1228779-96-1

Basic information

• Product Name: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide
• Synonyms: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide;abt-1－199;3-nitro-4-[(oxan-4-ylmethyl)amino]benzene-1-sulfonamide;3-Nitro-4-[[(tetrahydropyran-4-yl)methyl]amino]benzenesulfonamide;THP-sulfonamide;Venetoclax Intermediate;Benzenesulfonamide, 3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]-;ABT-199 intermedate3
• CAS NO: 1228779-96-1
• Molecular Formula: C₁₂H₁₇N₃O₅S
• Molecular Weight: 315.34548
• EINECS: 1592732-453-0
• Mol File: 1228779-96-1.mol
• Article Data: 21

Chemical Properties

• Boiling Point: 542.0±60.0 °C(Predicted)
• Appearance: /
• Density: 1.412±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.58±0.60(Predicted)
• CAS DataBase Reference: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(CAS DataBase Reference)
• NIST Chemistry Reference: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(1228779-96-1)
• EPA Substance Registry System: 3-nitro-4-((tetrahydro-2H-pyran-4-yl)MethylaMino)benzenesulfonaMide(1228779-96-1)

Safety Data

• Hazardous Substances Data: 1228779-96-1(Hazardous Substances Data)

Usage

Uses

3-?Nitro-?4-?(((tetrahydro-?2H-?pyran-?4-?yl)?methyl)?amino)?benzenesulfonamide is a reagent used in the synthesis of BTK, PI3K and JAK-2 inhibitors.

Synthetic route

4-tetrahydropyranmethylamine (130290-79-8) + 4-fluoro-3-nitrobenzenesulfonamide (406233-31-6) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 5h;	97%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 16h;	95%
With sodium carbonate In isopropyl alcohol at 55 - 65℃; for 4h;	94%

4-tetrahydropyranmethylamine (130290-79-8) + 4-Chloro-3-nitrobenzenesulfonamide (97-09-6) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 12h;	91%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 24h; Inert atmosphere; Large scale;	88%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃;	78%

tetrahydro-2H-pyran-4-carbonitrile (4295-99-2) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

2-Chloronitrobenzene (88-73-3) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: chlorosulfonic acid / 18 h / 20 - 100 °C 1.2: 5 h / -10 - 23 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (362703-30-8) → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / N,N-dimethyl-formamide / 7 h / pH 9 - 11 2: copper(I) oxide / toluene / 7 h / 107 °C 3: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 4: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

4-cyanotetrahydro-2H-pyran-4-carboxylic acid → 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: copper(I) oxide / toluene / 7 h / 107 °C 2: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 25 h / 55 - 70 °C View Scheme

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15h; Inert atmosphere;	100%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 48h;	61.3%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;	80 mg

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid → 2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	93%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (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] (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-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1257044-40-8)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 3h; Reagent/catalyst; Temperature;	91.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃; for 12h; Inert atmosphere; Large scale;	86%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25℃;	84%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C40H40ClN5O7S → C51H53ClN8O11S2

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 30 - 35℃;	89%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C41H43ClN4O5S → C52H56ClN7O9S2

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30 - 35℃;	88%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C40H40ClN5O7S → C51H53ClN8O11S2

Conditions	Yield
With dmap; 1,1'-carbonyldiimidazole In dichloromethane at 30 - 35℃;	87%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(tertbutoxycarbonyl)piperazin-1-yl)benzoic acid → C35H41N7O9S

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 0.24h;	80%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid → tert-butyl 4-[3-bromo-4-([3-nitroso-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]carbamoyl)phenyl]piperazine-1-carboxylate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 12h;	79.73%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (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 → 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 (1257044-40-8)

Conditions	Yield
Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide; 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 With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25 - 30℃; for 8h; Stage #2: With N,N-dimethylethylenediamine In dichloromethane at 20 - 30℃; for 4h;	70%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 25 - 30℃; for 24h;

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-bromo-4-(4-[[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoic acid → 2-bromo-4-(4-[[2-(4-chlorophenyl)-5-methoxy-5-methylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 12h;	65.54%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(13S)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0[3,7]] tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(13S)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	57.72%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)benzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	57.3%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (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 → 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 (1257044-40-8)

Conditions	Yield
Stage #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 With triethylamine In dichloromethane at 20 - 25℃; Stage #2: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap; diisopropyl-carbodiimide In dichloromethane at 35 - 40℃;	55%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-([3-nitro-4-[(oxan-4-ylmethyl)amino]benzene]sulfonyl)-2-[13-oxa-2,4,10-triazatricyclo[7.4.0.0^[3,7]]trideca-1,3(7),5,8-tetraen-10-yl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	54%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	54%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + C33H33(2)H2ClN4O3 → C45H48(2)H2ClN7O7S

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;	53%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (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] (1235865-77-6) → venetoclax sodium

Conditions	Yield
Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide; [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] With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Stage #2: With sodium hydroxide In methanol at 55 - 60℃; for 2h;	53%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15]]hexadeca-1(9),2,5,7-tetraen-10-yl]benzoic acid → 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[(11S,15R)-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0^[3,7].0^[11,15] ]hexadeca-1(9),2,5,7-tetraen-10-yl]-N-[3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl]benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	45.84%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid → (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions

Yield

Stage #1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 4h; Stage #2: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap In dichloromethane

42.5%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid → 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)-2-(4-(trifluoromethyl)-3 4-dihydro-2H-pyrrolo[3’,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1 (7H)-yl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoic acid → 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3‘,2’:5,6]pyrido[2,3- b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;	40%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(12,12-difluoro-14-oxa-2,4,10-triazatricyclo[7.5.0.0^[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoic acid → 4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3’,2’:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	39.68%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	39.68%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2 H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	39.6%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid TFA salt → 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions

Yield

Stage #1: 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid TFA salt With 4-methyl-morpholine In dichloromethane at 0 - 20℃; for 16h;

39%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + benzoic acid (65-85-0) → N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Conditions	Yield
With dmap; 1,2-dichloro-ethane In tetrahydrofuran; dichloromethane at 20℃; for 16h;	38%

3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1228779-96-1) + 4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}(2H8)piperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid → 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

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;	36%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;

Upstream product

• 130290-79-8 4-tetrahydropyranmethylamine 
• 406233-31-6 4-fluoro-3-nitrobenzenesulfonamide 
• 97-09-6 4-Chloro-3-nitrobenzenesulfonamide 
• 4295-99-2 tetrahydro-2H-pyran-4-carbonitrile 
• 88-73-3 2-Chloronitrobenzene 
• 362703-30-8 methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate 
• 848821-06-7 4-cyanotetrahydro-2H-pyran-4-carboxylic acid 

Downstream Products

• 1228779-93-8 4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetra-hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide 
• 1379647-80-9 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 sulfate 

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