CN105111135A - Preparation method of substituted urea derivative - Google Patents
Preparation method of substituted urea derivative Download PDFInfo
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- CN105111135A CN105111135A CN201510568738.2A CN201510568738A CN105111135A CN 105111135 A CN105111135 A CN 105111135A CN 201510568738 A CN201510568738 A CN 201510568738A CN 105111135 A CN105111135 A CN 105111135A
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- 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
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- C07D211/58—Nitrogen atoms attached in position 4
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Abstract
The invention relates to a novel preparation method of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidyl-4-yl)urea hemitartrate (pimavanserin tartrate), particularly a pharmaceutical compound for treating Parkinson's disease, of which the structural formula is disclosed as Formula (I). The invention also relates to a novel intermediate of the preparation method.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, the preparation method treating a Parkinson's disease psychosis medicinal compound tartrate Mo Fanselinxin more specifically to a kind of and the new intermediate of this preparation method.
Background technology
Current whole world parkinsonian about 700 ten thousand to one 10,000,000, and China just has 2,600,000, ranks first in the world, and also will increase by 100,000 neopathy patients every year.The parkinsonian of more than 50% once had mental symptom (PDP).These mental symptom main manifestations are illusion and vain hope, bring larger challenge to the treatment of parkinsonian and nursing.Dopamine HCL is the main target for the treatment of of Parkinson disease, causes the dyskinesia of disturbances in patients with Parkinson disease to worsen, be not suitable for such patient at present because most of antipsychotics can block Dopamine HCL in brain.
Parkinson's disease psychosis is the major cause that Parkinsonian enters old nurse apartment, and Parkinson's disease psychosis does not ratify other drug now except low dosage leoponex, so once approval significantly should be able to improve standard treatment.Because leoponex has serious potential safety hazard, dangerous quantity of leucocyte can be caused to decline, and leoponex has drowsiness side effect in addition.
A tartrate Mo Fanselin (Pimavanserin of company of Acadia research and development, Nuplazid) Parkinson's disease mental symptom is used for the treatment of, for the similar thing of non-Dopamine HCL neurotransmitter, selectively can block five hydroxytryptamine 2A acceptor and do not affect the effect of Dopamine HCL.Its structural formula is as follows:
。
There is the currently known methods of a several tartrate Mo Fanselin for the preparation of formula (I).Publication number US20070260064A1 and CN101778821A application discloses following preparation method:
。
This method uses phosgene to prepare target compound, and toxicity is very big, and environmental pollution is serious, is not suitable for suitability for industrialized production, and the polymeric impurities that this phosgene method produces three and is difficult to remove, yield is extremely low.
CN104844502A application discloses following preparation method
。
Though the method employs chloro-formic ester replace phosgene, avoid the phosgene of severe toxicity, but chloro-formic ester still toxicity is huge, environmental pollution is serious, starting raw material N-(4-the luorobenzyl)-1-methyl piperidine-4-amine simultaneously used is pale yellowish oil liquid, purity is low, poor stability, not easily uses as stable starting raw material.
A tartrate Mo Fanselin belongs to urea derivative, as urea derivative, is usually prepared by following six kinds of modes: 1. amine substance and CO
2reaction generates urea derivative; 2. amine substance and phosgene reaction generate urea derivative; 3. amine substance and isocyanate reaction generate urea derivative; 4. amine substance and CO react and generate urea derivative under orgnometallic catalyst catalysis; 5. amine substance and chloro-formic ester react and generate urea derivative; 6. amine substance and urea or carbonate reaction generate urea derivative.Above method 2. ~ material toxicity that 5. uses is huge, the raw material that 6. method generally uses is not easily obtained and expensive, method 1. in CO
2though cheap and easy to get, need High Temperature High Pressure, have huge advantage at the urea derivative preparing symmetrical structure, but preparing the urea derivative of unsymmetrical structure, side reaction reaches 35% more than.
Therefore exploitation urea derivative new synthetic method, be significant.
Summary of the invention
Our target is the preparation method developing a kind of tartrate Mo Fanselinxin, avoids above-mentioned preparation method's shortcoming and for economical with suitability for industrialized production.
In process of the test, we are surprisingly found out that, use new intermediate, through type II intermediate and formula III intermediate reaction, then salify, we have obtained formula I, and there is very high yield and almost can't detect any impurity, this completes the present invention.
。
Our technological line of invention is as follows:
。
Wherein, during the free alkali of formula II intermediate and formula III intermediate reaction preparation formula I, reaction solvent, through groping in a large number, have selected non-polar solvent, described non-polar solvent is the one in methylene dichloride, ethylene dichloride, trichloromethane and toluene, preferred methylene dichloride; Reaction acid binding agent and reaction promotor are chosen as organic bases, and described organic bases is the one in triethylamine or pyridine, preferred triethylamine.
When preparation formula II intermediate, selecting type IV intermediate reacts with N, N'-carbonyl dimidazoles in polar aprotic mixed solvent, answers temperature to be 15 ~ 30 DEG C.
。
The polar aprotic mixed solvent that we select is the wantonly one or two solvent system in N, N'-dimethyl formamide, N, N'-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, acetone and acetonitrile, the mixed solvent system of preferred N, N'-dimethyl formamide and acetonitrile.
When preparing formula III intermediate, dissolved by formula V intermediate in what Virahol, the hydrogen chloride solution of instillation Virahol, regulates pH to 1 ~ 2 and obtains.
。
When preparation formula I, select alcohols as one-tenth salt solvent, wherein said alcoholic solvent is Virahol, ethanol, preferred Virahol.The process for purification of a formula I tartrate Mo Fanselin is the mixed system of formic acid and acetone, and the volume ratio of its formic acid and acetone is 1:6 ~ 1:10.
The present invention compared with prior art, has significant advantage:
Step is simple, green reaction, Atom economy, to environment almost pollution-free, product purity is high, almost inclusion-free.
Embodiment
The following examples can conduct further description the present invention, but these embodiments should as limitation of the scope of the invention.
embodiment 1:
1, the preparation of N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate (formula III intermediate)
In 10L dry reaction still, add Virahol 6000ml and N-(4-luorobenzyl)-1-methyl piperidine-4-amine (formula V) (555g, 2.5mol), stir, be cooled to 0 ~ 5 DEG C, the hydrogen chloride solution of instillation Virahol, regulates pH to 1 ~ 2, insulated and stirred 1h, filter, the appropriate washed with isopropyl alcohol of solid, 70 ~ 80 DEG C of vacuum-dryings obtain N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate 674g, yield 91.3%.
2, N-(4-isobutoxy benzyl)-1
hthe preparation of-imidazoles-methane amide (formula II intermediate)
In 20L dry reaction still, under room temperature condition, add dry N, N'-dimethyl formamide 2500ml, dry acetonitrile 8500ml, (4-isobutoxy phenyl)-methylamine (formula IV) (538g is added under stirring, 3.0mol) and N, N'-carbonyl dimidazoles (CDI) (584g, 3.6mol), stirring reaction 15h at 20 ~ 25 DEG C of temperature, react complete, be evaporated to dry, resistates adds methylene dichloride 7000ml, stirring and dissolving, organic phase saturated aqueous common salt (1000ml × 3) washing, anhydrous Na
2sO
4drying, crosses and filters siccative, obtain off-white color pressed powder N-(4-isobutoxy benzyl)-1 after pressure reducing and steaming solvent
h-imidazoles-methane amide 705g, yield 86.0%.
3, the preparation of 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea (Mo Fanselin)
In 20L dry reaction still, add methylene dichloride 8500ml, N-(4-isobutoxy benzyl)-1 successively
h-imidazoles-methane amide (formula II intermediate) (437g, 1.6mol), stirring and dissolving, add N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate (formula III intermediate) (472g, 1.6mol) and triethylamine (596ml, 4.3mol), stirring at room temperature 20h, react complete, filter, filtrate adds water 1000ml, stir 10min, stratification, organic layer saturated aqueous common salt (800ml × 3) washing, anhydrous Na
2sO
4drying, crosses and filters siccative, is evaporated to dry semi-solid 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea 558g, yield 81.6%.
4, the preparation of 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea half tartrate (a tartrate Mo Fanselin)
In 20L dry reaction still, add Virahol 6000ml and-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea (550g, 1.29mol), be heated to 60 ~ 65 DEG C, under stirring, add tartrate (99g, the solution of 700ml Virahol 0.66mol), insulated and stirred 2h, is cooled to 0 ~ 5 DEG C, stirs 1h, filter, the appropriate washed with isopropyl alcohol of solid, 60 ~ 65 DEG C of vacuum-dryings obtain a tartrate Mo Fanselin 577g, yield 89.1%.
5, the refining preparation of a tartrate Mo Fanselin
A tartrate Mo Fanselin 30g, formic acid 30ml, is heated to 50 ~ 55 DEG C, adds needle-use activated carbon 1.0g, stir 20min, filter decarburization, filtrate adds acetone 240ml at 40 ~ 45 DEG C, is cooled to 0 ~ 5 DEG C under stirring, filter, solid proper amount of acetone is washed, and 60 ~ 65 DEG C of vacuum-dryings obtain a tartrate Mo Fanselin 28.3, yield 94.3%.HPLC content 99.9%, [HPLC normalization method: chromatographic column Shimadzu C18 post (4.6mm × 250mm, 5m); Moving phase 0.21% heptane sulfonic acid sodium salt (add Glacial acetic acid and be adjusted to pH4.5)-acetonitrile (15: 85); Determined wavelength 256nm; Column temperature 30 DEG C; Flow velocity 1.0ml/min].
1H—NMR（400MHz，CDCl
3/TMS，ppm）：
δ：6.88～7.32(m，8H，Ar-
H)，4.94（s，2H，NC
H 2 ），6.47(t，1H，J＝9.0Hz，N
H)，4.32(d，2H，J＝6.0Hz，NHC
H 2)，3.89(d，2H，J＝6.0Hz，OC
H 2)，3.66～3.70(m，1H，J＝9.0Hz，NC
H)，2.59～2.64(m，4H，J＝9.0Hz，C-(C
H 2)
2)，2.26（s，3H，NC
H 3 ），1.89～1.92(m，H，J＝9.0Hz，C
H(CH
3)
2)，1.66～1.69(m，4H，J＝9.0Hz，CH(C
H 2)
2)，1.54(d，6H，J＝6.0Hz，CH(C
H 3)
2)。
MS:m/z（M
+）428（M-C
4H
6O
6+H）。
embodiment 2:
1, the preparation of N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate (formula III intermediate)
In the dry there-necked flask of 2000ml, add Virahol 600ml and N-(4-luorobenzyl)-1-methyl piperidine-4-amine (formula V) (55.5g, 0.25mol), stir, be cooled to 0 ~ 5 DEG C, the hydrogen chloride solution of instillation Virahol, regulates pH to 1 ~ 2, insulated and stirred 1h, filter, the appropriate washed with isopropyl alcohol of solid, 70 ~ 80 DEG C of vacuum-dryings obtain N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate 68g, yield 91.4%.
2, N-(4-isobutoxy benzyl)-1
hthe preparation of-imidazoles-methane amide (formula II intermediate)
In the dry there-necked flask of 2000ml, under room temperature condition, add dry N, N'-N,N-DIMETHYLACETAMIDE 250ml, dry acetonitrile 850ml, (4-isobutoxy phenyl)-methylamine (formula IV) (53.8g is added under stirring, 0.3mol) and N, N'-carbonyl dimidazoles (CDI) (58.4g, 0.36mol), stirring reaction 15h at 20 ~ 25 DEG C of temperature, react complete, be evaporated to dry, resistates adds methylene dichloride 700ml, stirring and dissolving, organic phase saturated aqueous common salt (100ml × 3) washing, anhydrous Na
2sO
4drying, crosses and filters siccative, obtain off-white color pressed powder N-(4-isobutoxy benzyl)-1 after pressure reducing and steaming solvent
h-imidazoles-methane amide 71g, yield 86.1%.
3, the preparation of 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea (Mo Fanselin)
In the dry there-necked flask of 2000ml, add methylene dichloride 900ml, N-(4-isobutoxy benzyl)-1 successively
h-imidazoles-methane amide (formula II intermediate) (44g, 0.16mol), stirring and dissolving, add N-(4-luorobenzyl)-1-methyl piperidine-4-amine hydrochlorate (formula III intermediate) (47g, 0.16mol) and triethylamine (60ml, 0.43mol), stirring at room temperature 20h, react complete, filter, filtrate adds water 100ml, stir 10min, stratification, organic layer saturated aqueous common salt (80ml × 3) washing, anhydrous Na
2sO
4drying, crosses and filters siccative, is evaporated to dry semi-solid 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea 57g, yield 81.9%.
4, the preparation of 1-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea half tartrate (a tartrate Mo Fanselin)
In the dry there-necked flask of 1000ml, add Virahol 600ml and-(4-luorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidine-4-base) urea (55g, 0.13mol), be heated to 60 ~ 65 DEG C, under stirring, add tartrate (10g, the solution of 70ml Virahol 0.066mol), insulated and stirred 2h, is cooled to 0 ~ 5 DEG C, stirs 1h, filter, the appropriate washed with isopropyl alcohol of solid, 60 ~ 65 DEG C of vacuum-dryings obtain a tartrate Mo Fanselin 59g, yield 90.3%.
5, the refining preparation of a tartrate Mo Fanselin
A tartrate Mo Fanselin 30g, formic acid 30ml, is heated to 50 ~ 55 DEG C, adds needle-use activated carbon 1.0g, stir 20min, filter decarburization, filtrate adds acetone 240ml at 40 ~ 45 DEG C, is cooled to 0 ~ 5 DEG C under stirring, filter, solid proper amount of acetone is washed, and 60 ~ 65 DEG C of vacuum-dryings obtain a tartrate Mo Fanselin 27.8, yield 94.1%.HPLC content 99.8%, [HPLC normalization method: chromatographic column Shimadzu C18 post (4.6mm × 250mm, 5m); Moving phase 0.21% heptane sulfonic acid sodium salt (add Glacial acetic acid and be adjusted to pH4.5)-acetonitrile (15: 85); Determined wavelength 256nm; Column temperature 30 DEG C; Flow velocity 1.0ml/min].
Claims (8)
1. a method of 1-(4-luorobenzyl)-3-(4-isobutoxy the benzyl)-1-(1-methyl piperidine-4-base) urea half tartrate (a tartrate Mo Fanselin) of preparation formula I,
It is characterized in that under non-polar solvent and organic bases, by the free alkali of formula II intermediate and formula III intermediate reaction preparation formula I, the free alkali of formula I again in what alcoholic solvent with tartaric acid:
。
2. method according to claim 1, is characterized in that: the preparation method of formula II intermediate, is reacted by formula IV intermediate in polar aprotic mixed solvent with N, N'-carbonyl dimidazoles,
。
3. method according to claim 1, is characterized in that: the preparation method of formula III intermediate, is dissolved by formula V intermediate in what Virahol, and the hydrogen chloride solution of instillation Virahol, regulates pH to 1 ~ 2,
。
4. method according to claim 1, is characterized in that: described non-polar solvent is the one in methylene dichloride, ethylene dichloride, trichloromethane and toluene; Described organic bases is the one in triethylamine or pyridine.
5. method according to claim 1, is characterized in that: described alcoholic solvent is Virahol, ethanol, preferred Virahol.
6. method according to claim 2, it is characterized in that: described polar aprotic mixed solvent is N, N'-dimethyl formamide, N, wantonly one or two solvent system in N'-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, acetone and acetonitrile, the mixed solvent system of preferred N, N'-dimethyl formamide and acetonitrile.
7. method according to claim 2, is characterized in that: described temperature of reaction is 15 ~ 30 DEG C.
8. method according to claim 1, is characterized in that: the process for purification of a tartrate Mo Fanselin of described formula I is the mixed system of formic acid and acetone, and the volume ratio of its formic acid and acetone is 1:6 ~ 1:10.
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| CN105481757A (en) * | 2015-12-25 | 2016-04-13 | 北京康立生医药技术开发有限公司 | Preparation method of pimavanserin |
| CN105523993A (en) * | 2015-12-28 | 2016-04-27 | 重庆两江药物研发中心有限公司 | N-(4-fluorobenzyl)-N-(1-methylpiperidinyl-4-yl)-N'-4-(2-methylpropoxyl)phenylmethyl)urea tartrate crystal form C, and preparation method and application thereof |
| CN105820110A (en) * | 2016-05-09 | 2016-08-03 | 杭州科巢生物科技有限公司 | Novel synthesis method for pimavanserin |
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| WO2017054786A1 (en) * | 2015-10-02 | 2017-04-06 | Zentiva, K. S. | A production method of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin- 4-yl)urea and its deuterated analogs |
| CN107021917A (en) * | 2016-02-02 | 2017-08-08 | 江苏恩华药业股份有限公司 | Novel crystal forms of the tartrates of piperazine Ma Selin half and preparation method thereof |
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