Method for preparing pimavanserin
Technical Field
The invention relates to the technical field of a preparation method of pimavanserin.
Background
Pimavanserin (pimavanserin), the chemical name of which is 1- (4-fluorobenzyl) -3- (4-isobutyloxybenzyl) -1- (1-methylpiperidin-4-yl) urea tartrate, and the structure of the free base of the tartrate is shown as the formula (I). Pimavanserin, originally developed by ACADIA pharmaceutical Inc, is a selective 5-HT2A inverse agonist and has been shown to be effective and well tolerated in the treatment of parkinson's disease psychotic disorders, and it does not block dopamine receptors and therefore does not lead to worsening of parkinson's disease symptoms.
The synthesis of pimavanserin is described in patents CN1443167 and CN 1816524.
At present, the preparation of pimavanserin by the following method is disclosed at home and abroad:
a) US2008/0280886 discloses the preparation of pimavanserin starting from methyl 4-hydroxyphenylacetate. The route is as follows:
route a) takes 4-hydroxyphenylmethyl acetate and isobutyl bromide as raw materials, and the raw materials are reacted to obtain 4-isobutoxyphenylmethyl acetate, which is hydrolyzed to obtain 4-isobutoxyphenylacetic acid, and then the 4-isobutoxyphenylacetic acid is reacted with diphenylphosphoryl azide to generate 4-isobutoxyphenylisocyanate, and finally the 4-isobutoxyphenylisocyanate is reacted with N- (4-fluorophenyl) -1-methylpiperidine-4-amine to obtain the pimavanserin free base. The method has more steps, wherein the synthesis condition of the key intermediate 4-isobutoxy phenyl isocyanate is more complex, and the used diphenyl phosphorazide is active in property, is not easy to store and is not suitable for large-scale industrial production.
b) Patent US2007/0260064 discloses a similar synthetic method and synthesizes pimavanserin.
Route b) p-hydroxybenzaldehyde and isobutyl bromide are used as raw materials to react to obtain 4-isobutoxy benzaldehyde, 4-isobutoxy benzaldehyde oxime is further synthesized, 4-isobutoxy benzylamine is obtained by reduction, 4-isobutoxy phenyl isocyanate is obtained by condensation with phosgene, and finally the p-moplanin free alkali is obtained by reaction with N- (4-fluorophenyl) -1-methylpiperidine-4-amine. The method also needs to pass through a 4-isobutoxy phenyl isocyanate intermediate process, and has more steps and more complex synthesis conditions.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the method for preparing the pimavanserin, which has the advantages of high efficiency, high yield, low cost, safety, environmental protection, suitability for industrial production and higher application value.
In order to realize the purpose, the invention uses 4-isobutoxybenzylamine or salt thereof, a carbonylation reagent and N- (4-fluorobenzyl) -1-methylpiperidine-4-amine or salt thereof as raw materials to prepare the pimavanserin by a condensation one-pot method.
The invention specifically adopts the following technical scheme:
the method for preparing the pimavanserin shown in the formula (IV) by a one-pot method is characterized in that the pimavanserin (compound IV) is prepared by the one-pot method by taking a compound shown in the formula (II), a carbonylation reagent shown in the formula (III) and a compound shown in the formula (I) as raw materials, and the reaction equation is shown as follows:
wherein:
i is N- (4-fluorobenzyl) -1-methylpiperidin-4-amine or a salt thereof;
II is 4-isobutoxy benzylamine or salt thereof;
III is a carbonylation reagent, which is selected from one or more of phosgene, chloroformic acid chloromethyl ester, bis (trichloromethyl) carbonate, N-carbonyl diimidazole, dimethyl carbonate, diethyl carbonate and p-nitro phenyl chloroformate.
In the present invention, the salts of the compounds I and II are not particularly limited, and pharmaceutically acceptable salts known in the art may be used.
Next, the present invention does not specifically require the order of the reaction of the compound of formula (II), the carbonylation reagent of formula (III) and the compound of formula (I), and it is preferred that the compound of formula (II) is used as a starting material, reacted with the carbonylation reagent of formula (III), and then reacted with the compound of formula (I) to prepare pimavanserin (compound IV) by a one-pot method.
The method for preparing the pimavanserin by the one-pot method is characterized by further comprising the step of adding alkali into the reaction.
The one-pot method for preparing pimavanserin is characterized in that the molar ratio of the compound (II) to the carbonylation reagent shown in the formula (III) is 1: (0.5 to 3.0), preferably 1: (0.5 to 2.0), more preferably 1: (0.5 to 1.5).
The one-pot method for preparing pimavanserin is characterized in that the molar ratio of the compound (II) to the compound (I) is 1.0: (0.5 to 2.0), preferably 1.0: (0.8 to 1.2), more preferably 1.0 (0.9 to 1.1).
The method for preparing the pimavanserin by the one-pot method is characterized in that the reaction temperature is-20 ℃ to the boiling point of a solvent, and the reaction time is 2.5-24 hours.
More preferably, the reaction temperature is-5 to 25 ℃ and the reaction time is 5.5 to 13 hours.
The base is not particularly limited in the present invention, and any base known in the art for converting an organic salt into a corresponding free base or neutralizing an acid generated in a condensation reaction may be used, and preferably one or a mixture of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium hydrogen carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tributylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, imidazole, N, N, N ', N' -tetramethylethylenediamine is used.
The amount of base is not particularly critical in the present invention, and any amount known in the art to convert an organic salt to the corresponding free base or to neutralize the acid produced in the condensation may be used.
The solvent for the reaction is not particularly required in the invention, and any solvent which is known in the art and can dissolve the reaction raw materials and can not react with the raw materials can be used, and one or a mixture of several of N, N-dimethylformamide, dichloromethane, chloroform, methanol, ethanol, isopropanol, butanol, tert-butanol, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, 1, 4-dioxane, ethyl acetate, dimethyl sulfoxide, toluene and water is preferred.
In addition, when the compound of the formula (II) is used as a raw material, reacts with a carbonylation reagent shown in the formula (III) and then reacts with the compound of the formula (I) to prepare the pimavanserin (compound IV) by a one-pot method, the method for preparing the pimavanserin by the one-pot method is characterized in that the temperature of the compound of the formula (II) and the formula (III) is-20-25 ℃, and the reaction time is 0.5-2 hours; preferably, the temperature of the formula (II) and the formula (III) is-5 to 15 ℃, and the reaction time is 0.5 to 1 hour.
The method for preparing the pimavanserin by the one-pot method is characterized in that the reaction temperature of the pimavanserin and the formula (I) is-5-boiling point of a solvent, and the reaction time is 0.5-24 hours; preferably, the reaction temperature with the formula (I) is-5 to 25 ℃, and the reaction time is 2 to 20 hours, more preferably 5 to 12 hours.
Compared with the prior art, the invention has the following beneficial effects: the original multi-step reaction is combined into one step, the material transfer and unit operation are reduced, the production efficiency is improved, the yield is greatly improved (the yield is more than 60 percent), the production cost is reduced, and the used reagent is safe and environment-friendly.
The present invention is further illustrated by the following examples, which are intended to provide further details of the practice of the invention, but are not intended to limit the scope of the invention.
Detailed description of the preferred embodiments
Example 1: adding dichloromethane (5.0g) and 4-isobutoxybenzylamine (1.0g) into a reaction tube, cooling to 0-5 ℃, adding N, N' -carbonyldiimidazole (1.0g), keeping at 0-5 ℃ for half an hour, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (1.0g), stirring at 0-5 ℃ for 6 hours, heating to 22 ℃, keeping overnight (12 hours), adding water (3 multiplied by 10g), washing, taking an organic phase, concentrating to obtain a viscous oily substance, and separating white powdery solid by column chromatography (1.17g, yield 61.0%).
1H NMR:(400MHz,d-DMSO)δ:7.27-7.23(m,2H),7.13-7.09(m,2H),6.88-6.85(t,1H),6.85-6.83(m,2H),4.41(d,J=5.6Hz,2H),3.93-3.88(m,1H),3.71(d,J=5.6Hz,2H),2.70(d,J=11.2Hz,2H),2.31(s,1H),2.10(s,3H),2.03-1.96(m,1H),1.90-1.85(m,2H),1.56-1.50(m,2H),1.44-1.41(m,2H),0.98(s,3H),0.96(s,3H);
13C NMR:(100MHz,d-DMSO)δ:162.5,160.1,158.0,157.9,137.8,137.6,137.5,133.6,129.4,128.9,128.8,128.7,128.6,125.8,115.3,115.1,114.5,74.2,55.4,52.8,46.3,44.4,43.6,30.4,28.2,21.5,19.5;
MS-ESI(M+1):428.
Example 2: dissolving 4-isobutoxybenzylamine (100.0g) in dichloromethane (500ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyldiimidazole (100.0g), keeping the temperature at 0-5 ℃ for half an hour, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (100.0g), slowly heating to 18-22 ℃, keeping stirring for 12 hours, adding water (3 x 500g) to wash an organic phase for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (600g), stirring for crystallization, filtering, and drying a filter cake to obtain a target product (163.0 g of white powdery solid, 85.0%).
Example 3: dissolving triphosgene (14.8g) in dichloromethane (200ml), cooling to-5 ℃, slowly and sequentially dropwise adding 4-isobutoxybenzylamine (17.9g) and triethylamine (30.3g), continuously keeping for 1 hour after adding, slowly and dropwise adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 5 hours, washing an organic phase with water (3 x 200g) for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (110g), stirring for crystallization, filtering, and drying a filter cake to obtain a target product (34.5 g of white powdery solid, 81.6%).
Example 4: triphosgene (14.8g) is dissolved in toluene (200ml), the temperature is reduced to-20 ℃, 4-isobutoxybenzylamine (17.9g) and triethylamine (30.3g) are sequentially and slowly added dropwise, the temperature is raised to 5 ℃ after the addition, the temperature is kept for 1 hour, N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g) is slowly added dropwise, the temperature is slowly raised to 80 ℃ after the addition, the stirring is kept for 5 hours, the organic phase is washed three times by water (3 x 200g), heptane (100ml) is added into the organic phase, precipitated solid is filtered and dried, and the target product (light yellow solid powder, 21.6g, 51.0%) is obtained.
Example 5: dissolving triphosgene (14.8g) in trichloromethane (300ml), cooling to-5 ℃, adding 4-isobutoxybenzylamine hydrochloride (21.6g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), continuously keeping for 1 hour after adding, slowly adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine p-toluenesulfonate (39.0g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 6 hours, washing an organic phase with water (3 x 200g) for three times, evaporating the solvent by organic phase under reduced pressure, adding isopropyl acetate (110g), stirring for crystallization, filtering, and drying to obtain a target product (35.2 g of white powder, 82.4%).
Example 6: dissolving 4-isobutoxy benzylamine acetate (23.9g) in dichloromethane (120ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyl diimidazole (17.0g), slowly dropwise adding N, N-diisopropylethylamine (13.5g), keeping at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine oxalate (26.0g), slowly dropwise adding N, N-diisopropylethylamine (13.0g), slowly heating to 15-25 ℃, keeping stirring for 10 hours, the organic phase was washed three times with water (3X 200g), the solvent was evaporated under reduced pressure from the organic phase, isopropyl acetate (110g) was added, heptane (55g) was added after stirring uniformly, and the precipitated solid was filtered and dried to obtain the objective product (37.6 g, 90.4% as a white powder).
Example 7: dissolving 4-isobutoxy benzylamine acetate (23.9g) in dichloromethane (120ml), cooling to 0-5 ℃, slowly adding p-nitrochloroformic acid phenyl ester (20.1g), slowly dropwise adding triethylamine (11.0g), keeping the temperature at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine oxalate (26.0g), slowly dropwise adding triethylamine (11.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 10 hours, adding water (4 x 200g), washing an organic phase for four times, evaporating the solvent by organic phase under reduced pressure, adding ethyl acetate (100g), adding N-heptane (50g) after uniformly stirring, filtering and drying a precipitated solid to obtain a target product (32.5 g of white to light yellow powder, 78.1%).
Example 8: dissolving 4-isobutoxy benzylamine acetate (24.0g) in dichloromethane (150ml), cooling to 0-5 ℃, slowly adding N, N' -carbonyldiimidazole (17.0g), slowly dropwise adding triethylamine (11.0g), keeping the temperature at 0-5 ℃ for half an hour after adding, adding N- (4-fluorobenzyl) -1-methylpiperidine-4-amine (22.0g), slowly heating to 15-25 ℃ after adding, keeping stirring for 8 hours, adding water (3 x 200g) to wash an organic phase for three times, evaporating the solvent under the organic phase pressure, adding isopropyl acetate (100g), adding N-heptane (60g) after uniformly stirring, filtering to separate out a solid, and drying to obtain a target product (38.2 g of white powder and 90.3%).