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Method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene

A technology of pimavanserin and tartrate, which is applied in the field of synthesis of pharmaceutical molecules, can solve the problems of great impact on operator's health, expensive DPPA, unfavorable to industrialized production, etc., so as to reduce production safety risks and avoid Raney nickel. easy-to-use, easy-to-achieve effects

Active Publication Date: 2018-12-07
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Disadvantages of this route: (1) The use of hydrogen to participate in the reaction needs to be carried out under high pressure, and the safety risk is high; the reaction requires a catalyst palladium carbon, which is expensive
(2) Toxic phosgene is involved in the reaction, which has a great impact on the health of the operator, is not conducive to environmental protection, has high safety risks, and is not conducive to industrial production
[0018] The DPPA used in this route is expensive, and the azide compound intermediate will pass through the reaction process, and the generated azide compound has safety hazards such as explosion and high toxicity.

Method used

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  • Method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene
  • Method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene
  • Method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation of compound 3 from compound 1

[0079]

[0080] 1) Add p-hydroxybenzaldehyde (14.6g, 122.8mmo1), anhydrous potassium carbonate (25.4g, 184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF into a 250mL three-necked flask, and heat to 85°C;

[0081] 2) Slowly add chloroisobutane (34.1g, 368.4mmol) to the reaction system, after the addition is complete, the system reacts at 85°C for 6h;

[0082] 3) Stop the reaction, cool the system to room temperature, filter, and rinse the filter cake twice with 90 mL of ethyl acetate;

[0083] 4) Pour the filtrate into 250 mL of water, separate the organic phase, extract the water phase three times with 90 mL of ethyl acetate, combine the organic phases, wash once with 150 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin the filtrate to obtain 19.4 g Compound, light yellow liquid, yield 90%.

[0084] MS (m / z): [M+H] + =176.2; The NMR data of compound 3 are as follows: 'H NMR (400MHz, C...

Embodiment 2

[0100] Preparation of compound 3 from compound 1

[0101]

[0102]1) Add p-hydroxybenzaldehyde (14.6g, 122.8mmo1), anhydrous potassium carbonate (25.4g, 184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF into a 250mL three-necked flask, and heat to 90°C;

[0103] 2) Slowly add bromoisobutane (50.5g, 368.4mmol) into the reaction system, after the addition is complete, the system reacts at 90°C for 5h;

[0104] 3) Stop the reaction, cool the system to room temperature, filter, and rinse the filter cake twice with 90 mL of ethyl acetate;

[0105] 4) Pour the filtrate into 250 mL of water, separate the organic phase, extract the water phase three times with 90 mL of ethyl acetate, combine the organic phases, wash once with 150 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin the filtrate to obtain 19.8 g Compound, light yellow liquid, yield 92%.

[0106] Preparation of compound 4 from compound 3

[0107]

[0108] 5) Add 4-isobutoxyben...

Embodiment 3

[0118] Preparation of compound 3 from compound 1

[0119]

[0120] 1) Add p-hydroxybenzaldehyde (14.6g, 122.8mmo1), anhydrous potassium carbonate (25.4g, 184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF into a 250mL three-necked flask, and heat to 100°C;

[0121] 2) Slowly add iodoisobutane (67.8g, 368.4mmol) into the reaction system, after the addition is complete, the system reacts at 100°C for 5h;

[0122] 3) Stop the reaction, cool the system to room temperature, filter, and rinse the filter cake twice with 90 mL of ethyl acetate;

[0123] 4) Pour the filtrate into 250 mL of water, separate the organic phase, extract the water phase three times with 90 mL of ethyl acetate, combine the organic phases, wash once with 150 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin the filtrate to obtain 19.6 g Compound, light yellow liquid, yield 91%.

[0124] Preparation of compound 4 from compound 3

[0125]

[0126] 5) Add 4-isobutoxyb...

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Abstract

The invention discloses a method for safely preparing pimavanserin and tartrate thereof by utilizing triphosgene. The synthetic route is as shown in the specification. The raw materials used by the method disclosed by the invention are safe, the cost is low, and the production cost is effectively reduced. The method disclosed by the invention is mild in reaction conditions, usage of phosgene thatis high in toxicity and difficult to operate can be avoided, and industrial production is easily realized.

Description

technical field [0001] The invention relates to the field of synthesis of medicine molecules, in particular to a synthesis process of medicine molecules, in particular to a method for preparing pipimavanserin and pimavanserin tartrate. Background technique [0002] At present, there are about 7 million to 10 million Parkinson's disease patients in the world, and China has 2.6 million people, ranking first in the world, and there will be an increase of 100,000 new patients every year. More than 50% of patients with Parkinson's disease have had psychotic symptoms (PDP). These psychiatric symptoms mainly manifest as hallucinations and delusions, which bring greater challenges to the treatment and care of patients with Parkinson's disease. Parkinson's disease psychosis is a major reason people with Parkinson's disease enter aged care housing. There are currently no approved drugs for Parkinson's disease psychosis other than low-dose clozapine (Clozaril), which has serious safe...

Claims

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Application Information

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IPC IPC(8): C07D211/58C07C59/255C07C51/41
CPCC07D211/58C07B2200/07C07C51/412C07C59/225C07D211/98
Inventor 王标姜桥李冰冰彭木荣谢伟健
Owner LIVZON NEW NORTH RIVER PHARMA
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