Preparation method of aripiprazole lauroxil

A technology of lauroyl aripiprazole and aripiprazole, which is applied in the field of drug synthesis, can solve the problems of inconvenient industrial production, difficulty in complete desolventization, and high risk, and achieve the goal of shortening drying time and reducing organic solvents and water Residue, Residue reduction effect

Pending Publication Date: 2019-09-06
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0015] (1) The sodium hydrogen used in the reaction is a highly active inorganic strong base, which produces flammable and explosive hydrogen when it meets water, which is highly dangerous; (2) 1,4-dioxane has a high boiling point, and the precipitation is not easy to complete (3) product purification adopts column chromatography operation, which is not convenient for suitability for industrialized production

Method used

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  • Preparation method of aripiprazole lauroxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2 Preparation of (1H)-ketone (hydroxymethyl aripiprazole):

[0057] Aripiprazole (45g, 100.63mmol), aqueous formaldehyde (37% mass concentration, 120mL), triethylamine (7mL, 50.32mmol, 0.50eq molar equivalent to aripiprazole) and N,N -The mixture of dimethylformamide (135mL) was heated to 80°C, reacted for 2.5h, cooled to room temperature, and suction filtered; the filter cake was washed twice with acetonitrile, each time 30mL, and air-dried to obtain 53.6g of product, the yield It is 96% and the purity is 90.12%.

[0058] 1 H NMR (CDCl 3 ,400MHZ) δ1.62~1.78(m, 2H), 1.77~1.91(m, 2H), 2.43~2.77(m, 8H), 2.82(t, 2H), 3.11(s, 4H), 3.71(s, 1H), 4.01(t, 2H), 5.33(s, 2H), 6.57(dd, 1H), 6.86(d, 1H), 6.96(m, 1H), 7.04(d, 1H), 7.10~7.20(m , 2H); m / z (M+H)=478.

Embodiment 2

[0060] Intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2 Preparation of (1H)-ketone (hydroxymethyl aripiprazole):

[0061] Aripiprazole (26g, 58.15mmol), aqueous formaldehyde (37% mass concentration, 90mL), triethylamine (4mL, 29.07mmol, 0.50eq molar equivalent to aripiprazole) and N,N -The mixture of dimethylformamide (78mL) was heated to 80°C, reacted for 2.5h, cooled to room temperature, filtered with suction, the filter cake was washed twice with acetone, 26mL each time, and air-dried to obtain 26.1g product, the yield It is 94%, and the purity is 91.34%.

[0062] The product obtained is substantially the same as the hydrogen spectrum information in Example 1.

Embodiment 3

[0064] Intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2 Preparation of (1H)-ketone (hydroxymethyl aripiprazole):

[0065] Aripiprazole (26g, 58.15mmol), aqueous formaldehyde (37% mass concentration, 90mL), triethylamine (4mL, 29.07mmol, 0.50eq molar equivalent to aripiprazole) and N,N -The mixture of dimethylformamide (78mL) was heated to 80°C, reacted for 2.5h, cooled to room temperature, filtered with suction, the filter cake was washed twice with ethanol, 26mL each time, and air-dried to obtain 24.2g product, the yield It is 87.2%, and the purity is 91.05%.

[0066] The product obtained is substantially the same as the hydrogen spectrum information in Example 1.

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Abstract

The invention belongs to the technical field of medicine synthesis methods, and provides a preparation method of aripiprazole lauroxil. The preparation method comprises the following steps: (1) carrying out a hydroxymethylation reaction: contacting and reacting aripiprazole, an aqueous formaldehyde solution having a mass concentration of 35-40 wt% and an alkali in an organic solvent to obtain hydroxymethyl aripiprazole; and (2) carrying out a lauroylation reaction: contacting and reacting the hydroxymethyl aripiprazole, an organic alkali and lauroyl chloride in a solvent which is immiscible with water at 20-30 DEG C, and then recrystallizing the obtained reaction product in a crystallization solvent to obtain the aripiprazole lauroxil. The method of the invention can improve the yield of the two-step reaction of hydroxymethylation and lauroylation and the purity of the product, and also can shorten the reaction time, simplify the post-treatment process and reduce the material cost.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis methods, in particular to a preparation method of lauroyl aripiprazole. Background technique [0002] Aripiprazole lauroyl is the prodrug of the active drug aripiprazole, and its long-acting suspension injection is an atypical antipsychotic developed by Alkermes plc of the United States using the LinkeRx technology platform. It was approved by the FDA in October 2015. in the treatment of schizophrenia. The efficacy and safety of this product are similar to those of aripiprazole, and it can be administered once every 1-2 months, which can meet the needs of different individuals. Common adverse reactions include insomnia, akathisia, and headache. The compound molecular structure is as follows: [0003] [0004] Patent document US20140221653 discloses the synthetic route of lauroyl aripiprazole, specifically as follows: [0005] Route 1: [0006] . [0007] The synthetic route uses a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 潘钧铸吴超柱冯森王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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