199739-10-1

Usage

Uses

Used in Pharmaceutical Industry:
Paliperidone Palmitate [USAN] is used as a long-acting injectable atypical antipsychotic for the treatment of schizophrenia. Its administration method allows for monthly injections, which was approved by the CFDA in 2011, and is indicated for both acute and maintenance treatment of the condition. This long-acting formulation helps patients adhere to their treatment plan, reducing the risk of relapse and improving overall management of schizophrenia.

Side effects

The review of the literature also underlined that paliperidone palmitate is well tolerated, compared with placebo. Frequency and severity of side-effects such as extrapyramidal symptoms, hyperprolactinemia and weight gain, was similar or less than those found in treatment with other atypical antipsychotics, including long-acting ones.

Synthetic route

palmitic anhydride (623-65-4) + paliperidone (144598-75-4) → paliperidone palmitate (199739-10-1)

Conditions	Yield
Stage #1: palmitic anhydride; paliperidone With dmap In toluene at 20 - 70℃; for 3h; Stage #2: With tert-butyl methyl ether In toluene at 10℃; for 1h; Product distribution / selectivity;	88.5%

1-hexadecylcarboxylic acid (57-10-3) + paliperidone (144598-75-4) → paliperidone palmitate (199739-10-1)

Conditions	Yield
With dmap; pivaloyl chloride; triethylamine In tetrahydrofuran at 20℃; for 24h; Product distribution / selectivity;	80%

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) + 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (84163-13-3) → paliperidone palmitate (199739-10-1)

Conditions	Yield
Stage #1: 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride With potassium carbonate In acetonitrile at 25 - 60℃; for 1.16667h; Stage #2: 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one palmitate ester With tetrabutylammomium bromide; potassium iodide at 20 - 75℃; for 14h;	80%
Stage #1: 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride With potassium carbonate In acetonitrile at 25 - 60℃; for 1.16667h; Stage #2: 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one palmitate ester With tetra-(n-butyl)ammonium iodide; potassium iodide In acetonitrile at 25 - 75℃; for 16h;	80%

paliperidone (144598-75-4) + n-hexadecanoyl chloride (112-67-4) → paliperidone palmitate (199739-10-1)

Conditions	Yield
Stage #1: paliperidone With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: n-hexadecanoyl chloride In N,N-dimethyl-formamide at 0℃; for 5h; Product distribution / selectivity;	53.1%
With dmap; triethylamine In dichloromethane at 15℃; for 8h; Temperature;

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 sodium (1172995-09-3) + n-hexadecanoyl chloride (112-67-4) → paliperidone palmitate (199739-10-1)

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; for 2h;	10 %Chromat.

1-hexadecylcarboxylic acid (57-10-3) → paliperidone palmitate (199739-10-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 1.2: 2 h / 25 - 40 °C 2.1: potassium carbonate / acetonitrile / 1.17 h / 25 - 60 °C 2.2: 14 h / 20 - 75 °C View Scheme

paliperidone palmitate (199739-10-1) → paliperidone (144598-75-4)

Conditions	Yield
Stage #1: paliperidone palmitate With hydrogenchloride In water at 75 - 80℃; for 2h; Stage #2: With sodium hydroxide In methanol; dichloromethane; water; isopropyl alcohol at 10 - 30℃; for 1h; pH=10 - 12; Reflux;	90%
With hydrogenchloride In water at 75 - 80℃; for 2h;	90%

paliperidone palmitate (199739-10-1) → 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7-dihydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (913728-82-2) + 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-9-pentadecyl-4H-pyrido[1,2-a]pyrimidin-4-one (913728-83-3) + paliperidone (144598-75-4)

Conditions	Yield
Product distribution / selectivity; X-irradiation;

Upstream product

• 1415488-05-9 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one palmitate ester 
• 84163-13-3 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride 
• 130049-82-0 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 
• 57-10-3 1-hexadecylcarboxylic acid 
• 1172995-09-3 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 sodium 
• 112-67-4 n-hexadecanoyl chloride 
• 623-65-4 palmitic anhydride 
• 144598-75-4 paliperidone 

Downstream Products

• 144598-75-4 paliperidone 
• 913728-82-2 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7-dihydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 
• 913728-83-3 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-9-pentadecyl-4H-pyrido[1,2-a]pyrimidin-4-one 

Relevant academic research and scientific papers

Synthesis process of paliperidone palmitate

Belonging to the technical field of pharmaceutical compositions, the invention relates to a synthesis process of paliperidone palmitate. Through synthesis of P (paliperidone), refinement of P synthesis of PP (paliperidone palmitate) and refinement of PP, the paliperidone palmitate can be prepared. According to the invention, the process is controllable, the cost is low, the impurities are controllable, the refining process is simple and convenient, the product purity is high, and the yield is high.

PREPARATION OF 3-[2-[4-((6-FLUORO-1, 2-BENZISOXAZOL-3-YL)-L-PIPERIDINYL)-6, 7, 8, 9-TETRAHYDRO-9-HYDROXY-2-METHYL-4H-PYRIDO[ 1, 2-A]-PYRIMIDIN-4-ONE (PALIPERIDONE) AND PALIPERIDONE PALMITATE.

An improved process for the synthesis of 3-[2-[4-((6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (Paliperidone) and Paliperidone Palmitate through a novel intermediate (2-Chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1,2-a]pyrimidine-4-one Palmitate ester.

PREPARATION OF 3-[2-[4-((6-FLUORO-1, 2-BENZISOXAZOL-3-YL)-L-PIPERIDINYL)-6, 7, 8, 9-TETRAHYDRO-9-HYDROXY-2-METHYL-4H-PYRIDO[ 1, 2-A]-PYRIMIDIN-4-ONE (PALIPERIDONE) AND PALIPERIDONE PALMITATE.

Provided is a process for the synthesis of 3-[2-[4-((6-fluoro-1,2-benzisoxazol-3-y l)-1-piperidinyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin -4-one (Paliperidone) and Paliperidone Palmitate through a novel intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin -4-one palmitate ester. A process for preparing a compound of formula VIII through a compound of formula VII is also provide.

PROCESSES FOR THE PREPARATION AND PURIFICATION OF PALIPERIDONE PALMITATE

The present invention encompasses processes for the preparation and purification of paliperidone palmitate.