CN105820110B - Mo Fanselin synthetic methods - Google Patents
Mo Fanselin synthetic methods Download PDFInfo
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- CN105820110B CN105820110B CN201610302251.4A CN201610302251A CN105820110B CN 105820110 B CN105820110 B CN 105820110B CN 201610302251 A CN201610302251 A CN 201610302251A CN 105820110 B CN105820110 B CN 105820110B
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- PXRXCOSSFJAOBH-XZDBBAETSA-N CCCC(C)[C@@H]([C@H](C)CC)NNCC1CCN(C)CC1 Chemical compound CCCC(C)[C@@H]([C@H](C)CC)NNCC1CCN(C)CC1 PXRXCOSSFJAOBH-XZDBBAETSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention provides a kind of Mo Fanselin novel synthesis, including being that raw material prepares active carbamide compound formula (1) with Formula (1a), it carries out that a Mo Fanselin free alkalis formula (3) is obtained by the reaction under alkaline system with Formula (2) again, then Mo Fanselin free alkalis are obtaining half tartrate formulas (4) of a Mo Fanselin, simple, of low cost, the suitable industrialized production of the process route with tartaric acid.Wherein HmA is the general formula of m member acid, HnA is the general formula of n member acid, and m and n are 1,2 or 3, and it is sulfuric acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid to be respectively selected from.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to the preparation method of a Mo Fanselin and is used to prepare a Mo Fanselin
Midbody compound, specifically, the invention discloses one kind of the preparation method of series compound and Mo Fanselin are new
Preparation method.
Background technology
Whole world parkinsonian about 7 million to one 10,000,000 at present occupy the world the wherein China just has 2,600,000
One, specific drug is lacked to Parkinsonian symptoms at present.Mo Fanselin (or piperazine Ma Selin, Pimavanserin) is by U.S. Ah card
The novel non-dopamine neurotransmitter of one kind of Di Ya exploitations similar to object, can selectivity block five hydroxytryptamine 2A receptors without shadow
The effect of dopamine is rung, Short Term Clinical experiment shows to have a better effect Parkinson's disease with related psychotic patient with sympotoms tool, because
This has very vast market prospect.
Mo Fanse standing forest minor structures are 1- (4- luorobenzyls) -3- (4- isobutoxies benzyl) -1- (1- methyl piperidines -4-
Base) urea, at present in the synthetic method of document report, key reaction be how the urea molecular skeleton of rapid build product,
WO2006036874A1 disclose report a Mo Fanselin preparation method it is as follows：
The route steps are longer, and reduction oxime has used palladium carbon as catalyst when preparing benzylamine, and cost is higher, and is making
The phosgene of severe toxicity is used during standby isocyanates, not only operation is dangerous big in this way, but also consersion unit, waste liquid are useless
Gas disposal is also required to reach very high standard, is unfavorable for technique amplification.
United States Patent (USP) US2008280886A reports following route, prepares isocyanates using Curtius rearrangements, but make
With expensive DPPA, cost is higher to be also not suitable for technique amplification.
China Patent Publication No. CN104961672A and CN104844502A report following route respectively,
After these methods protect the amino of a wherein critical segment molecule with chloro-formate, recycle amine transesterification with it is another
One fragments molecules dock to obtain target molecule, although avoiding the use of phosgene, the chloro-formate used still toxicity compared with
Greatly, and in reaction by-product is more, technique zoom comparison trouble.
China Patent Publication No. CN105111135A reports following route
Active urea intermediate is obtained by the reaction using 4- isobutoxies benzylamine and carbonyl dimidazoles in this method, then with another segment
Docking obtains target molecule, although this method is avoided using hypertoxic hazardous agents, but not to the synthesis of starting material into
Row optimization, does not also purify intermediate, and route steps are slightly long, and conventional efficient is not high, and the purifying of final products is relatively more tired
It is difficult.
Invention content
In view of the deficiencies of the prior art, simple, of low cost, suitable work that the object of the present invention is to provide a kind of process routes
The synthetic method of the Mo Fanselin of industry metaplasia production and the new intermediate for preparing a Mo Fanselin.
For realization goal of the invention, the technical solution that the present invention takes is：
A kind of Mo Fanselin novel synthesis, including active carbamide compound formula (1) is prepared with Formula (1a), then
It carries out that a Mo Fanselin free alkalis formula (3) is obtained by the reaction under alkaline system with Formula (2), then Mo Fanselin is free
Alkali is obtaining half tartrate formulas (4) of a Mo Fanselin with tartaric acid：
Wherein HmA is the general formula of m member acid, HnA is the general formula of n member acid, and m and n are 1,2 or 3, be respectively selected from for sulfuric acid,
Hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.
Preferably, alkali is selected from organic base and inorganic base in the alkylated reaction, inorganic base is selected from potassium carbonate, carbonic acid
One kind in sodium, sodium hydroxide, potassium hydroxide, saleratus, organic base are selected from diisopropylethylamine, triethylamine, 1,8- phenodiazines
11 carbon -7- alkene (DBU) of miscellaneous two ring [5.4.0] or triethylene diamine；Reaction dissolvent is selected from dimethylformamide, dimethylacetamide
It is one or more in amine, dichloromethane, tetrahydrofuran, 1,4- dioxane, acetonitrile or acetone；Reaction temperature is 0~80 DEG C.
Preferably, in the salt-forming reaction, solvent is selected from water, methanol, ethyl alcohol, isopropanol, ethyl acetate, tetrahydrochysene furan
It mutters, 1,4- dioxane, acetone, acetonitrile or toluene or their mixed solution；Reaction temperature is 0~90 DEG C.
The invention further relates to Mo Fanselin intermediate amine salt formulas (1a) and active carbamide compound formula (1) and its preparation sides
Method：
The structural formula of Mo Fanselin intermediate compound of formula (1a) is：
Wherein HmA is the general formula of m member acid, and m 1,2 or 3 is selected from as sulfuric acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulphur
Acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.
The structural formula of Mo Fanselin intermediate activity carbamide compounds formula 1 is：
A kind of preparation method of amine salt compound formula 1a and active carbamide compound formula 1, including：
1) 4- fluorobenzaldehydes and 4- amino -1- methyl piperidines are subjected to reductive amination process, formula 1a is obtained through salt-forming reaction
Compound；
2) compound of formula 1a is reacted after alkali is free with dicarbapentaborane imidazoles in a solvent, is obtained after recrystallization shown in formula 1
Active carbamide compound：
Preferably, go back original reagent is selected from sodium borohydride, acetic acid hydroboration in reductive amination process in the step 1
Sodium, sodium cyanoborohydride etc., reaction dissolvent are selected from dimethylformamide, dimethylacetylamide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy six
Ring, dichloromethane or toluene；Reaction temperature is 0~50 DEG C.
Preferably, in salt-forming reaction in the step 1, at the sour H of saltmA is the general formula of m member acid, can be selected from sulphur
Acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, tartaric acid
Deng；Solvent is selected from methanol, ethyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetone, acetonitrile or toluene etc.；
Reaction temperature is 0~90 DEG C.
Preferably, the alkali in the step 2 is selected from organic base and inorganic base, inorganic base is selected from potassium carbonate, sodium carbonate, hydrogen
Sodium oxide molybdena, potassium hydroxide, saleratus, organic base are selected from diisopropylethylamine, triethylamine, 1,8- diazabicylos [5.4.0]
11 carbon -7- alkene (DBU) or triethylene diamine；Solvent is selected from dimethylformamide, dimethylacetylamide, dichloromethane, tetrahydrochysene
Furans, 1,4- dioxane, acetonitrile；Reaction temperature is 0~50 DEG C.
The invention further relates to Mo Fanselin intermediate compound of formula 2 and preparation method thereof：
The structural formula of Mo Fanselin intermediate compound of formula 2 is：
Wherein HnA is the general formula of n member acid, and n 1,2 or 3 is selected from as sulfuric acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulphur
Acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.
A kind of preparation method of Formula 2, including：
1) 4- 4-hydroxy-benzonitriles and 1- bromines iso-butane are alkylated reaction response under alkaline system and obtain Formula
2a；
2) Formula 2a is completed into reduction reaction under the action of catalyst, obtains crude free base formula 2a, finally by
It purifies to obtain Formula 2 at salt；
Preferably, alkali is selected from organic base and inorganic base in the alkylated reaction, inorganic base is selected from potassium carbonate, carbonic acid
Sodium, sodium hydroxide, potassium hydroxide, saleratus, organic base are selected from diisopropylethylamine, triethylamine, 1,8- diazabicylos
[5.4.0] 11 carbon -7- alkene (DBU) or triethylene diamine；Reaction dissolvent is selected from dimethylformamide, dimethylacetylamide, four
Hydrogen furans, 1,4- dioxane, isopropanol, acetonitrile or acetone；Reaction temperature is 0~80 DEG C.
Preferably, in the reduction reaction, catalyst can select Raney's nickel, palladium carbon, copper chloride etc. or not select
Use catalyst；Reducing agent selects hydrogen, tetrahydrochysene lithium aluminium, borine, sodium borohydride, potassium borohydride etc.；Solvent be selected from methanol, ethyl alcohol,
Isopropanol, ethyl acetate, tetrahydrofuran, 1,4- dioxane or toluene etc.；Reaction temperature is -20~90 DEG C.
As in the preferably described salt-forming reaction, at the sour H of saltnA is the general formula of n members sour (n 1,2 or 3), can be selected from
Sulfuric acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, winestone
Acid etc.；Solvent is selected from methanol, ethyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetone, acetonitrile or toluene
Deng；Reaction temperature is 0~90 DEG C.
Beneficial effects of the present invention are embodied in：Route of the present invention efficiently synthesizes out two critical segment molecularizations by new method
Object formula (1) compound and formula (2) compound are closed, by the way that 4- (4- fluorobenzylaminos) -1- methyl piperidines and carbonyl dimidazoles is anti-
Should after obtain active urea intermediate formula (1), which is easy crystallization purifying, then with active urea intermediate formula (1) and another
Efficiently docking obtains target molecule formula (3) to section Formula (2), finally obtains final products formula (4) at salt.Entire methods experiment
It is easy to operate, reaction step is shortened, not only yield is higher, and obtained product purity is also higher, while being suitble to amplification production.
Specific implementation mode：
It elaborates below to the embodiment of the present invention, the present embodiment is carried out lower based on the technical solution of the present invention
Implement, gives detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
Addition 4- fluorobenzaldehydes (12.41g, 100mmol) in three-necked flask, 4- amino -1- methyl piperidines (11.42g,
100mmol) and dichloromethane (124mL), it is stirred to react 1~2 hour, acetic acid 25mL is added, acetic acid hydroboration is added in batches
Sodium (42.39g, 200mmol) reacts at room temperature 6-8 hours, and reaction terminates plus reaction is quenched in water 100mL, and 10% hydroxide is added
Sodium solution adjusts pH value to 9~10, and liquid separation, water phase uses dichloromethane (143mL) to extract 2 times again, merges organic phase saturated common salt
It washes 2 times (143mL), sodium sulphate drying is concentrated to give grease and isopropanol (200mL) stirring and dissolving is added, is heated to 55~60
DEG C, it is added dropwise to 85% phosphoric acid (8.07g, 70mmol), a small amount of crystal seed is added, is down to room temperature crystallization, is filtered, it is dry, obtain chemical combination
Object 1a-1 (23.87g, 83%).ESI m/z=223.2 (M+1),1HNMR(DMSO-d6,400MHz)δ7.80-7.63(m,
2H),7.16-6.92(m,2H),4.03-3.73(m,1H),2.82-2.71(m,2H),2.24(s,3H),2.05-1.95(m,
4H),1.56-1.39(m,2H)。
Embodiment 2
Addition 4- fluorobenzaldehydes (12.41g, 100mmol) in three-necked flask, 4- amino -1- methyl piperidines (11.42g,
100mmol) and dichloromethane (124mL), it is stirred to react 1~2 hour, acetic acid 25mL is added, sodium borohydride is added in batches
(7.57g, 200mmol) is reacted at room temperature 6-8 hours, and reaction terminates plus reaction is quenched in water 100mL, and 10% sodium hydroxide is added
Solution adjusts pH value to 9~10, and liquid separation, water phase uses dichloromethane (143mL) to extract 2 times again, merges organic phase saturated salt solution
It washes 2 times (143mL), sodium sulphate drying is concentrated to give grease and tetrahydrofuran (200mL) stirring and dissolving is added, is heated to 45~55
DEG C, it is added dropwise to pyrovinic acid (19.22g, 200mmol), a small amount of crystal seed is added, is down to room temperature crystallization, is filtered, it is dry, obtain chemical combination
Object 1a-2 (29.84g, 72%).
ESIm/z=223.2 (M+1),1HNMR(DMSO-d6,400MHz)δ7.83-7.59(m,2H),7.17-6.89(m,
2H),4.04-3.70(m,1H),2.85-2.72(m,2H),2.35(s,6H),2.23(s,3H),2.05-1.95(m,4H),
1.55-1.42(m,2H)。
Embodiment 3
Addition 4- fluorobenzaldehydes (12.41g, 100mmol) in three-necked flask, 4- amino -1- methyl piperidines (11.42g,
100mmol) and dichloromethane (124mL), it is stirred to react 1~2 hour, acetic acid 25mL is added, sodium borohydride is added in batches
(7.57g, 200mmol) is reacted at room temperature 6-8 hours, and reaction terminates plus reaction is quenched in water 100mL, and 10% sodium hydroxide is added
Solution adjusts pH value to 9~10, and liquid separation, water phase uses dichloromethane (143mL) to extract 2 times again, merges organic phase saturated salt solution
It washes 2 times (143mL), sodium sulphate drying is concentrated to give grease and ethyl acetate (200mL) stirring and dissolving is added, is heated to 45~55
DEG C, it is added dropwise to acetic acid (12.01g, 200mmol), a small amount of crystal seed is added, is down to room temperature crystallization, is filtered, it is dry, obtain compound 1a-
3 (27.05g, 79%).
ESI m/z=223.2 (M+1),1HNMR(DMSO-d6,400MHz)δ7.81-7.61(m,2H),7.15-6.85
(m,2H),4.05-3.72(m,1H),2.84-2.70(m,2H),2.24(s,3H),2.04-1.92(m,4H),1.80-1.40
(m,8H)。
Embodiment 4
Addition 4- fluorobenzaldehydes (12.41g, 100mmol) in three-necked flask, 4- amino -1- methyl piperidines (11.42g,
100mmol) and dichloromethane (124mL), it is stirred to react 1~2 hour, acetic acid 25mL is added, sodium borohydride is added in batches
(7.57g, 200mmol) is reacted at room temperature 6-8 hours, and reaction terminates plus reaction is quenched in water 100mL, and 10% sodium hydroxide is added
Solution adjusts pH value to 9~10, and liquid separation, water phase uses dichloromethane (143mL) to extract 2 times again, merges organic phase saturated salt solution
It washes 2 times (143mL), sodium sulphate drying is concentrated to give grease and tetrahydrofuran (200mL) stirring and dissolving is added, is heated to 45~55
DEG C, p-methyl benzenesulfonic acid hydrate (38.04g, 200mmol) is added, a small amount of crystal seed is added, is down to room temperature crystallization, filters, it is dry,
Obtain compound 1a-4 (41.94g, 74%).
ESI m/z=223.2 (M+1),1HNMR(DMSO-d6,400MHz)δ7.85-7.60(m,6H),7.17-6.89
(m,6H),4.04-3.70(m,1H),2.85-2.72(m,2H),2.38(s,6H),2.23(s,3H),2.05-1.95(m,4H),
1.55-1.42(m,2H)。
Embodiment 5
Compound 1a-1 (28.76g, 100mmol) is added in three-necked flask, n,N-Dimethylformamide (150mL) is added
Stirring and dissolving, be added triethylamine (20.24g, 200mmol), stirring 20~30 minutes after be added carbonyl dimidazoles (17.03g,
105mmol), it reacts at room temperature 6-8 hours.Reaction terminates to be cooled to room temperature addition water (300mL), dichloromethane (300mL) stirring point
Liquid, water phase use dichloromethane (150mL) to extract 2 times again, merge organic phase saturated salt solution (150mL) and wash 2 times, sodium sulphate is dry
Dry, concentration removes most of solvent, and petroleum ether (300mL) is added, and heats recrystallization, mashing, and filtration drying obtains in white solid
Mesosome 3 (27.84g, yield 88%).ESIm/z=317.2 (M+1),1HNMR(DMSO-d6,400MHz)δ8.04(s,1H),
7.75-7.38(m,3H),7.23-6.92(m,3H),,3.89(m,1H),2.82-2.65(m,2H),2.20(s,3H),2.23-
2.02(m,4H),1.54-1.26(m,2H)ppm。
Embodiment 6
Addition compound 4-hydroxy base cyanophenyl (11.91g, 100mmol) in three-necked flask, acetone (120mL), stirring and dissolving,
Potassium carbonate (27.64g, 200mmol) is added, is stirring evenly and then adding into isobutane bromide (20.55g, 150mmol), is heated to 50
DEG C reaction 4-6 hours.Reaction terminates rotation and removes most of acetone, and water (120mL), ethyl acetate (120mL), liquid separation, water phase is added
It uses ethyl acetate (60mL) to extract 1 time again, merges organic phase saline solution (120mL) and wash 1 time, anhydrous sodium sulfate drying is filtered, dense
Contracting, obtains grease 2a crude products and directly casts single step reaction.
ESIm/z=176.1 (M+1).
Embodiment 7
Compound 2a (by 4 gained of embodiment, counting 100mmol) is added in there-necked flask, copper chloride (3.36g, 25mmol) is different
Propyl alcohol (200mL), water (20mL) are added potassium borohydride (16.18g, 300mmol), are heated to interior temperature in batches after stirring evenly
60~65 DEG C are reacted 5~8 hours.It reacts and terminates to be added, concentration removing part methanol, addition ethyl acetate (200mL), liquid separation,
Water phase uses saturated common salt water washing 2 times again, and p-methyl benzenesulfonic acid hydrate (38.04g, 200mmol) is added, it is small to be stirred at room temperature 3~4
When, a large amount of solids are precipitated, filter, dry intermediate 2-1 (26.36g, two step yields 75%).ESI m/z=180.1 (M+
1),1HNMR (DMSO-d6,400MHz) δ 7.64 (d, J=7.8Hz, 2H), 7.35-7.10 (m, 4H) 6.87 (d, J=8.4Hz,
2H), 3.70 (d, J=6.4Hz, 2H), 3.62 (s, 2H), 2.37 (s, 3H), 2.15-2.00 (m, 1H), 1.03 (d, J=
6.4Hz,6H)ppm。
Embodiment 8
Add and compound 2a (by 4 gained of embodiment, counting 100mmol), Raney's nickel (1.2g), methanol are added in hydrogen kettle
(200mL), switching hydrogen 3 times, keeps reacting kettle inner pressure 10Mpa, is heated to 40~50 DEG C of reactions of interior temperature after switching nitrogen 1 time
4-6 hours.Reaction terminates to release hydrogen, diatomite filtering, and methanol (50mL) washs, and concentration removes part methanol, and isopropyl is added
Alcohol (200mL) is added p-methyl benzenesulfonic acid hydrate (38.04g, 200mmol), is stirred at room temperature 1~2 hour, a large amount of solids are precipitated,
It is cooled to 0 DEG C to be beaten 2~3 hours, filtering, dry intermediate 2-2 (16.44g, two step yields 72%).
Embodiment 9
Compound 1 (31.64g, 100mmol), compound 2-1 (36.90g, 105mmol), dichloro are added in three-necked flask
Methane (320mL) is stirring evenly and then adding into triethylamine (20.24g, 200mmol), reacts at room temperature 4-6 hours, and reaction terminates to be added
Water (320mL), liquid separation, water phase use dichloromethane (60mL) to extract 2 times again, merge organic phase saline solution (160mL) and wash 2 times, nothing
Aqueous sodium persulfate is dried, and is filtered, and concentration obtains grease Mo Fanselin unhindered aminas 3 and directly casts single step reaction.
Embodiment 10
It is added compound 3 (meter 100mmol) in three-necked flask, absolute ethyl alcohol (463mL), it is heated to 60 after stirring evenly~
65 DEG C, tartaric acid (7.08g, 52mmol) is added, a small amount of product crystal seed is added in stirring after ten minutes, is slowly cooled to room temperature mashing,
Filtering, dry half tartrates 4 (41.60g, two step yields 83%) of product Mo Fanselin.
Claims (6)
1. a kind of Mo Fanselin synthetic methods, it is characterised in that include the activity for preparing formula (1) with the compound of formula (1a)
Carbamide compound, then carry out with Formula (2) that a Mo Fanselin free alkalis formula (3) is obtained by the reaction under alkaline system, then
Mo Fanselin free alkalis are obtaining half tartrate formulas (4) of a Mo Fanselin with tartaric acid:
Wherein HmA is the general formula of m member acid, HnA is the general formula of n member acid, and m and n are 1,2 or 3, are respectively selected from as sulfuric acid, salt
Acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, pyrovinic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.
2. one kind Mo Fanselin synthetic methods according to claim 1, it is characterised in that described and Formula (2)
Alkali is selected from organic base and inorganic base in reaction, and inorganic base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, saleratus
In one kind, organic base be selected from diisopropylethylamine, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU)
Or triethylene diamine；Reaction dissolvent is selected from dimethylformamide, dimethylacetylamide, dichloromethane, tetrahydrofuran, 1,4- dioxies
It is one or more in six rings, acetonitrile or acetone；Reaction temperature is 0~80 DEG C.
3. one kind Mo Fanselin synthetic methods according to claim 1, it is characterised in that molten in the salt-forming reaction
Agent be selected from water, methanol, ethyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetone, acetonitrile or toluene or
Their mixed solution；Reaction temperature is 0~90 DEG C.
4. a kind of Mo Fanselin intermediate activity carbamide compound formulas (1), structural formula are：
5. a kind of preparation method of active carbamide compound formula (1) as claimed in claim 4, it is characterised in that including：
1) 4- fluorobenzaldehydes and 4- amino -1- methyl piperidines are subjected to reductive amination process, formula (1a) is obtained through salt-forming reaction
Compound；
2) compound of formula (1a) is reacted after alkali is free with dicarbapentaborane imidazoles in a solvent, and the work of formula (1) is obtained after recrystallization
Property carbamide compound：
Wherein HmA is the general formula of m member acid, and m 1,2 or 3 is selected from as sulfuric acid, hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methyl
Sulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid or tartaric acid.
6. the preparation method of activity carbamide compound formula (1) according to claim 5, it is characterised in that in the step 1
Go back original reagent is selected from sodium borohydride in reductive amination process, and acetic acid sodium borohydride, sodium cyanoborohydride, reaction dissolvent is selected from diformazan
Base formamide, dimethylacetylamide, tetrahydrofuran, 1,4- dioxane, dichloromethane or toluene；Reaction temperature is 0~50 DEG C；
Solvent is selected from methanol, ethyl alcohol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4- dioxies six in salt-forming reaction in the step 1
Ring, acetone, acetonitrile or toluene；Reaction temperature is 0~90 DEG C；Alkali in the step 2 is selected from organic base and inorganic base, inorganic base
Selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, saleratus, organic base is selected from diisopropylethylamine, triethylamine, 1,
11 carbon -7- alkene (DBU) of 8- diazabicylos [5.4.0] or triethylene diamine；Solvent is selected from dimethylformamide, dimethyl second
Amide, dichloromethane, tetrahydrofuran, 1,4- dioxane, acetonitrile；Reaction temperature is 0~50 DEG C.
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| CN201610302251.4A CN105820110B (en) | 2016-05-09 | 2016-05-09 | Mo Fanselin synthetic methods |
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| CN201610302251.4A CN105820110B (en) | 2016-05-09 | 2016-05-09 | Mo Fanselin synthetic methods |
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| CN105820110B true CN105820110B (en) | 2018-07-24 |
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| CZ2015688A3 (en) * | 2015-10-02 | 2017-04-12 | Zentiva, K.S. | A method of producing 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl) of urea and its deuterated analogs |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| WO2017165635A1 (en) | 2016-03-25 | 2017-09-28 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome p450 modulators |
| EP3558311A1 (en) | 2016-12-20 | 2019-10-30 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of alzheimer's disease psychosis |
| US20180208556A1 (en) * | 2017-01-20 | 2018-07-26 | Sci Pharmtech, Inc. | Method for Preparing Pimavanserin |
| EP3615028A1 (en) | 2017-04-28 | 2020-03-04 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| CN106946764A (en) * | 2017-05-11 | 2017-07-14 | 成都百裕制药股份有限公司 | A kind of method for preparing the tartrate crystal formation B of piperazine Ma Selin half |
| US20210077479A1 (en) | 2017-08-30 | 2021-03-18 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| CN108947891B (en) | 2018-07-26 | 2021-02-09 | 丽珠集团新北江制药股份有限公司 | Method for safely preparing pimavanserin and tartrate thereof by using triphosgene |
| CN108794351B (en) * | 2018-07-26 | 2021-02-09 | 丽珠集团新北江制药股份有限公司 | Preparation method of pimavanserin key intermediate |
| CN111333567A (en) * | 2018-12-19 | 2020-06-26 | 北京万全德众医药生物技术有限公司 | Novel pimavanserin preparation method |
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