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

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

• 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 

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 

Relevant articles and documents

Method for utilizing microchannel reactor to synthesize paliperidone midbody

The invention discloses a method for utilizing a microchannel reactor to synthesize a paliperidone midbody, and belongs to the technical field of psychotropic medicine synthesis in organic synthesis.By means of the method, a paliperidone hydrogen-adding reaction precursor 3-(2-chloroethyl)-2-methyl-9-hydroxyl-4H-pyridino-[1,2-A]pyrimidine-4-ketone is added into an organic solvent, after a catalyst of activated-carbon-loaded precious metal is added, the mixture is used as a first material, and the first material is delivered into a preheating module of the microchannel reactor to be preheated;the preheated first material and hydrogen are delivered to a reaction module of the microchannel reactor separately to be reacted, reaction liquid flowing out of an outlet of the microchannel reactoris collected, and the paliperidone midbody is obtained through aftertreatment. By means of the synthesis method, the reaction time can be effectively shortened, the potential safety hazard of a hydrogen leakage combustion explosion is greatly lowered, and the method is applicable to synthesizing the paliperidone midbody.

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.

Processes for the preparation of paliperidone

The present invention relates to a novel process for the preparation of paliperidone and its intermediates and also relates to an improved process for the preparation of paliperidone compound of formula (I).

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 PALIPERIDONE

The present invention relates to an improved process for the preparation of pure Paliperidone of Formula I.

NOVEL AND IMPROVED PROCESSES FOR THE PREPARATION OF PALIPERIDONE

The present invention relates to a novel process for the preparation of paliperidone and its intermediates and also relates to an improved process for the preparation of paliperidone compound of formula (I).

PROCESS FOR PREPARING PALIPERIDONE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention discloses the process for the preparation of paliperidone and its pharmaceutically acceptable salts comprising (a) condensing 2-amino-3-hydroxy- pyridine with 2-acetylbutyro lactone in the presence of an acid catalyst to isolate 9- hydroxy-3-(2-hydroxyethyl)-2-rnethyl-4H-pyrido[l, 2-a] pyrimidin-4-one; treating 9- hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l, 2-a] pyrimidin-4-one with a chlorinating agent; hydrogenating the product in the presence of one or more lewis acids to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one; and condensing3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one. The present invention also discloses processes for the preparation of intermediates useful in the preparation of paliperidone and its pharmaceutically acceptable salts.

AN IMPROVED PROCESS FOR THE PREPARATION OF PURE PALIPERIDONE

The present invention relates to an improved process for the preparation of pure Paliperidone of formula (I). The present invention more specifically provides an improved process for the preparation of pure Paliperidone which may contain impurities in the acceptable level of pharmacopoeia requirement specifically 3-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl]-piperidin-1-yl]-ethyl}-2- methyl-7,8-dihydro-6H-pyrido[1,2-a]pyrimidine-4,9-dione of Formula (IV).

PROCESS OF SYNTHESIS OF PALIPERIDONE

The invention relates to an improved process for preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, an intermediate used in the synthesis of paliperidone and process for converting the same to Paliperidone.