330786-24-8

Basic information

• Product Name: 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine
• Synonyms: ibrutinib N-2;1H-Pyrazolo[3,4-d]pyriMidin-4-aMine, 3-(4-phenoxyphenyl)-;Ibrutinib intermeidate N-2;Ibrutinib INT1;Ibrutinib Impurity 8;-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine;5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylamine (N-2);5-(3-Phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• CAS NO: 330786-24-8
• Molecular Formula: C₁₇H₁₃N₅O
• Molecular Weight: 303.31802
• EINECS: 1592732-453-0
• Product Categories: Ibrutinib;Anticancer
• Mol File: 330786-24-8.mol
• Article Data: 40

Chemical Properties

• Boiling Point: 577.4±50.0 °C(Predicted)
• Appearance: /
• Density: 1.380±0.06 g/cm3(Predicted)
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: DMSO (Slightly), Ethanol (Slightly)
• PKA: 10.40±0.30(Predicted)
• CAS DataBase Reference: 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine(330786-24-8)
• EPA Substance Registry System: 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine(330786-24-8)

Safety Data

• Hazardous Substances Data: 330786-24-8(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 330786-24-8 differently. You can refer to the following data:
1. As Ibrutinib intermediates, 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyriMidin-4-ylaMine can be used as organic synthesis intermediates and pharmaceutical intermediates, mainly used in laboratory research and development and chemical production processes.
2. 3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is a useful synthetic intermediate in the synthesis of Ibrutinib (I124970); a highly selective Bruton’s tyrosine kinase (BTK) irreversible inhibitor.

Synthesis

2 g of 3-iodo-4-aminopyrazolo[3,4-d]pyrimidine (7.7 mmol),3.28 g p-phenoxybenzeneboronic acid (15.4 mmol)And 5.28 g of K3PO4 (23.0 mmol) were dissolved in 25 mL of dioxane and 10 mL of water.After stirring for 5-8 minutes, argon gas was passed for 20 minutes.An additional 1.4 g of tetrakis(triphenylphosphine)palladium (1.2 mmol) was added.After heating again for 10 minutes, the heating was started, and the reaction was carried out at 120 ° C for 24 hours.After the reaction was completed, it was cooled to room temperature, stirred for 24 hours to wait for product to precipitate, and the reaction mixture was washed with 25 mL of water and filtered.The filtered solid was again washed with 75 ml of methanol, washed with 50 mL of ethanol, and dried in a dry box.There was obtained 1.75 g of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine in a yield of 75%.

Synthetic route

3-amino-5-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
at 150℃; for 8h;	90%
at 160 - 180℃; for 6h;	51%
at 180℃; for 4h;

C17H11ClN4O → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With ammonia In methanol for 12h; Reflux;	89.2%

5-amino-3-(4-phenoxy)phenyl-4-cyano-2,3-dihydropyrazole + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Stage #1: 5-amino-3-(4-phenoxy)phenyl-4-cyano-2,3-dihydropyrazole; formamide With formic acid at 115 - 120℃; for 4h; Stage #2: With dihydrogen peroxide at 45 - 50℃; for 3h; Temperature;	88.5%

(4-amino-6-chloropyrimidin-5-yl)(4-phenoxyphenyl)methanone → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With hydrazine hydrate In ethanol at 20℃; for 1h; Solvent;	87.3%
With triethylamine; hydrazine In tetrahydrofuran; 2-methyltetrahydrofuran at 95℃; for 2h;

4-Phenoxybenzoic acid (2215-77-2) + 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With [2,2]bipyridinyl; copper (I) acetate; caesium carbonate In dimethyl sulfoxide at 140℃; for 10h; Inert atmosphere;	83.7%

4-phenoxyiodobenzene (2974-94-9) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With potassium tert-butylate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere;	82%

4-Phenoxybenzoic acid (2215-77-2) + 3-bromo-4-aminopyrazolo<3,4-d>pyrimidine (83255-86-1) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With 1,10-Phenanthroline; sodium carbonate; copper(I) bromide In N,N-dimethyl acetamide at 150℃; for 24h; Inert atmosphere;	81.5%

3-amino-5-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile + formamidine acetic acid (3473-63-0) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
In toluene for 4h; Reflux;	80%

4-phenoxyphenylboronic acid (51067-38-0) + 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane at 180℃; for 0.166667h; Suzuki Coupling; Microwave irradiation; Inert atmosphere;	79%
With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate In 1,4-dioxane; water for 24h; Inert atmosphere; Reflux;	77%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 120℃; for 24h; Inert atmosphere;	75%

4-phenoxyphenylboronic acid (51067-38-0) + 3-bromo-4-aminopyrazolo<3,4-d>pyrimidine (83255-86-1) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 135℃; for 30h; Inert atmosphere;	78.8%
With tetrakis(triphenylphosphine) palladium(0); potassium phosphate tribasic trihydrate In 1,4-dioxane; water at 135℃; Inert atmosphere;	78.8%

5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (330792-70-6) + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
at 180℃; for 4h; Suzuki Coupling;	66%
With acetic acid; N,N-dimethyl-formamide dimethyl acetal at 120℃;
at 135 - 140℃; Temperature;	70 g

3-chloro-4-amino-1H-pyrazolo[3,4-d]pyrimidine (637338-78-4) + 4-Phenoxybenzoic acid (2215-77-2) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With pyridine; potassium phosphate; copper(l) iodide In N,N-dimethyl-formamide at 150℃; for 12h; Solvent; Reagent/catalyst; Temperature; Inert atmosphere;	64.1%

4-Phenoxybenzoic acid (2215-77-2) + 3-methanesulfonyloxy-4-amino-1H-pyrazolo[3,4-d]pyrimidine → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With copper(l) iodide; bathophenanthroline; potassium tert-butylate In 5,5-dimethyl-1,3-cyclohexadiene for 48h; Inert atmosphere; Reflux;	61.1%

4-phenoxyphenylboronic acid (51067-38-0) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In water; N,N-dimethyl-formamide at 120℃; Inert atmosphere;	40%

phenyl 4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)]phenyl ether (269410-26-6) + 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In water; N,N-dimethyl-formamide at 120℃; for 12h; Inert atmosphere;	37%

1-tert-butyl-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500789-47-9) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With hydrogenchloride; formic acid; water for 0.5h; Heating / reflux;

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 2: potassium phosphate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 0.17 h / 180 °C / Inert atmosphere; Microwave irradiation; Sealed tube View Scheme
Multi-step reaction with 2 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 2 h / 80 °C 2: potassium phosphate monohydrate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 2 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 24 h / 75 °C 2: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 60 h / 90 °C View Scheme

4-Phenoxybenzoic acid (2215-77-2) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / 1 h / Reflux 1.2: -10 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 3.1: hydrazine hydrate / ethanol / 1 h 4.1: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride / toluene / 1 h / Reflux 1.2: 0 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 3.1: hydrazine hydrate / ethanol; water / 1 h / Heating 4.1: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: thionyl chloride / 1 h / Reflux 2: N-ethyl-N,N-diisopropylamine / toluene; tetrahydrofuran / -10 - 20 °C 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 4: hydrazine hydrate / ethanol / 1 h / Heating 5: 4 h / 180 °C / Inert atmosphere View Scheme

2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile (330792-68-2) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 1 h 3: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol; water / 1 h / Heating 3: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 1 h / Heating 3: 4 h / 180 °C / Inert atmosphere View Scheme

2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile (330792-69-3) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 1 h 2: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol; water / 1 h / Heating 2: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 1 h / Heating 2: 4 h / 180 °C / Inert atmosphere View Scheme

4-phenoxybenzoyl chloride (1623-95-6) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / toluene; tetrahydrofuran / -10 - 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; acetonitrile; methanol / 48 h / 0 - 20 °C / Inert atmosphere 3: hydrazine hydrate / ethanol / 1 h / Heating 4: 4 h / 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium hydride / 2-methyltetrahydrofuran / 0.5 h 2: sodium hydrogencarbonate / 1,4-dioxane / 70 °C 3: hydrazine hydrochloride; triethylamine / ethanol / 85 °C 4: N,N-dimethyl-formamide dimethyl acetal; acetic acid / 120 °C View Scheme
Multi-step reaction with 4 steps 1: sodium hydroxide / acetone; water / 2 h / 10 - 30 °C 2: sodium hydrogencarbonate / water; 1,4-dioxane / 2 h / Reflux 3: hydrazine hydrate / ethanol / 1 h / Reflux 4: 8 h / 150 °C View Scheme

(4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hypochlorite solution; potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 1 h 2: N-ethyl-N,N-diisopropylamine; hydrazine hydrate / tetrahydrofuran / 4 h / 0 - 25 °C / Inert atmosphere 3: ammonia / methanol / 12 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: manganese(IV) oxide / dichloromethane / 5 h 2: ammonia / ethanol / 5 h / 0 °C 3: hydrazine hydrate / ethanol / 1 h / 20 °C View Scheme

4-Bromodiphenyl ether (101-55-3) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 1.2: 1 h / -80 - 25 °C / Inert atmosphere 2.1: sodium hypochlorite solution; potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 1 h 3.1: N-ethyl-N,N-diisopropylamine; hydrazine hydrate / tetrahydrofuran / 4 h / 0 - 25 °C / Inert atmosphere 4.1: ammonia / methanol / 12 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -20 °C 1.2: 1 h / 0 °C 2.1: manganese(IV) oxide / dichloromethane / 5 h 3.1: ammonia / ethanol / 5 h / 0 °C 4.1: hydrazine hydrate / ethanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium; iodine / tetrahydrofuran / 40 °C / Inert atmosphere 1.2: 0 - 25 °C 2.1: potassium hydroxide; palladium on activated charcoal / 1,4-dioxane / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran / 18 h / -78 - -40 °C / Inert atmosphere 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium phosphate / N,N-dimethyl-formamide; water / 12 h / 120 °C / Inert atmosphere View Scheme

2,6-dichloro-pyrimidine carbaldehyde (5305-40-8) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 1.2: 1 h / -80 - 25 °C / Inert atmosphere 2.1: sodium hypochlorite solution; potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; dichloromethane / 1 h 3.1: N-ethyl-N,N-diisopropylamine; hydrazine hydrate / tetrahydrofuran / 4 h / 0 - 25 °C / Inert atmosphere 4.1: ammonia / methanol / 12 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -20 °C 1.2: 1 h / 0 °C 2.1: manganese(IV) oxide / dichloromethane / 5 h 3.1: ammonia / ethanol / 5 h / 0 °C 4.1: hydrazine hydrate / ethanol / 1 h / 20 °C View Scheme

4,6-dichloro-pyrimidine-5-carboxylic acid → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / diethyl ether / 0.5 h / 20 °C / Inert atmosphere 2: aluminum (III) chloride / dichloromethane / 50 °C / Inert atmosphere 3: ammonia / toluene / 60 °C / Schlenk technique; Inert atmosphere 4: triethylamine; hydrazine / 2-methyltetrahydrofuran; tetrahydrofuran / 2 h / 95 °C View Scheme

4,6-dichloropyrimidine-5-carboxylic acid chloride (87600-97-3) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 50 °C / Inert atmosphere 2: ammonia / toluene / 60 °C / Schlenk technique; Inert atmosphere 3: triethylamine; hydrazine / 2-methyltetrahydrofuran; tetrahydrofuran / 2 h / 95 °C View Scheme

(4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonia / ethanol / 5 h / 0 °C 2: hydrazine hydrate / ethanol / 1 h / 20 °C View Scheme

Dichloro-methyl-(4-phenoxy-phenyl)-silane (25268-16-0) + 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With palladium on activated charcoal; potassium hydroxide In 1,4-dioxane Concentration; Reagent/catalyst; Inert atmosphere; Reflux;

phenol (108-95-2) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4.17 h / 25 - 120 °C 1.2: 8.17 h / 0 - 30 °C 2.1: pivaloyl chloride; dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 8 h / 0 - 70 °C / Inert atmosphere 3.1: sodium carbonate / 1,4-dioxane / 5 h / 0 - 75 °C 4.1: hydrazine hydrate / methanol / 2 h / 25 - 30 °C 5.1: zinc(II) chloride / o-xylene / 20.17 h / 25 - 120 °C View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate; copper(l) iodide / N,N-dimethyl-formamide / 7 h / 100 °C 2.1: sodium hydroxide; water / ethanol / 1 h / 60 °C 3.1: thionyl chloride / dichloromethane / 11 h / 30 °C 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 20 °C 4.2: 1 h / 0 °C 5.1: potassium carbonate / 1,4-dioxane / 2 h / 70 °C 6.1: hydrazine hydrate / ethanol / 1 h / 80 °C 7.1: 3 h / 170 °C / Inert atmosphere View Scheme

4-fluorobenzaldehyde (459-57-4) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4.17 h / 25 - 120 °C 1.2: 8.17 h / 0 - 30 °C 2.1: pivaloyl chloride; dmap; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 8 h / 0 - 70 °C / Inert atmosphere 3.1: sodium carbonate / 1,4-dioxane / 5 h / 0 - 75 °C 4.1: hydrazine hydrate / methanol / 2 h / 25 - 30 °C 5.1: zinc(II) chloride / o-xylene / 20.17 h / 25 - 120 °C View Scheme

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 4-fluorobenzaldehyde (459-57-4) → 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl]benzaldehyde (330794-01-9)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide	92%
With caesium carbonate In N,N-dimethyl-formamide	92%
With caesium carbonate In N,N-dimethyl-formamide	92%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + diethyl (4-hydroxybutyl)phosphonate (63075-64-9) → C25H30N5O4P

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃;	92%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;	92%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + ethylene dibromide (106-93-4) → 1-(2-bromoethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	91%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 3-hydroxypyrrolidine (100243-39-8) → (R)-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]-pyrimidin-4-amine (1418272-84-0)

Conditions	Yield
Stage #1: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-hydroxypyrrolidine With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20 - 50℃;	89%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + (S)-3-hydroxypiperidine-N-carboxylate methyl ester → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With di-isopropyl azodicarboxylate In tetrahydrofuran at 35℃; Inert atmosphere;	88.6%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (143900-44-1) → (3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1022150-11-3)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In ethyl acetate at 10 - 30℃; Solvent; Darkness; Industrial scale;	88.1%
Stage #1: tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; Mitsunobu Displacement; Inert atmosphere; Stage #2: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine In tetrahydrofuran at 0 - 20℃; for 5h; Stage #3: With zinc(II) chloride In tetrahydrofuran at 30 - 40℃; for 2.5h;	80.2%
Stage #1: tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 0.166667h; Mitsunobu Displacement; Inert atmosphere; Stage #2: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine In tetrahydrofuran at 0 - 20℃; for 5h; Mitsunobu Displacement; Inert atmosphere;	72%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + N-tert-butoxycarbonyl-3-piperidinol (85275-45-2) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With diethylazodicarboxylate In 1,4-dioxane at 20℃; Inert atmosphere;	85.3%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + C21H23NO7S → C31H28N6O5

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	85%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (143900-44-1) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; Temperature; Mitsunobu Displacement; Inert atmosphere; Large scale;	85%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 30℃; for 25h; Concentration; Temperature;	80.45%
Stage #1: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h; Mitsunobu Displacement; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 5h;	69%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + (S)-N-trifluoroacetyl-3-hydroxypiperidine (1126736-20-6) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Stage #1: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; (S)-N-trifluoroacetyl-3-hydroxypiperidine With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 30℃; for 4.5h; Mitsunobu Displacement; Inert atmosphere; Stage #2: With water; sodium hydroxide In methanol at 20 - 30℃; for 2h; Stage #3: With hydrogenchloride In methanol; water at 45 - 55℃; for 3h;	84.8%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 2-(N-tert-butoxycarbonylamino)ethanol (26690-80-2) → tert-butyl (2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)carbamate (1414357-83-7)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Mitsunobu Displacement;	84.1%
With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 5h;
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h; Mitsunobu Displacement;
With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 5h;
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 5h;

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + triphenylphosphine (603-35-0) + tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (143900-44-1) → C45H43N6O3P

Conditions	Yield
Stage #1: triphenylphosphine With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 5℃; Mitsunobu Displacement; Inert atmosphere; Stage #2: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate In tetrahydrofuran at 0 - 5℃; Reagent/catalyst;	84%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 3-(4-hydroxyphenyl)-1-(piperidin-1-yl)prop-2-en-1-one → (S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere;	83.65%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + (E/Z)-2-buten-1-ol (6117-91-5) → C21H19N5O

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere;	82.74%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + t-butyl-3(S)-chloro-piperidine-1-carboxylate → (3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1022150-11-3)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12h;	82%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 1-Bromo-2-bromomethyl-benzene (3433-80-5) → 1-(2-bromobenzyl)-3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	82%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 3-methoxycarbonylbenzyl bromide (1129-28-8) → C26H21N5O3

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 8h;	81.6%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + (S)-3-hydroxypiperidine-N-carboxylate allyl ester → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With azodicarboxylic acid diphenyl ester In ethyl acetate at 50℃; Inert atmosphere;	81.3%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + 4-chlorobenzyl bromide (622-95-7) → 1-(4-chlorobenzyl)-3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	81%

(S)-3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (940890-90-4) + 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) → (3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1022150-11-3)

Conditions	Yield
Stage #1: 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine With potassium carbonate In N,N-dimethyl-formamide at 21 - 22℃; for 2h; Stage #2: (S)-3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide at 80℃; for 14h; Concentration;	80%
With dmap; caesium carbonate In N,N-dimethyl-formamide at 90℃; for 8h;	70%

o-fluorobenzyl bromide (446-48-0) + 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) → 1-(2-fluorobenzyl)-3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	80%

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) + Cyclopentanol (96-41-3) → PCI-29732 (330786-25-9)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere;	79.62%

Upstream product

• 2215-77-2 4-Phenoxybenzoic acid 
• 330792-68-2 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile 
• 330792-69-3 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile 
• 51067-38-0 4-phenoxyphenylboronic acid 
• 2380-63-4 4-Aminopyrazolo<3,4-d>pyrimidin 
• 77287-34-4 formamide 
• 109-77-3 malononitrile 
• 83255-86-1 3-bromo-4-aminopyrazolo<3,4-d>pyrimidine 
• 637338-78-4 3-chloro-4-amino-1H-pyrazolo[3,4-d]pyrimidine 
• 151266-23-8 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 
• 2974-94-9 4-phenoxyiodobenzene 
• 3473-63-0 formamidine acetic acid 
• 21218-94-0 methyl 4-phenoxybenzoate 
• 619-44-3 methyl 4-iodobenzoate 

Downstream Products

• 936563-86-9 tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate 
• 1354826-10-0 C₂₁H₂₂N₆O 
• 1354825-81-2 C₂₇H₂₅N₇O₂ 
• 1354826-09-7 C₂₁H₂₀N₆O₃ 
• 1448850-34-7 tert-butyl 6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate 
• 1022150-11-3 (3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine 
• 1642571-07-0 (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride 
• 936563-87-0 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one 
• 1288338-97-5 1,3-bis((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one 
• 2031255-23-7 1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one 

Relevant articles and documents

BENZENESULFONAMIDE DERIVATIVES AND USES THEREOF

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A PROCESS FOR PREPARATION OF 1H-PYRAZOLO[3,4-D] PYRIMIDINE DERIVATIVES

The present invention relates to an efficient and industrially advantageous process for the preparation of 1H-pyrazolo[3,4-d] pyrimidine derivatives. In particular the present invention provides a process for the preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidine and tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)piperidine-1-carboxylate. Said compounds are important intermediates in the synthesis of ibrutinib. The method provided for preparing intermediates of ibrutinib has the advantages of a simple operation, high yield and low costs.

Preparation method of precursor of ibrutinib

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