly charged. The resulting suspension was slowly cooled to 10 C. and then filtered. The wet cake was washed twice with a 1:1 mix of dichloromethane and ethyl acetate (2 vol, 64 mL). After drying the wet cake at 90 C., 32 g (84%) of Compound (I) was isolated. 1H NMR (DMSO-d6): delta 0.90 (s, 6H), 1.24 (m, 2H), 1.36 (t, J=6.4 Hz, 2H), 1.60 (m, 2H), 1.87 (m, 1H), 1.93 (s, br, 2H), 2.12 (m, 2H), 2.19 (m, 4H), 2.74 (s, br, 2H), 3.06 (m, 4H), 3.26 (m, 4H), 3.83 (m, 2H), 6.17 (d, J=2.1 Hz, 1H), 6.37 (dd, J=3.4, 1.9 Hz, 1H), 6.66 (dd, J=9.1, 2.2 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 2H), 7.48 (m, 3H), 7.78 (dd, J=9.3, 2.3 Hz, 1H), 8.02 (d, J=2.61 Hz, 1H), 8.54 (d, J=2.33 Hz, 1H), 8.58 (t, J=5.9 Hz, 1H, NH), 11.65 (m, 1H).
65% In 25 ml water compound is added in the bottle (J) 100 mg, EDCI67mg, dichloromethane 10 ml, reaction solution stirring 30 minutes, the compound is added (K) (in accordance with WO2012058392 method preparation) 55 mg, finally adding catalytic DMAP, reaction solution adding stirring reaction sleepovers, to splines end of the detection reaction TLC solvent, ABT-199 HPLC purified to get the pure product 98 mg, yield 65%.
62.5% The sulfonamide (compound 3, 158.9 g), DMAP (123.7 g), EDCI (126.5 g) and dichloromethane (3678 mL) were combined at 25C (reactor I). In a second reactor (reactor II), the benzoic acid derivative (compound 2, 340.0 g), Et3N (140 mL) and dichloromethane (2936 mL) were combined and stirred for 15 minutes. The resulting acid solution (reactor II) was slowly added to the suspension of the sulfonamide (reactor I) within 120 minutes and reaction mixture agitated until reaction completion. After 22 hours the reaction mixture was washed with 10% acetic acid solution twice (2x2056 mL). The lower organic layer was diluted with more dichloromethane (882 mL) and methanol (146 mL), before separation of the organic layer. After phase separation the organic layer was washed with 5% aq. NaHCO3 (2059 mL) and then with 5% NaCl solution (2059 mL) at room temperature. The lower organic layer was separated and the concentrated to dryness, resulting a yellow solid. Dichloromethane (2014 mL) and methanol (206 mL) were added, the suspension was heated to 38C under stirring. Ethyl acetate (1840 mL) was added slowly within 40 minutes to the yellow solution. Heating was turned off and the suspension was cooled to 0-5 C and stirred at 5C overnight. The filtrated product was washed with Ethyl acetate (735 ml) and dried under vacuum (100 mbar) at 50C overnight to yield Venetoclax as yellow solid (273.6 g; 62.5 %, HPLC purity 95.36 A%).
55% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Product distribution / selectivity; To a solution of 2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4- chlorophenyl)-4,4-dimethylcyclohex- 1 -enyl)methyl)piperazin- 1 -yl)benzoic acid( 16g,28mmol) and 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide(8.83g, 28mmol) in DCM(300mL) was added EDCI(10.74g, 56mmol) and DMAP(6.85g, 56mmol). The mixture was stirred at r.t. overnight. LC/MS showed the expected product as a single peak. The mixture was diluted with DCM(500ml) and washed with aq. NaHC03, water, brine and dried over Na2S04. The residue after evaporation of solvent was dissolved in DCM and loaded on a column and eluted with 30% ethyl acetate in DCM followed by 1 to 2% MeOH in DCM to give 24.5g pure product(95% purity) which was dissolved in DMSO and MeOH(l :l) and TFA(2eq) and loaded on a 330g C18 column (6g a time)to give 13.5g pure(>99.7% purity) product(55%yield). The API was extracted using dichloromethane and then, the solvent was removed using rotary evaporator. The resulting solid was suspended in acetonitrile at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.
50% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; Formula 2(100 g) and triethylamine (35.2 g) was stirred in dichloromethane (500 mL). In another flask, formula 9(46.9 g), 4-dimethylaminopyridine (42.68 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide(46.96 g) in dichloromethane (1.2 L) was stirred. The solution of formua-2 was added slowly to the solution of formula 9 at ambient temperature and the reaction was stirred for 12 hours. The organic layer was washed with 10% acetic acid solution (750 mL) twice, followed by 5% aqueous NaHCO3 (750 mL) and 5% aqueous NaCI (750 mL). The dichloromethane layer was concentrated under vacuum at 40C. Dichloromethane (900 mL) was added and the r eaction mixture was heated to 38C. Methanol (100 mL) and ethyl acetate (800 mL) were added at 38 The reaction mass was cooled to 27±3C, stirred for 2 hours, and filtered. The solid was washed with a mixture of dichloromethane (150 mL) and ethyl acetate (150 mL). The solid was dried under vacuum at 60±5C for 4 hours. Dry weight: 76 g (Yie Id = 50%).
32% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 24h; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide EXAMPLE 5K (3.39 g), EXAMPLE 5A (1.87 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in CH2Cl2 (40 mL) for 24 hours. The reaction was cooled and chromatographed on silica gel with 25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1% acetic acid, to give the product (1.62 g, 32%) as a white solid. 1H NMR (300 MHz, dimethylsulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).
32% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 24h; Compound L, the free base of venetoclax (4-(4-[2-(4-chlorophenyl)-4,4- dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide), may be prepared as follows. Compound K (3.39 g), Compound A (1.87 g), 1-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in CH2Cl2 (40 mL) for 24 hours. The reaction was cooled and chromatographed on silica gel with 25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1% acetic acid, to give the product (1.62 g, 32%) as a solid.1H NMR (300 MHz, dimethylsulfoxide-d6) 11.65 (br s, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).
32% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 24h; (0104) Compound 5K (3.39 g), Compound 5A (1.87 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in CH2Cl2 (40 ml) for 24 hours. The reaction was cooled and chromatographed on silica gel with 25-100% ethyl acetate/hexanes, then 10% methanol/ethyl acetate with 1% acetic acid, to give the product (1.62 g, 32%) as a white solid. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta 11.65 (br s, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73(m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 24h; EXAMPLE 1 J (3.39 g), EXAMPLE 2A (1.87 g), l-ethyl-3-[3-(dimethylamino)propyl]- carbodiimide hydrochloride (2.39 g), and 4-dimethylaminopyridine (1.09 g) were stirred in CH2C12 (40 mL) for 24 hours. The residue was purified by flash chromatography, eluting with 25-100%o ethyl acetate in hexanes, then 10% methanol in ethyl acetate with 1% acetic acid to give the product as a white solid. .H NMR (300MHz, dimethylsulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m, 4H), 3.07 (m, 4H), 2.73(m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1.38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).
4.5 g 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )benzenesulfonamide ( 4.73 g) wasdissolved m dichloromethane (124.8 mL) at 34C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.66 g) and 4-Dimethylaminopyridine(3.33 g) was added to the above solution and stirred for 10 minutes at 35C. A mixture of2-( ( 1H -pyrrolo [2,3-b ]pyridin-5-yl)oxy)-4-( 4-( ( 4'-chloro-5,5-dimethy 1-3,4,5 ,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (7.8 g), triethylamine (3.8 g) indichloromethane (70.2 mL) was stirred for 15 minutes at 35C and it was added dropwise to the above mixture in 15 minutes at the same temperature. The reaction mixturewas stirred for 23 hours at 31 oc and then evaporated the solvent from the reactionmixture to obtain residue. This residue was dissolved in ethyl acetate (80 mL) and washedthe solution with 10% acetic acid (2x80 mL), saturated aqueous sodium bicarbonatesolution (2x80 mL) and then with brine solution (2x80 mL). The separated organic layerwas dried over sodium sulfate and evaporated the solvent completely. The crude productwas combined with acetonitrile (112 mL) and stirred for 2 hour at 34C and filtered thesolid. The solid was dissolved in acetonitrile (60 mL) at 70C and stirred for 1 hour at thesame temperature. The solution was cooled and filtered the solid to obtain titlecompound. Yield: 4.5 g; Purity by HPLC: 99.65%
31 g With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 22h; In round bottom flask equipped with mechanical stirrer and thermometer, to dichloromethane (400 ml), 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (VI) (17.6 g), 4-dimethylaminopyridine (DMAP) (4.25 g) and l-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride (EDC.HCI) (20.12 g) were added. To this mixture was added a solution of intermediate (V) (40 g) in dichloromethane (400 ml) and trimethyl amine (18.8 ml) and maintained for 22 hrs. To this mixture was then added water (400 ml), the dichloromethane layer was separated, washed with water and concentrated under reduced pressure. The residue obtained was purified by using mixture of ethyl acetate and xylene to give venetoclax (31 g)

  • 4
  • [ 1235865-77-6 ]
  • [ 1257046-28-8 ]
  • [ 1257046-27-7 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; for 18h; Example 130D 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-[(3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide To a solution of EXAMPLE 3J (90 mg), EXAMPLE 130C (64.2 mg), triethylamine (0.077 ml), N,N-dimethylpyridin-4-amine (38.5 mg) in a mixture of dichloromethane (5 ml) and N,N-dimethylformamide (0.5 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, hydrochloric acid (60.4 mg) and the mixture was stirred 18 hours. This was concentrated on high vacuum and the crude was purified by reverse phase chromatography with ammonium acetate buffer/acetonitrile. 1H NMR (500 MHz, pyridine-d5) delta 13.03 (s, 1H), 9.27 (d, 1H), 8.59 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H), 7.65-7.67 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.06 (m, 1H), 3.98 (d, 2H), 3.35 (t, 2H), 3.07 (m, 4H), 2.73-2.80 (m, 4H), 2.68-2.72 (m, 1H), 2.36 (q, 1H), 2.11-2.30 (m, 9H), 1.97 (m, 2H), 1.62-1.71 (m, 3H), 1.48-1.58 (m, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; for 18h; (0413) To a solution of Compound 3J (90 mg), Compound 130C (64.2 mg), triethylamine (0.077 ml), N,N-dimethylpyridin-4-amine (38.5 mg) in a mixture of dichloromethane (5 ml) and N,N-dimethylformamide (0.5 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, hydrochloric acid (60.4 mg) and the mixture was stirred 18 hours. This was concentrated on high vacuum and the crude was purified by reverse phase chromatography with ammonium acetate buffer/acetonitrile. 1H NMR (500 MHz, pyridine-d5) delta 13.03 (s, 1H), 9.27 (d, 1H), 8.59 (d, 1H), 8.43 (d, 1H), 8.37 (dd, 1H), 8.11 (d, 1H), 7.65-7.67 (m, 2H), 7.44 (d, 2H), 7.07 (d, 2H), 6.88 (d, 1H), 6.76 (dd, 1H), 6.54 (d, 1H), 6.48 (m, 1H), 4.06 (m, 1H), 3.98 (d, 2H), 3.35 (t, 2H), 3.07 (m, 4H), 2.73-2.80 (m, 4H), 2.68-2.72 (m, 1H), 2.36 (q, 1H), 2.11-2.30 (m, 9H), 1.97 (m, 2H), 1.62-1.71 (m, 3H), 1.48-1.58 (m, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
  • 5
  • [ 1235865-77-6 ]
  • [ 1256546-39-0 ]
  • [ 1257049-26-5 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; Example 277P N-[(5-chloro-6-[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide EXAMPLE 277J (0.063 g), EXAMPLE 277O (0.042 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.032 g), and 4-dimethylaminopyridine (0.027 g) were combined in a 4-mL vial with dichloromethane (1.0 mL) and stirred overnight at ambient temperature. The reaction mixture was chromatographed directly without aqueous workup on silica gel with 0-4% methanol in dichloromethane as the eluent. Fractions containing the desired product were concentrated, slurried in acetonitrile, concentrated and dried overnight in a vacuum oven at 80 C. to give the title compound. 1H NMR (500 MHz, pyridine-d5) delta 13.05 (s, 1H), 9.13 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.67 (m, 1H), 7.66 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.51 (m, 2H), 4.63 (m, 4H), 4.53 (d, 2H), 3.39 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.51 (m, 2H), 2.25 (m, 2H), 2.18 (m, 2H), 2.13 (m, 4H), 2.06 (t, 2H), 1.97 (s, 2H), 1.89 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; (0848) Compound 277J (0.063 g), Compound 277O (0.042 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.032 g), and 4-dimethylaminopyridine (0.027 g) were combined in a 4-ml vial with dichloromethane (1.0 ml) and stirred overnight at ambient temperature. The reaction mixture was chromatographed directly without aqueous workup on silica gel with 0-4% methanol in dichloromethane as the eluent. Fractions containing the desired product were concentrated, slurried in acetonitrile, concentrated and dried overnight in a vacuum oven at 80 C. to give the title compound. 1H NMR (500 MHz, pyridine-d5) delta 13.05 (s, 1H), 9.13 (d, 1H), 8.72 (d, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.67 (m, 1H), 7.66 (d, 1H), 7.44 (m, 2H), 7.07 (m, 2H), 6.76 (dd, 1H), 6.51 (m, 2H), 4.63 (m, 4H), 4.53 (d, 2H), 3.39 (m, 1H), 3.07 (m, 4H), 2.77 (s, 2H), 2.51 (m, 2H), 2.25 (m, 2H), 2.18 (m, 2H), 2.13 (m, 4H), 2.06 (t, 2H), 1.97 (s, 2H), 1.89 (m, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
  • 6
  • [ 1235865-77-6 ]
  • [ 1228836-22-3 ]
  • [ 1257044-51-1 ]
YieldReaction ConditionsOperation in experiment
Example 11D 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide To a mixture of EXAMPLE 3J (59.8 mg, 0.105 mmol), EXAMPLE 11B (33 mg, 0.105 mmol) and N,N-dimethylpyridin-4-amine (38.4 mg, 0.314 mmol) in dichloromethane (5 ml) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (24.07 mg, 0.13 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 40-60% acetonitrile/0.1% trifluoroacetic acid in water to give the title compound as the trifluoroacetate salt. The trifluoroacetic acid salt was dissolved in dichloromethane (6 ml) and washed with 50% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) delta 11.68 (s, 1H), 11.40 (s, br, 1H), 8.53-8.58 (m, 2H), 8.04 (d, 1H), 7.80 (dd, 1H), 7.47-7.54 (m, 3H), 7.34 (d, 2H), 7.02-7.09 (m, 3H), 6.67 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.79 (dd, 1H), 3.69-3.73 (m, 1H), 3.22-3.37 (m, 3H), 3.16-3.21 (m, 1H), 3.07 (s, 4H), 2.74 (s, 2H), 2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.86-1.93 (m, 1H), 1.79-1.85 (m, 1H), 1.58-1.64 (m, 1H), 1.42-1.51 (m, 1H), 1.38 (t, 2H), 1.25-1.34 (m, 1H), 0.92 (s, 6H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; (0122) To a mixture of Compound 3J (59.8 mg, 0.105 mmol), Compound 11B (33 mg, 0.105 mmol) and N,N-dimethylpyridin-4-amine (38.4 mg, 0.314 mmol) in dichloromethane (5 ml) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (24.07 mg, 0.13 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by reverse phase HPLC on a C18 column using a gradient of 40-60% acetonitrile/0.1% trifluoroacetic acid in water to give the title compound as the trifluoroacetate salt. The trifluoroacetic acid salt was dissolved in dichloromethane (6 ml) and washed with 50% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) delta 11.68 (s, 1 H), 11.40 (s, br, 1 H), 8.53-8.58 (m, 2 H), 8.04 (d, 1 H), 7.80 (dd, 1 H), 7.47-7.54 (m, 3 H), 7.34 (d, 2 H), 7.02-7.09 (m, 3 H), 6.67 (dd, 1 H), 6.39 (dd, 1 H), 6.19 (d, 1 H), 3.79 (dd, 1 H), 3.69-3.73 (m, 1 H), 3.22-3.37 (m, 3 H), 3.16-3.21 (m, 1 H), 3.07 (s, 4 H), 2.74 (s, 2 H), 2.09-2.24 (m, 6 H), 1.95 (s, 2 H), 1.86-1.93 (m, 1 H), 1.79-1.85 (m, 1 H), 1.58-1.64 (m, 1 H), 1.42-1.51 (m, 1 H), 1.38 (t, 2 H), 1.25-1.34 (m, 1 H), 0.92 (s, 6 H).
  • 7
  • [ 1235865-77-6 ]
  • 4-((trans-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonamide [ No CAS ]
  • 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide A mixture of EXAMPLE 337J (3.0 g), EXAMPLE 337M (1.98 g), N,N-dimethylpyridin-4-amine (1.93 g) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.31 g) in dichloromethane (50 ml) was stirred overnight and concentrated. The residue was purified by reverse chromatography, eluted with 40%-70% acetonitrile in 0.1% TFA water. The desired fractions were concentrated to remove acetonitrile, neutralized with NaHCO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4, concentrated and dried to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) delta 11.68 (s, 1H), 8.52-8.58 (m, 2H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.53 (d, 1H), 7.47-7.52 (m, 2H), 7.30-7.37 (m, 2H), 7.07 (d, 1H), 7.01-7.06 (m, 2H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 4.25 (s, 1H), 3.25-3.32 (m, 4H), 3.07 (s, 4H), 2.75 (s, 2H), 2.09-2.24 (m, 6H), 1.95 (s, 2H), 1.50-1.73 (m, 5H), 1.28-1.43 (m, 4H), 1.06-1.18 (m, 5H), 0.92 (s, 6H).
  • 8
  • [ 1235865-77-6 ]
  • 4-((cis-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrobenzenesulfonamide [ No CAS ]
  • 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide A mixture of EXAMPLE 338J (144 mg), EXAMPLE 338M (95 mg), N,N-dimethylpyridin-4-amine (123 mg) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (62.7 mg) in dichloromethane (7 ml) was stirred overnight and concentrated. The residue was purified by reverse chromatography, eluted with 40%-70% acetonitrile in 0.1% TFA water. The desired fractions were concentrated, neutralized with NaHCO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered, concentrated and dried to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) delta 11.69 (s, 1H), 11.38 (s, 1H), 8.59 (t, 1H), 8.55 (d, 1H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.54 (d, 1H), 7.46-7.52 (m, 2H), 7.30-7.38 (m, 2H), 7.00-7.10 (m, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.95 (s, 1H), 3.25 (t, 4H), 3.07 (s, 4H), 2.75 (s, 2H), 2.10-2.26 (m, 6H), 1.95 (s, 2H), 1.29-1.62 (m, 8H), 1.16-1.30 (m, 2H), 1.08 (s, 3H), 0.92 (s, 6H).
  • 19
  • [ 1235865-77-6 ]
  • {5-[5-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(4-[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyl dihydrogen phosphate trifluoroacetate [ No CAS ]
  • 20
  • [ 1235865-77-6 ]
  • C56H73ClN7O11PS [ No CAS ]
  • 21
  • [ 1235865-77-6 ]
  • trans-4-((4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide [ No CAS ]
  • trans-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; A mixture of EXAMPLE 1L (35 mg), EXAMPLE 1 J (53 mg), 4-dimethylaminopyridine (46 mg) and l-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (21.5 mg) indichloromethane was stirred overnight and concentrated. The residue was purified by reverse phase HPLC, eluting with 40% - 70% acetonitrile in 0.1% trifluoroacetic acid water over 40 minutes. The desired fractions were concentrated to remove acetonitrile, neutralized with NaHCC^ and extracted with dichloromethane. The organic layer was dried over Na2S04, filtered, concentrated and dried to provide the title compound. .H NMR (500 MHz, dimethylsulfoxide-de) delta 11.69 (s, 1 H), 11.37 (s, 1 H), 8.52 - 8.62 (m, 2 H), 8.04 (d, 1 H), 7.79 (dd, 1 H), 7.47 - 7.55 (m, 3 H), 7.34 (d, 2 H), 7.02 - 7.09 (m, 3 H), 6.68 (dd, 1 H), 6.39 (dd, 1 H), 6.19 (d, 1 H), 3.21 - 3.27 (m, 5 H), 3.02 - 3.12 (m, 5 H), 2.75 (s, 2 H), 2.20 (s, 4 H), 2.14 (s, 2 H), 1.93 - 2.04 (m, 4 H), 1.79 (d, 2 H), 1.55 - 1.65 (m, 1 H), 1.38 (t, 2 H), 0.97 - 1.12 (m, 4 H), 0.92 (s, 6 H).
  • 22
  • [ 1235865-77-6 ]
  • 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide hydrochloride [ No CAS ]
  • 23
  • [ 1235865-77-6 ]
  • 4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 1O 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(2R)-1,4-dioxan-2-ylmethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide EXAMPLE 1N (170 mg), EXAMPLE 1J (340 mg), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (150 mg), and 4-dimethylaminopyridine (130 mg) were stirred in CH2Cl2 (5 mL) overnight. N1,N1-dimethylethane-1,2-diamine (0.19 mL) was then added and the mixture was stirred for 90 minutes. Dichloromethane (15 mL) was added, and the reaction mixture was washed with 10% acetic acid:0.75% NaCl in water (2*12 mL). The combined aqueous layers were back-extracted with dichloromethane, and the combined organics were washed with brine, and dried over Na2SO4. After filtration and concentration, the crude material was chromatographed on silica gel with 3/7 dichloromethane/ethyl acetate. The material was then chromatographed on silica gel with 1.5-2.5% CH3OH in dichloromethane. The material was triturated with CH3CN to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) delta ppm 11.65 (s, 1H), 8.55 (t, 1H), 8.54 (d, 1H), 8.01 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 3H), 7.32 (d, 2H), 7.07 (d, 1H), 7.02 (d, 2H), 6.66 (dd, 1H), 6.37 (m, 1H), 6.18 (d, 1H), 3.77 (m, 3H), 3.63 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.06 (br m, 4H), 2.74 (br s, 2H), 2.19 (br m, 4H), 2.13 (br m, 2H), 1.94 (br m, 2H), 1.37 (t, 2H), 0.90 (s, 6H).
  • 24
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-bromobenzoate [ No CAS ]
  • [ 1235865-77-6 ]
  • 26
  • [ 1228943-80-3 ]
  • [ 1235865-77-6 ]
  • 29
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate [ No CAS ]
  • [ 1235865-77-6 ]
YieldReaction ConditionsOperation in experiment
Ca. 85% With potassium tert-butylate; In 2-methyltetrahydrofuran; water; at 55℃;Inert atmosphere; Solution preparation: 10% KH2PO4 (aq): KH2PO4 (6 g) in water (56 g); 2:1 heptane/2-MeTHF:heptane (16 mL) in 2-MeTHF (8 mL). Compound (K) (5.79 g), potassium tert-butoxide (4.89 g), 2-methyltetrahydrofuran (87 mL), and water (0.45 mL) were combined in a suitable reactor under nitrogen and heated to 55 C. until reaction completion. The reaction mixture was cooled to 22 C., washed with the 10% KH2PO4 solution (31 g) twice. The organic layer was then washed with water (30 g). After removal of the aqueous layer, the organic layer was concentrated to 4 volumes (?19 mL) and heated to no less than 50 C. Heptane (23 ml) was slowly added. The resulting suspension was cooled to 10 C. Solids were then collected by vacuum filtration with recirculation of the liquors and the filter cake washed with 2:1 heptane/2-MeTHF (24 ml). Drying of the solids at 80 C. under vacuum yielded 4.0 g of Compound (L) in approximately 85% weight-adjusted yield. 1H NMR (DMSO-d6): delta 0.91 (s, 6H), 1.37 (t, J=6.4 Hz, 2H), 1.94 (s, br, 2H), 2.15 (m, 6H), 2.71 (s, br, 2H), 3.09 (m, 4H), 6.31 (d, J=2.3 Hz, 1H), 6.34 (dd, J=3.4, 1.9 Hz, 1H), 6.7 (dd, J=9.0, 2.4 Hz, 1H), 7.02 (m, 2H), 7.32 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.44 (t, J=3.0 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H) & 11.59 (m, 1H).
  • 31
  • [ 1679-18-1 ]
  • [ 1235865-77-6 ]
  • 32
  • C16H21ClO3S [ No CAS ]
  • [ 1235865-77-6 ]
  • 33
  • [ 392-09-6 ]
  • [ 1235865-77-6 ]
  • 34
  • C15H11N3O5 [ No CAS ]
  • [ 1235865-77-6 ]
  • 35
  • C15H13N3O3 [ No CAS ]
  • [ 1235865-77-6 ]
  • 36
  • methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate [ No CAS ]
  • [ 1235865-77-6 ]
  • 38
  • [ 1235865-77-6 ]
  • 6-(2-nitro-4-sulfamoylphenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]
  • 6-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.07% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; A solution of 2 - ((lH-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- 2-yl) piperazin-1-yl) benzoic acid (160 mg, 0.28 mmol, 1.05 eq) and 6- (2-nitro 4-sulfamoylphenoxy-2-azaspiro [3.3] heptane-2-carboxylate (110 mg, 0.27 mmol, 1.0 eq) was added to DCM (10 mL) followed by EDCI (80 mg , 0.42 mmol, 1.57 eq) and 4-DMAP (40 mg, 0.33 mmol, 1.23 eq)Room temperature reaction for 16 h. After the reaction, the color becomes darker and becomes dark yellow. TLC point plate analysis, in the middle of a new two raw materials, sulfonamide raw materials there is a little bit. The reaction was stopped and the reaction was poured into water (40 mL) and extracted with DCM (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, dried over the column, and the column was passed through a column of EA / EtOH (v / v) = 20/1 to give 200 mg of a white solid product. Yield 77.07%.
  • 39
  • [ 406233-31-6 ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-fluoro-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With trichlorophosphate; at 85℃; for 5h; 4-fluoro-3-nitrobenzenesulfonamide (235 mg, 1.06 mmol, 1.00 eq) and2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- , 6-tetrahydro- [1,1'-biphenyl] -2-yl) methyl) piperazin-1-yl) benzoic acid(600 mg, 1.06 mmol, 1.0 eq) (see Example 1, Step 14) was added to 6 mL of phosphorus oxychloride and reacted at 85 C for 5 h. The reaction solution was poured into 20 mL of ice water and extracted with EA (10 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, dried over the column, PE / EA (v / v) = 2/1 and DCM / EtOH (v / v) = 10/1 as an eluent to give 830 mg of a white solid product in 100% yield.
96.3% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 30℃; for 16h; Compound (II) (20.0 g, 35.0 mmol)Dissolved in 300mL of dichloromethane (DCM),Add sequentially at room temperature3-nitro-4-fluorobenzenesulfonamide (8.5 g, 38.5 mmol),4-dimethylaminopyridine (DMAP) (6.4 g, 52.5 mmol),1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCL) (10.1 g, 52.5 mmol).The reaction was stirred at a temperature of 20 to 30 C for 16 hours.After the reaction was completed, it was washed once by adding 100 mL of a 5% acetic acid aqueous solution.Then wash it again with 100 mL of water.The organic phase is dried with 20 g of sodium sulfate.Filter, spin dry,The fluorine-containing compound (III) solid was 26.1 g, and the yield was 96.3%.Used directly for the next step.
  • 41
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-N-((3-nitro-4-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)phenyl)sulfonyl)benzamide [ No CAS ]
  • 42
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)sulfonyl)benzamide [ No CAS ]
  • 43
  • [ 1235865-77-6 ]
  • C50H57ClN8O7S [ No CAS ]
  • 44
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(2-azaspiro[3.3]heptan-6-yloxy)3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 45
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)-N-(3-nitro-4-((2-(tetrahydro-2H-pyran-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)phenylsulfonyl)benzamide [ No CAS ]
  • 46
  • [ 1235865-77-6 ]
  • 6-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]
  • 47
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(2-azaspiro[3.3]heptan-6-ylamino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzamide [ No CAS ]
  • 48
  • [ 1235865-77-6 ]
  • 4-(6-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)-2-azaspiro[3.3]heptan-2-yl)tetrahydro-2H-pyran-3-carboxylic acid methyl ester [ No CAS ]
  • 49
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(6-(tetrahydro-2H-pyran-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)benzamide [ No CAS ]
  • 50
  • [ 1235865-77-6 ]
  • 6-(4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]
  • 51
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrole[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl)sulfonyl)benzamide [ No CAS ]
  • 52
  • [ 1235865-77-6 ]
  • 4-((4-oxaspiro[2.4]heptan-6-yl)oxy)-3-nitrobenzenesulfonamide [ No CAS ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(4-oxaspiro[2.4]heptan-6-yloxy)3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% With dmap; In dichloromethane; at 0 - 20℃; 4- (4-oxaspiro [2.4] heptan-6-yloxy) -3-nitrobenzenesulfonamide (0.2 g, 0.64 mmol, 1 eq)2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- , 6-tetrahydro- [1,1'-biphenyl] -2-yl) methyl) piperazin-1-yl) benzoic acid(0.147 g, 0.77 mmol, 1.2 eq), DMAP (0.234 g, 1.92 mmol, 3 eq), 10 mL & lt; RTI ID = 0.0 & gt;DCM was placed in a one-necked flask and stirred at 0 C for half an hour before reacting at room temperature,The reaction was complete with the addition of 5 mL of water, quenching the reaction, separating the organic phase, drying, column chromatography, EA: DCM (v / v) = 1: 1 to give 0.2 g of product as a yield of 35%.
  • 53
  • [ 1235865-77-6 ]
  • 4-(2-(4-oxaspiro[2.4]heptan-6-yloxy)ethoxy)-3-nitrobenzenesulfonamide [ No CAS ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(2-(4-oxaspiro[2.4]heptan-6-yloxy)ethoxy)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; 2 - ((1H-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- (0.191 g, 0.335 mmol, 1 eq) (see Step 14 of Example 1), and the title compound was prepared from 6-tetrahydro- [1,1'-biphenyl]4- (2- (4-oxaspiro [2.4] heptan-6-yloxy) ethoxy) -3-nitrobenzenesulfonamide (0.120 g, 0.335 mmol, 1 eq)EDCI (0.077 g, 0.402 mmol, 1.2 eq), DMAP (0.123 g, 1.00 mmol, 3 eq) and 10 mL DCM were placed in a one-necked flask at 0 C for half an hour and then reacted at room temperature. TLC was complete. Quenching reaction, liquid separation, organic phase drying, spin drying, column chromatography EA: DCM = 1: 1 to get the product 0.150g, yield 49%.
  • 54
  • [ 1235865-77-6 ]
  • 2-nitro-4-sulfamoylphenyl trifluoromethanesulfonate [ No CAS ]
  • 4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
53.9% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h; A solution of 2 - ((lH-pyrrolo [2,3-b] pyridin-5-yl) oxy) -4- (4 - ((4'-chloro-5,5-dimethyl- 5,6-tetrahydro- [1,1'-biphenyl] -2-yl) methyl) piperazin-1-yl) benzoic acid (see Example 1, step 14) (60 mg, 0.105 mmol, 1.0 eq) (40 mg, 0.114 mmol, 1.09 eq) was added to DCM (10 mL) followed by EDCI (40 mg, 0.209 mmol, 1.99 eq) and 4 (4 mL), 2-nitro-4-sulfamoylphenyl trifluoromethanesulfonate (26mg, 0.213mmol, 2.03eq), room temperature reaction 3h, TLC point plate analysis, the basic reaction of acid raw materials, directly to the reaction liquid spin dry, column, PE / EA (v / v) = 1/1 Eluting with a pale yellow solid product 52 mg, yield 53.9%
  • 55
  • [ 1228780-72-0 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid [ No CAS ]
  • [ 1235865-77-6 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; lithium hexamethyldisilazane; In tetrahydrofuran; toluene; at 55 - 56℃; for 0.5h;Inert atmosphere; In a 500-mL three necked round bottom flask equipped with magnetic stirrer, thermometer, condenser, charged 4-bromo-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoic acid (8.67 g, 26 mmol), (4-(N,N-dimethylamino)phenyl)-di-tert-butyl-phosphine (APhos, 895 mg, 0.78 mmol, 0.13 equiv), tris(dibenzylideneacetone)-dipalladium(0) (1.54 g, 1.69 mmol, 0.065 equiv), THF (87 mL) and <strong>[1228780-72-0]1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazine</strong> in toluene (31.2 g, 29 mmol, 1. 12 equiv). The reaction mixture was stirred under inert atmosphere, 1.5 M lithium bis(trimethylsilyl)amide in THF (74 mL, 112 mmol, 4.3 equiv) was added, and heated to 55-56C. The reaction mixture was stirred at 55-56C for 30 min then quenched by addition of cold (2-8C) 12% aqueous NaCl (347 mL). After phase separation the organic layer was filtered and concentrated in vacuum to 1/3 volume. The residue was added to a cold (0-5C) suspension of perlite (22 g) in n-heptane (364 mL). The suspension was stirred for 1 hour at 0-5C then filtered. The wet-cake was washed with n-heptane (3 x87 mL), and dried under vacuum at 20-25C for 2 hours. The solid was suspended in THF (87 mL), filtered and the wet cake was washed with THF (4x87 mL). HPLC-analysis of the combined THF solution comprised 8.3 g of VNT-08 content (yield: 56%).
  • 56
  • 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazine dihydrochloride [ No CAS ]
  • [ 1235865-77-6 ]
  • 57
  • [ 179232-29-2 ]
  • [ 1235865-77-6 ]
  • 58
  • [ 1235865-77-6 ]
  • [ 76-05-1 ]
  • 2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid trifluoroacetic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% In tetrahydrofuran; at 50 - 55℃; for 0.5h; In a 100-mL three necked round bottom flask equipped with magnetic stirrer, thermometer, condenser, charged 15 mL of 2-[(1H-Pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid in THF (assay: 1 g, 1.75 mmol), heated up to 50-55C and 0.4 mL (5.25 mmol) trifluoroacetic acid in THF (2 mL) was added. The reaction mixture was stirred for 30 min at 50-55C and n-heptane (25 mL) was added dropwise at this temperature. The reaction mixture was cooled to 0-5C, stirred for 30 min and filtered. The wet cake was washed with n-heptane (2.5 mL) and dried under vacuum at 40- 45C overnight to obtain desired compound (assay: 0.85 g, 85%, TFA: 14.8%).
  • 59
  • [ 1235865-77-6 ]
  • 2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With sulfuric acid; In tetrahydrofuran; at 50 - 55℃; for 0.5h; In a 500-mL three necked round bottom flask equipped with magnetic stirrer, thermometer, condenser, charged 150 mL of 2-[(1H-Pyrrolo[2,3-b]pyridine-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoic acid in THF (assay: 12 g, 21 mmol), heated up to 50-55C and 3.36 mL (63 mmol) sulfuric acid in THF (23.5 mL) was added. The reaction mixture was stirred for 30 min at 50-55C and n-heptane (300 mL) was added dropwise at this temperature. The reaction mixture was cooled to 0-5C, stirred for 30 min and filtered. The wet cake was washed with n-heptane (30 mL) and dried under vacuum at 40-45C overnight to obtain desired compound (assay: 11 g, 92%, sulfate: 14.5%).
  • 60
  • [ 1235865-77-6 ]
  • [ 1257044-40-8 ]
  • 61
  • [ 1235865-77-6 ]
  • 3-nitro-4-((((2R,3R,4R,5R)-3,4,5-tris((trimethylsilyl)oxy)tetrahydrofuran-2-yl)methyl)amino)benzenesulfonamide [ No CAS ]
  • C44H48ClN7O10S [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% A mixture of intermediate 1 (2.42 g, 4.28 mmol)DMAP (1.05 g, 8.59 mmoL),EDCI (1.07 g, 5.58 mmoL) andDichloromethane (30.0 mL) was added to the reaction flask 1.A solution of 4- [4 - [[2- (4-chlorophenyl) -4,4-dimethyl-1-cyclohexen-1-yl] methyl] -1-piperazine] 1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzoic acid (2.5 g, 4.4 mmoL)Triethylamine (0.87 g) andDichloromethane (12.0 mL) was added to the reaction flask 2. [The solution in the reaction flask 2 was slowly added dropwise to the reaction flask 1,After the dropwise addition was stirred overnight, the TLC monitored the reaction completely.N, N'-dimethylethylenediamine (0.94 g) was added,Oil bath to 55 ,Then add 10% acetic acid (18.5 mL) and stir overnight.Cooling, liquid separation. The organic phase was washed once with 10% acetic acid (18.5 mL).Dichloromethane (7.5 mL) was added to the organic phase.Followed by 5% aqueous sodium bicarbonate (18.5 mL) and5% sodium chloride (18.5 mL).The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography. The elution solvent was dichloromethane / methanol = 10/1,2.4 g of a white solid, yield 63%.
  • 62
  • [ 1235865-77-6 ]
  • 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylmethylamino)phenylsulfonyl)benzamide [ No CAS ]
  • 63
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((1-(4-azidobutanoyl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 64
  • [ 1235865-77-6 ]
  • 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((1-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethyl)piperidin-4-yl)methylamino)-3-nitrophenylsulfonyl)benzamide [ No CAS ]
  • 65
  • [ 1235865-77-6 ]
  • 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((1-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)piperidin-4-yl)methylamino)-3-nitrophenylsulfonyl)benzamide [ No CAS ]
  • 66
  • [ 1235865-77-6 ]
  • C17H26N4O6S [ No CAS ]
  • tert-butyl 4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; Example 14: Synthesis of XZ-14523 Preparation of tert-butyl 4-((4-(N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4- chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2- nitrophenylamino)methyl)piperidine-1-carboxylate (52) A mixture of compound 50 (571 mg), 51 (415 mg), DMAP (244 mg), EDCI (250 mg), and TEA (280 muL) in 20 mL DCM was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified via column chromatography using DCM and methanol as eluents to give 758 mg pure product as yellow solid. Yield 79%. 1H NMR (400 MHz, CDCl3) delta 10.14 (br s, 1H), 9.72 (br s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.52 (t, J = 5.4 Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H), 8.16 (dd, J = 9.2, 2.1 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.53-7.43 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.94-6.83 (m, 3H), 6.60-6.47 (m, 2H), 5.98 (d, J = 2.1 Hz, 1H), 4.27-4.13 (m, 2H), 3.32-3.20 (m, 2H), 3.13-3.01 (m, 4H), 2.83-2.65 (m, 4H), 2.26-2.10 (m, 6H), 1.96 (s, 2H), 1.92-1.74 (m, 3H), 1.47 (s, 9H), 1.40 (t, J = 6.4 Hz, 2H), 1.25-1.18 (m, 2H), 0.93 (s, 6H) ppm.
  • 67
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzonitrile [ No CAS ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With water; potassium hydroxide; In ethanol; at 60 - 140℃; for 48h; A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-( 4-(( 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1, 1 '-biphenyl]-2-yl)methyl)piperazin-1-yl)benzonitrile (0.5 g),potassium hydroxide (0.5 g), ethanol (5 mL) and water (5 mL) was heated and stirred at60C for 24 hours and 140C for 24 hours to obtain the mixture of title compounds.Individual compounds of benzamide and benzoic acid were separated usingchromatography.
  • 68
  • [ 1235865-77-6 ]
  • venetoclax trifluoroacetic acid salt [ No CAS ]
  • 69
  • [ 1235865-77-6 ]
  • venetoclax oxalic acid salt [ No CAS ]
  • 70
  • [ 1235865-77-6 ]
  • venetoclax maleic acid salt [ No CAS ]
  • 71
  • [ 1235865-77-6 ]
  • venetoclax isethionic acid salt [ No CAS ]
  • 72
  • [ 1235865-77-6 ]
  • venetoclax hydrochloride salt [ No CAS ]
  • 73
  • [ 1235865-77-6 ]
  • venetoclax ortho-phosphoric acid salt [ No CAS ]
  • 74
  • [ 1235865-77-6 ]
  • venetoclax citric acid salt [ No CAS ]
  • 75
  • [ 1235865-77-6 ]
  • venetoclax methanesulfonic acid salt [ No CAS ]
  • 76
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzonitrile [ No CAS ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 77
  • [ 1228780-72-0 ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 78
  • [ 98549-88-3 ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 79
  • [ 105942-08-3 ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 80
  • [ 1228837-05-5 ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 81
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzonitrile [ No CAS ]
  • [ 1235865-77-6 ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide [ No CAS ]
  • 82
  • [ 1235865-77-6 ]
  • 8-(2-nitro-4-aminosulfonylphenylamino)octanoic acid ethyl ester [ No CAS ]
  • ethyl 8-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)octanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.175 mmol)Ethyl 8-(2-nitro-4-aminosulfonylphenylamino)octanoate 68mg (0.175mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) 167mg (0.875mmol), 4- dimethylaminopyridine 25.6mg (0.21mmol) ,With anhydrous DCM as solvent, at room temperature for 24h. After the reaction was completed, with 1 M hydrochloric acid,Saturated sodium bicarbonate, saturated brine, the aqueous phase was extracted with EA, the organic phase was combined,Concentration gave 160 mg of a solid which was purified by column chromatography with a yield of 85%.
85% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid (5) was synthesized by the method reported. [Nat Med. 2013, 19(2): 202-8] To a solution of compound 5 (100 mg, 0.175 mmol) in anhydrous dichloromethane, compound 4g (68 mg, 0.175 mmol), EDCI (167 mg, 0.875 mmol) and DMAP (25.6 mg, 0.21 mmol) were added. Afterwards, the mixture solution was stirred for 24 h at room temperature. Completion of the reaction was confirmed by TCL. The reaction mixture was washed with HCl (1 M), NaHCO3 saturated solution and brine, concentrated and purified to afford 6g (160 mg, 85% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 11.70 (s, 1H), 8.64 - 8.49(m, 2H), 8.03 (d, J= 2.4 Hz, 1H), 7.86 - 7.74 (m, 1H), 7.56 - 7.45 (m, 3H), 7.33 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.5 Hz, 3H), 6.67 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 6.19 (s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.09 (s, 4H), 2.79 (s, 2H), 2.23 (m, 8H), 1.94 (s, 2H), 1.67 - 1.48 (m, 4H), 1.42 - 1.23 (m, 10H), 1.15 (t, J = 7.1 Hz, 3H), 0.91 (s, 6H). MS (ESI) m/z: 940.71 [M+H]+, 938.77 [M-H]-.
  • 83
  • [ 183208-36-8 ]
  • [ 1235865-77-6 ]
  • 84
  • 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene [ No CAS ]
  • [ 1235865-77-6 ]
  • 85
  • [ 1583-58-0 ]
  • [ 1235865-77-6 ]
  • 86
  • [ 1235865-77-6 ]
  • C19H26N6O4S [ No CAS ]
  • C52H59ClN10O6S [ No CAS ]
  • 87
  • [ 1235865-77-6 ]
  • C19H31N5O6S [ No CAS ]
  • C52H64ClN9O8S [ No CAS ]
  • 88
  • [ 1235865-77-6 ]
  • 4-(((1-methyl-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-methyl-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
  • 89
  • [ 1235865-77-6 ]
  • 4-(((1-(cyanoimino)-1-oxidohexahydro-1λ6-thiopyran-4-yl)methyl)amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-(cyanoimino)-1-oxidohexahydro-1λ<SUP>6</SUP>-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
  • 90
  • [ 1235865-77-6 ]
  • (S)-4-((1-(1-(cyanoimino)-1-oxido-1λ6-thiomorpholino)propan-2-yl)amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5.6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(1-(cyanoimino)-1-oxido-1λ<SUP>6</SUP>-thiomorpholino)propan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
  • 91
  • [ 1235865-77-6 ]
  • (S)-4-((1-(1-(methylimino)-1-oxido-1λ6-thiomorpholino)propan-2-yl)amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(1-(methylimino)-1-oxidothiomorpholino)propan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
  • 92
  • [ 1235865-77-6 ]
  • 4-(((4-((diethyl(oxo)-λ6-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrobenzene-1-sulfonamide [ No CAS ]
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-((diethyl(oxo)-λ<SUP>6</SUP>-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide [ No CAS ]
  • 93
  • [ 195062-61-4 ]
  • [ 1235865-77-6 ]
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