260273-82-3

Basic information

• Product Name: 3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (Paliperidone)
• Synonyms: 3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (Paliperidone);3-(2-chloroethyl)-2-Methyl-9-hydroxy-4H-pyrido[1,2-a]pyriMidine-4-one;3-(2-Chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;9-Hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one
• CAS NO: 260273-82-3
• Molecular Formula: C₁₁H₁₁ClN₂O₂
• Molecular Weight: 238.673
• Product Categories: APIs Intermediate
• Mol File: 260273-82-3.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 413.1±55.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3(Predicted)
• Solubility: Dichloromethane; Methanol
• PKA: 8.05±0.20(Predicted)
• CAS DataBase Reference: 3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (Paliperidone)(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (Paliperidone)(260273-82-3)
• EPA Substance Registry System: 3-(2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (Paliperidone)(260273-82-3)

Safety Data

• Hazardous Substances Data: 260273-82-3(Hazardous Substances Data)

Usage

Uses

3-(2-Chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is a byproduct in the synthesis of 5-Fluoro Paliperidone (F595170), which is a Paliperidone (P141000) impurity.

Synthetic route

3-acetyl-2-oxo-4,5-dihydrofuran (517-23-7) + 2-amino-3-benzyloxypyridine (24016-03-3) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
With ammonium hydroxide; trichlorophosphate In water; toluene
Stage #1: 2-amino-3-benzyloxypyridine With trichlorophosphate In toluene at 25 - 30℃; Stage #2: 3-acetyl-2-oxo-4,5-dihydrofuran In toluene at 50 - 95℃; Stage #3: With sodium hydroxide In dichloromethane; water pH=4.7 - 5.0;
Stage #1: 2-amino-3-benzyloxypyridine With trichlorophosphate In toluene Stage #2: 3-acetyl-2-oxo-4,5-dihydrofuran In toluene at 90 - 95℃; for 7h; Stage #3: With water In toluene at 90 - 95℃; for 1h; Product distribution / selectivity;

2-amino-3-hydroxypyridine (16867-03-1) + 3-acetyl-2-oxo-4,5-dihydrofuran (517-23-7) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
With trichlorophosphate In water; toluene
Stage #1: 2-amino-3-hydroxypyridine; 3-acetyl-2-oxo-4,5-dihydrofuran With trichlorophosphate at 60 - 65℃; for 10h; Stage #2: With ammonia In water pH=5.5;

9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (147687-17-0) → 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
With hydrogenchloride; hydrogen; 1% Pd/C In methanol; water at 25 - 30℃; under 735.572 - 1471.14 Torr; for 1h; Product distribution / selectivity; Autoclave;	A 28.8 %Chromat. B 62 %Chromat.

3-acetyl-2-oxo-4,5-dihydrofuran (517-23-7) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / xylene / 20.5 h / 25 - 142 °C 2: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 21 h / 38 - 43 °C View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / xylene / 20.5 h / 25 - 142 °C 2: hydrogenchloride / isopropyl alcohol; methanol / 1 h / 60 - 65 °C / pH 1 - 3 3: ethylenediaminetetraacetic acid / water View Scheme

9-hydroxy-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (181525-38-2) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
Stage #1: 9-hydroxy-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 38 - 43℃; for 21h; Stage #2: With ammonia In water
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol; methanol / 1 h / 60 - 65 °C / pH 1 - 3 2: ethylenediaminetetraacetic acid / water View Scheme

2-amino-3-hydroxypyridine (16867-03-1) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / xylene / 20.5 h / 25 - 142 °C 2: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 21 h / 38 - 43 °C View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / xylene / 20.5 h / 25 - 142 °C 2: hydrogenchloride / isopropyl alcohol; methanol / 1 h / 60 - 65 °C / pH 1 - 3 3: ethylenediaminetetraacetic acid / water View Scheme

3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (849727-62-4) → 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3)

Conditions	Yield
Stage #1: 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride With ethylenediaminetetraacetic acid In water Stage #2: With sodium carbonate In water

3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3) → 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0)

Conditions	Yield
Stage #1: 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one With hydrogenchloride; palladium 10% on activated carbon In ethanol; water Green chemistry; Stage #2: With hydrogen In ethanol; water at 80℃; under 11251.1 Torr; Catalytic behavior; Solvent; Reagent/catalyst; Temperature; Pressure; Green chemistry;	99.32%
Stage #1: 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one With hydrogen; palladium 10% on activated carbon In acetic acid at 25 - 30℃; under 2206.72 Torr; Stage #2: With sodium hydroxide In dichloromethane; water pH=5.5 - 6.0; Product distribution / selectivity;
With hydrogen; palladium 10% on activated carbon In acetic acid at 35℃; under 735.572 - 2206.72 Torr; Product distribution / selectivity;

1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (43213-61-2) + 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3) → 3-[2-(3,4-dihydro-1H-benzo[4,5]furo[3,2-c]pyridin-2-yl)-ethyl]-9-hydroxy-2-methyl-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With sodium carbonate In various solvent(s) Condensation; Heating;

3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3) → 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-acetyloxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1117803-76-5)

Conditions	Yield
With hydrogen; acetic anhydride; acetic acid; palladium In water

3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (260273-82-3) → 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one hydrochloride

Conditions	Yield
With hydrogenchloride In methanol pH=0 - 1;

Upstream product

• 517-23-7 3-acetyl-2-oxo-4,5-dihydrofuran 
• 24016-03-3 2-amino-3-benzyloxypyridine 
• 16867-03-1 2-amino-3-hydroxypyridine 
• 147687-17-0 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 849727-62-4 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride 
• 181525-38-2 9-hydroxy-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 

Downstream Products

• 1117803-76-5 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-acetyloxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 130049-82-0 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 
• 144598-75-4 paliperidone 

Relevant articles and documents

METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER

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AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE

The present invention relates to a process for preparation and purification of 3-[2-[4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[1,2-a]pyrimidin-4-one, also known as paliperidone or 9-hydroxy risperidone.

PROCESS FOR PREPARATION OF 9-HYDROXY-3-(2-CHLOROETHYL)-2-METHYL-4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE HYDROCHLORIDE

Described herein is an improved, commercially viable and industrially advantageous process for the preparation of paliperidone intermediate 9-hydroxy-3-(2-chloroethyl)-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one and its hydrochloride salt. The process provides the paliperidone intermediate in higher yield and reduced reaction time compared to the previously disclosed processes, thereby providing for production of paliperidone and its pharmaceutically acceptable acid addition salts in high purity and in high yield.