CN106518751A - Preparation method for pimavanserin - Google Patents
Preparation method for pimavanserin Download PDFInfo
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- CN106518751A CN106518751A CN201510577381.4A CN201510577381A CN106518751A CN 106518751 A CN106518751 A CN 106518751A CN 201510577381 A CN201510577381 A CN 201510577381A CN 106518751 A CN106518751 A CN 106518751A
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- 0 CCC(CCC1)CCC1*(C)CC(C=CC=C(C)N)=C Chemical compound CCC(CCC1)CCC1*(C)CC(C=CC=C(C)N)=C 0.000 description 3
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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
Abstract
The invention relates to a one-pot preparation method for pimavanserin. The method prepares pimavanserin (a compound IV) from 4-isobutoxybenzylamine as shown in a formula (II) or a salt thereof, a carbonylation reagent as shown in a formula (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine as shown in a formula (I) by using a one-pot process. The method is highly efficient, high in yield, low in cost, safe, environment friendly and suitable for industrial production, and has great application value.
Description
Technical field
The present invention relates to the preparation method technical field of a Mo Fanselin.
Background technology
Mo Fanselin (pimavanserin), chemical name 1- (4- luorobenzyls) -3- (4- isobutyl group oxy-benzyls) -1- (1- methyl piperidine -4-
Base) urea tartrate, shown in its free alkali structure such as formula (I).Mo Fanselin is Acadia Pharm Inc. (ACADIA
Pharmaceuticals Inc.) original grinds exploitation, is a kind of selective 5-HT2A inverse agonists, evidence show the medicine in treatment
Effective and better tolerance in terms of Parkinson's insanity, and it will not block dopamine receptor, therefore it is not result in Parkinson
Disease symptoms deteriorate.
The synthesis of Mo Fanselin is had been described in patent CN1443167 and CN 1816524.
Disclosed employing following methods prepare a Mo Fanselin both at home and abroad at present：
A) US2008/0280886 is disclosed by initiation material of 4- hydroxyphenylacetic acid methyl esters and is prepared a Mo Fanselin.Route is as follows：
With 4- hydroxyphenylacetic acid methyl esters and isobutyl bromide as raw material, reaction obtains 4- isobutoxy methyl phenylacetates, the latter to route a)
Hydrolysis obtains 4- isobutoxy phenylacetic acids, then generates 4- isobutyl phenyl ether based isocyanates with diphenyl phosphate azide reaction, finally
A Mo Fanselin free alkali is obtained with the reaction of N- (4- fluorophenyls) -1- methyl piperidine -4- amine.The route steps are more, wherein crucial
Intermediate 4- isobutyl phenyl ether based isocyanate synthesis conditions are complex, and diphenyl phosphate azide property used is vivaciously difficult storage,
Be not suitable for a large amount of industrialized productions.
B) patent US2007/0260064 discloses similar synthetic method, and has synthesized a Mo Fanselin.
Route b) obtains 4- isobutoxy benzaldehyde as raw material reaction with parahydroxyben-zaldehyde and isobutyl bromide, and one-step synthesis of going forward side by side is obtained
To 4- isobutoxy benzaldoximes, restore and obtain 4- isobutoxy benzylamines, it is different by being condensed to yield 4- isobutoxy phenyls with phosgene
Cyanate, finally obtains a Mo Fanselin free alkali with the reaction of N- (4- fluorophenyls) -1- methyl piperidine -4- amine.The method also wants Jing
4- isobutoxy phenyl isocyanate intermediate processes are crossed, step is more, and synthesis condition is complex.
The content of the invention
The purpose of the present invention is the defect for overcoming prior art, there is provided it is a kind of efficiently, in high yield, low cost, and safety and environmental protection,
It is suitable for industrialized production, has the method for a preparation Mo Fanselin of larger using value.
In order to realize foregoing invention purpose, the present invention is with 4- isobutoxies benzylamine or its salt, carbonylation agent, N- (4- luorobenzyls) -1-
Methyl piperidine -4- amine or its salt are raw material, and Jing condensation one kettle ways prepare a Mo Fanselin.
The present invention is specifically adopted the following technical scheme that：
The method that one kettle way prepares a Mo Fanselin shown in formula (IV), it is characterised in that with formula (II) compound, formula (III)
Shown carbonylation agent, formula (I) compound are raw material, and one kettle way prepares a Mo Fanselin (compound IV), reactional equation
Formula is as follows：
Wherein：
I is N- (4- luorobenzyls) -1- methyl piperidine -4- amine or its salt；
II is 4- isobutoxies benzylamine or its salt；
III is carbonylation agent, selected from phosgene, chloro-carbonic acid dichloro methyl esters, double (trichloromethyl) carbonic esters, N, two miaow of N- carbonyls
Azoles, dimethyl carbonate, diethyl carbonate, to one or more in nitro phenyl chloroformate.
In the present invention, the present invention does not have particular/special requirement, pharmaceutically acceptable salt well known in the art to the salt of compound I and II
.
Secondly, what the present invention was reacted to the carbonylation agent shown in formula (II) compound, formula (III), formula (I) compound is suitable
Sequence does not have particular/special requirement, preferably with formula (II) compound as raw material, reacts with the carbonylation agent shown in formula (III), then
React with formula (I) compound, one kettle way prepares a Mo Fanselin (compound IV).
The method that described one kettle way prepares a Mo Fanselin, it is characterised in that also include alkali is added in reaction.
The method that described one kettle way prepares a Mo Fanselin, it is characterised in that compound (II) and the carbonyl shown in formula (III)
The mol ratio of base reagent is 1：(0.5～3.0), preferably 1：(0.5～2.0), more preferably 1：(0.5～1.5).
The method that described one kettle way prepares a Mo Fanselin, it is characterised in that compound (II) and compound (I) mole
Than for 1.0：(0.5～2.0), preferably 1.0：(0.8～1.2), more preferably 1.0:(0.9～1.1).
The method that described one kettle way prepares a Mo Fanselin, it is characterised in that reaction temperature is -20 DEG C～solvent boiling point, is reacted
Time is 2.5～24 hours.
It is furthermore preferred that reaction temperature is -5～25 DEG C, the reaction time is 5.5～13 hours.
The present invention does not have particular/special requirement to the alkali, well known in the art that organic salt is converted into corresponding free alkali or neutralization condensation
The alkali of the acid produced in reaction, preferred potassium hydroxide, NaOH, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate,
Lithium carbonate, silver carbonate, sodium acid carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, trimethylamine, triethylamine, tri-n-butylamine,
4- dimethylamino pyridines, N, N- dimethylanilines, 11 carbon -7- alkene of 1,8- diazabicylos [5.4.0], N-methylmorpholine, N, N- bis- are different
Propylethylamine, pyridine, 2,6- lutidines, imidazoles, N, N, N ', the mixture of one or more in N '-tetramethylethylenediamine.
The present invention does not have a particular/special requirement to the amount of the alkali, it is well known in the art by organic salt be converted into corresponding free alkali amount or
The amount of the acid produced in neutralization condensation.
The present invention does not have a particular/special requirement to the solvent of the reaction, it is well known in the art by reaction raw materials dissolve and not with raw material reaction
Solvent, preferred DMF, dichloromethane, chloroform, methyl alcohol, ethanol, isopropanol, butanol,
The tert-butyl alcohol, 1-METHYLPYRROLIDONE, tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-dioxane, ethyl acetate, dimethyl sulfoxide, toluene,
The mixture of one or more in water.
In addition, working as with formula (II) compound as raw material, react with the carbonylation agent shown in formula (III), then with formula (I)
Compound reacts, when one kettle way prepares a Mo Fanselin (compound IV), the method that described one kettle way prepares a Mo Fanselin,
Characterized in that, formula (II) is -20～25 DEG C with the temperature of formula (III), the reaction time is 0.5～2 hour；Preferably, formula (II)
Temperature with formula (III) is -5～15 DEG C, and the reaction time is 0.5～1 hour.
The method that described one kettle way prepares a Mo Fanselin, it is characterised in that the reaction temperature with formula (I) is -5 DEG C～solvent
Boiling point, reaction time are 0.5～24 hour；Preferably, it is -5～25 DEG C with the reaction temperature of formula (I), the reaction time is 2～20
Hour, more preferably 5～12 hours.
Compared with prior art, the invention has the advantages that：Original multistep reaction is combined into into a step, material is reduced
Transfer and unit operation, while improve production efficiency, greatly improved yield (yield of the present invention is more than 60%), drop
Low production cost, and the reagent safety environmental protection for using.
The present invention is further illustrated by way of example again below, provides the implementation detail of the present invention, but is not
It is intended to limit protection scope of the present invention.
Specific embodiment mode
Embodiment 1：In reaction tube, add dichloromethane (5.0g), 4- isobutoxy benzylamines (1.0g) to be cooled to 0～5 DEG C,
N, N'- carbonyl dimidazoles (1.0g) is added to be kept for half an hour in 0～5 DEG C, add N- (4- luorobenzyls) -1- methyl piperidines -4- amine (1.0g),
0～5 DEG C is stirred 6 hours, is warming up to 22 DEG C, keeps overnight (12h), adding water (3 × 10g) washing, taking organic phase, concentrate
Sticky oil thing is obtained, (1.17g, yield is 61.0%) for column chromatography for separation white powdery solids.
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.
Embodiment 2：4- isobutoxy benzylamines (100.0g) is dissolved in into dichloromethane (500ml), 0～5 DEG C is cooled to, it is slow to add
Enter N, N'- carbonyl dimidazoles (100.0g) are kept for half an hour in 0～5 DEG C, add N- (4- luorobenzyls) -1- methyl piperidine -4- amine
(100.0g) 18～22 DEG C, are to slowly warm up to, are kept stirring for 12 hours, addition water (3 × 500g) washing organic phase three times has
Machine mutually removes solvent under reduced pressure, adds isopropyl acetate (600g), stirring and crystallizing to filter, filtration cakes torrefaction, obtains target product (white
Color pulverulent solids 163.0g, 85.0%).
Embodiment 3：Triphosgene (14.8g) is dissolved in into dichloromethane (200ml), -5～5 DEG C are cooled to, 4- is slowly added dropwise successively
Isobutoxy benzylamine (17.9g) and triethylamine (30.3g), continue to be kept for 1 hour after addition, are slowly added dropwise N- (4- luorobenzyls) -1-
Methyl piperidine -4- amine (22.0g), is to slowly warm up to 15～25 DEG C after addition, after being kept stirring for 5 hours, using water (3 × 200g)
Washing organic phase three times, organic phase removes solvent under reduced pressure, adds isopropyl acetate (110g), stirring and crystallizing to filter, and filter cake is done
It is dry, obtain target product (white powdery solids 34.5g, 81.6%).
Embodiment 4：Triphosgene (14.8g) is dissolved in into toluene (200ml), -20 DEG C are cooled to, 4- isobutyl oxygen is slowly added dropwise successively
Base benzylamine (17.9g) and triethylamine (30.3g), are warming up to 5 DEG C after addition, continue to be kept for 1 hour, be slowly added dropwise N- (4- fluorine
Benzyl) -1- methyl piperidines -4- amine (22.0g), 80 DEG C are to slowly warm up to after addition, after being kept stirring for 5 hours, using water (3 × 200g)
Washing organic phase three times, adds heptane (100ml) in organic phase, will separate out solid and filter, and be dried, obtain target product (yellowish
Color pressed powder 21.6g, 51.0%).
Embodiment 5：Triphosgene (14.8g) is dissolved in into chloroform (300ml), -5～5 DEG C are cooled to, 4- isobutoxies are added
Benzylamine hydrochloride (21.6g), is slowly added dropwise DIPEA (13.0g), continues holding 1 hour, slowly after addition
N- (4- luorobenzyls) -1- methyl piperidines -4- amine tosilate (39.0g) is added, DIPEA is slowly added dropwise
(13.0g) 15～25 DEG C are to slowly warm up to after addition, after being kept stirring for 6 hours, organic phase three are washed using water (3 × 200g)
Secondary, organic phase removes solvent under reduced pressure, adds isopropyl acetate (110g), stirring and crystallizing to filter, dry that target product is (white
Color powder 35.2g, 82.4%).
Embodiment 6：4- isobutoxies benzylamine acetate (23.9g) is dissolved in into dichloromethane (120ml), 0～5 DEG C is cooled to,
N is slowly added to, N'- carbonyl dimidazoles (17.0g) are slowly added dropwise DIPEA (13.5g), add after 0～5 DEG C
Kept for half an hour, add N- (4- luorobenzyls) -1- methyl piperidines -4- amine oxalates (26.0g), be slowly added dropwise N, N- diisopropyl second
Amine (13.0g), is to slowly warm up to 15～25 DEG C after addition, be kept stirring for 10 hours, adds water (3 × 200g) washing organic phase
Three times, organic phase removes solvent under reduced pressure, adds isopropyl acetate (110g), is stirring evenly and then adding into heptane (55g), will separate out
Solid filter, be dried, obtain target product (white powder 37.6g, 90.4%).
Embodiment 7：4- isobutoxies benzylamine acetate (23.9g) is dissolved in into dichloromethane (120ml), 0～5 DEG C is cooled to,
It is slowly added to nitro phenyl chloroformate (20.1g), is slowly added dropwise triethylamine (11.0g), adds and kept for half an hour after 0～5 DEG C,
N- (4- luorobenzyls) -1- methyl piperidines -4- amine oxalates (26.0g) is added, triethylamine (11.0g) is slowly added dropwise, is slowly risen after addition
Temperature is kept stirring for 10 hours to 15～25 DEG C, addition water (4 × 200g) washing organic phase four times, and organic phase removes solvent under reduced pressure,
Ethyl acetate (100g) is added, normal heptane (50g) is stirring evenly and then adding into, solid will be separated out and filtered, be dried, and obtain target product
(white to pale yellow powder 32.5g, 78.1%).
Embodiment 8：4- isobutoxies benzylamine acetate (24.0g) is dissolved in into dichloromethane (150ml), 0～5 DEG C is cooled to, slowly
N, N'- carbonyl dimidazoles (17.0g) is added to be slowly added dropwise triethylamine (11.0g), add and kept for half an hour after 0～5 DEG C, plus
Enter N- (4- luorobenzyls) -1- methyl piperidines -4- amine (22.0g), after addition, be to slowly warm up to 15～25 DEG C, be kept stirring for 8 hours,
Addition water (3 × 200g) washing organic phase three times, organic phase removes solvent under reduced pressure, adds isopropyl acetate (100g), and stirring is equal
It is even after add normal heptane (60g), filter separate out solid, be dried, obtain target product (white powder 38.2g, 90.3%).
Claims (10)
1. the method that one kettle way prepares a Mo Fanselin shown in formula (IV), it is characterised in that with formula (II) compound, formula (III)
Shown carbonylation agent, formula (I) compound are raw material, and one kettle way prepares a Mo Fanselin (compound IV), reactional equation
Formula is as follows：
Wherein：
I is N- (4- luorobenzyls) -1- methyl piperidine -4- amine or its salt；
II is 4- isobutoxies benzylamine or its salt；
III is carbonylation agent, selected from phosgene, chloro-carbonic acid dichloro methyl esters, double (trichloromethyl) carbonic esters, N, two miaow of N- carbonyls
Azoles, dimethyl carbonate, diethyl carbonate, to one or more in nitro phenyl chloroformate.
2. method according to claim 1, also includes alkali is added in reaction.
3. method according to claim 1 and 2, it is characterised in that compound (II) and the carbonyl shown in formula (III)
The mol ratio of base reagent is 1：(0.5～3.0).
4. method according to claim 3, it is characterised in that compound (II) and the carbonylation examination shown in formula (III)
The mol ratio of agent is 1：(0.5～1.5).
5. method according to claim 1 and 2, it is characterised in that compound (II) and compound (I) mole
Than for 1.0：(0.5～2.0).
6. method according to claim 5, it is characterised in that compound (II) with the mol ratio of compound (I) is
1.0：(0.8～1.2).
7. method according to claim 1 and 2, it is characterised in that reaction temperature is -20 DEG C～solvent boiling point, during reaction
Between be 2.5～24 hours.
8. method according to claim 7, it is characterised in that reaction temperature is -5～25 DEG C, the reaction time is 5.5～13
Hour.
9. method according to claim 1 and 2, it is characterised in that the solvent of reaction selected from DMF,
Dichloromethane, chloroform, methyl alcohol, ethanol, isopropanol, butanol, the tert-butyl alcohol, 1-METHYLPYRROLIDONE, tetrahydrofuran,
Acetonitrile, Isosorbide-5-Nitrae-dioxane, the mixture of one or more in ethyl acetate, dimethyl sulfoxide, toluene, water.
10. method according to claim 2, described alkali may be selected from potassium hydroxide, NaOH, lithium hydroxide, carbon
Sour potassium, sodium carbonate, cesium carbonate, lithium carbonate, silver carbonate, sodium acid carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate,
Trimethylamine, triethylamine, tri-n-butylamine, 4- dimethylamino pyridines, N, N- dimethylanilines, 11 carbon -7- of 1,8- diazabicylos [5.4.0]
Alkene, N-methylmorpholine, N, N- diisopropylethylamine, pyridine, 2,6- lutidines, imidazoles, N, N, N ', N '-tetramethyl second two
The mixture of one or more in amine.
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| CN201510577381.4A CN106518751B (en) | 2015-09-11 | 2015-09-11 | Method for preparing pimavanserin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101500568A (en) * | 2006-05-15 | 2009-08-05 | 阿卡蒂亚药品公司 | Pharmaceutical formulations of pimavanserin |
| CN104844502A (en) * | 2015-06-05 | 2015-08-19 | 济南涛瑞医药科技有限公司 | Preparation method of Pimavanserin |
-
2015
- 2015-09-11 CN CN201510577381.4A patent/CN106518751B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101500568A (en) * | 2006-05-15 | 2009-08-05 | 阿卡蒂亚药品公司 | Pharmaceutical formulations of pimavanserin |
| CN104844502A (en) * | 2015-06-05 | 2015-08-19 | 济南涛瑞医药科技有限公司 | Preparation method of Pimavanserin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Effective date of registration: 20211206 Address after: 264006 No.1 Heilongjiang Road, Yantai Economic and Technological Development Zone, Yantai City, Shandong Province Patentee after: SHANDONG SIMCERE BIO-PHARMACEUTICAL Co.,Ltd. Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Patentee after: SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Patentee before: Xiansheng Pharmaceutical Co., Ltd |