CN105418460A - Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof - Google Patents
Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof Download PDFInfo
- Publication number
- CN105418460A CN105418460A CN201410392056.6A CN201410392056A CN105418460A CN 105418460 A CN105418460 A CN 105418460A CN 201410392056 A CN201410392056 A CN 201410392056A CN 105418460 A CN105418460 A CN 105418460A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- fanselin
- similar compound
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *c1ccc(CNC2CCN(*)CC2)cc1 Chemical compound *c1ccc(CNC2CCN(*)CC2)cc1 0.000 description 5
- UCENRSLMAQPAPO-UHFFFAOYSA-N CN(CC1)CCC1C1CC1 Chemical compound CN(CC1)CCC1C1CC1 UCENRSLMAQPAPO-UHFFFAOYSA-N 0.000 description 1
- YTJBJDRAYOXUCL-UHFFFAOYSA-N CN(CC1)CCC1NCC(C=C1)=CCC1F Chemical compound CN(CC1)CCC1NCC(C=C1)=CCC1F YTJBJDRAYOXUCL-UHFFFAOYSA-N 0.000 description 1
- OZAFYQUMOQHXMC-UHFFFAOYSA-N CNCC(CC1)=CC=C1[F]=C Chemical compound CNCC(CC1)=CC=C1[F]=C OZAFYQUMOQHXMC-UHFFFAOYSA-N 0.000 description 1
- GILKLRXBHCAHPJ-UHFFFAOYSA-N CNc(cc1)ccc1OC(Cl)=O Chemical compound CNc(cc1)ccc1OC(Cl)=O GILKLRXBHCAHPJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to an intermediate of pimavanserin and a similar compound thereof, and a preparation method thereof, and a method for preparing pimavanserin and a similar compound thereof. According to the present invention, the raw materials required by the intermediate have characteristics of low price, easy obtaining, easy separation purification and no requirement of post-treatment, the next step reaction can be directly performed through the one-pot method to prepare the pimavanserin and the similar compound thereof, the operation is simple, and the economical, efficient, safe and environmentally friendly synthesis process is provided for the preparation of the pimavanserin and the similar compound thereof; and with the application of the intermediate to prepare the pimavanserin, the high toxicity and the use of the difficultly-operated phosgene can be avoided, and the total yield of the reaction can achieves the level in the prior art even the higher level.
Description
Technical field
The present invention relates to the synthesis of a Mo Fanselin and similar compound thereof.
Background technology
Neurodegenerative conditions (ND) is that a class has common pathophysiological feature and within for some time, occurs related human's disease of the Progressive symmetric erythrokeratodermia degenerative change of the neural group of selectivity.The spinocerebellar ataxia that these nerve degenerative diseases include but not limited to the dyskinesia that Alzheimer's and relevant dementia, Parkinson's disease, huntington's chorea, LewyBody are sick and relevant and spinocebellar ataxia (Friedrich'sAtaxia) and are correlated with.
Acadia Pharmaceutical, Inc. finds the behavior that N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N '-(4-(2-methyl propoxy-)-phenyl methyl) urea (Pimavanserin, a Mo Fanselin) and relevant compound can be used in controlling to occur in all these morbid states and neuropsychiatric profiles through research.Mo Fanselin is a kind of serum 5-HT 2A receptor (5-HT2A) selectivity inverse agonist, and because of its highly selective compared with other antipsychotics side effects are few at present, previously research shows that it is safe and effective to Parkinson's disease mental symptom.Nearest one group adopts a psychotic phase iii clinical trial of Mo Fanselin treatment Parkinson to show, this medicine significantly can improve the mental symptom of parkinsonian, and better tolerance, without serious adverse reaction, obstacle of taking action can not be increased the weight of.
So far, have not been reported about a domestic patent for Mo Fanselin synthesis.External Patents report is also less.Such as patent US2008/0280886A1, US7601740B2, US7790899B2 and Patents thereof report the synthesis of a Mo Fanselin, and wherein US2008/0280886A1 and US7601740B2 reports following synthetic route:
US7790899B2 reports following synthetic route:
Above-mentioned two kinds of routes are all for key intermediate synthesis final product with 1-isobutoxy-4-isocyanatometyl benzene (compound 4).The method of US2008/0280886A1 report has used this reagent costly of DPPA, will through trinitride intermediate in reaction process, generate nitrine by product, there is blast, the potential safety hazards such as severe toxicity, and US7790899B2 has used hypertoxic phosgene, scale operation has had certain potential safety hazard.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, there is provided a kind of new Mo Fanselin and similar compound intermediate thereof, the preparation for a Mo Fanselin and similar compound thereof provides the synthesis technique of more economical, efficient a, safety and environmental protection.
The present invention also provides a preparation method of Mo Fanselin intermediate simultaneously and utilizes the method for a Mo Fanselin Intermediate Preparation Mo Fanselin and similar compound thereof.
For solving above technical problem, a kind of technical scheme that the present invention takes is as follows:
An a kind of Mo Fanselin and similar compound intermediate thereof, it has the structure shown in general formula I:
In formula I:
R
1alkyl;
R is phenyl, and it is not substituted or is selected from halogen, nitro, and one or more in cyano group replaced; Or R is the alkyl polyhalides hydrocarbon of carbon number 2 ~ 6, in described alkyl polyhalides hydrocarbon halogen be selected from fluorine, chlorine or bromine one or more.
Preferably, R
1for the aliphatic group of carbon number 1 ~ 6.More preferably, R
1for methyl, ethyl, propyl group, normal-butyl, isobutyl-, sec.-propyl, n-pentyl, n-hexyl or the tertiary butyl, be wherein most preferably with isobutyl-.
Preferably, at least three halogen atoms are contained in described alkyl polyhalides hydrocarbon.Multiple halogen atom can be identical or different.
Further preferably, R for being selected from phenyl, oil of mirbane, trichloroethyl, trifluoroethyl, the one in three bromomethyl.
According to a concrete preferably aspect of the present invention, described intermediate is compound 14-a, compound 14-b or compound 14-c:
The another technical scheme that the present invention takes is: the preparation method of an a kind of above-mentioned Mo Fanselin and similar compound intermediate thereof, it comprises makes formula II compound and formula III compound in a solvent, there is the lower step that substitution reaction occurs in acid binding agent, reaction equation is as follows:
R in formula II, formula III
1with the definition of R respectively with R in formula I
1identical with the definition of R, in formula III, X is F, Cl, Br or I.
Preferably, R in formula II
1for isobutyl-, in formula III, X is chlorine or bromine.
Further, described reaction adopts acetonitrile as solvent, specifically be implemented as follows: the acetonitrile solution adding formula III compound in reaction vessel, after nitrogen replacement, be cooled to less than 5 DEG C, the acetonitrile solution of formula II compound and acid binding agent is slowly added drop-wise in reaction system, in controlling, temperature is no more than 5 DEG C, and dropwise, system is slowly warming up to room temperature, continue reaction more than 1.5h, stopped reaction.
Further, after stopped reaction, add water and ethyl acetate, layering, get organic phase, washing, dry, filter, filtrate separation and purification obtains a formula I i.e. described Mo Fanselin and similar compound intermediate thereof.
According to a concrete aspect: described intermediate is compound 14-a, its preparation method comprises the step that compound 10 and compound 6-a are reacted, and reaction equation is as follows:
A specific implementation process is; The acetonitrile solution of compound 6-a is joined in reaction vessel, displacement nitrogen, in dislocation ice-water bath, at 0 ~ 4 DEG C, the acetonitrile solution of compound 10 and triethylamine is slowly added drop-wise to reaction system, in controlling, temperature is no more than 4 DEG C, dropwise, system is slowly warming up to room temperature, continues reaction 2 ~ 3h, stopped reaction, reaction solution adds water and ethyl acetate, layering, takes out organic phase, aqueous phase is extracted with ethyl acetate twice, merge organic phase, saturated NaCl solution is washed once, anhydrous sodium sulfate drying, filter, filtrate separation and purification obtains compound 14-a.
According to another concrete aspect: described intermediate is compound 14-b, its preparation method comprises the step that compound 10 and compound 6-b are reacted, and reaction equation is as follows:
A specific implementation process is; The acetonitrile solution of compound 6-b is joined in reaction vessel, displacement nitrogen, in dislocation ice-water bath, at 0 ~ 4 DEG C, the acetonitrile solution of compound 10 and triethylamine is slowly added drop-wise to reaction system, in controlling, temperature is no more than 4 DEG C, dropwise, system is slowly warming up to room temperature, continues reaction 2 ~ 3h, stopped reaction, reaction solution adds water and ethyl acetate, layering, takes out organic phase, aqueous phase is extracted with ethyl acetate twice, merge organic phase, saturated NaCl solution is washed once, anhydrous sodium sulfate drying, filter, filtrate separation and purification obtains compound 14-b.
According to another concrete aspect: described intermediate is compound 14-c, its preparation method comprises the step that compound 10 and compound 6-c are reacted, and reaction equation is as follows:
A specific implementation process is; The acetonitrile solution of compound 6-c is joined in reaction vessel, displacement nitrogen, in dislocation ice-water bath, at 0 ~ 4 DEG C, the acetonitrile solution of compound 10 and triethylamine is slowly added drop-wise to reaction system, in controlling, temperature is no more than 4 DEG C, dropwise, system is slowly warming up to room temperature, continues reaction 2 ~ 3h, stopped reaction, reaction solution adds water and ethyl acetate, layering, takes out organic phase, aqueous phase is extracted with ethyl acetate twice, merge organic phase, saturated NaCl solution is washed once, anhydrous sodium sulfate drying, filter, filtrate separation and purification obtains compound 14-c.
The present invention also provides a kind of structural formula such as formula the preparation method of the Mo Fanselin shown in V and similar compound thereof, and it comprises the step that the intermediate and formula I that make the present invention above-mentioned and formula IV compound react, and reaction equation is as follows:
In formula IV and V, R
2represent halogen; R
3for the aliphatic group of carbon number 1 ~ 6.
The reaction of an above-mentioned preparation Mo Fanselin and similar compound thereof can be carried out under solvent and acid binding agent exist.Solvent can be such as acetonitrile, DMSO etc.Acid binding agent can be those such as triethylamines that this area is commonly used, and DIPEA etc., are not particularly limited.
Preferably, described method also comprises the step of the method preparation I compound adopting the present invention above-mentioned.
Preferably, not treated by the reaction solution after formula II compound and formula III compounds accepted way of doing sth I, be directly used in synthesis type V compound, namely adopt one kettle way to prepare a Mo Fanselin and similar compound thereof.
According to a concrete aspect, in formula I and V, R
1for isobutyl-, in formula IV and V, R
2for F; R
3for methyl, ethyl, propyl group, sec.-propyl or isobutyl-.More specifically, in formula V, R
1for isobutyl-, R
2for F; R
3for methyl, now, a formula V compound i.e. Mo Fanselin.
Due to the enforcement of technique scheme, the present invention compared with prior art tool has the following advantages:
The invention provides a kind of new Mo Fanselin and similar compound intermediate thereof, this intermediate has following advantage:
1, required low in raw material price, is easy to get;
2, intermediate and product separation purifying easily, even do not need aftertreatment, can do a next step preparation Mo Fanselin and similar compound thereof by direct one kettle way, simple to operate;
3, can avoid toxicity very greatly and the use of not easy-operating phosgene;
4, the equal or higher level with prior art can be reached by its preparation Mo Fanselin and similar compound overall yield of reaction thereof.
Embodiment
The present invention relates to novel Mo Fanselin intermediate and take these intermediates to prepare the method for a Mo Fanselin and similar compound thereof.With the example that is prepared as of a Mo Fanselin, the solution of the present invention is described in detail below.
In the specific embodiment of the present invention: a Mo Fanselin adopts following route to synthesize:
More specifically, in selecting type Ia, R is that phenyl, p-nitrophenyl and trichloroethyl are illustrated.In intermediate compound involved by above-mentioned route, except Compound I a, remaining compound and their synthesis are all known, and these compounds can be purchased or be synthesized by known synthetic method, are not limited to above-mentioned route.
Below in conjunction with specific embodiment, the present invention is described in further details.Should be understood that these embodiments are for illustration of ultimate principle of the present invention, principal character and advantage, and the present invention is not limited by the following examples.The implementation condition adopted in embodiment can do further adjustment according to specific requirement, and not marked implementation condition is generally the condition in normal experiment.
embodiment 1 prepares compound 8 by compound 7
Compound 7 (10.0g is added in 250mL there-necked flask, 81.9mmol), Anhydrous potassium carbonate (22.6g, 163.8mmol), potassiumiodide (1.4g, 8.2mmol) and 50mLDMF, be heated to 85 DEG C, in reaction system, slowly add isobutane bromide (22.4g, 163.8mmol), finish, system reacts 3h under 85 DEG C of conditions, then continue slowly to add isobutane bromide (11.2g, 81.9mmol) to system, system continues to react 3h under 85 DEG C of conditions.Stopped reaction, system is cooled to room temperature, filters, filter cake 100mL ethyl acetate rinse 2 times.Filtrate poured in 250mL water, separate organic phase, aqueous phase uses 100mL extraction into ethyl acetate three times respectively, merges organic phase, wash once with the saturated NaCl aqueous solution of 150mL, anhydrous sodium sulfate drying, dry complete, filter, filtrate is spin-dried for obtain 14.0g compound 8, weak yellow liquid, yield 96%.
Compound 8 nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 9.87 (s, 1H), 7.82 (d, 2H), 6.99 (d, 2H), 3.80 (d, 2H), 2.17-2.06 (m, 1H), 1.04 (d, 6H).
embodiment 2 prepares compound 9 by compound 8
Compound 8 (10.0g, 56.1mmol) is added successively, 250mL ethanol, K in 500mL single port bottle
2cO
3(38.7g, 280.5mmol); Oxammonium hydrochloride (19.5g, 280.5mmol) is dissolved in 15mL water, then is joined in system, finish, system temperature rising reflux 2h, stopped reaction, is cooled to room temperature, system is filtered, filtrate is revolved and is steamed to 100mL, is poured in 250mL water, with 100mL extraction into ethyl acetate three times.Merge organic phase, wash once with the saturated NaCl aqueous solution of 150mL, anhydrous sodium sulfate drying, dry complete, filter, filtrate is concentrated obtains crude product, column chromatography purification (developping agent polarity: petrol ether/ethyl acetate=20/1) is adopted to obtain 8.1g compound 9, white solid, yield 75%.
Compound 9 nuclear magnetic data is as follows:
1hNMR (400MHz, DMSO) δ 10.94 (s, 1H), 8.06 (s, 1H), 7.50 (d, 2H), 6.95 (d, 2H), 3.76 (d, 2H), 2.08-1.94 (m, 1H), 0.98 (d, 6H).
embodiment 3 prepares compound 10 by compound 9
Compound 9 (4.0g, 20.7mmol) is added, ethanol 60mL, acetic acid (2.0g, 33.1mmol) and Pd/C (1.2g, Pd content 10%) in 250mL there-necked flask.Finish, system is normal pressure catalytic hydrogenation at room temperature.After reaction 12h, filter, filter cake 30mL washing with alcohol, merging filtrate, obtain oily matter by concentrated for filtrate.Oily matter adds 50mL ethyl acetate and 100mL sherwood oil shakes up, and after static 3h, separates out a large amount of white solid (acetate form of compound 10).Filtration obtains white solid 2.3g, add the 20mL30%NaOH aqueous solution, be extracted with ethyl acetate three times (15mL × 3), merge organic phase, use 10mL water respectively, the saturated NaCl solution washing of 10mL once, anhydrous sodium sulfate drying, filters, and filtrate concentrates to obtain 1.3g compound 10, weak yellow liquid, yield 35%.
Compound 10 nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 7.29 (d, 2H), 6.88 (d, 2H), 3.97 (s, 2H), 3.70 (d, 2H), 2.13-2.03 (m, 1H), 1.02 (d, 6H).
embodiment 4 prepares compound 5 by compound 11 and 12
Compound 11 (3.7g is added in 100mL, 30mmol), compound 12 (3.7g, 33mmol), 30mL methyl alcohol, system is cooled to 0 DEG C, slowly adds sodium triacetoxy borohydride (7.6g about half an hour to it, 36mmol), system at room temperature reacts 12h.30mL10%NaOH solution is added in system, be concentrated into 20ml, system is extracted with ethyl acetate three times (30mL × 3), merge organic phase, the saturated NaCl solution of 20mL is washed once, anhydrous sodium sulfate drying, filter, filtrate concentrating to obtain yellow liquid, and underpressure distillation (139-140 DEG C/20mbar) obtains 4.7g compound 5, yield 71%.
Compound 5 nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 7.32-7.24 (m, 2H), 7.04-6.96 (m, 2H), 3.78 (s, 2H), 2.85-2.76 (m, 2H), 2.51-2.41 (m, 1H), 2.26 (s, 3H), 2.02-1.84 (m, 4H), 1.50-1.38 (m, 2H).
embodiment 5 prepares compound 14-a by compound 10 with compound 6-a
The 3mL acetonitrile solution of compound 6-a (235mg, 1.5mmol) is added, displacement N in 25mL there-necked flask
2, in dislocation ice-water bath.At 0 DEG C, by compound 10 (269mg, 1.5mmol) and triethylamine (152mg, 1.5mL acetonitrile solution 1.5mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, layering.Take out organic phase, aqueous phase is extracted with ethyl acetate twice (20mL × 2), merge organic phase, the saturated NaCl solution washing of 20mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity PE/EA=10/1) that adopts of filtrate obtains compound 394mg compound 14-a, white solid, yield 88%.
Compound 14-a nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 7.39-7.31 (m, 2H), 7.28-7.23 (m, 2H), 7.22-7.16 (m, 1H), 7.14 (d, 2H), 6.91-6.85 (m, 2H), 5.26 (s, 1H), 4.37 (d, 2H), 3.72 (d, 2H), 2.14-2.02 (m, 1H), 1.03 (d, 6H).
embodiment 6 prepares a Mo Fanselin by compound 14-a and compound 5
Compound 14-a (200mg, 0.67mmol) is added, compound 5 (163mg, 0.73mmol) and 4.5mL acetonitrile in 25mL single port bottle.Add triethylamine (135mg, 1.34mmol) under stirring at room temperature, system is warmed up to 60 DEG C of reaction 12h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, layering.Take out organic phase, aqueous phase is extracted with ethyl acetate twice (20mL × 2), merge organic phase, with 20%NaOH solution washing 2 times (15mL × 2), 15mL water washing once, the saturated NaCl solution washing of 15mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity DCM/MeOH=20/1) that adopts of filtrate obtains 191mg light yellow solid, be a Mo Fanselin, yield 67%.
Mo Fanselin nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 7.21-7.15 (m, 2H), 7.06-6.94 (m, 4H), 6.78 (d, 2H), 4.50-4.42 (m, 1H), 4.38-4.30 (m, 3H), 4.28 (d, 2H), 3.68 (d, 2H), 2.86 (d, 2H), 2.25 (s, 3H), 2.12-2.00 (m, 3H), 1.76-1.58 (m, 4H), 1.01 (d, 6H).
embodiment 7 prepares compound 14-b by compound 10 with compound 6-b
The 4mL acetonitrile solution of compound 6-b (403mg, 2.0mmol) is added, displacement N in 25mL there-necked flask
2, in dislocation ice-water bath.At 0 DEG C, by compound 10 (358mg, 2.0mmol) and triethylamine (202mg, 2mL acetonitrile solution 2.0mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, layering.Take out organic phase, aqueous phase is extracted with ethyl acetate twice (20mL × 2), merge organic phase, the saturated NaCl solution washing of 20mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity PE/EA=10/1) that adopts of filtrate obtains 523mg white solid, be compound 14-b, yield 76%.
Compound 14-b nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 8.26-8.20 (m, 2H), 7.35-7.29 (m, 2H), 7.27-7.22 (m, 2H), 6.92-6.86 (m, 2H), 5.45-5.35 (m, 1H), 4.38 (d, 2H), 3.72 (d, 2H), 2.14-2.02 (m, 1H), 1.03 (d, 6H).
embodiment 8 prepares a Mo Fanselin by compound 14-b and compound 5
The 4mL acetonitrile solution of compound 14-b (344mg, 1.0mmol) is added, displacement N in 25mL there-necked flask
2, in dislocation ice-water bath.At 0 DEG C, by compound 5 (244mg, 1.1mmol) and triethylamine (111mg, 2mL acetonitrile solution 1.1mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, merge organic phase, with 30%NaOH solution washing 3 times (15mL × 3), 15mL water washing once, the saturated NaCl solution washing of 15mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity DCM/MeOH=20/1) that adopts of filtrate obtains 344mg light yellow solid, be a Mo Fanselin, yield 81%.
embodiment 9 prepares compound 14-c by compound 10 with compound 6-c
The 3mL acetonitrile solution of compound 6-c (318mg, 1.5mmol) is added, displacement N in 25mL there-necked flask
2, in dislocation ice-water bath.At 0 DEG C, by compound 10 (269mg, 1.5mmol) and triethylamine (152mg, 1.5mL acetonitrile solution 1.5mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, layering.Take out organic phase, aqueous phase is extracted with ethyl acetate twice (20mL × 2), merge organic phase, the saturated NaCl solution washing of 20mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity PE/EA=10/1) that adopts of filtrate obtains compound 444mg white solid, be compound 14-c, yield 83%.
Compound 14-c nuclear magnetic data is as follows:
1hNMR (400MHz, CDCl
3) δ 7.23-7.17 (m, 2H), 6.88-6.83 (m, 2H), 5.22 (s, 1H), 4.74 (s, 2H), 4.34 (d, 2H), 3.70 (d, 2H), 2.12-2.01 (m, 1H), 1.01 (d, 6H).
embodiment 10 prepares a Mo Fanselin by compound 14-C and compound 5
Compound 14-c (200mg, 0.56mmol) is added, compound 5 (139mg, 0.62mmol) and 4.5mLDMSO in 25mL single port bottle.Add DIPEA (361mg, 2.8mmol) under stirring at room temperature, system is warmed up to 100 DEG C of reaction 12h.Reaction solution send HPLC to detect, and according to HPLC data presentation, yield is about 20%.
embodiment 11 is by compound 10 and compound 6-a, and compound 5 one kettle way prepares a Mo Fanselin
The 4mL acetonitrile solution of compound 6-a (358mg, 2.3mmol) is added, displacement N in 25mL there-necked flask
2, in dislocation ice-water bath.At 0 DEG C, by compound 10 (412mg, 2.3mmol) and triethylamine (232mg, 2.0mL acetonitrile solution 2.3mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.The 2.0mL acetonitrile solution of compound 5 (511mg, 2.3mmol) and triethylamine (464mg, 4.6mmol) is added in system.Be warming up to 60 DEG C of reaction 12h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, layering.Take out organic phase, aqueous phase is extracted with ethyl acetate twice (20mL × 2), merge organic phase, with 20%NaOH solution washing 2 times (15mL × 2), 15mL water washing once, the saturated NaCl solution washing of 15mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity DCM/MeOH=20/1) that adopts of filtrate obtains 823mg light yellow solid, be a Mo Fanselin, yield 83%.
embodiment 12 is by compound 10 and compound 6-b, and compound 5 one kettle way prepares a Mo Fanselin
Add the 4mL acetonitrile solution of compound 6-b (403mg, 2.0mmol) in 25mL there-necked flask, displacement N2, in dislocation ice-water bath.At 0 DEG C, by compound 10 (358mg, 2.0mmol) and triethylamine (202mg, 2.0mL acetonitrile solution 2.0mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 4 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 2h.Reaction solution is moved in ice-water bath, at 0 DEG C, by compound 5 (488mg, 2.2mmol) with triethylamine (202mg, 2.0mL acetonitrile solution 2.0mmol) is slowly added drop-wise to reaction system, and in controlling, temperature is no more than 5 DEG C, dropwises, system is slowly warming up to room temperature, continues reaction 12h.Stopped reaction, reaction solution adds 20mL water and 20mL ethyl acetate, merge organic phase, with 30%NaOH solution washing 3 times (15mL × 3), 15mL water washing once, the saturated NaCl solution washing of 15mL once, anhydrous sodium sulfate drying, filters, and the concentrated column chromatography purification (eluent polarity DCM/MeOH=20/1) that adopts of filtrate obtains 628mg light yellow solid, be a Mo Fanselin, yield 74%.
Above to invention has been detailed description; its object is to allow the personage being familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence change that all spirit according to the present invention are done or modification, all should be encompassed in protection scope of the present invention.
Claims (12)
1. a Mo Fanselin and a similar compound intermediate thereof, is characterized in that: described intermediate has the structure shown in general formula I:
In formula I:
R
1alkyl;
R is phenyl, and it is not substituted or is selected from halogen, acyl group, ester group, nitro, and one or more in cyano group replaced; Or R is the alkyl polyhalides hydrocarbon of carbon number 2 ~ 6, in described alkyl polyhalides hydrocarbon halogen be selected from fluorine, chlorine or bromine one or more.
2. according to claim 1 Mo Fanselin and similar compound intermediate thereof, is characterized in that: described R
1for the aliphatic group of carbon number 1 ~ 6.
3. according to claim 2 Mo Fanselin and similar compound intermediate thereof, is characterized in that: described R
1for methyl, ethyl, propyl group, normal-butyl, isobutyl-, sec.-propyl, n-pentyl, n-hexyl or the tertiary butyl.
4. according to claim 1 Mo Fanselin and similar compound intermediate thereof, is characterized in that: containing at least three halogen atoms in described alkyl polyhalides hydrocarbon.
5. the Mo Fanselin according to claim 1 or 2 or 3 or 4 and similar compound intermediate thereof, is characterized in that: R for being selected from phenyl, oil of mirbane, trichloroethyl, trifluoroethyl, the one in three bromomethyl.
6. according to claim 1 Mo Fanselin and similar compound intermediate thereof, is characterized in that: described intermediate is compound 14-a, compound 14-b or compound 14-c:
7. the preparation method of as claimed in claim 1 Mo Fanselin and similar compound intermediate thereof, it is characterized in that: comprise and make formula II compound and formula III compound in a solvent, there is the lower step that substitution reaction occurs in acid binding agent, reaction equation is as follows:
R in formula II, formula III
1with the definition of R respectively with R in formula I
1identical with the definition of R, in formula III, X is F, Cl, Br or I.
8. preparation method according to claim 7, is characterized in that: R in formula II
1for isobutyl-, in formula III, X is chlorine or bromine.
9. a structural formula is such as formula the preparation method of the Mo Fanselin shown in V and similar compound thereof, it is characterized in that: comprise the step that the intermediate any one of claim 1 to 6 described in claim and formula I and formula IV compound are reacted, reaction equation is as follows:
In formula IV and V, R
2represent halogen; R
3for the aliphatic group of carbon number 1 ~ 6.
10. the preparation method of according to claim 9 Mo Fanselin and similar compound thereof, is characterized in that: described method also comprises the step of the method preparation I compound adopted any one of claim 7 to 8 described in claim.
The preparation method of 11. according to claim 9 Mo Fanselin and similar compound thereof, is characterized in that: not treated by the reaction solution after formula II compound and formula III compounds accepted way of doing sth I, is directly used in synthesis type V compound.
The preparation method of 12. according to claim 11 Mo Fanselin and similar compound thereof, is characterized in that: in formula I and V, R
1for isobutyl-, in formula IV and V, R
2for F; R
3for methyl, ethyl, propyl group, sec.-propyl or isobutyl-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410392056.6A CN105418460B (en) | 2014-08-11 | 2014-08-11 | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410392056.6A CN105418460B (en) | 2014-08-11 | 2014-08-11 | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105418460A true CN105418460A (en) | 2016-03-23 |
| CN105418460B CN105418460B (en) | 2017-04-12 |
Family
ID=55497066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410392056.6A Active CN105418460B (en) | 2014-08-11 | 2014-08-11 | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105418460B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017015272A1 (en) * | 2015-07-20 | 2017-01-26 | Acadia Pharmaceuticals Inc. | Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c |
| CN107200707A (en) * | 2017-05-16 | 2017-09-26 | 河北科技大学 | A kind of Mo Fanselin preparation method |
| EP3351532A1 (en) * | 2017-01-20 | 2018-07-25 | SCI Pharmatech, Inc. | Method for preparing pimavanserin |
| CN108358817A (en) * | 2018-03-05 | 2018-08-03 | 丽珠集团新北江制药股份有限公司 | A kind of preparation method of Mo Fanselin intermediate and Mo Fanselin |
| CN109734652A (en) * | 2019-03-07 | 2019-05-10 | 夸克侠医药科技(辽宁)有限公司 | A kind of preparation method of high-purity Mo Fanselin |
| CN110156664A (en) * | 2019-05-29 | 2019-08-23 | 常州大学 | A kind of synthetic method of piperazine Ma Selin |
| US10449185B2 (en) | 2017-08-30 | 2019-10-22 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10517860B2 (en) | 2016-03-25 | 2019-12-31 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| WO2020020064A1 (en) | 2018-07-26 | 2020-01-30 | 丽珠集团新北江制药股份有限公司 | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene |
| CN110894186A (en) * | 2018-09-12 | 2020-03-20 | 浙江京新药业股份有限公司 | Preparation method of pimavanserin and intermediate thereof |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11135211B2 (en) | 2017-04-28 | 2021-10-05 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| US11464768B2 (en) | 2016-12-20 | 2022-10-11 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5208247A (en) * | 1991-08-01 | 1993-05-04 | American Cyanamid Company | Pyridinium compounds which are useful as antagonists of platelet activating factor |
| WO2003065989A2 (en) * | 2002-02-08 | 2003-08-14 | Bristol-Myers Squibb Company | (oxime)carbamoyl fatty acid amide hydrolase inhibitors |
| CN1878750A (en) * | 2003-10-03 | 2006-12-13 | 赛诺菲-安万特 | Arylalkylcarbamate derivatives, preparation method thereof and use of same in therapeutics |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
-
2014
- 2014-08-11 CN CN201410392056.6A patent/CN105418460B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5208247A (en) * | 1991-08-01 | 1993-05-04 | American Cyanamid Company | Pyridinium compounds which are useful as antagonists of platelet activating factor |
| WO2003065989A2 (en) * | 2002-02-08 | 2003-08-14 | Bristol-Myers Squibb Company | (oxime)carbamoyl fatty acid amide hydrolase inhibitors |
| CN1878750A (en) * | 2003-10-03 | 2006-12-13 | 赛诺菲-安万特 | Arylalkylcarbamate derivatives, preparation method thereof and use of same in therapeutics |
| CN101778821A (en) * | 2007-05-15 | 2010-07-14 | 阿卡蒂亚药品公司 | Synthesizing of N-(4-luorobenzyl)-N-(1-methyl piperidine-4-yl)-N '-(4-(2-methyl propoxy-) phenyl methyl) urea and tartrate and crystal formation |
Non-Patent Citations (2)
| Title |
|---|
| J. MICHAEL CHONG ET AL.: "Preparation of Alkyl tert-Butyl Iminodicarbonates", 《JOURNAL OF THE ORGANIC CHEMISTRY》 * |
| RENATO SKERLJ ET AL.: "Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication", 《MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11840515B2 (en) | 2015-07-20 | 2023-12-12 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c |
| WO2017015272A1 (en) * | 2015-07-20 | 2017-01-26 | Acadia Pharmaceuticals Inc. | Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c |
| US10981870B2 (en) | 2015-07-20 | 2021-04-20 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form |
| US10597363B2 (en) | 2015-07-20 | 2020-03-24 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C |
| US10981871B2 (en) | 2015-07-20 | 2021-04-20 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11191757B2 (en) | 2016-03-25 | 2021-12-07 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US10517860B2 (en) | 2016-03-25 | 2019-12-31 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11464768B2 (en) | 2016-12-20 | 2022-10-11 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis |
| EP3351532A1 (en) * | 2017-01-20 | 2018-07-25 | SCI Pharmatech, Inc. | Method for preparing pimavanserin |
| US11135211B2 (en) | 2017-04-28 | 2021-10-05 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| CN107200707A (en) * | 2017-05-16 | 2017-09-26 | 河北科技大学 | A kind of Mo Fanselin preparation method |
| US10449185B2 (en) | 2017-08-30 | 2019-10-22 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10849891B2 (en) | 2017-08-30 | 2020-12-01 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10646480B2 (en) | 2017-08-30 | 2020-05-12 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US11452721B2 (en) | 2017-08-30 | 2022-09-27 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| CN108358817A (en) * | 2018-03-05 | 2018-08-03 | 丽珠集团新北江制药股份有限公司 | A kind of preparation method of Mo Fanselin intermediate and Mo Fanselin |
| US10934257B2 (en) | 2018-07-26 | 2021-03-02 | Livzon New North River Pharmaceutical Co., Ltd. | Method for preparing pimavanserin and tartrate thereof by using triphosgene |
| WO2020020064A1 (en) | 2018-07-26 | 2020-01-30 | 丽珠集团新北江制药股份有限公司 | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene |
| CN110894186A (en) * | 2018-09-12 | 2020-03-20 | 浙江京新药业股份有限公司 | Preparation method of pimavanserin and intermediate thereof |
| CN110894186B (en) * | 2018-09-12 | 2022-05-24 | 浙江京新药业股份有限公司 | Preparation method of pimavanserin and intermediate thereof |
| CN109734652A (en) * | 2019-03-07 | 2019-05-10 | 夸克侠医药科技(辽宁)有限公司 | A kind of preparation method of high-purity Mo Fanselin |
| CN110156664A (en) * | 2019-05-29 | 2019-08-23 | 常州大学 | A kind of synthetic method of piperazine Ma Selin |
| CN110156664B (en) * | 2019-05-29 | 2022-03-01 | 常州大学 | Method for synthesizing pimavanserin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105418460B (en) | 2017-04-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105418460B (en) | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof | |
| CN106432030B (en) | A kind of preparation method of Bu Waxitan | |
| CN102875537A (en) | Novel preparation method of antithrombosis medicine | |
| CN108503564A (en) | A kind of Mivacurium Chloride intermediate and the method using intermediate synthesis Mivacurium Chloride | |
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| CN105392772A (en) | Process for the preparation of key intermediates of omarigliptin | |
| CN105722829B (en) | The method of regio-selective synthesis pyrazoles | |
| CN103601645B (en) | The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| US20210380569A1 (en) | Process for Preparation of Optically Enriched Isoxazolines | |
| CN105669651A (en) | Preparation technique of dabigatran methanesulfonate | |
| EP3029028B1 (en) | Novel method for synthesizing key intermediate of apixaban | |
| CA2998643C (en) | Synthesis of terphenyl compounds | |
| DK3250556T3 (en) | PROCEDURES FOR THE PREPARATION OF COMPOUNDS, SUCH AS 3-ARYL BUTANALS THAT CAN BE USED FOR THE SYNTHESIS OF MEDETOMIDINE | |
| CN107324982B (en) | 1-trifluoromethyl-tetrasubstituted cyclopentene derivative and preparation method and application thereof | |
| CN103435490B (en) | Synthesis method for 2,2,4,4,6,6-hexanitro-adamantane | |
| CN106883192B (en) | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification | |
| CN104844554A (en) | Most effective process for base-free preparation of ketone intermediates usable for manufacture of nebivolol | |
| CN105418436B (en) | A kind of preparation method of melitracen hydrochloride | |
| CN104136422A (en) | Compound, method for producing compound, and method for purifying compound | |
| Fan et al. | Cyclic glyceryl sulfate: a simple and versatile bio-based synthon for the facile and convergent synthesis of novel surface-active agents | |
| KR20190039087A (en) | Purified intermediates for the preparation of purified < RTI ID = 0.0 > Senicry < / RTI & | |
| JP4509327B2 (en) | Process for producing N, N-disubstituted-4-aminocrotonic acid ester | |
| CN112939830B (en) | Nucleophilic reaction method of alkenyl thioether to o-methylene benzoquinone | |
| CN109721529B (en) | Simple preparation method of 2, 5-dichloropyridine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |