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Chemical Structure| 1257044-40-8
Chemical Structure| 1257044-40-8
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Product Details of [ 1257044-40-8 ]

CAS No. :1257044-40-8 MDL No. :MFCD23160052
Formula : C45H50ClN7O7S Boiling Point : -
Linear Structure Formula :- InChI Key :LQBVNQSMGBZMKD-UHFFFAOYSA-N
M.W : 868.44 Pubchem ID :49846579
Synonyms :
ABT-199;GDC-0199;RG 7601. Venetoclax.;RG7601

Safety of [ 1257044-40-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P202-P260-P301+P312-P302+P352-P305+P351+P338-P308+P313 UN#:N/A
Hazard Statements:H302-H315-H319-H361-H373 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1257044-40-8 ]

* 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.

  • Downstream synthetic route of [ 1257044-40-8 ]

[ 1257044-40-8 ] Synthesis Path-Downstream   1~79

  • 1
  • [ 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)

  • 2
  • [ 130290-79-8 ]
  • [ 406233-31-6 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
, wherein the compound is selected from the group consisting of 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; 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; trans-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; cis-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; 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; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 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; N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]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; ...
, wherein the compound is selected from: ... N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indazol-4-yl)oxy]benzamide; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(5-cyano-6-[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; N-({5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-2-[(3-chloro-1H-indazol-4-yl)oxy]-4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl }piperazin- l -yl)benzamide; 4-[4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(2H8)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; N-({5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)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; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(6-[(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino}-5-nitropyridin-3-yl) sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-(4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-nitro-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-pyrrolo [2,3-b]pyridin-5-yloxy)benzamide; ...
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 20℃;Purification / work up; Compound 1 free base solid was suspended in tetrahydrofuran (THF) at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.
  • 18
  • [ 1257044-40-8 ]
  • 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 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; acetonitrile; Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of acetonitrile. Hydrochloric acid (1M, 25 mu) was added to the suspension while stirring (molar ratio of Compound l :acid = 1 : 1.4). Compound 1 quickly reacted with hydrochloric acid and formed a clear solution. Yellowish solids, which later crystallized from the solution, were confirmed to be Compound 1 hydrochloride in a 1 : 1 stoichiometric ratio of free base to HC1.
  • 19
  • [ 1257044-40-8 ]
  • [ 1379647-80-9 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; In isopropyl alcohol; at 70℃; Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of 2-propanol at 70C. Sulfuric acid (1M, 25 mu) was added to the suspension while stirring (molar ratio of Compound 1 :acid = 1 : 1.4). Compound 1 quickly dissolved by reacting with sulfuric acid. Yellowish solids crystallized from the solution immediately after the dissolution occurred. The crystalline solid was confirmed to be Compound 1 sulfate with a stoichiometry of 1 : 1 using ion chromatography.
  • 22
  • [ 1228943-80-3 ]
  • [ 1257044-40-8 ]
  • 24
  • 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazine dihydrochloride [ No CAS ]
  • [ 1257044-40-8 ]
  • 27
  • 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 ]
  • [ 1257044-40-8 ]
  • 29
  • [ 1679-18-1 ]
  • [ 1257044-40-8 ]
  • 30
  • C16H21ClO3S [ No CAS ]
  • [ 1257044-40-8 ]
  • 31
  • [ 392-09-6 ]
  • [ 1257044-40-8 ]
  • 32
  • C15H11N3O5 [ No CAS ]
  • [ 1257044-40-8 ]
  • 33
  • C15H13N3O3 [ No CAS ]
  • [ 1257044-40-8 ]
  • 34
  • methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate [ No CAS ]
  • [ 1257044-40-8 ]
  • 36
  • C15H19ClO3S [ No CAS ]
  • C30H33N7O7S [ No CAS ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; 56g Ven-20 (88 mmol) and 600 mL of DMF were added to the reaction flask, 34 g of Ven-7 (176 mmo) and 120 g ofpotassium carbonate (176 mmo) were added and the temperature was raised to 80C for 24 h.Add 6L water stirring precipitation of yellow solid, filter, filter cake with 3L water, 3L ethanol wash, the crude product.The crude product was recrystallized from 2L acetonitrile, filtered, 500 mL of acetonitrile, anddried at 50 C to obtain 61 g of a yellow solid in 80% yield.HPLC purity: 99.5%, retention time consistent with the standard, thelargest single impurity content of 0.08%.
  • 38
  • tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ No CAS ]
  • [ 1257044-40-8 ]
  • 39
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(tertbutoxycarbonyl)piperazin-1-yl)benzoic acid [ No CAS ]
  • [ 1257044-40-8 ]
  • 40
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid [ No CAS ]
  • [ 1257044-40-8 ]
  • 42
  • [ 1228779-96-1 ]
  • 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 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
In a 100-mL flask (flask I) 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 TFA salt (compound 2b) (assay: 7.45 mmol), Et3N (2 mL, 14.61 mmol) and dichloromethane (43 mL) were combined at 20-25C and stirred for complete dissolution. In a 100-mL three necked round bottom flask (flask II) equipped with mechanical stirrer, thermometer, 3-nitro-4-[[(tetrahydropyran-4-yl)methyl]amino]-benzenesulfonamide (2.30 g, 7.31 mmol), DMAP (1.79 g, 14.68 mmol), N,N-diisopropylcarbodiimide (1.5 mL, 9.64 mmol) and dichloromethane (53 mL) were combined and stirred for 15 minutes. The resulting acid solution (flask I) was slowly added to the suspension of the sulfonamide (flask II) within 1 hour and reaction mixture agitated at 20- 25C until reaction completion. The reaction mixture was extracted with 10% aqueous acetic acid (2x29 mL), 5% aqueous NaHCO3 (29 mL) and 5% aqueous NaCl (29 mL). After phase separation the organic layer was evaporated. Yield: 80%, HPLC: 57.7A%
  • 43
  • [ 1228779-96-1 ]
  • 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 sulfate [ No CAS ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
55% In a 100-mL flask (flask I) 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 salt (compound 2a) (assay: 14.88 mmol), Et3N (12 mL, 87.5 mmol) and dichloromethane (85 mL) were combined at 20-25C and stirred for complete dissolution. In a 250-mL three necked round bottom flask (flask II) equipped with magnetic stirrer, thermometer, 3-nitro-4-[[(tetrahydropyran-4-yl)methyl]amino]-benzenesulfonamide (4.60 g, 14.58 mmol), DMAP (7.12 g, 58.34 mmol), N,N-diisopropylcarbodiimide (6 mL, 38.5 mmol) and dichloromethane (106 mL) were combined and stirred for 15 minutes. The resulting acid solution (flask I) was slowly added to the suspension of the sulfonamide (flask II) within 1 hour and reaction mixture agitated at 35-40C until reaction completion. The reaction mixture was extracted with 10% aqueous acetic acid (2x57 mL), 5% aqueous NaHCO3 (57 mL) and 5% aqueous NaCl (57 mL). After phase separation the organic layer was evaporated. Yield: 55%
  • 44
  • [ 1235865-77-6 ]
  • [ 1257044-40-8 ]
  • 45
  • 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 ]
  • [ 1257044-40-8 ]
  • 46
  • [ 1257044-40-8 ]
  • [ 76-05-1 ]
  • venetoclax trifluoroacetic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
545 mg In acetone; at 28℃; for 4h; Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28C and trifluoroacetic acid(TFA) (0.048 mL) was added at the same temperature. The reaction mixture was stirredfor 4 hours at 28C and filtered the solid. The solid was washed with acetone (10 mL) anddried for 20 hours under reduced pressure at 28C and for 45 minutes at 50C to obtainthe title compound with melting range of 230-232C. Yield: 545 mg and HPLC purity:99.37%
  • 47
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzonitrile [ No CAS ]
  • [ 1257044-40-8 ]
  • 48
  • [ 1257044-40-8 ]
  • venetoclax hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
440 mg With hydrogenchloride; In 1,4-dioxane; acetone; at 28℃; for 17h; Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28C and hydrochloric acid(0.25 mL of 4 M hydrochloride in 1,4-dioxane) was added at the same temperature. Thereaction mixture was stirred for 17 hours at 28C and filtered the solid. The solid waswashed with acetone (10 mL) and dried for 6 hours at 28C under reduced pressure and45 minutes at 50C under reduced pressure to obtain the title compound with meltingrange of 200-202C. Yield: 440 mg and HPLC purity: 99.278%
  • 49
  • [ 1257044-40-8 ]
  • venetoclax ortho-phosphoric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
400 mg With phosphoric acid; In acetone; at 28℃; for 16.5h; Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28C and ortho-phosphoricacid (0.032 mL) was added at the same temperature. The reaction mixture was stirred for16.5 hours at 28C and filtered the solid. The solid was washed with acetone (10 mL) anddried for 6 hours at 28C under reduced pressure and 45 minutes at 50C under reducedpressure to obtain the title compound with melting range of 200-202C. Yield: 400 mgand HPLC purity: 99.165%
  • 50
  • [ 1257044-40-8 ]
  • [ 144-62-7 ]
  • venetoclax oxalic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
369 mg In ethanol; at 28 - 90℃; for 3h; Venetoclax (500 mg) was dissolved in ethanol (10 mL) at 28C and oxalic acid (57.0 mg in 5 mL of ethanol) was added at the same temperature. The reaction mixture was heatedto 90C and stirred at this temperature for 3 hours. Cooled the reaction mixture to 28Cand stirred for 14 hours at the same temperature. The solid was filtered and washed withethanol (10 mL). The solid was dried for 24 hours at under reduced pressure at 28C andat 50C for 45 minutes to obtain the title compound with melting range of 220-223C.Yield: 369 mg and HPLC purity: 99.08%
  • 51
  • [ 1257044-40-8 ]
  • [ 110-16-7 ]
  • venetoclax maleic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
372 mg In acetone; at 28℃; for 17h; Venetoclax (500 mg) was dissolved in acetone (8 mL) at 28C and maleic acid (73.5 mgin 2 mL of acetone) was added at the same temperature. The reaction mixture was stirredfor 17 hours at 28C and filtered the solid. The solid was washed with acetone (10 mL)and dried for 6 hours at 28C under reduced pressure and 45 minutes at 50C underreduced pressure to obtain the title compound with melting range of 204-206C. Yield:372 mg and HPLC purity: 99.518%
  • 52
  • [ 107-36-8 ]
  • [ 1257044-40-8 ]
  • venetoclax isethionic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
500 mg In acetone; at 28℃; for 17h; Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28C and isethionic acid (0.049mL) was added at the same temperature. The reaction mixture was stirred for 17 hours at28C and filtered the solid. The solid was washed with acetone (10 mL) and dried for 6hours at 28C under reduced pressure and 45 minutes at 50C under reduced pressure toobtain the title compound with melting range of 172-174C. Yield: 500 mg and HPLCpurity: 99.539%
  • 53
  • [ 1257044-40-8 ]
  • [ 77-92-9 ]
  • venetoclax citric acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
532 mg In acetone; at 28℃; for 18h; Venetoclax (500 mg) was dissolved in acetone (8 mL) at 28C and citric acidmonohydrate (133 mg in 2 mL of acetone) was added at the same temperature. Thereaction mixture was stirred for 18 hours at 28C and filtered the solid. The solid waswashed with acetone (10 mL) and dried for 6 hours at 28C under reduced pressure and45 minutes at 50C under reduced pressure to obtain the title compound with meltingrange of 168-170C. Yield: 532 mg and HPLC purity: 98.796%
  • 54
  • [ 75-75-2 ]
  • [ 1257044-40-8 ]
  • venetoclax methanesulfonic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
448 mg In acetone; at 28℃; for 17h; Venetoclax (500 mg) was dissolved in acetone (10 mL) at 28C and methanesulfonic acid(0.04 mL) was added at the same temperature. The reaction mixture was stirred for 17hours at 28C and filtered the solid. The solid was washed with acetone (10 mL) anddried for 12 hours at 28C under reduced pressure and 45 minutes at 50C under reducedpressure to obtain the title compound with melting range of 165-168C. Yield: 448 mgand HPLC purity: 99.51%
  • 55
  • [ 1257044-40-8 ]
  • [ 64-19-7 ]
  • venetoclax acetic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
452 mg In acetone; at 28 - 60℃; for 15h; Acetic acid (0.036 mL) was added to a mixture of Venetoclax (500 mg) in acetone (10mL) at 28C and heated to 60C. The reaction mixture was stirred for 1 hour at 60C andcooled to 28C. The reaction mixture was stirred for 14 hours at the same temperature andfiltered. The solid was washed with acetone (10 mL) and dried for 6 hours at 28C underreduced pressure and 45 minutes at 50C under reduced pressure to obtain the titlecompound with melting range of 158-160C. Yield: 452 mg and HPLC purity: 99.333%
  • 56
  • [ 105942-08-3 ]
  • [ 1257044-40-8 ]
  • 57
  • 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzonitrile [ No CAS ]
  • [ 1257044-40-8 ]
  • 58
  • [ 4295-99-2 ]
  • [ 1257044-40-8 ]
  • 59
  • [ 183208-36-8 ]
  • [ 1257044-40-8 ]
  • 60
  • 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene [ No CAS ]
  • [ 1257044-40-8 ]
  • 61
  • [ 1583-58-0 ]
  • [ 1257044-40-8 ]
  • 62
  • [ 88-73-3 ]
  • [ 1257044-40-8 ]
  • 63
  • [ 362703-30-8 ]
  • [ 1257044-40-8 ]
  • 64
  • 4-cyanotetrahydro-2H-pyran-4-carboxylic acid [ No CAS ]
  • [ 1257044-40-8 ]
  • 65
  • C15H13FN2O3 [ No CAS ]
  • [ 1257044-40-8 ]
  • 66
  • 2-chloro-4,4-dimethylcyclohexanecarbaldehyde [ No CAS ]
  • [ 1257044-40-8 ]
  • 67
  • [ 130290-79-8 ]
  • 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 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
89.3% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60 - 65℃; for 5h; Fluorinated compound (III) (25.0 g, 32.3 mmol)Soluble in 200mL tetrahydrofuran (THF),Add tetrahydropyran-4-methylamine (5.6 g, 48.5 mmol) at room temperatureAnd N,N-diisopropylethylamine (DIPEA) (6.27 g, 48.5 mmol).The temperature was raised to 60 to 65 C and the reaction was stirred for 5 hours.The TLC test showed that the reaction of the starting material was completed.After the reaction is completed, the pressure is concentrated.The concentrate was added to 500 mL of dichloromethane and stirred with 200 mL of purified water.After stirring, the aqueous phase is separated.The organic phase was washed once with 150 mL of 1% aqueous acetic acid solution.Then wash it again with 200mL of water.The organic phase is dried with 20 g of sodium sulfate.Filtration, spin-drying, recrystallization from 200 mL of tetrahydrofuran.Filtered and dried to obtain the vitamin Dine (I) pale yellow powder 25.1g,The yield was 89.3%.ApplicantMass spectrometry is a structure of formula I,The purity by HPLC was 99.82% as shown in Figure 1.
  • 68
  • [ 130290-79-8 ]
  • [ 1257044-99-7 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
87.6% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80 - 85℃; for 12h; Chlorine-containing compound (III) (25.0 g, 31.6 mmol)Soluble in 500mL acetonitrile,Add at room temperatureTetrahydropyran-4-methylamine (5.5g, 47.5mmol)And N,N-diisopropylethylamine (DIPEA) (6.1 g, 47.5 mmol).The reaction was heated to 80-85 C and stirred for 12 hours.The TLC test showed that the reaction of the starting material was completed.After the reaction is completed, the pressure is concentrated.The concentrate was added to 500 mL of dichloromethane and stirred with 200 mL of purified water.After stirring, the aqueous phase is separated.The organic phase was washed once with 150 mL of 1% aqueous acetic acid solution.Then wash it again with 200mL of water.The organic phase is dried with 20 g of sodium sulfate.Filter, spin dry,The crude product was recrystallized with 200 mL, filtered,Dry DeVipneride (I) light yellow powder 24.1g,The yield was 87.6%.The mass spectrometric analysis by the applicant is a structure of formula I,By HPLC analysis, the purity was 99.86%.as shown in picture 2.
  • 69
  • [ 406233-31-6 ]
  • [ 1235865-77-6 ]
  • [ 1257044-40-8 ]
  • 70
  • [ 1228779-96-1 ]
  • 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)benzoic acid hydrochloride [ No CAS ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
70% A mixture of dichloromethane (12.0 L), 2-((lH-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4- ((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro[l,r-biphenyl]-2-yl)methyl) piperazin-l- yl)benzoicacid hydrochloride (600.0 g), triethylamine (299.79 g), 4- dimethylaminopyridine (180.97 g), 3-nitro-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)benzenesulfonamide (342.56 g) and N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (283.97 g) was stirred at 25 to 30 degree Celsius for 8h. The reaction mixture was treated with N,N-dimethylethylenediamine (217.63 g) at 20 to 30 degree Celsius and stirred for 4h. The organic layer was washed with water (6.0 L) and concentrated under vacuum. The residue was dissolved in dichlo methane- methanol mixture (1:5) (7.2 L) and treated with acetic acid-methanol mixture (415.11 g acetic acid and 600 mL methanol) and stirred at 20 to 30 degree Celsius. The resulting slurry was cooled to 0 to 5 degree Celsius, filtered and washed with methanol (600 mL). The solid was dissolved in (9:1) mixture of dicloromethane-methanol (4.8 L) at 35 to 45 degree Celsius, diluted with methanol (1680 mL) and stirred for 8h at 20 to 30 degree Celsius. The resulting slurry was cooled to 0 to 5 degree Celsius, filtered, washed with methanol (600 mL) and the solid was dried under vacuum at 60 to 65 degree Celsius for 18 h to provide 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl}- piperazin-l-yl)-N-({3-nitro-4[(tetrahydro-2H-pyran-4ylmethyl)amino]- phenyl} sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benz amide. Yield: 70.0% (600g) HPLC Purity: -99.9% 1H NMR data-(DMSO-d6): d 0.921 (s, 6H), 1.204-1.308, 1.598-1.626 (m, d, J=l l.2Hz, 4H), 1.382 (t, J=6.4Hz, 4H), 1.883 (m, 1H), 1.951 (s, 2H), 2.144 (t, br, 2H), 2.199 ( s, br, 4H), 2.754 (s, 2H), 3.073 (s, br, 4H), 3.237-3.291, 3.829-3.865 (m, dd, J=2.8, 3.2, 11.2, l l.6Hz, 6H), 6.189 (d, J=2.0Hz, 1H), 6.388 (dd, J=2.0, 3.6Hz, 1H), 6.678 (d, J=2.0, 2.4, 9.2, 9.6Hz, 1H), 7.037 (d, J=8.8Hz, 2H) 7.11 (d, J=9.2Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 7.495 (m, 2H), 7.535 ( d, J=2.4Hz, 1H), 7.801 (dd, J=2.0, 2.4, 8.8, 9.2Hz, 1H), 8.038 (d, J=2.0Hz, 1H), 8.558 (d, J=2.4Hz, 1H), 8.598 (t, 1H), 11.366 (s, br, 1H), 11.679 (s, 1H).
  • 71
  • potassium 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 ]
  • [ 1257044-40-8 ]
  • 72
  • 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 hydrochloride [ No CAS ]
  • [ 1257044-40-8 ]
  • 73
  • [ 1228779-96-1 ]
  • 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)benzoic acid hydrochloride [ No CAS ]
  • [ 1257044-40-8 ]
  • C79H84Cl2N10O9S [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 3-L jacketed reactor (Kettle 1) equipped with a mechanical stirrer, nitrogen inlet/outlet, temperature control unit and reflux condenser was inerted with nitrogen and charged with 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (19.7 g, 0.95 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 22.1 g, 1.75 equiv), 4-dimethylaminopyridine (DMAP, 16.1 g, 2 equiv) and dichloromethane (DCM, 200 ml_, 5 vo I). In a separate 1-L reactor (Kettle 2) equipped with a mechanical stirrer, nitrogen inlet/outlet was charged with 2-((1 H-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)benzoic acid hydrochloride salt (40.0 g, 65.8 mmol), and DCM (400 mL, 10 vol). Triethylamine (36.7 mL, 4.00 equiv) was added in one portion. The solution in Kettle 2 was dosed into Kettle 1 using a transfer pump. The batch was stirred at room temperature for 5-25 h then acetic acid (10% v/v, 10 Vol, 400 mL) was added to the batch and stirred for 15 min.
  • 74
  • [ CAS Unavailable ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
90% With lithium hydroxide In methanol at 20 - 68℃; 1.6 Step 6: Preparation of Venetoclax: Intermediate V5 (56.8g, 56mmol, 1.0eq) and 300mL methanol were added to a 1000mL reaction flask, stirred to dissolve, lithium hydroxide (2.7g, 112mmol, 2.0eq) was added in portions at room temperature, stirred,The temperature was raised to 65-68 ° C to reflux the reaction, and the reaction was monitored by TLC.After the reaction is completed, most of the methanol is distilled off under reduced pressure and the temperature is reduced to 30 ° C.To the residue was added 500mL water and 800mL ethyl acetate,After stirring, the layers were left standing; the aqueous layer was extracted with ethyl acetate (300 mL × 2), and the organic phases were combined,Washed with saturated aqueous sodium chloride solution (300mL × 1), dried over anhydrous sodium sulfate, filtered with suction,The filtrate is concentrated under reduced pressureObtained solid crude.The crude product was recrystallized with 300 mL of ethyl acetate and n-hexane (2: 1),43.4g Venetoclax product was obtained.Yield: 90%.
  • 75
  • [ CAS Unavailable ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
92% With caesium carbonate In isopropyl alcohol at 20 - 80℃; 2.6 Step 6: Preparation of Venetoclax: Intermediate V5 (56.8g, 56mmol, 1.0eq) and 300mL methanol were added to a 1000mL reaction flask, stirred to dissolve, lithium hydroxide (2.7g, 112mmol, 2.0eq) was added in portions at room temperature, stirred,The temperature was raised to 65-68 ° C to reflux the reaction, and the reaction was monitored by TLC.After the reaction is completed, most of the methanol is distilled off under reduced pressure and the temperature is reduced to 30 ° C.To the residue was added 500mL water and 800mL ethyl acetate,After stirring, the layers were left standing; the aqueous layer was extracted with ethyl acetate (300 mL × 2), and the organic phases were combined,Washed with saturated aqueous sodium chloride solution (300mL × 1), dried over anhydrous sodium sulfate, filtered with suction,The filtrate is concentrated under reduced pressureObtained solid crude.The crude product was recrystallized with 300 mL of ethyl acetate and n-hexane (2: 1),43.4g Venetoclax product was obtained.Yield: 90%.
  • 76
  • [ CAS Unavailable ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
90% With lithium hydroxide In isopropyl alcohol at 20 - 80℃; 3.6 Step 6: Preparation of Venetoclax: In a 500mL reaction flask, add intermediate V5 (44.1g, 42mmol, 1.0eq) and 300mL isopropanol, stir to dissolve, add lithium hydroxide (2.5g, 105mmol, 2.5eq) in portions at room temperature, stir, and warm up To reflux at 75-80 ,TLC monitors the reaction. After the reaction was completed, most of the methanol was distilled off under reduced pressure, and the temperature was lowered to 30 ° C. 300mL and 600mL of ethyl acetate were added to the residue. After stirring, the mixture was allowed to stand for separation. The organic phase was washed with saturated aqueous sodium chloride solution (300 mL × 1), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a crude solid product.This crude product was recrystallized with 300 mL of ethyl acetate and n-hexane (2: 1) to obtain 32.7 g of Venetoclax product. Yield: 90%.
  • 77
  • [ CAS Unavailable ]
  • [ 77-92-9 ]
  • [ 1257044-40-8 ]
YieldReaction ConditionsOperation in experiment
In water; dimethyl sulfoxide at 52℃; 5 Example 5 Preparation of amorphous form of venetoclax: Dimethyl sulfoxide (275 ml) was charged to the reaction vessel and the temperature was adjusted to 30±5°C, if required. Venetoclax sodium (100 g) was added to reaction vessel at 30±5°C. The reaction vessel was flushed with 25 ml dimethyl sulfoxide at 30±5°C. The reaction mass was stirred for 25-55 minutes at 30±5°C. The reaction mass was filtered at 30±5°C and washed with 30 ml dimethyl sulfoxide at 30±5°C. (0282) Meanwhile 1900 ml DM water was charged to another reaction vessel and temperature was adjusted to 30±5°C, if required. Citric acid monohydrate (11.8 g) was charged in to DM water at 30±5°C. The solution of citric acid monohydrate was stirred to get clear solution. The solution was filtered at 30±5°C. The reaction vessel was washed with 200 ml DM water and filtered it at 30±5°C. (0283) The venetoclax and dimethyl sulfoxide mixture, and solution of citric acid monohydrate was combined through addition vessel. The reaction mass was stirred for 85-95 minutes at 52+3 °C. The reaction mass was filtered at 52+3 °C. The wet cake was washed with (pre -heated) (2 X 100 ml) DM water at 52+3°C. The material is dried and unloaded. DM water (900 ml) was charged to reaction vessel and the temperature of DM water was raised to 52+3°C. The unloaded wet cake was charged to the DM water at 52+3°C. The reaction vessel was flushed with 100 ml DM water. The reaction mass was stirred for 3 hours+5 minutes at 52+3°C. The reaction mass was filtered at 52+3°C. The wet cake was washed with (pre-heated) (2 X 100 ml) DM water at 52+3 °C. The material is dried and unloaded. The wet cake was dried in vacuum tray dryers for 1 hour + 10 minutes under vacuum without applying any utility and then dried at 70+5°C for 09 hours + 10 minutes. Material was unloaded and milled. The milled material was collected in a cleaned container having double polythene bags. DM water (900 ml) was charged in to reaction vessel. The temperature of DM water was raised to 52±3°C. The milled material was charged in to the DM water at 52±3°C. The reaction vessel was flushed with 100 ml DM water at 52±3°C. The reaction mass was stirred for 3 hours+5 minutes at 52+3 °C. The reaction mass was filtered at 52+3 °C. The wet cake was washed with (pre -heated) (2 X 100 ml) DM water at 52+3°C. The material is dried and unloaded. The wet cake was dried in VTD for 1 hour + 10 minutes under vacuum without applying any utility and then dried at 70+5 °C for 06 hours + 10 minutes. The material was milled and collected in a cleaned container having double polythene bags. Tray filled with DM water was placed at lower bottom shelf of VTD. The temperature of VTD was raised to 70+5 °C without applying vacuum. The vacuum oven was maintained without applying Vacuum for 20-40 minutes at 70+5 °C. The above milled material was charged in VTD. The material was dried under vacuum for 2 hours+10 min at 70+5°C. The material was unloaded and packed.
  • 78
  • [ 1228779-96-1 ]
  • [ 2254393-29-6 ]
  • [ 1257044-40-8 ]
  • [ 2469279-00-1 ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 27℃; for 11h; Overall yield = 4.62 g; 4 Example-4: Preparation of Venetoclax. 2-((lH-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [l,l'-biphenyl]-2-yl)methyl)piperazin-l-yl)benzoic acid hydrochloride (5 g), 3-nitro-4- (((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (2.85 g), EDC.HC1 (2.366 g), DMAP (2.011 g), triethylamine (2.91 g), dichloromethane (125 mL) were charged into a round bottom flask at 27°C. The reaction mass was stirred for 11 hrs at 27°C. Water (100 mL) and dichloromethane (50 mL) were added to the reaction mass at 27°C. The reaction mass was stirred for 20 minutes at 27°C. The resulted organic layer and aqueous layers were separated. The organic layer washed with 5%aq. acetic acid solution (50 mL), 5%aq.NaHC03 solution (100 mL) and 10%aq.NaCl solution(50 mL). The organic layer was evaporated under vacuum at 35°C. 1,4 dioxane (15 mL) was added to the reaction mass at 50°C. The organic layer was evaporated under vacuum at 50°C. 1,4 dioxane (50 mL) was added to the resulted reaction mass at 50°C. The reaction mass was heated to 75°C. The reaction mass was stirred for 10 minutes at 75°C. The reaction was seeded with Venetoclax (0.025 g) at 55°C. The reaction mass was cooled to 28°C and stirred for 9 hrs. The reaction mass was filtered and washed with 1,4-dioxane (20 mL). The resulted solid and 1,4 dioxane(110 mL) were charged into a round bottom flask at 28°C. The reaction mass was heated to 70°C. The reaction mass was stirred for 35 minutes at 70°C. The reaction mass was seeded with Venetoclax (0.025 g) at 52°C. The reaction mass was cooled to 28°C and stirred for 11 hrs. The reaction mass was filtered under vacuum and washed with 1,4-dioxane (20 mL). The solid was suck dried for 20 minutes. The solid was dried under vacuum at 60°C. Product weight: 4.62 g; Purity by HPLC: 99.5%; N-Oxide impurity by HPLC: 0.007%
  • 79
  • [ 1257044-40-8 ]
  • [ 76-05-1 ]
  • [ 229625-50-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
25% Stage #1: 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-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; di-tert-butyl chloromethyl phosphate With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 1.5h; Stage #2: trifluoroacetic acid In dichloromethane for 1h;
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