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

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

Used in Pharmaceutical Industry:
N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is used as an intermediate in the synthesis of (3S,4R)-Tofacitinib (T528010) for its role as a Janus kinase 3 (Jak3) inhibitor. The application reason is that it helps in the development of drugs that can inhibit selected members of the STE7 and STE20 subfamily of kinases, which are involved in various cellular processes and are potential therapeutic targets for various diseases.
Used in Research and Development:
In the field of research and development, N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is used as a key compound in the synthesis of novel Jak3 inhibitors. The application reason is to explore the potential of these inhibitors in treating various diseases by targeting the specific kinases involved in their pathogenesis.
Used in Drug Design and Optimization:
N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine is also used in drug design and optimization processes. The application reason is to improve the potency, selectivity, and pharmacokinetic properties of Jak3 inhibitors, leading to more effective and safer therapeutic options for patients.

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

• 479633-63-1 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine 
• 1354621-59-2 cis-N-benzyl-3-methylamino-4-methylpiperidine 
• 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 

Downstream Products

• 1259404-17-5 tasocitinib 
• 540737-29-9 Tofacitinib citrate 
• 540737-29-9 tofacitinib hemi-citrate 
• 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.

Preparation method of tofacitinib hydrolysis impurity

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a tofacitinib hydrolysis impurity. The method comprises the following steps: dissolving isopropyl malonate in an organic solvent, adding N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, conducting stirring at room temperature until the reaction is finished, and recrystallizing the reaction solution to obtain the tofacitinib hydrolysis impurity. The synthesis method provided by the invention is simple, the tofacitinib hydrolysis impurity obtainedby the method is recrystallized for separation, the purity is high, the yield is high, and the impurity compound can be used as an impurity reference substance in tofacitinib finished product detection standards.

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.

Process for the preparation of tofacitinib and intermediates thereof

Provided is a process for the preparation of high purity tofacitinib, which reduces formation of N-methyl impurity. The invention also provides novel intermediates used in the process to prepare tofacitinib. There is provided an improved process for the preparation of tofacitinib (I), comprising the steps of: adding cyanoacetic acid in molar equivalent 0.2-1.2 to compound of formula (II-S), followed by addition of carbodiimide coupling agent of formula (III), optionally reacting tofacitinib base with citric acid.

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.

PROCESSES FOR PREPARING (3R,4R)-1-BENZYL-N,4-DIMETHYLPIPERIDIN-3-AMINE OR A SALT THEREOF AND PROCESSES FOR PREPARING TOFACITINIB USING THE SAME

The present invention provides a novel process for preparing (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine or a salt thereof, which is an intermediate useful for the preparation of tofacitinib. The present invention also provides a novel intermediate used in the process, i.e., isopropanol solvate of methyl ((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)carbamate dibenzoyl-L-tartrate. The present invention also provides a novel intermediate, having excellent stability, useful for the preparation of tofacitinib, i.e., (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine acetate. In addition, the present invention provides a process for preparing tofacitinib or a pharmaceutically acceptable salt thereof using the process.

Synthesis method of tofacitinib key intermediate

The invention relates to a method for preparing high-purity (N-methyl N ((3R, 4R)-4-methylpiperidine-3-yl)-7H-pyrrolo [2, 3-d] pyrimidine-4-amine (tofacitinib key intermediate). According to the method, 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine is taken as an initial raw material, benzyl protection, condensation reaction and dibenzyl protection removal reaction are carried out, and then purification is carried out, so that the product disclosed by the invention is obtained. The purity of the product (N-methyl N ((3R, 4R)-4-methylpiperidine-3-yl)-7H-pyrrolo [2, 3-d] pyrimidine-4-amine is 98% orabove; the total yield of the synthesis method is 80% or above; and the synthesis method is suitable for industrial production.

Synthesis method of tofacitinib citrate

The invention relates to the technical field of medicinal chemistry, and discloses a synthesis method of tofacitinib citrate. The method comprises 1) preparing 2,4-dihydroxy pyrrolopyrimidine: adding4-aminouracil and anhydrous sodium acetate into water (in a molar ratio of (1: 3)-(1: 5)), heating to 60-80 DEG C, slowly adding a 2-chloroacetaldehyde aqueous solution having a concentration of 40%,stirring to react for 4-6 hours, cooling to room temperature, filtering, washing a solid with water, and drying under reduced pressure to obtain 2,4-dihydroxy pyrrolopyrimidine. According to the synthesis method of tofacitinib citrate, through two times of impurity removal, the purity of the produced tofacitinib citrate finished product is higher, subsequent purification is not needed, the synthesis time is short, the process is simple, the method is suitable for factory production, the production time of the tofacitinib citrate finished product can be saved, the production efficiency of the tofacitinib citrate finished product is improved, and the tofacitinib citrate is more convenient to use.

Preparation method of tofacitinib or salt thereof (by machine translation)

The preparation method of the tofacitinib intermediate V compound comprises the following steps: (1) a compound II and a compound III are subjected to a photoreaction reaction to generate an intermediate IV; (2) an intermediate IV and a methylation reagent are subjected to methylation reaction to generate a compound of formula V; wherein R is. 1 And R2 Are each independently an amino protecting group. The preparation method disclosed by the invention does not need to be subjected to isomer resolution purification in the preparation method, avoids using tetrahydroaluminum hydride, is low in synthesis cost, high in yield, simple in reaction condition and post-treatment operation and suitable for industrial production. (by machine translation)

Preparation method of tofacitinib citrate

The invention relates to the field of medicine synthesis, and particularly discloses a preparation method of tofacitinib citrate. The preparation method comprises the following steps: S1, dissolving acompound SM1, a compound SM2 and an alkaline reagent in a solvent A, and performing a reaction to obtain a first compound; S2, taking and mixing a catalyst, a solvent B and the first compound, introducing hydrogen, and carrying out a catalytic hydrogenation reaction to obtain a second compound; S3, taking and mixing active anhydride, a solvent C and the second compound, and carrying out an acylation reaction to obtain a third compound, wherein R in the active anhydride comprises an alkyl group or an aryl group; and S4, taking and mixing citric acid, a solvent D and the third compound, and carrying out a salt-forming reaction to obtain a compound T that is the tofacitinib citrate. The preparation method has the advantages of easily available initial raw materials, no use of complex or toxic compounds, short synthesis process route, simple and convenient reaction operation of each step, high total yield and high productivity, and is suitable for large-scale industrial production.