733039-20-8

Usage

Uses

Used in Pharmaceutical Industry:
5-Bromo-2-chloro-N-cyclopentylpyrimidin-4-amine is used as a chemical intermediate for the development of cdk4 inhibitors. These inhibitors are designed to treat cell proliferative disorders by targeting the cdk4 protein, which is involved in the regulation of cell cycle progression. By inhibiting cdk4, these compounds can potentially control the uncontrolled cell growth associated with various diseases, including cancer.
Used in Research and Development:
In addition to its application in the pharmaceutical industry, 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine can also be utilized in research and development settings. Scientists and researchers can use 5-broMo-2-chloro-N-cyclopentylpyriMidin-4-aMine to study the structure-activity relationships of cdk4 inhibitors and to develop new, more effective drugs for the treatment of cell proliferative disorders.
Used in Drug Synthesis:
5-Bromo-2-chloro-N-cyclopentylpyrimidin-4-amine is used as a key building block in the synthesis of various 2-aminopyridine-based cdk4 inhibitors. These inhibitors can be further optimized and modified to improve their potency, selectivity, and pharmacokinetic properties, ultimately leading to the development of more effective therapeutic agents for the treatment of cell proliferative disorders.

InChI:InChI=1/C9H11BrClN3/c10-7-5-12-9(11)14-8(7)13-6-3-1-2-4-6/h5-6H,1-4H2,(H,12,13,14)

Synthetic route

+ Cyclopentamine → 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8)

Conditions	Yield
In 1,4-dioxane at 20℃; for 6h;	100%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 6h; Inert atmosphere;	100%
With sodium hydrogencarbonate In dichloromethane at 20℃; for 13h; Reagent/catalyst; Solvent;	97.5%

cyclopentyl chloride (930-28-9) + 4-amino-5-bromo-2-chloropyrimidine (205672-25-9) → 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8)

Conditions	Yield
With triethylamine In methanol at 20℃;	92.74%
With copper diacetate; sodium hydroxide In dichloromethane at 80℃; for 10h;	77%

Cyclopentyl bromide (137-43-9) + 4-amino-5-bromo-2-chloropyrimidine (205672-25-9) → 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8)

Conditions	Yield
With copper(II) trifluoroacetate; sodium hydroxide In 1,4-dioxane at 80℃; for 6h; Reagent/catalyst; Solvent; Temperature;	90%

2,4-dichloro-5-bromopyrimidine (36082-50-5) + Cyclopentamine (1003-03-8) → 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + 5-bromo-4-chloro-N-cyclopentyl-2-pyrimidinamine

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0) In 1,4-dioxane at 20℃; Reagent/catalyst;

2-butenoic acid (3724-65-0) + 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → 2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one (1013916-37-4)

Conditions	Yield
With triethylamine; palladium dichloride In 1-methyl-pyrrolidin-2-one at 20 - 75℃; for 6h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere;	94.8%
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine With triethylamine; palladium dichloride In tetrahydrofuran at 60℃; for 5h; Stage #2: 2-butenoic acid In tetrahydrofuran for 2h; Temperature; Reagent/catalyst; Solvent;	89.08%
Stage #1: 2-butenoic acid; 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine With bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In tetrahydrofuran at 75℃; for 20h; Heck Reaction; Inert atmosphere; Stage #2: In acetic anhydride at 75℃; for 2h; Temperature; Reagent/catalyst; Solvent;	80%
With triethylamine; palladium dichloride In 1-methyl-pyrrolidin-2-one at 75℃; for 6h; Temperature; Inert atmosphere;

tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (571188-59-5) + 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → tert-butyl 4-(6-{[5-bromo-4-(cyclopentylamino)pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate (733038-80-7)

Conditions	Yield
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine With potassium carbonate In dichloromethane at 60℃; for 0.5h; Stage #2: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate In dichloromethane at 20 - 60℃; for 1h;	85%
Stage #1: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate; 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine In xylene; butan-1-ol at 100 - 140℃; Stage #2: With sodium hydroxide In water; ethyl acetate; xylene; butan-1-ol

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + prop-1-yne (74-99-7) → 2-chloro-4-cyclopentylamino-5-(propynyl)pyrimidine

Conditions	Yield
With triphenylphosphine; palladium dichloride In N,N-dimethyl-formamide at 50℃; for 20h; Reagent/catalyst; Solvent; Temperature;	85%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + methyl iodide (74-88-4) → (5-bromo-2-chloropyrimidin-4-yl)cyclopentylmethylamine

Conditions	Yield
With sodium hydride In tetrahydrofuran for 1.5h;	84%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + (E)-but-2-enoic acid (107-93-7) → 2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one (1013916-37-4)

Conditions	Yield
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine; (E)-but-2-enoic acid With palladium diacetate; triethylamine In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere; Stage #2: With acetic anhydride In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere;	81%
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine; (E)-but-2-enoic acid With N-ethyl-N,N-diisopropylamine; palladium(II) chloride benzonitrile complex; tris-(o-tolyl)phosphine In tetrahydrofuran at 70℃; for 16h; Stage #2: With acetic anhydride In tetrahydrofuran for 1.5h;	68%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + propargyl alcohol (107-19-7) → 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-ol (1374639-76-5)

Conditions	Yield
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine With copper(l) iodide; palladium on activated charcoal; N-ethyl-N,N-diisopropylamine; bis[2-(diphenylphosphino)phenyl] ether In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: propargyl alcohol In tetrahydrofuran for 5.5h; Reflux; Stage #3: With bis[2-(diphenylphosphino)phenyl] ether for 4h; Reflux;	74.5%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-butylamine In tetrahydrofuran at 29℃; for 20h; Sonogashira Cross-Coupling; Inert atmosphere; Reflux;	62%
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine; propargyl alcohol With tetrabutyl ammonium fluoride; bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran; water at 25 - 67℃; for 2h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In ethyl acetate	47.4%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → 2-chloro-4-cyclopentylaminopyrimidine-5-aldehyde

Conditions	Yield
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine With isopropylmagnesium chloride In tetrahydrofuran at 0 - 5℃; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 20℃; Inert atmosphere;	74%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + acrylic acid (79-10-7) → C12H14ClN3O2

Conditions	Yield
With copper(l) iodide; N-ethyl-N,N-diisopropylamine; triphenylphosphine; nickel dichloride In ethanol at 65℃; for 8h; Inert atmosphere;	73.1%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + propynoic acid ethyl ester (623-47-2) → C14H16ClN3O2

Conditions	Yield
With 1,4-diaza-bicyclo[2.2.2]octane; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In acetonitrile at 0 - 60℃; Inert atmosphere;	73%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + N,N-dimethylpropynamide (2682-34-0) → 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (1211443-61-6)

Conditions	Yield
With N,N'-Diphenyloxamid; potassium carbonate; copper(l) chloride In dimethyl sulfoxide at 90 - 100℃; for 12h; Reagent/catalyst;	73%
With N,N,N,N,-tetramethylethylenediamine; potassium carbonate; copper(l) chloride In dimethyl sulfoxide at 90 - 100℃; for 12h; Reagent/catalyst;	71%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + sodium thiomethoxide (5188-07-8) → 5‑bromo‑N‑cyclopentyl‑2‑(methylthio)pyrimidin‑4‑amine (733039-23-1)

Conditions	Yield
In dimethyl sulfoxide	72%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + (2-tert-butoxy-2-oxoethyl)zinc(II) bromide (51656-70-3) → tert-butyl 2-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acetate

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene In tetrahydrofuran; 1,4-dioxane at 20℃; for 1h; Inert atmosphere;	67%
With tris-(dibenzylideneacetone)dipalladium(0); monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene In tetrahydrofuran; 1,4-dioxane at 20℃; for 1h; Inert atmosphere;	67%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → 5-bromo-N4-cyclopentylpyrimidine-2,4-diamine (1169698-46-7)

Conditions	Yield
With ammonia In water; isopropyl alcohol at 120℃; for 22h;	66%
With ammonium hydroxide In isopropyl alcohol at 120℃; for 22h; Sealed tube; Inert atmosphere;	66%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + hydroxy-1-propyne (6175-54-8) → 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-ol (1374639-76-5)

Conditions	Yield
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; tetrabutyl ammonium fluoride In tetrahydrofuran at 70℃; for 5h;	65.9%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + 4-amino-N-(1-methylpiperidin-4-yl)benzamide (50534-11-7) → C22H29BrN6O

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 80℃; for 18h;	63%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + Propiolaldehyde diethyl acetal (10160-87-9) → [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl amine (1211442-87-3)

Conditions	Yield
Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine; Propiolaldehyde diethyl acetal With triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: copper(l) iodide In tetrahydrofuran at 60℃; for 48h; Product distribution / selectivity; Inert atmosphere;	54%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Sonogashira coupling;	41%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + trimethylsilylacetylene (1066-54-2) → 2-chloro-N-cyclopentyl-5-((trimethylsilyl)ethynyl)pyrimidin -4-amine (1383481-56-8)

Conditions	Yield
With 1-methyl-pyrrolidin-2-one; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 50℃; for 8h; Inert atmosphere;	53.1%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (119285-07-3) → 4-[5-(5-BROMO-4-CYCLOPENTYLAMINOPYRIMIDIN-2-YLAMINO)-PYNIDIN-2-YL]-PIPERAZINE-1-CARBOXYLIC acid tert-butyl ester (733039-28-6)

Conditions	Yield
With sodium t-butanolate In toluene at 115℃; for 48h;	45%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + 4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (876126-60-2) → C23H31BrN6O2

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 80℃; for 18h;	31%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + Methyl 2-butynoate (23326-27-4) → 2-chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (959799-27-0)

Conditions	Yield
With potassium carbonate; lithium chloride; palladium diacetate In N,N-dimethyl-formamide at 120℃; for 5h;	25%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) + Pent-3-yn-2-ol (57984-70-0, 58072-60-9, 90242-65-2, 27301-54-8) → 1-(2-Chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-ethanol (959799-21-4)

Conditions	Yield
With potassium acetate; lithium chloride; palladium diacetate In N,N-dimethyl-formamide at 120℃; for 5h;	14.8%

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (1211443-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 3: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: 1,4-diaza-bicyclo[2.2.2]octane; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / acetonitrile / 0 - 60 °C / Inert atmosphere 2: copper(l) chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 85 - 90 °C / Inert atmosphere 3: sodium hydroxide / methanol; water / 10 - 25 °C 4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / N,N-dimethyl-formamide; tetrahydrofuran / 0 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine; palladium dichloride / N,N-dimethyl-formamide / 20 h / 50 °C 2.1: tetrabutyl ammonium fluoride / ethanol / 16 h / 60 °C 3.1: N-Bromosuccinimide / 1,2-dichloro-ethane / 3 h / 20 °C / Sealed tube 3.2: 24 h / 100 °C / Sealed tube View Scheme

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → (7-cyclopentyl-Ν,Ν-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo [2,3-d]pyrimidine-6-carboxamide) (1211441-98-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 3.1: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 4.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 5.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 5.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 View Scheme
Multi-step reaction with 5 steps 1.1: triphenylphosphine; palladium dichloride / N,N-dimethyl-formamide / 20 h / 50 °C 2.1: tetrabutyl ammonium fluoride / ethanol / 16 h / 60 °C 3.1: N-Bromosuccinimide / 1,2-dichloro-ethane / 3 h / 20 °C / Sealed tube 3.2: 24 h / 100 °C / Sealed tube 4.1: potassium carbonate / dichloromethane / 0.5 h / 60 °C 4.2: 1 h / 60 °C 5.1: phosphoric acid / dichloromethane View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: sodium t-butanolate; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate / N,N-dimethyl acetamide / 0 - 110 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 10 - 25 °C View Scheme
Multi-step reaction with 7 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: sodium hydroxide / methanol; water / 10 - 45 °C 5.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran; N,N-dimethyl-formamide / 0 - 25 °C 6.1: sodium t-butanolate; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate / N,N-dimethyl acetamide / 0 - 110 °C / Inert atmosphere 7.1: hydrogenchloride / methanol; water / 10 - 25 °C View Scheme
Multi-step reaction with 7 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: caesium carbonate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 0 - 110 °C / Inert atmosphere 5.1: lithium hydroxide monohydrate / methanol; water / 10 - 45 °C 6.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran; N,N-dimethyl-formamide / 0 - 30 °C 7.1: hydrogenchloride / methanol; water / 10 - 25 °C View Scheme

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (1374639-77-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: N-butylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / tetrahydrofuran / 20 h / 29 °C / Inert atmosphere; Reflux 2: trifluoroacetic acid / tetrahydrofuran / 12 h / 29 - 60 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; tetrabutyl ammonium fluoride / tetrahydrofuran / 5 h / 70 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 70 °C View Scheme

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → N,N‐dimethyl‐7‐cyclopentyl‐2‐{[5‐(4-tert-butoxycarbonylpiperazin‐1‐yl)pyridin‐2‐yl]amino}‐7H‐pyrrolo[2,3‐d]pyrimidine‐6‐carboxamide (1374639-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 3: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 4: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: triphenylphosphine; palladium dichloride / N,N-dimethyl-formamide / 20 h / 50 °C 2.1: tetrabutyl ammonium fluoride / ethanol / 16 h / 60 °C 3.1: N-Bromosuccinimide / 1,2-dichloro-ethane / 3 h / 20 °C / Sealed tube 3.2: 24 h / 100 °C / Sealed tube 4.1: potassium carbonate / dichloromethane / 0.5 h / 60 °C 4.2: 1 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: sodium t-butanolate; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate / N,N-dimethyl acetamide / 0 - 110 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: caesium carbonate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 0 - 110 °C / Inert atmosphere 5.1: lithium hydroxide monohydrate / methanol; water / 10 - 45 °C 6.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran; N,N-dimethyl-formamide / 0 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0 - 5 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 45 - 50 °C 3.1: potassium tert-butylate / N,N-dimethyl-formamide / 0 - 30 °C 4.1: sodium hydroxide / methanol; water / 10 - 45 °C 5.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran; N,N-dimethyl-formamide / 0 - 25 °C 6.1: sodium t-butanolate; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate / N,N-dimethyl acetamide / 0 - 110 °C / Inert atmosphere View Scheme

5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine (733039-20-8) → 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate

Conditions

Yield

Multi-step reaction with 6 steps 1.1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 3.1: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 4.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 5.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 5.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 6.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere View Scheme

Upstream product

• 36082-50-5 2,4-dichloro-5-bromopyrimidine 
• 1003-03-8 Cyclopentamine 
• 137-43-9 Cyclopentyl bromide 
• 205672-25-9 4-amino-5-bromo-2-chloropyrimidine 
• 930-28-9 cyclopentyl chloride 

Downstream Products

• 733039-23-1 5?bromo?N?cyclopentyl?2?(methylthio)pyrimidin?4?amine 
• 733038-80-7 tert-butyl 4-(6-{[5-bromo-4-(cyclopentylamino)pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate 
• 959799-27-0 2-chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester 
• 1013916-37-4 2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one 
• 1374639-76-5 3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)prop-2-yn-1-ol 
• 1211443-61-6 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide 
• 1178566-48-7 2-chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine 
• 1651214-74-2 4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridine-3-yl]piperazine-1-carboxylic acid tert-butyl ester 
• 571190-30-2 PD 0332991 
• 866084-31-3 tert?butyl 4?(6?((6?(1?butoxyvinyl)?8?cyclopentyl?5?methyl?7?oxo?7,8?dihydropyrido[2,3?d]pyrimidin?2?yl)amino)pyridin?3?yl)piperazine?1?carboxylate 
• 571188-82-4 tert?butyl 4?(6?((6?bromo?8?cyclopentyl?5?methyl?7?oxo?7,8?dihydropyrido[2,3?d]pyrimidin?2?yl)amino)pyridin?3?yl)piperazine?1?carboxylate 
• 1016636-76-2 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridine[2,3-d]pyrimidin-8-hydro-7-one 
• 1383481-65-9 C₂₁H₂₀ClN₅ 
• 1383481-46-6 C₂₃H₂₉N₇O₂ 

Relevant academic research and scientific papers

Preparation method of palbociclib intermediate

The invention discloses a preparation method of a palbociclib intermediate. The method comprises the following steps: preparing 5-bromine-2-chloro-N-cyclopentylamine pyrimidine-4 amine from 5-bromine-2,4-dichloropyrimidine and cyclopentylamine by taking solvents such as dichloromethane and water as solvents and taking inorganic base as an acid-binding agent; with DIEA as an acid-binding agent, DMF as a solvent and TBAB as a phase transfer catalyst, in the presence of water, catalyzing with a trace amount of palladium, and carrying out normal hexane reflux dehydration; further subjecting the acetic anhydride to dehydration cyclization, such that 2-chloro-8-cyclopentyl-5-methylpyridino[2,3-D]pyrimidine-7-(8H)-ketone is obtained; and reacting the obtained compound with NBS (N-bromosuccinimide) in acetonitrile to obtain the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyridino[2, 3-D]pyrimidine-7(8H)-ketone. The method is mild in reaction, simple and convenient to operate, recyclable in solvent, less in environmental pollution, high in yield, low in cost, high in product quality and suitable for industrial production.

Preparation method of palbociclib

The invention provides a preparation method of palbociclib. Specifically, ethyl acetoacetate and acetaldehyde are subjected to condensation hydrolysis to prepare 2-acetyl-2-butenoic acid instead of crotonic acid, and tedious steps such as acetyl group loading are not needed, so a synthesis route is simplified. The preparation method is simple and safe, product purity is high, and product yield is improved.

Synthesis and cytotoxic studies of pyrrolopyrimidine derivatives

The synthesis and in vitro cytotoxicity of new pyrrolopyrimidine derivatives is reported in this work. All the compounds were characterized by IR, NMR and MS. They are examined for cytotoxic activity against HeLa. Pyrrolopyrimidine derivatives of benzyl amine (8g) and 4-bromoaniline (8k) showed a potent activity, which is comparable to that of standard Sorafenib.

Preparation method of CDK4/6 kinase inhibitor SHR6390

The invention relates to a preparation method of a CDK4/6 kinase inhibitor SHR6390. According to the preparation method disclosed by the invention, the SHR6390 can be rapidly and effectively prepared through six steps of chemical reactions. In the first step of reaction, the advantage of high reaction activity of the fourth site of pyrimidine is fully utilized, a target product compound 3 can be well obtained under mild conditions, in the fourth step of reaction, after-treatment of the synthesis reaction of a compound 8 is simple, a good white solid product can be obtained basically through filtration and washing, purification is not needed, and the method is suitable for amplification and process production.

Discovery of 5-methylpyrimidopyridone analogues as selective antimycobacterial agents

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and extensive drug-resistant strains (XDR-TB), there is an urgent need to develop novel drugs for the treatment of tuberculosis. Here, we designed and synthesized a series of 5-methylpyrimidopyridone analogues as potential antitubercular agents. The most potent compound 6q exhibited a MIC value of 4 μM in vitro against Mycobacterium tuberculosis. The antitubercular activities of the synthesized compounds were impacted by the amantadine and 2-chlorophenyl groups, and were enhanced by the presence of 3-methyl(4-dimethylamino)piperidinylphenyl. Molecular modeling and binding studies suggest that PknB is the potential molecular target of 5-methylpyrimidopyridone compounds. This study provides insights for the future development of new antimycobacterial agents with novel mechanisms of action.

CYCLIN-DEPENDENT KINASE 2 BIOMARKERS AND USES THEREOF

Biomarkers are provided that are predictive and/or indicative of a subject's responsiveness to a cyclin-dependent kinase 2 (CDK2) inhibitor. The biomarkers, compositions, and methods described herein are useful in selecting appropriate treatment modalities for a subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 and for monitoring treatment.

PYRROLO[2,3-D]PYRIMIDINONE COMPOUNDS AS CDK2 INHIBITORS

The present application provides pyrrolo[2,3-d]pyrimidinone (I) inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

Preparation method of palbociclib parent nucleus structure compound

The invention provides a preparation method of a palbociclib mother nucleus structure compound. The preparation method comprises the following step: preparing the palbociclib parent nucleus structurecompound as shown in a formula (I) which is described in the specification by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw material, wherein the intermediate 1 and the intermediate 2 are as described in the specification, and X is selected from halogen. The method is wide in the source of the starting material, simple in operation process, less in side reaction and high in purity, and accords with the concept of modern green industrial production.

CDK9 inhibitor, preparation method and application thereof

The invention provides a CDK9 inhibitor, the CDK9 inhibitor is a pyrimidopyrrole kinase inhibitor, and the chemical structural general formula of the CDK9 inhibitor is shown as the formula I in the specification, the CDK9 inhibitor is the pyrimidopyrrole kinase inhibitor, the protein target adapted to the pyrimidopyrrole kinase is serine/threonine kinase CDK9. The CDK9 inhibitor shows relatively high specificity and low cytotoxicity, and the CDK9 inhibitor which is used for preventing or treating tumor growth and metastasis, has selectivity on CDK9, and is small in toxic and side effects and strong in action effect is provided, so that the CDK9 inhibitor is used for regulating and controlling the biological function of CDK9 and inhibiting the growth and proliferation processes of tumors.

Preparation process of palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine

Relating to the technical field of drugs, the invention provides an industrial preparation process of a palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine (M1). The process comprises the steps of: (1) under a room temperature condition, selecting a weak alkaline inorganic salt as an acid-binding agent, adopting a low-boiling point solvent as the reaction solvent, adding cyclopentylamine dropwise into 2, 4-dichloro-5-bromopyrimidine (M0), and carrying out reaction for 12-15h; (2) performing pumping filtration to remove inorganic salt, concentrating mother liquor to dry, andrecrystallizing the residue with a solvent of little polarity to obtain the intermediate M1, with the reaction formula shown as the specification. The preparation process provided by the invention has the advantages of simple operation steps, mild reaction conditions and simpler post-treatment needed by reaction, greatly improves the product yield and purity, effectively reduces the generation of2-substituted impurities, and is of great significance for promotion of palbociclib technology and better application to clinical patients.