1022150-12-4

Basic information

• Product Name: 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine
• Synonyms: 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine;(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyriMidin-4-aMine;3-(4-Phenoxy-phenyl)-1-(R)-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine;Btk inhibitor 1 (R enantioMer);ibrutinib N-1;3-(4-phenoxyphenyl)-1-(3-piperidyl)pyrazolo[3,4-d]pyriMidin-4-aMine;Ibrutinib intermeidate N-1;3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• CAS NO: 1022150-12-4
• Molecular Formula: C₂₂H₂₂N₆O
• Molecular Weight: 386.44968
• EINECS: 200-001-8
• Product Categories: Ibrutinib
• Mol File: 1022150-12-4.mol
• Article Data: 36

Chemical Properties

• Boiling Point: 626.3±55.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3(Predicted)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.00±0.10(Predicted)
• CAS DataBase Reference: 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine(1022150-12-4)
• EPA Substance Registry System: 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyriMidin-4-ylaMine(1022150-12-4)

Safety Data

• Hazardous Substances Data: 1022150-12-4(Hazardous Substances Data)

Usage

Description

IBT6A is a Btk kinase inhibitor. This compound is a precurser for the manufacture of ibrutinib.

Uses

(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is an intermediate used to prepare pyrazolo-pyrimidine compounds as inhibitors of Bruton''s tyrosine kinase. It is also an intermediate for Ibrutinib (I124970) derivatives.

InChI:InChI=1S/C22H22N6O/c23-21-19-20(15-8-10-18(11-9-15)29-17-6-2-1-3-7-17)27-28(22(19)26-14-25-21)16-5-4-12-24-13-16/h1-3,6-11,14,16,24H,4-5,12-13H2,(H2,23,25,26)

Synthetic route

(3R)‐4‐amino‐3‐(4-phenoxyphenyl)‐1‐(1‐tert-butoxycarbonylpiperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1022150-11-3) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane for 2h; Inert atmosphere;	100%
With hydrogenchloride In methanol; water at 50℃;	98%
With hydrogenchloride In methanol at 20℃; for 2h;	92%

(3R)-3-[4-(benzyloxycarbonylamino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylic acid benzyl ester → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With palladium on activated charcoal	99%

4-phenoxyphenylboronic acid (51067-38-0) + C10H13BrN6*2ClH → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water for 5h; Solvent; Reagent/catalyst; Suzuki Coupling; Inert atmosphere; Reflux;	90%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water for 5h; Reagent/catalyst; Solvent; Suzuki Coupling; Inert atmosphere; Reflux;	90%

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%

4-phenoxyphenylboronic acid (51067-38-0) + 3-bromo-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane; water for 5h; Suzuki Coupling; Inert atmosphere; Reflux;	87.1%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane for 4h; Inert atmosphere; Reflux;	0.5 g

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) + 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) + (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) + (S)-3-hydroxypiperidine-N-carboxylate benzyl ester (94944-69-1) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In acetonitrile at 0℃; Inert atmosphere; Large scale;	74.4%

(R)-1-(1-benzylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With hydrogen In methanol; water at 50℃; under 1034.32 Torr; for 2h; Acidic conditions;	67.4%
With hydrogenchloride; 10 wt% Pd(OH)2 on carbon In methanol at 40 - 50℃;
With palladium 10% on activated carbon; hydrogen In methanol

4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12.5 h / 10 - 20 °C 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 72 h / 70 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 5 h / 80 °C 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12.5 h / 10 - 20 °C 3: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 60 °C 2: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-iodo-succinimide / N,N-dimethyl-formamide / 60 °C 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 72 h / 70 °C 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme

(R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1276110-38-3) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme

tert-butyl (3S)-3-[[(4-methylbenzene)sulfonyl]oxy]piperidine-1-carboxylate (1353993-49-3) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme

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
Multi-step reaction with 4 steps 1: pyridine / 5.5 h / 0 - 25 °C 2: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine / 5.5 h / 0 - 25 °C 2: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine / 5.5 h / 0 - 25 °C 2: caesium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme

4-phenoxyphenylboronic acid (51067-38-0) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 12 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 80 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

C29H27N5O3 → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2-ethoxy-ethanol / 6 h / 120 °C 2: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 55 - 60 °C / 2250.23 Torr View Scheme

C30H28N6O3 → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol at 55 - 60℃; under 2250.23 Torr;

C28H27N5O → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2-ethoxy-ethanol / 8 h / 20 - 120 °C / Inert atmosphere 2: hydrogenchloride; 10 wt% Pd(OH)2 on carbon / methanol / 40 - 50 °C View Scheme

2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile (330792-69-3) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / ethanol; water / 1 h / 5 - 25 °C / Inert atmosphere 2: 2-ethoxy-ethanol / 6 h / 120 °C 3: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 55 - 60 °C / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: triethylamine / ethanol; water / 1 h / 5 - 30 °C / Inert atmosphere 2: 2-ethoxy-ethanol / 8 h / 20 - 120 °C / Inert atmosphere 3: hydrogenchloride; 10 wt% Pd(OH)2 on carbon / methanol / 40 - 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrazine hydrate / ethanol / 1 h / Reflux 2.1: 8 h / 150 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 21 - 22 °C 3.2: 14 h / 80 °C 4.1: hydrogenchloride / ethyl acetate / 0.5 h View Scheme

C13H19N3O2*2ClH → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / ethanol; water / 1 h / 5 - 25 °C / Inert atmosphere 2: 2-ethoxy-ethanol / 6 h / 120 °C 3: 10 wt% Pd(OH)2 on carbon; hydrogen / methanol / 55 - 60 °C / 2250.23 Torr View Scheme

(R)-tert-butyl 3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1612774-50-1) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2-ethoxy-ethanol / 8 h / 20 - 120 °C / Inert atmosphere 2: hydrogenchloride; methanol / 3 h / 50 °C View Scheme

C12H19N3*2ClH → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / ethanol; water / 1 h / 5 - 30 °C / Inert atmosphere 2: 2-ethoxy-ethanol / 8 h / 20 - 120 °C / Inert atmosphere 3: hydrogenchloride; 10 wt% Pd(OH)2 on carbon / methanol / 40 - 50 °C View Scheme

3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.17 h / Heating; Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 2 h / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 1.2: 12 h / 0 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / water; ethyl acetate / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 2: hydrogenchloride / methanol / 2 h / 20 °C View Scheme

2,6-dichloro-pyrimidine carbaldehyde (5305-40-8) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 6 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 5.1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 6.1: hydrogenchloride / methanol / 2 h / 20 °C View Scheme

4-Bromodiphenyl ether (101-55-3) → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 6 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 5.1: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 6.1: hydrogenchloride / methanol / 2 h / 20 °C View Scheme
Multi-step reaction with 3 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 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 25 h / 0 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 - -65 °C / Inert atmosphere 1.2: 3 h / -60 - 0 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 80 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 20 °C View Scheme

(4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: manganese(IV) oxide / dichloromethane / 5 h 2: ammonia / ethanol / 5 h / 0 °C 3: hydrazine hydrate / ethanol / 1 h / 20 °C 4: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 5: hydrogenchloride / methanol / 2 h / 20 °C View Scheme

(4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: ammonia / ethanol / 5 h / 0 °C 2: hydrazine hydrate / ethanol / 1 h / 20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 4: hydrogenchloride / methanol / 2 h / 20 °C View Scheme

(4-amino-6-chloropyrimidin-5-yl)(4-phenoxyphenyl)methanone → (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrazine hydrate / ethanol / 1 h / 20 °C 2: caesium carbonate / N,N-dimethyl-formamide / 12 h / 100 °C 3: hydrogenchloride / methanol / 2 h / 20 °C View Scheme

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + 2-chloropropionyl chloride (625-36-5) → (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidin-1-yl)-3-chloropropyl-1-one

Conditions	Yield
With sodium hydrogencarbonate In tetrahydrofuran at -20℃; for 3h; Concentration; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	99%
With sodium acetate In water at 5 - 15℃; for 1h; Reagent/catalyst; Solvent; Inert atmosphere;	94.9%
Stage #1: (R)-3-(4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine With 2,6-di-tert-butyl-4-methyl-phenol In 2-methyltetrahydrofuran at 10℃; for 0.333333h; Stage #2: 2-chloropropionyl chloride With sodium hydrogencarbonate In 2-methyltetrahydrofuran; water at 10℃; for 3h; Reagent/catalyst; Temperature; Inert atmosphere;	87.9%
With N-ethyl-N,N-diisopropylamine In dichloromethane at -20 - -10℃; Inert atmosphere;	830 mg
With sodium hydrogencarbonate In 2-methyltetrahydrofuran; water

3-bromopropionyl bromide (7623-16-7) + (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) → (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidin-1-yl)-3-bromopropyl-1-one

Conditions	Yield
In tetrahydrofuran at -20℃; for 3h; Inert atmosphere;	99%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + 1-[2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrimidin-5-yl]piperidine-4-carboxylic acid → tert-butyl 4-[5-[4-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-1-piperidyl]pyrimidin-2-yl]piperazine-1-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h;	99%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + cyanoacetic acid (372-09-8) → (R)-3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(3-keto)propionitrile (1412418-10-0)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; Cooling with ice;	95%
Stage #1: cyanoacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane for 0.166667h; Cooling with ice; Stage #2: (R)-3-(4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine In dichloromethane at 20℃; for 2h; Cooling with ice;	95%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	90%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + (2E)‐4‐[4‐(2‐{[(tert‐butoxy)carbonyl]amino}ethyl)piperazin‐1‐yl]but‐2‐enoic acid → tert-butyl (R,E)-(2-(4-(4-(3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide Inert atmosphere;	87%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + 5-chloro-1H-benzo[d][1,2,3]triazol-1-yl acrylate → ibrutinib

Conditions	Yield
With triethylamine In tetrahydrofuran at 0 - 30℃; for 1h;	86.64%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + 8-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]octanoic acid → C43H45N9O6

Conditions	Yield
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	86%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	86%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + methanesulfonyl chloride (124-63-0) → (R)-1-(1-(methylsulfonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	85%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + 9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]nonanoic acid → C44H47N9O6

Conditions	Yield
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	85%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	85%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + Ethanesulfonyl chloride (594-44-5) → (R)-1-(1-(ethylsulfonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	83%

n-propanesulfonyl chloride (10147-36-1) + (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) → (R)-3-(4-phenoxyphenyl)-1-(1-(propylsulfonyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	83%

3,3-dimethylbutanoic acid chloride (7065-46-5) + (R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) → (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3,3-dimethylbutan-1-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	82%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + cyclopropanecarboxylic acid chloride (4023-34-1) → (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(cyclopropyl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	82%

(R)-3-(4-phenoxyphenyl)-1-(1-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1022150-12-4) + acrylic acid methyl ester (292638-85-8) → ibrutinib

Conditions	Yield
With zirconium(IV) tert-butoxide; benzotriazol-1-ol In toluene at 60℃; for 12h; Temperature;	82%

Upstream product

• 5305-40-8 2,6-dichloro-pyrimidine carbaldehyde 
• 101-55-3 4-Bromodiphenyl ether 
• 1276110-38-3 (R)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester 
• 2380-63-4 4-Aminopyrazolo<3,4-d>pyrimidin 
• 151266-23-8 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 
• 5305-45-3 4,6-dichloro-5-cyanopyrimidine 
• 188111-79-7 tert-butyl (3R)3-aminopiperidine-1-carboxylate 
• 330786-24-8 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 94944-69-1 (S)-3-hydroxypiperidine-N-carboxylate benzyl ester 
• 85275-45-2 N-tert-butoxycarbonyl-3-piperidinol 
• 77287-34-4 formamide 

Downstream Products

• 1412418-18-8 (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile 
• 1412418-65-5 _{(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile} 
• 936563-87-0 ibrutinib 
• 1710768-30-1 (R,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)-4-(4-(2-aminoethyl)piperazin-1-yl)but-2-en-1-one 
• 1553977-42-6 3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3.4-d]pyrimidin-4-amine hydrochloride salt 

Relevant articles and documents

A synthetic method of ibutinib

The present invention provides a preparation method of ibutinib and its application, by optimizing the feeding ratio and reaction conditions, increasing the purification step of the intermediate, and the use of inorganic alkali instead of organic base as an acid binding agent, significantly reducing the impurity content of ibutinib synthetic intermediates and final products, especially the content of isomer impurities, to ensure the quality of drugs and clinical drug safety provides a strong guarantee.

PROCESSES AND INTERMEDIATES FOR PREPARING A BTK INHIBITOR

Disclosed is a process for the preparation of certain intermediates, e.g. a process for preparing a compound of formula (I) wherein, R1, R2 and X1 are as defined in the description, and which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

Preparation method of precursor of ibrutinib

The invention relates to the pharmaceutical industry, in particular to a preparation method of a drug intermediate, and specifically discloses a preparation method of a precursor of ibrutinib. The preparation method comprises the following steps: (1) reacting a compound (III) with triphenylphosphine and azodicarbonic acid diester to obtain an intermediate (III-B); (2) reacting the intermediate (III-B) with a compound (IV) under the action of a catalyst to obtain an intermediate (V-C); and (3) reacting the intermediate (V-C) under the action of hydrochloric acid to obtain (R)-3-(4-phenoxy phenyl)-1-(piperidine-3-yl)-1H-pyrazolo [3, 4-d] pyrimidine-4-amine (I). The method has the advantages of high yield, high purity, convenience in purification, simplicity and convenience in operation and the like, is suitable for industrial production, and contributes to reducing the cost to a certain extent.