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Pimavanserin intermediate and preparation method of pimavanserin

A technology of pimavanserin and intermediates, which is applied in the field of synthesis of pharmaceutical molecules, can solve the problems of large impact on operator's health, unfavorable to industrialized production, high toxicity of chloroformate, etc., and achieves reduction of synthesis cost and easy realization. , the effect of low cost

Inactive Publication Date: 2018-08-03
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 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
[0015] Although this method uses chloroformate instead of highly toxic phosgene, the toxicity of chloroformate is still huge, the environmental pollution is serious, and there are many reaction steps and the yield is low

Method used

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  • Pimavanserin intermediate and preparation method of pimavanserin
  • Pimavanserin intermediate and preparation method of pimavanserin
  • Pimavanserin intermediate and preparation method of pimavanserin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of compound 5-a from compound 3 and compound 4-a

[0065]

[0066] Add compound 3 (5g, 28.05mmoL), compound 4-a (2.3g, 30.86mmoL), acetic acid (2.0g, 33.66mmoL), and 30mL dichloromethane into a 100mL three-necked flask. Sodium triacetoxyborohydride (8.9g, 42.1mmoL) was added slowly, and the system reacted at room temperature for 12h. Add 30mL 10% NaOH solution dropwise to the system, stir and separate the liquids, extract the aqueous phase twice with dichloromethane (30mL*2), combine the organic phases, wash once with 30mL saturated NaCl solution, dry over anhydrous sodium sulfate, filter, and the filtrate Concentration gave an off-white solid, which was recrystallized through ethyl acetate / n-heptane = 1 / 10 to obtain compound 5-a, a white solid, 5.73 g, with a yield of 86%.

[0067] MS (m / z): [M+H] + =228.3; Compound 5-a NMR data is as follows: 'H NMR (400MHz, CDCl 3 )(ppm):7.82(d,2H),7.13(d,2H),6.85(s,1H),4.26(s,2H),4.01(d,2H),3.74(s,3H),2.10-1.95 ...

Embodiment 2

[0073] Preparation of compound 5-b from compound 3 and compound 4-b

[0074]

[0075] Add compound 3 (5g, 28.05mmoL), compound 4-b (2.75g, 30.86mmoL), acetic acid (2.0g, 33.66mmoL), and 30mL dichloromethane into a 100mL three-necked flask. Sodium triacetoxyborohydride (8.9g, 42.1mmoL) was added slowly, and the system reacted at room temperature for 12h. Add 30mL 10% NaOH solution dropwise to the system, stir and separate the liquids, extract the aqueous phase twice with dichloromethane (30mL*2), combine the organic phases, wash once with 30mL saturated NaCl solution, dry over anhydrous sodium sulfate, filter, and the filtrate Concentration gave an off-white solid, which was recrystallized through ethyl acetate / n-heptane = 1 / 10 to obtain compound 5-b, a white solid, 6.2 g, with a yield of 88%.

[0076] MS (m / z): [M+H] + =252.3; The NMR data of compound 5-b are as follows: 'H NMR (400MHz, CDCl 3 )(ppm):7.88(d,2H),7.11(d,2H),6.89(s,1H),4.23(s,2H),3.92-3.79(m,4H),3.74(s,3H...

Embodiment 3

[0081] Preparation of compound 5-c from compound 3 and compound 4-c

[0082]

[0083] Add compound 3 (5g, 28.05mmoL), compound 4-c (4.2g, 30.86mmoL), acetic acid (2.0g, 33.66mmoL), 30mL dichloromethane into a 100mL three-necked flask, cool the system to 0°C, Sodium triacetoxyborohydride (8.9g, 42.1mmoL) was added slowly, and the system reacted at room temperature for 12h. Add 30mL 10% NaOH solution dropwise to the system, stir and separate the liquids, extract the aqueous phase twice with dichloromethane (30mL*2), combine the organic phases, wash once with 30mL saturated NaCl solution, dry over anhydrous sodium sulfate, filter, and the filtrate Concentration gave an off-white solid, which was recrystallized from ethyl acetate / n-heptane = 1 / 8 to obtain compound 5-c, a white solid, 7.3 g, with a yield of 87%.

[0084] MS (m / z): [M+H] + =300.4; Compound 5-c NMR data are as follows: 'H NMR (400MHz, CDCl 3 )(ppm):7.87-7.75(m,2H),7.45-7.37(m,3H),7.33(d,2H),7.03(d,2H),4.25(s,...

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Abstract

The invention discloses a pimavanserin intermediate and a preparation method of pimavanserin. A structural general formula of the pimavanserin intermediate is shown in the description; the pimavanserin intermediate is prepared by carrying out reductive amination on 4-isobutoxybenzaldehyde and carbamate; a synthesis route is shown in the description; the pimavanserin is obtained through ammonolysisreaction. According to the preparation method of the pimavanserin intermediate, the target intermediate is obtained in one step through reductive amination reaction and reaction steps of the pimavanserin are extremely simplified; used raw materials are safe and the cost is low; reaction conditions are moderate and phosgene which has great toxicity and is uneasy to operate is not used, so that thepreparation method is easy to realize in industry; the intermediate and a product are easy to separate and purify, and the next-step reaction can be directly carried out to prepare the pimavanserin,without the need of separating the pimavanserin; the preparation method is simple to operate and the yield is higher than that of the prior art; the synthesis cost of the pimavanserin is reduced.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical molecules, in particular to a synthesis process of pharmaceutical intermediates, in particular to a method for preparing pimavanserin intermediates and pimavanserin. 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), whi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C271/48C07C269/06C07D211/58
CPCC07C269/06C07D211/58C07C271/16C07C271/48
Inventor 王标唐阳刚李敬辉李坚胜邓意
Owner LIVZON NEW NORTH RIVER PHARMA
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