477600-74-1

Basic information

• Product Name: N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
• Synonyms: N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;N-Methyl-N-((3R,4R)-4-Methylpiperidin-3-yl)-7HMethylpiperidin-3-yl)-7Hpyrrolo[ 2,3-d]pyriMidin-4-aMine;(3R,4R)-N,4-diMethyl-N-{7H-pyrrolo[2,3-d]pyriMidin-4-yl}piperidin-3-aMine;7H-Pyrrolo[2,3-d]pyriMidin-4-aMine, N-Methyl-N-[(3R,4R)-4-Methyl-3-piperidinyl]-;N-Methyl-N-((3R,4R)-4-Methyl-piperidin-3-yl)-N-Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-aMine;(3R,4R)-Methyl{(4-Methylpiperidin-3-yl)(7H-pyrrolo[2,3-d]pyriMidin-4-yl)}aMine;1H-Pyrrolo[2,3-d]pyriMidin-4-aMine,N-Methyl-N-[(3R,4R)-4-Methyl-3-piperidinyl]- (9CI);H-Pyrrolo[2,3-d]pyriMidin-4-aMine
• CAS NO: 477600-74-1
• Molecular Formula: C₁₃H₁₉N₅
• Molecular Weight: 245.32346
• Mol File: 477600-74-1.mol
• Article Data: 38

Chemical Properties

• Appearance: /
• Density: 1.198 g/cm³
• Refractive Index: 1.636
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Aqueous Acid (Slightly), Methanol (Slightly), Water (Slightly, Heated)
• PKA: 13.36±0.50(Predicted)
• CAS DataBase Reference: N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(CAS DataBase Reference)
• NIST Chemistry Reference: N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(477600-74-1)
• EPA Substance Registry System: N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(477600-74-1)

Safety Data

• Hazardous Substances Data: 477600-74-1(Hazardous Substances Data)

Usage

Uses

N-Methyl-N-((3S,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, is an intermediate in the synthesis of (3S,4R)-Tofacitinib (T528010), an enantiopure stereoisomer of the drug, Janus kinase 3(Jak3) inhibitor (CP-690,550) that has been found to inhibit selected members of the STE7 and STE20 subfamily of kinases.

InChI:InChI=1/C13H19N5/c1-9-3-5-14-7-11(9)18(2)13-10-4-6-15-12(10)16-8-17-13/h4,6,8-9,11,14H,3,5,7H2,1-2H3,(H,15,16,17)/t9-,11+/m1/s1

Synthetic route

(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-2-chloro-N-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In water at 65 - 75℃; under 1551.49 Torr; for 3h; Inert atmosphere;	96%
With triethylsilane; 5%-palladium/activated carbon; acetic acid In methanol at 30℃; for 0.166667h;	93.1%
With 10 wt% Pd(OH)2 on carbon; hydrazine hydrate; acetic acid In ethanol at 70 - 75℃; for 2h; Reagent/catalyst;	75.8%

(3R,4R)-tert-butyl 4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (1450663-24-7) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With zinc dibromide In dichloromethane for 12h;	95%

((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amine → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With palladium 10% on activated carbon; 20% palladium hydroxide-activated charcoal; hydrogen In methanol at 45℃; under 6000.6 Torr;	93%
With 20% palladium hydroxide-activated charcoal; ammonium formate In methanol at 60℃; for 6h; Solvent; Reagent/catalyst; Temperature; Inert atmosphere;	93.3%
With 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid In methanol; water at 50℃; under 3000.3 - 4500.45 Torr; for 12h;	92.38%

C20H25N5*CH2O2 → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With potassium carbonate In dichloromethane; water at 20℃; for 1h;	91%

C27H31N5 → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With palladium on activated charcoal; hydrogen In ethanol at 60 - 70℃;	85%

3-(3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-(yl)amino)piperidin-1-yl)-3-oxopropionic acid → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With sulfuric acid at 90℃;	28.9%

(S)-5-hydroxypiperidin-2-one (24211-54-9) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 1H-imidazole / 24.5 h / 5 - 20 °C 2.1: 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 2.2: 2 h 3.1: n-butyllithium; hexamethyldisilazan / tetrahydrofuran; hexane / 0.5 h / -78 °C 3.2: 2 h / -78 °C 4.1: magnesium / diethyl ether 4.2: 0.25 h / -20 °C 4.3: 2 h / 20 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 7.1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 8.1: zinc dibromide / dichloromethane / 12 h View Scheme

(5S)-5-tert-butyldiphenylsilyloxy-piperidine-2-one (176966-76-0) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 1,4-diaza-bicyclo[2.2.2]octane; n-butyllithium / tetrahydrofuran / 1 h / -78 °C 1.2: 2 h 2.1: n-butyllithium; hexamethyldisilazan / tetrahydrofuran; hexane / 0.5 h / -78 °C 2.2: 2 h / -78 °C 3.1: magnesium / diethyl ether 3.2: 0.25 h / -20 °C 3.3: 2 h / 20 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 6.1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 7.1: zinc dibromide / dichloromethane / 12 h View Scheme

7-deazaadenine (1500-85-2) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: water; acetonitrile / 0.25 h / 20 °C 1.2: 1 h 2.1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 3.1: zinc dibromide / dichloromethane / 12 h View Scheme

tert-butyl (5S)-5-tert-butyldiphenylsilyloxy-piperidine-2-one-1-carboxylate (176966-77-1) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: n-butyllithium; hexamethyldisilazan / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 2 h / -78 °C 2.1: magnesium / diethyl ether 2.2: 0.25 h / -20 °C 2.3: 2 h / 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 5.1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 6.1: zinc dibromide / dichloromethane / 12 h View Scheme

tert-butyl (5S)-5-(tert-butyldiphenylsilyloxy)-3,4-dehydro-piperidine-2-one-1-carboxylate (176966-78-2) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: magnesium / diethyl ether 1.2: 0.25 h / -20 °C 1.3: 2 h / 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 4.1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 5.1: zinc dibromide / dichloromethane / 12 h View Scheme

(4R,5S)-5-(tert-Butyl-diphenyl-silanyloxy)-4-methyl-2-oxo-piperidine-1-carboxylic acid tert-butyl ester (176966-79-3) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 3: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 4: zinc dibromide / dichloromethane / 12 h View Scheme

tert-butyl (3S,4R)-3-(tert-butyldiphenylsilyloxy)-4-methyl-piperidine-1-carboxylate (176966-86-2) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 20 °C 2: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 3: zinc dibromide / dichloromethane / 12 h View Scheme

tert-butyl (3S,4R)-3-hydroxy-4-methyl-piperidine-1-carboxylate (176966-87-3) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: di-isopropyl azodicarboxylate; triphenylphosphine / 1,4-dioxane / 2 h / 100 °C 2: zinc dibromide / dichloromethane / 12 h View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / 1,4-dioxane / 4 h / 0 - 90 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 24 h / 20 °C 3.1: hydrogenchloride / tetrahydrofuran / 1 h / 20 °C View Scheme

methyl-(1-trityl-4-methylpiperidin-3-yl)carbamate (1616760-91-8) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 2.1: ethyl acetate / 3 h / 25 - 30 °C 3.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 4.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 5.2: Reflux View Scheme
Multi-step reaction with 6 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 3.1: water; methanol / 8 - 9 h / 20 - 70 °C 4.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 5.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 6.2: Reflux View Scheme
Multi-step reaction with 7 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 2: ethyl acetate / 3 h / 25 - 30 °C 3: potassium carbonate / ethyl acetate; water / pH 9 - 10 4: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 5: sodium hydroxide / water; acetone / 55 - 60 °C 6: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 7: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

1-triryI-N,4-dimethylpiperidin-3-amine hydrochloride → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: water; methanol / 8 - 9 h / 20 - 70 °C 2.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 3.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 4.2: Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / water / pH 7 - 8 2.1: ethyl acetate / 3 h / 25 - 30 °C 3.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 4.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 5.2: Reflux View Scheme
Multi-step reaction with 6 steps 1: water; methanol / 8 - 9 h / 20 - 70 °C 2: potassium carbonate / ethyl acetate; water / pH 9 - 10 3: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 4: sodium hydroxide / water; acetone / 55 - 60 °C 5: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 6: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

1-triryI-N,4-dimethylpiperidin-3-amine (1616833-40-9) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ethyl acetate / 3 h / 25 - 30 °C 2.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 3.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 4.2: Reflux View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 2.1: water; methanol / 8 - 9 h / 20 - 70 °C 3.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 4.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 5.2: Reflux View Scheme
Multi-step reaction with 6 steps 1: ethyl acetate / 3 h / 25 - 30 °C 2: potassium carbonate / ethyl acetate; water / pH 9 - 10 3: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 4: sodium hydroxide / water; acetone / 55 - 60 °C 5: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 6: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

(3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine di-p-toluyl-D-tartaric acid salt → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 2.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 3.2: Reflux View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / ethyl acetate; water / pH 9 - 10 2: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 3: sodium hydroxide / water; acetone / 55 - 60 °C 4: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 5: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / ethyl acetate; water / pH 9 - 10 2: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 3: trifluoroacetic acid / dichloromethane / 3 h / 5 - 10 °C 4: sodium hydroxide / water; acetone / 50 - 55 °C 5: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

(3R,4R)-1-trityl-N,4-dimethylpiperidin-3-amine (1616760-93-0) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 2.2: Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 2: sodium hydroxide / water; acetone / 55 - 60 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 4: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 2: trifluoroacetic acid / dichloromethane / 3 h / 5 - 10 °C 3: sodium hydroxide / water; acetone / 50 - 55 °C 4: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

2,4-dichloro-7-p-methylbenzenesulfonyl-7H-pyrrole[2,3-d]pyrimidin-4-amine (934524-10-4) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 70 - 75 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 2.2: Reflux View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 2.2: Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 70 - 75 °C 2: sodium hydroxide / water; acetone / 55 - 60 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 4: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (90213-66-4) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; acetone / 2 - 3 h / 0 - 30 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 70 - 75 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 3.2: Reflux View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; acetone / 2 - 3 h / 0 - 30 °C 2.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 3.2: Reflux View Scheme
Multi-step reaction with 5 steps 1: sodium hydroxide / water; acetone / 2 - 3 h / 0 - 30 °C 2: potassium carbonate / N,N-dimethyl-formamide / 10 h / 70 - 75 °C 3: sodium hydroxide / water; acetone / 55 - 60 °C 4: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 5: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

C39H38ClN5O2S (1616760-94-1) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Stage #1: C39H38ClN5O2S With palladium 10% on activated carbon; hydrogen In methanol at 45 - 55℃; under 3750.38 Torr; for 10h; Stage #2: With sodium hydroxide In methanol; water Reflux;
Multi-step reaction with 3 steps 1: sodium hydroxide / water; acetone / 55 - 60 °C 2: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 3: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 3 h / 5 - 10 °C 2: sodium hydroxide / water; acetone / 50 - 55 °C 3: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

C20H24ClN5O2S (1616760-95-2) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water; acetone / 50 - 55 °C 2: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

C32H32ClN5 (1616760-96-3) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 2: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

N-((3R,4R)-4-methyl-piperidin-3-yl)-N-methyl-2-chloro-7H-pyrrolo[2,3-D]pyrimidine-4-amine (1616760-97-4) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
With 10% palladium hydroxide on charcoal; hydrogen In methanol at 50 - 55℃; under 5250.53 - 6000.6 Torr; for 4h; Solvent; Reagent/catalyst; Temperature; Pressure; Time;	25 g

O-methyl-N-(4-methylpyridin-3-yl)carbamate (694495-63-1) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 10 steps 1: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 2: triethylamine / acetonitrile / 10 h / 65 - 70 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 5: water; methanol / 8 - 9 h / 20 - 70 °C 6: potassium carbonate / ethyl acetate; water / pH 9 - 10 7: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 8: sodium hydroxide / water; acetone / 55 - 60 °C 9: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 10: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 10 steps 1: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 2: triethylamine / acetonitrile / 10 h / 65 - 70 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 5: water; methanol / 8 - 9 h / 20 - 70 °C 6: potassium carbonate / ethyl acetate; water / pH 9 - 10 7: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 8: trifluoroacetic acid / dichloromethane / 3 h / 5 - 10 °C 9: sodium hydroxide / water; acetone / 50 - 55 °C 10: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 7 steps 1.1: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 2.1: triethylamine / acetonitrile / 10 h / 65 - 70 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 4.1: ethyl acetate / 3 h / 25 - 30 °C 5.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 6.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 7.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 7.2: Reflux View Scheme

3-amino-4-methylpyridine (3430-27-1) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 10 steps 1: potassium tert-butylate / 1 h / 10 - 15 °C 2: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 3: triethylamine / acetonitrile / 10 h / 65 - 70 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 5: ethyl acetate / 3 h / 25 - 30 °C 6: potassium carbonate / ethyl acetate; water / pH 9 - 10 7: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 8: sodium hydroxide / water; acetone / 55 - 60 °C 9: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 10: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 10 steps 1: potassium tert-butylate / 1 h / 10 - 15 °C 2: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 3: triethylamine / acetonitrile / 10 h / 65 - 70 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 5: ethyl acetate / 3 h / 25 - 30 °C 6: potassium carbonate / ethyl acetate; water / pH 9 - 10 7: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 8: trifluoroacetic acid / dichloromethane / 3 h / 5 - 10 °C 9: sodium hydroxide / water; acetone / 50 - 55 °C 10: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 11 steps 1: potassium tert-butylate / 1 h / 10 - 15 °C 2: 5wt.% Rh on activated alumina; hydrogen / acetic acid / 10 h / 70 - 75 °C / 5250.53 - 6000.6 Torr 3: triethylamine / acetonitrile / 10 h / 65 - 70 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 5: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 6: water; methanol / 8 - 9 h / 20 - 70 °C 7: potassium carbonate / ethyl acetate; water / pH 9 - 10 8: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 9: sodium hydroxide / water; acetone / 55 - 60 °C 10: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 11: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

methyl-(4-methylpiperidin-3-yI)carbamate → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triethylamine / acetonitrile / 10 h / 65 - 70 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 3.1: ethyl acetate / 3 h / 25 - 30 °C 4.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 5.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 6.2: Reflux View Scheme
Multi-step reaction with 7 steps 1.1: triethylamine / acetonitrile / 10 h / 65 - 70 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 3.1: hydrogenchloride / ethyl acetate / 0.5 h / 25 - 30 °C / pH 2 - 3 4.1: water; methanol / 8 - 9 h / 20 - 70 °C 5.1: potassium carbonate / ethyl acetate; water / pH 9 - 10 6.1: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 7.1: palladium 10% on activated carbon; hydrogen / methanol / 10 h / 45 - 55 °C / 3750.38 Torr 7.2: Reflux View Scheme
Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 10 h / 65 - 70 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 3: ethyl acetate / 3 h / 25 - 30 °C 4: potassium carbonate / ethyl acetate; water / pH 9 - 10 5: potassium carbonate / acetonitrile; N,N-dimethyl-formamide / 6 h / 70 - 75 °C 6: sodium hydroxide / water; acetone / 55 - 60 °C 7: trifluoroacetic acid / dichloromethane / 1 h / 5 - 10 °C 8: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 50 - 55 °C / 5250.53 - 6000.6 Torr View Scheme

N-(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (477600-70-7) → tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / water / 48 h / 110 °C / Sealed tube 2: hydrogen; palladium 10% on activated carbon; 20% palladium hydroxide-activated charcoal / methanol / 45 °C / 6000.6 Torr View Scheme

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + formaldehyd (50-00-0) → C14H21N5

Conditions	Yield
With acetic acid; zinc In water at 20℃; Reagent/catalyst; Concentration;	99.25%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + ethyl 2-cyanoacetate (105-56-6) + citric acid (77-92-9) → Tofacitinib citrate

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In butan-1-ol at 80℃; for 0.166667h;	96.4%
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; ethyl 2-cyanoacetate With 1,8-diazabicyclo[5.4.0]undec-7-ene In butan-1-ol at 40℃; for 20h; Inert atmosphere; Stage #2: citric acid In water; butan-1-ol at 22 - 81℃; for 2.5h; Inert atmosphere;	93%
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; ethyl 2-cyanoacetate With 1,8-diazabicyclo[5.4.0]undec-7-ene In butan-1-ol at 35 - 45℃; for 7h; Inert atmosphere; Stage #2: citric acid In water; butan-1-ol at 20 - 90℃; Inert atmosphere;	90.3%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + cyanoacetic acid (372-09-8) → tasocitinib

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Schlenk technique;	96%
With potassium carbonate; 4-pyrrolidin-1-ylpyridine; diisopropyl-carbodiimide In dichloromethane at 35℃; for 1h; pH=7 - 8; Solvent; Reagent/catalyst; Temperature; Inert atmosphere; Industrial scale;	89.7%
With 1,1'-carbonyldiimidazole In dichloromethane at 40℃; for 10h;	89.21%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + ethyl 2-cyanoacetate (105-56-6) → tasocitinib

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol at 5 - 20℃; for 8h; Temperature; Solvent;	91%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20 - 30℃; for 24h;	78%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 60 - 65℃; Solvent;	76.9%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + cycl-isopropylidene malonate (2033-24-1) → 3-(3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-(yl)amino)piperidin-1-yl)-3-oxopropionic acid

Conditions	Yield
In acetonitrile at 20℃; Solvent; Temperature;	87.7%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + ethyl 2-cyanoacetate (105-56-6) → 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile citrate

Conditions	Yield
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; ethyl 2-cyanoacetate With 1,8-diazabicyclo[5.4.0]undec-7-ene In butan-1-ol at 40℃; for 18h; Stage #2: With citric acid monohydrate In water; butan-1-ol at 80℃; for 0.5h;	87.6%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + succinimidyl cyanoacetate (56657-76-2) → tasocitinib

Conditions	Yield
In ethanol at 20℃; for 2h;	86%
In ethanol at 25℃; for 3h; Temperature; Time;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In toluene at 40℃; for 2h; Large scale;

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + diethyl malonate (105-53-3) → C18H25N5O3

Conditions	Yield
With triethylamine In methanol for 9h; Reflux;	85%

5-methyl-1,2-oxazole-4-carboxylic acid (42831-50-5) + tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) → ((3R,4R)-4-methyl-3-(methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(5-methylisoxazol-4-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 3h; Inert atmosphere; Cooling with ice; Enzymatic reaction;	80%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + cyanoacetic acid (372-09-8) → N-methyl-N-[(3R,4R)-4-methyl-3-piperidyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine cyanoacetate

Conditions	Yield
In acetonitrile at 60 - 65℃;	80%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + cyanoacetic acid (372-09-8) + citric acid (77-92-9) → Tofacitinib citrate

Conditions	Yield
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; cyanoacetic acid With benzotriazol-1-ol In dichloromethane at 20℃; for 12h; Stage #2: citric acid In acetone at 40℃; for 2h;	70%
Stage #1: cyanoacetic acid With pivaloyl chloride; triethylamine In dichloromethane at -15 - 0℃; for 2.5h; Stage #2: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate In dichloromethane at 0℃; for 1h; Stage #3: citric acid In water; acetone at 55 - 65℃;	67.3%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + 1-cyano-cyclopropanecarboxylic acid (6914-79-0) → 1-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carbonyl)cyclopropanecarbonitrile

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at -10 - 10℃;	56.82%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + 5-cyclopropylisoxazole-4-carboxylic acid (124845-04-1) → (5-cyclopropylisoxazol-4-yl)((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidin-1-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 1.5h; Inert atmosphere; Cooling with ice;	53%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + 5-Isopropyl-4-isoxazolecarboxylic acid (134541-05-2) → C20H26N6O2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 1.5h; Inert atmosphere; Cooling with ice;	53%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + N-((tert-butyloxy)carbonyl)iminodiacetic acid (56074-20-5) → C30H41N11O2

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide at 5 - 30℃; Reagent/catalyst; Temperature;	43.7%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + 2,2'-(4-methoxybenzyl)imino-diacetic acid (1217900-36-1) → C30H41N11O2

Conditions	Yield
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; N-4-methoxyphenylmethyliminodiacetic acid With dmap; dicyclohexyl-carbodiimide at 10 - 35℃; Stage #2: With palladium on activated charcoal; hydrogen at -10℃; under 11251.1 Torr;	40.8%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + methoxycarbonylimino-di-acetic acid → C30H41N11O2

Conditions	Yield
With 4-pyrrolidin-1-ylpyridine; dicyclohexyl-carbodiimide at 5 - 40℃; Temperature;	35%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + methyl chloroformate (79-22-1) → methyl (3R,4R)-4-methyl-3-[methyl({7H-pyrrolo[2,3-d]pyrimidin-4-yl})amino]piperidine-1-carboxylate

Conditions	Yield
With potassium carbonate In dichloromethane at 0 - 20℃; for 0.333333h; Inert atmosphere; Schlenk technique;	34%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + (S)-4-nitrophenyl 3-hydroxypyrrolidine-1-carboxylate (1269920-81-1) → ((S)-3-hydroxypyrrolidin-1-yl)((3R,4R)-4-methyl-3-(methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methanone (1259403-96-7)

Conditions	Yield
With triethylamine In tert-butyl alcohol at 100℃; for 48h;	33%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + acryloyl chloride (814-68-6) → 1-((3R,4R)-4-methyl-3-(methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one

Conditions	Yield
In dichloromethane at 0℃; for 1h;	32%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + N-benzyliminodiacetic acid (3987-53-9) → C30H41N11O2

Conditions	Yield
Stage #1: tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate; N-benzyliminodiacetic acid With dmap; dicyclohexyl-carbodiimide at 10 - 30℃; Stage #2: With palladium on activated charcoal; hydrogen under 15001.5 Torr; for 10h; Temperature;	32%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + 5-Ethyl-4-isoxazolecarboxylic acid (134541-03-0) → (5-ethylisoxazol-4-yl)((3R,4R)-4-methyl-3-(methyl-(7H-pyrrolo[2,3-d]Pyrimidin-4-yl)amino)piperidin-1-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 1.5h; Inert atmosphere; Cooling with ice;	31%

3-methyl isoxazole-4-carboxylic acid (17153-20-7) + tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) → ((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)(3-methylisoxazol-4-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 3h; Inert atmosphere; Cooling with ice;	23%

tert-butyl (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (477600-74-1) + acetyl chloride (75-36-5) → 1-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

Conditions	Yield
In pyridine; dichloromethane at 20℃; for 18h;	15%

Upstream product

• 3612-20-2 1-phenylmethyl-4-piperidone 
• 78727-16-9 4-(methylamino)-7H-pyrrolo<2,3-d>pyrimidine 
• 41979-39-9 4-piperidone hydrochloride 
• 1206824-67-0 methyl (1-benzyl-4-methylpiperidin-3-yl)carbamate hydrochloride 
• 39929-79-8 pyrrolo<2,3-d>pyrimidin-2,4-dione 
• 384338-20-9 (3S,4R)-1-benzyl-4-methylpiperidin-3-ol 
• 32018-96-5 1-benzyl-4-methyl-piperidin-3-one 

Downstream Products

• 540737-29-9 Tofacitinib citrate 
• 540737-29-9 tofacitinib hemi-citrate 
• 1259404-17-5 tasocitinib 
• 1675248-18-6 C₁₈H₂₅N₅O₃ 
• 540737-29-9 tofacitinib citrate 
• 1675248-19-7 C₁₆H₂₂N₆O₂ 

Relevant articles and documents

Preparation method of tofacitinib citrate

The invention discloses a preparation method of tofacitinib citrate. The method comprises the following steps: by taking 7-tert-butyloxycarbonyl-4-amino-7H-pyrrolo[2, 3-D]pyrimidine and 1-benzyl-4-methyl-piperidine-3-ketone as initial raw materials, carrying out condensation under a weak acidic condition, then carrying out N methylation, selective reduction, debenzylation and Boc removal, and carrying out ester exchange and citric acid salification at a high temperature to obtain the tofacitinib citrate. The method has the advantages of mild reaction conditions, simple post-treatment mode, reduction of the generation amount of hazardous wastes, environmental protection, cost saving, and facilitation of industrial production.

Short enantioselective total synthesis of (+)-tofacitinib

An enantioselective total synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor has been achieved from the readily available 4-piperidone. Proline catalysed hydroxylation is the key step for the synthesis of enantiopure 1-benzyl-4-methylpiperidin-3-ol.

Synthesis method of tofacitinib citrate

The invention discloses a tofacitinib citrate synthesis method, belongs to the technical field of tofacitinib citrate preparation, and can effectively inhibit activity of Janus and JAK1 JAK3, block signal transduction of various inflammatory cytokines, and has an expensive catalyst application in the existing synthesis step. The method uses 1 - benzyl -4 - methyl -3 - (methylamino) piperidine hydrochloride as a raw material to prepare the tofacitinib citrate as a raw material, and then the citric acid tofacitinib citrate is obtained through twice refining 4 -7 - and the - 7H - yield and 2 the 3 - D purity of the tofacitinib citrate are improved.