130049-82-0

Basic information

• Product Name: 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
• Synonyms: 3-(2-CHLOROETHYL)-9-HYDROXY-2-METHYL-6,7,8,9-TETRAHYDRO-4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONE;3-(2-Chloroethyl)-2-methyl-9-hydroxy-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one;3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one;3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one;3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one ,98%;Paliperidone Intermediate 1;3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one
• CAS NO: 130049-82-0
• Molecular Formula: C₁₁H₁₅ClN₂O₂
• Molecular Weight: 242.7
• EINECS: 1308068-626-2
• Product Categories: Heterocyclic Compounds;Bases & Related Reagents;Heterocycles;Nucleotides
• Mol File: 130049-82-0.mol
• Article Data: 25

Chemical Properties

• Melting Point: 100-102°C
• Boiling Point: 389.3 °C at 760 mmHg
• Flash Point: 189.2 °C
• Appearance: pale-yellow solid
• Density: 1.41 g/cm³
• Vapor Pressure: 1.14E-07mmHg at 25°C
• Refractive Index: 1.634
• Storage Temp.: Refrigerator
• Solubility: Methanol (Slightly)
• PKA: 12.97±0.60(Predicted)
• CAS DataBase Reference: 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(130049-82-0)
• EPA Substance Registry System: 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(130049-82-0)

Safety Data

• Hazardous Substances Data: 130049-82-0(Hazardous Substances Data)

Usage

Chemical Properties

Pale-Yellow Solid

Uses

Paliperidone USP Related Compound C

InChI:InChI=1/C11H15ClN2O2/c1-7-8(4-5-12)11(16)14-6-2-3-9(15)10(14)13-7/h9,15H,2-6H2,1H3

Synthetic route

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;

3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (849727-62-4) → 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)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride With hydrogen; 5%-palladium/activated carbon In water; isopropyl alcohol at 55℃; under 760.051 Torr; Inert atmosphere; Stage #2: With potassium acetate In water Product distribution / selectivity;	92%
Stage #1: 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride In methanol at 50 - 55℃; Stage #2: With hydrogen; palladium 10% on activated carbon In methanol at 50 - 55℃; for 8h;	68.25%
Stage #1: 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride With pyrographite In methanol at 50 - 55℃; for 0.75h; Large scale; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol; dichloromethane at 25 - 30℃; under 2172.08 - 2947.82 Torr; Large scale;	39%

C11H14ClN3O2 (1204248-71-4) → 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: C11H14ClN3O2 With hydrogenchloride; titanium(III) chloride; water at 70℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In water	87%

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)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen In methanol; water; tert-butyl alcohol at 25 - 30℃; under 775.743 Torr; for 16h; Reagent/catalyst; Solvent; Pressure;	74.4%
With hydrogenchloride; hydrogen; palladium 10% on activated carbon In water at 25 - 30℃;	69%
With cyclohexene; palladium 10% on activated carbon for 19h; Product distribution / selectivity; Heating / reflux;

9-benzyloxy-3-(2-chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-79-5) → 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: 9-benzyloxy-3-(2-chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one With hydrogenchloride; hydrogen; 5% palladium over charcoal In methanol at 27℃; for 36h; pH=3.0; Inert atmosphere; Stage #2: With sodium hydroxide In water at 5℃; pH=10 - 11;	72.6%
With hydrogenchloride; hydrogen; palladium 10% on activated carbon In water at 25 - 30℃; under 735.572 - 1471.14 Torr; for 4 - 6h;	69%

3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-acetyloxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1117803-76-5) → 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
With sodium hydroxide In water

3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (1254173-48-2) → 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)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride With hydrogen; 1% Pd/C In acetic acid at 35℃; under 2206.72 - 2574.5 Torr; for 6h; Stage #2: With sodium hydroxide In water at 0℃; for 1h; pH=6; Product distribution / selectivity;

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.

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-ethyl-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (849903-79-3)

Conditions	Yield
With hydrogenchloride; hydrogen; 1% Pd/C In methanol; water at 25 - 30℃; under 735.572 - 1471.14 Torr; for 3.5h; Product distribution / selectivity; Autoclave;	A 48.9 %Chromat. B 39 %Chromat.

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one oxalate (1228559-69-0) → 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
With potassium acetate In water at 0 - 5℃; for 1h; pH=4.8;

3-acetyl-2-oxo-4,5-dihydrofuran (517-23-7) → 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
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: hydrogen; zinc(II) chloride / palladium on carbon / methanol / 35 - 55 °C View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / xylene / Reflux 2: thionyl chloride / N,N-dimethyl-formamide / 65 - 70 °C 3: hydrogen / palladium 10% on activated carbon / methanol / 23 - 30 °C / 1471.14 - 2206.72 Torr View Scheme
Multi-step reaction with 2 steps 1.1: trichlorophosphate / toluene 1.2: 7 h / 90 - 95 °C 1.3: 1 h / 90 - 95 °C 2.1: hydrogen / palladium 10% on activated carbon / acetic acid / 35 °C / 735.57 - 2206.72 Torr View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 0.25 h 1.2: 20 h / 70 °C / Reflux 2.1: hydrogenchloride / toluene; water / 9 h / 65 - 70 °C 3.1: hydrogen; palladium on activated charcoal; acetic acid / 6 h / 35 °C / 2250.23 - 2625.26 Torr / Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: trichlorophosphate / toluene / 24 h / 30 - 40 °C / Large scale 1.2: 0 - 5 °C / Large scale 2.1: pyrographite / methanol / 0.75 h / 50 - 55 °C / Large scale 2.2: 25 - 30 °C / 2172.08 - 2947.82 Torr / Large scale View Scheme

9-hydroxy-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (181525-38-2) → 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
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol; methanol / 1 h / 60 - 65 °C / pH 1 - 3 2: hydrogen; zinc(II) chloride / palladium on carbon / methanol / 35 - 55 °C View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / N,N-dimethyl-formamide / 65 - 70 °C 2: hydrogen / palladium 10% on activated carbon / methanol / 23 - 30 °C / 1471.14 - 2206.72 Torr View Scheme

2-amino-3-hydroxypyridine (16867-03-1) → 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
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: hydrogen; zinc(II) chloride / palladium on carbon / methanol / 35 - 55 °C View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / xylene / Reflux 2: thionyl chloride / N,N-dimethyl-formamide / 65 - 70 °C 3: hydrogen / palladium 10% on activated carbon / methanol / 23 - 30 °C / 1471.14 - 2206.72 Torr View Scheme
Multi-step reaction with 2 steps 1.1: trichlorophosphate / toluene / 24 h / 30 - 40 °C / Large scale 1.2: 0 - 5 °C / Large scale 2.1: pyrographite / methanol / 0.75 h / 50 - 55 °C / Large scale 2.2: 25 - 30 °C / 2172.08 - 2947.82 Torr / Large scale View Scheme
Multi-step reaction with 4 steps 1: sodium hydroxide; tetrabutylammomium bromide / water / 6 h / 40 - 75 °C / Large scale 2: toluene-4-sulfonic acid / toluene / Reflux; Large scale 3: trichlorophosphate / 1,2-dimethoxyethane / 6 h / Reflux; Large scale 4: hydrogenchloride; palladium 10% on activated carbon; hydrogen / water; methanol; tert-butyl alcohol / 16 h / 25 - 30 °C / 775.74 Torr View Scheme

3-acetyl-2-oxo-4,5-dihydrofuran (517-23-7) + 2-amino-3-benzyloxypyridine (24016-03-3) → 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
With hydrogenchloride; hydrogen; trichlorophosphate In cyclohexane; acetic acid; toluene

2-amino-3-benzyloxypyridine (24016-03-3) → 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
Multi-step reaction with 2 steps 1.1: trichlorophosphate / toluene 1.2: 7 h / 90 - 95 °C 1.3: 1 h / 90 - 95 °C 2.1: hydrogen / palladium 10% on activated carbon / acetic acid / 35 °C / 735.57 - 2206.72 Torr View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 0.25 h 1.2: 20 h / 70 °C / Reflux 2.1: hydrogenchloride / toluene; water / 9 h / 65 - 70 °C 3.1: hydrogen; palladium on activated charcoal; acetic acid / 6 h / 35 °C / 2250.23 - 2625.26 Torr / Autoclave View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / Reflux; Large scale 2: trichlorophosphate / 1,2-dimethoxyethane / 6 h / Reflux; Large scale 3: hydrogenchloride; palladium 10% on activated carbon; hydrogen / water; methanol; tert-butyl alcohol / 16 h / 25 - 30 °C / 775.74 Torr View Scheme

3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one hydrochloride → 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
With palladium on activated charcoal; hydrogen; acetic acid at 35℃; under 2250.23 - 2625.26 Torr; for 6h; Time; Temperature; Autoclave;	22 g

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + (Z)-(2,4-difluorophenyl) (4-piperidinyl)methanone, oxime monohydrochloride (138271-16-6) → C23H28F2N4O3

Conditions	Yield
With potassium iodide; sodium hydroxide In acetonitrile for 10h; Reflux;	99.2%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + chloromethyl methyl ether (107-30-2) → 3-(2-chloroethyl)-9-(methoxymethoxy)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-α]pyrimidin-4-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 45℃; Reagent/catalyst;	98%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 1-hexadecylcarboxylic acid (57-10-3) → 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one palmitate ester (1415488-05-9)

Conditions	Yield
Stage #1: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 1-hexadecylcarboxylic acid With dmap; triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Stage #2: With pivaloyl chloride In dichloromethane at 25 - 40℃; for 2h;	95%
Stage #1: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 1-hexadecylcarboxylic acid With dmap; triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Stage #2: With pivaloyl chloride In dichloromethane at 25 - 40℃; for 2h;	95%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (84163-13-3) → paliperidone (144598-75-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol for 24h; Reflux;	94%
With N-ethyl-N,N-diisopropylamine In methanol Product distribution / selectivity; Reflux;	93%
With N-ethyl-N,N-diisopropylamine In methanol at 60℃; Reagent/catalyst; Inert atmosphere;	90%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + methanesulfonyl chloride (124-63-0) → C12H17ClN2O4S

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 0.5h; Cooling with ice;	93%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 3-(1-chloropiperidin-4-yl)-6-fluoro benzisoxazole → paliperidone (144598-75-4)

Conditions	Yield
With diisopropylamine In methanol for 12h; Time; Inert atmosphere; Reflux;	88%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C18H19NOS*C2H2O4 → 9-hydroxy-2-methyl-3-(2-(methyl((S)-3-(naphthalen-1-yloxy)-3-(thiophen-3-yl)propyl)amino)ethyl)-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With 18-crown-6 ether; potassium carbonate In tetrahydrofuran Reflux;	82%

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)-9-fluoro-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 3h; Cooling with ice;	74%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + duloxetine hydrochloride (136434-34-9) → 9-hydroxy-2-methyl-3-(2-(methyl((S)-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl)amino)ethyl)-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 65℃; Inert atmosphere;	72%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + (2,4-difluorophenyl)-piperidin-4-yl-methanone oxime hydrochloride (135634-18-3) → 3-(2-{4-((2,4-difluorophenyl)hydroxyiminomethyl)piperidin-1-yl}ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one (1141761-80-9)

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile for 16h; Reflux;	70%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 6-fluoro-3-(4-piperidinyl)benzo[d]isoxazole (84163-77-9) → paliperidone (144598-75-4)

Conditions	Yield
With sodium hydrogencarbonate; potassium iodide In water; acetonitrile at 65℃; for 16h; Reagent/catalyst; Solvent; Temperature;	60%
With N-ethyl-N,N-diisopropylamine In methanol at 50 - 70℃;	55%
With sodium carbonate In ethanol at 58 - 62℃; for 24h; Product distribution / selectivity;

1-(benzo[b]thiophen-4-yl)piperazine hydrochloride + 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-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 85℃;	58%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 1-(2,3-dihydrobenzo[b]thiophen-4-yl)piperazine hydrochloride → 3-(2-(4-(2,3-dihydrobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 85℃;	56%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 4-(benzo[b]thiophen-4-yl)piperidine trifluoroacetate → 3-(2-(4-(benzo[b]thiophen-4-yl)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile for 12h; Reflux;	49%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C27H31F2N5O4 → 3-(2-(4-(4-fluoro-2-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperazin-1-yl)benzoyl)piperazine-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
Stage #1: C27H31F2N5O4 In ethanol at 20 - 30℃; Acidic conditions; Stage #2: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one With N-ethyl-N,N-diisopropylamine In methanol Reflux;	49%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 4-(piperazin-1-yl)thieno[2,3-c]pyridine trifluoroacetate → 9-hydroxy-2-methyl-3-(2-(4-(thieno[2,3-c]pyridin-4-yl)piperazin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 80℃;	46.6%

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)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (849727-63-5)

Conditions	Yield
With hydrogenchloride In water; butanone pH=2;	46%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C28H32F2N4O4 → 3-(2-(4-(4-fluoro-2-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperazin-1-yl)benzoyl)piperidine-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
Stage #1: C28H32F2N4O4 In ethanol at 20 - 30℃; Acidic conditions; Stage #2: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one With N-ethyl-N,N-diisopropylamine In methanol Reflux;	42%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + 4-(piperazin-1-yl)thieno[2,3-d]pyrimidine trifluoroacetate → 9-hydroxy-2-methyl-3-(2-(4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile Reflux;	41%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C28H32F2N4O4 → 3-(2-(4-(4-fluoro-2-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperidin-1-yl)benzoyl)piperazine-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
Stage #1: C28H32F2N4O4 In ethanol at 20 - 30℃; Acidic conditions; Stage #2: 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one With N-ethyl-N,N-diisopropylamine In methanol Reflux;	41%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C24H25F2N3O2*ClH → 3-(2-(4-(4-fluoro-2-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperidin-1-yl)benzoyl)piperidine-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol Reflux;	36%

3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (130049-82-0) + C24H26F2N4O*ClH → 3-(2-(4-(4-fluoro-2-(4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl)benzoyl)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol Reflux;	36%

Upstream product

• 147687-17-0 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 1254173-48-2 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride 
• 1228559-69-0 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one oxalate 
• 517-23-7 3-acetyl-2-oxo-4,5-dihydrofuran 
• 24016-03-3 2-amino-3-benzyloxypyridine 
• 16867-03-1 2-amino-3-hydroxypyridine 
• 181525-38-2 9-hydroxy-3-hydroxyethyl-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 1204248-71-4 C₁₁H₁₄ClN₃O₂ 
• 260273-82-3 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one 
• 130049-79-5 9-benzyloxy-3-(2-chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-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 
• 1117803-76-5 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-acetyloxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 

Downstream Products

• 144598-75-4 paliperidone 
• 1138463-56-5 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one 
• 1189516-65-1 R₁₂₅₂₃₉ 
• 130049-85-3 (+)-Paliperidone 
• 1141761-80-9 3-(2-{4-((2,4-difluorophenyl)hydroxyiminomethyl)piperidin-1-yl}ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one 
• 1388021-46-2 C₂₃H₂₈F₂N₄O₃ 
• 199739-10-1 paliperidone palmitate 
• 849727-63-5 (±)-3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride 

Relevant articles and documents

Preparation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, a Key Intermediate for the Synthesis of Paliperidone

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Preparation method of high-purity paliperidone intermediate

The invention belongs to the technical field of medicine, and particularly discloses a preparation method of a high-purity paliperidone intermediate 3-(2-chloroethyl)-9-hydroxyl-2-methyl-6,7,8,9-tetrahydro-4H-pyridino[1,2-a] pyrimidine-4-ketone. The preparation method particularly comprises the following steps: preparing 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyridino[1,2-a] pyrimidine-4-ketone by taking 2-amino-3-hydroxypyridine as a starting raw material and through benzyl protection, ring closure of alpha-acetyl-gamma-butyrolactone and chloro-substitution; dissolving the 9-(benzyloxy)-3-(2-chloroethyl)-2-methyl-4H-pyridino[1,2-a] pyrimidine-4-ketone into an alcohol solvent, adding acid and a palladium-charcoal catalyst, controlling hydrogen pressure, and after the reaction is completed, performing processes of filtering, concentrating, adjusting the pH value, extracting, concentrating and refining to obtain white-like powdered 3-(2-chloroethyl)-9-hydroxyl-2-methyl-6,7,8,9-tetrahydro-4H-pyridino[1,2-a] pyrimidine-4-ketone. The preparation method is short in cycle, the product is white-like, the yield reaches 70 percent or higher, the purity reaches 99 percent or higher, related impurities of chlorine-removed byproducts are avoided, and the preparation method is suitable for industrialized enlarged production.

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.