CN104829591B - Preparation method of deuterated pimozide - Google Patents
Preparation method of deuterated pimozide Download PDFInfo
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- CN104829591B CN104829591B CN201510206526.XA CN201510206526A CN104829591B CN 104829591 B CN104829591 B CN 104829591B CN 201510206526 A CN201510206526 A CN 201510206526A CN 104829591 B CN104829591 B CN 104829591B
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a preparation method of deuterated pimozide. The pimozide-d4 is synthesized from 4-bromopentafluorobenzene-d4 through eight steps. The provided preparation method has the advantages of reasonable technological design, simple operation, easy product separation and purification, easily-available raw materials, high yield, and high purity. The isotope abundance of the obtained target product is high. The prepared stable isotope-labeled pimozide-d4 can be well applied to clinical pharmacokinetics researches, so people can acknowledge the metabolism process and action mechanism of pimozide in human body more precisely and conveniently, and thus the deuterated pimozide has an important application value.
Description
Technical field
The invention belongs to the crude drug preparing technical field of cold labeling, and in particular to a kind of deuterated pimozide
Preparation method.
Background technology
Pimozide (Pimozide) its medicine another name is pimozide, Opiram, Orap in 1970 in Belgium first
Listing, which belongs to double fluorobenzene derivatives of droperidol, is clinically used for treating schizophrenia, mania and tourette syndrome.
This medicine has preferable anti-hallucination, vain hope effect, and the patient for making chronic retraction passive is active.With more long-acting anti-spirit
Disease effect.It is for acute and chronic schizophrenia, good to hallucination, vain hope, indifferent effect.To chronic retraction, sexually transmitted disease (STD) people is especially suitable.
Compared with chlorpromazine, the side effect such as its calmness, blood pressure lowering, cholinolytic is weaker.
The crude drug of stable isotope labelling is with common cold crude drug in chemical property and biological property
It is identical, simply with different nuclear physics property, which is commonly used to replace corresponding nonlabelled compound to detect and follow the trail of
Its position in vivo or in vitro, quantity and its transformation etc., preferably to study the metabolic process and the mechanism of action of crude drug.Surely
Qualitative isotope-labeled medicine can utilize its difference to common corresponding isotopic quality, by mass spectrograph, gas chromatography
The analytical instrument of quality such as instrument, nuclear magnetic resonance, NMR are determining.So as to the research being applied in terms of Clinical pharmacokinetics.
Pimozide-the d4 of cold labeling can be very good to be applied to Clinical pharmacokinetics in terms of research,
So as to more accurately and easily understand metabolic process and mechanism of action of the pimozide in human body, and with regard to stable isotope
The synthesis of the pimozide-d4 compounds of labelling not yet finds report at present.
The content of the invention
Goal of the invention：It is an object of the invention to provide a kind of preparation method with regard to pimozide-d4 compounds.
Technical scheme：To realize object above, the technical scheme that the present invention takes is：
A kind of preparation method of deuterated pimozide, the method are comprised the following steps：
(1) 4- bromofluorobenzene-d4 are taken first and are prepared into Grignard reagent, then with intermediate 2, at 20 DEG C～80 DEG C, reaction 2～
6 hours, intermediate 3 is obtained；
(2) intermediate 3 and thionyl chloride are taken, the reaction at a temperature of 60 DEG C～100 DEG C obtains intermediate 4；
(3) intermediate 4 is taken under the palladium carbon effect of catalyst 10%, hydrogenation obtains intermediate 5；
(4) intermediate 6 and intermediate 7 are taken, in the basic conditions, at a temperature of 60 DEG C～100 DEG C, under catalyst action
Carry out substitution reaction and generate intermediate 8；
(5) intermediate 8 is taken, in the presence of catalyst palladium carbon, Raney's nickel or ammonium formate, reduction obtains intermediate 9；
(6) intermediate 9 is taken, in the basic conditions, and reaction obtains intermediate 10 under cyclization reagent room temperature；
(7) intermediate 10 and trifluoroacetic acid, reaction under room temperature prepare intermediate 11 in 1～2 hour；
(8) take intermediate 11 and the reaction of intermediate 5 obtains intermediate 12.
Preferably, the preparation method of above-described deuterated pimozide, the 4- bromofluorobenzene-d4 of step (1) and
2 mol ratio of intermediate is 1：0.8～1：1.2；Preferably 1：1；Reaction temperature is 20 DEG C -80 DEG C, preferably 40 DEG C；Reaction dissolvent
For ether, toluene, preferably tetrahydrofuran, tetrahydrofuran.
Preferably, the preparation method of above-described deuterated pimozide, the anti-solvent-applied of step (2) are first
Benzene, benzene, dichloromethane；Preferably toluene；Reaction temperature is 60 DEG C -100 DEG C, and preferably 80 DEG C, intermediate 3 and dichloro carry out sulfone
Mol ratio is preferably 1：0.7.
Preferably, the preparation method of above-described deuterated pimozide, the reagent of step (3) hydrogenation is first
Alcohol, ethanol or isopropanol；Particularly preferably isopropanol.
Preferably, the preparation method of above-described deuterated pimozide, 6 He of intermediate described in step (4)
The mol ratio of intermediate 7 is 1：0.8～1：2, particularly preferably 1:1；The alkali of reaction is triethylamine, and potassium carbonate, sodium carbonate are special
Not You Xuanwei sodium carbonate, it is DMF, acetonitrile, ethanol or isopropanol to react the solvent used, particularly preferred DMF (N, N- dimethyl methyls
Amide)；Described catalyst is potassium iodide or sodium iodide.
Preferably, the preparation method of above-described deuterated pimozide, the reaction dissolvent described in step (5) is
Methanol, ethanol, isopropanol；Reaction temperature is 60～80 DEG C, and the response time is 1～2 hour.
Preferably, the preparation method of above-described deuterated pimozide, step (6) reaction alkali used is three
Ethamine, pyridine or 2-aminopropane.；It is triphosgene or carbon-based diimidazole into cyclization reagent.
Preferably, the preparation method of above-described deuterated pimozide, step (7) intermediate 10 is with dichloromethane
Alkane is solvent, reacts at room temperature 1 hour with trifluoroacetic acid and prepares intermediate 11.
Preferably, the preparation method of above-described deuterated pimozide, it is characterised in that during step (8) takes
Mesosome 11 and intermediate 5, make alkali with potassium carbonate, are flowed back overnight in glycerol formal, and reaction obtains intermediate 12.
Beneficial effect:The preparation method of the deuterated pimozide that the present invention is provided has advantages below：
The preparation method of the deuterated pimozide that the present invention is provided, filters out optimal reactions steps by many experiments,
The specific process parameters such as specific reaction temperature, time, whole technological design are rationally, workable, are capable of achieving business metaplasia
Produce, the yield per single step reaction is all very high, and raw material is easy to get, easy purification, purity is more than 99%, and total recovery is high, up to more than 90%,
And D abundance>99%.Pimozide-the d4 of the cold labeling that the present invention is prepared can be very good to be applied to face
Research in terms of bed pharmacokineticss, so as to more accurately and easily understand metabolic process and work of the pimozide in human body
With mechanism, with important application prospect.
Description of the drawings
Fig. 1 is the preparation technology flow chart of deuterated pimozide.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, it should be understood that the scope of the present invention not only limiting
In this, it is obvious to those of ordinary skill in the art change and modification be also contained in the present invention.
Embodiment 1
Such as the preparation technology flow chart that Fig. 1 is deuterated pimozide.
The preparation of intermediate 3:The magnesium powder for taking 0.43 gram is suspended in 3ml tetrahydrofurans, adds the iodine of catalytic amount, will be mixed
Compound is warmed up to 60C, solution of the 3 grams of deuterated fluorobromobenzenes of Deca (i.e. compound 1) in 7ml tetrahydrofurans, and Deca is about
10min, reaction after dripping be warmed up to 70C and react and obtain within 1.5 hours the Grignard reagent of deuterated fluorobromobenzene, then will obtain
Grignard reagent is cooled to room temperature, is added thereto to the tetrahydrofuran solution of 2.75 grams of intermediate 2, and 40 DEG C are reacted 1 hour, then will
Reactant liquor drops to room temperature, adds saturated aqueous ammonium chloride, is extracted with ethyl, and organic faciess are washed with saturated sodium-chloride again, had
Machine is mutually dried, the crude product purified by silica gel column chromatography purification purification being concentrated to give, and developing solvent is：Volume ratio is 30:1 petroleum ether：
Ethyl acetate, obtains 2.3 grams of target product intermediate 3, and yield is 52%.
The preparation of intermediate 4:Take 2.3 grams of intermediate 3 to be dissolved in toluene, add 0.74 gram of thionyl chloride, obtain
Reactant liquor, reacts 4 hours at 80 DEG C, and point plate observation raw material reaction completely, solvent is evaporated, the crude product purified by silica gel post layer for obtaining
Analysis purification, developing solvent are volume ratio 20:1 petroleum ether：Ethyl acetate；2.2 grams of intermediate 4 are obtained, yield is 89%.
The preparation of intermediate 5:Take 2.2 grams of intermediate 4 to be dissolved in 15ml isopropanols, add 10% palladium/carbon 150mg,
Hydrogenation is reacted 24 hours under 4 atmospheric pressure, and point plate observation raw material reaction completely, catalyst filtration is fallen, filtrate portion
It is evaporated and obtains 2.1 grams of target product intermediate 5 of target product, yield 95%.
The preparation of intermediate 8:Take 3.5 grams of o-fluoronitrobenzene (compound 6), the 4- amino piperidines of 5 grams of N-BOC protections
(compound 7), 3.9 grams of potassium carbonate, potassium iodide 40mg of catalytic amount, the mixture obtained in DMF are heated to 80 DEG C of reactions
16 hours, the orange solution of a clarification is obtained, reactant liquor completely, is down to room temperature, adds water by point plate observation raw material reaction
And ethyl acetate, isolate organic faciess, anhydrous sodium sulfate drying, concentration, the crude product purified by silica gel pillar purification for obtaining, developing solvent
For volume ratio 10:1 petroleum ether：Ethyl acetate, obtains 7.6 grams of target product intermediate 8, yield 95%.
The preparation of intermediate 9:Take 6.4 grams of intermediate 8 to be dissolved in 60ml methanol, add 8.6 grams of ammonium formate,
Reacting liquid temperature is increased to 60C and is reacted 1 hour by the palladium/carbon of 640mg10%, and point board raw material reaction is complete, and reactant liquor is cooled to
Room temperature, filters, and filtrate is evaporated, and the residue for obtaining is re-dissolved in dichloromethane, is washed with water, and organic faciess are branched away uses anhydrous sulfur
Sour sodium is dried, concentration, obtains 5.7 grams of target product intermediate 9, yield 98%.
The preparation of intermediate 10:The intermediate 9 for taking 5.7 grams is dissolved in the dichloromethane of 100ml, adds 4 grams of three second
Amine, 1.4 grams of triphosgene/bis- (trichloromethyl) carbonic esters, room temperature reaction half an hour, point plate observation raw material reaction are complete, to reaction
The hydrochloric acid of 1M is added in liquid, organic faciess are separated, water is mutually extracted with dichloromethane again, merge organic faciess, with anhydrous sodium sulfate drying,
Filter, the crude product dichloromethane being concentrated to give/Diethyl ether recrystallization purification obtains 4 grams of target products 10, yield 63%
The preparation of intermediate 11:Take 4 grams of intermediate 10 to be dissolved in 200ml dichloromethane, add 40ml trifluoroacetic acids, room
Temperature reaction 1 hour, completely, reactant liquor concentration, during the residue for obtaining is dissolved in dichloromethane and in water, uses ammonia to raw material reaction
PH is adjusted to 10, organic faciess are separated, anhydrous sodium sulfate drying is filtered, and concentration, the crude product dichloromethane/ether for obtaining are tied again
Crystalline substance obtains 2g target products 11, yield 73%.
The preparation of intermediate 12:Take 11,1.08 grams of intermediate 5 of 750mg intermediate, 400mg sodium carbonate, 19mg potassium iodide,
React 16 hours at 80 DEG C, point plate observation raw material reaction completely, adds 50ml water and 100ml ethyl acetate, separates organic faciess, use
Anhydrous sodium sulfate drying, filters, is evaporated, the crude product purified by silica gel pillar purification for obtaining, and it is 98 that eluant is volume ratio：The two of 2
Chloromethanes：Methanol, obtains 1.5 grams of target products 12, yield 93%, HPLC purity 99.22%.MS:464[M-H+],466[M+H+]。1HNMR (300MHz, CDCl3) is as follows, and detection isotope abundance is 99.8%.
Its 1HNMR (300MHz, CDCl3) information is：δ9.0(1H1s,NH),6.9-7.3(7H,m,Ar),4.2-4.4
(1H, m, CH), 3.9 (1H, t, CH, J=7.8MHz), 3.0 (2H, d, CH2, J=11.4MHz), 2.47 (2H, t, CH2, J=
6MHz), 2.45 (2H, t, CH2, J=6MHz), 2.07 (2H1q, J=6MHz), 1.7-1.9 (2H, m), 1.47 (2H, m).
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (1)
1. a kind of preparation method of deuterated pimozide, it is characterised in that the method is comprised the following steps：
(1) 4- bromofluorobenzene-d4 being taken first and being prepared into Grignard reagent, then with intermediate 2, at 20 DEG C～80 DEG C, reaction 2～6 is little
When, intermediate 3 is obtained；
(2) intermediate 3 and thionyl chloride are taken, the reaction at a temperature of 60 DEG C～100 DEG C obtains intermediate 4；
(3) intermediate 4 is taken under the palladium carbon effect of catalyst 10%, hydrogenation obtains intermediate 5；
(4) intermediate 6 and intermediate 7 are taken, in the basic conditions, at a temperature of 60 DEG C～100 DEG C, is carried out under catalyst action
Substitution reaction generates intermediate 8；
(5) intermediate 8 is taken, in the presence of catalyst palladium carbon, Raney's nickel or ammonium formate, reduction obtains intermediate 9；
(6) intermediate 9 is taken, in the basic conditions, and reaction obtains intermediate 10 under cyclization reagent room temperature；
(7) intermediate 10 and trifluoroacetic acid are taken, reaction under room temperature prepares intermediate 11 in 1～2 hour；
(8) take intermediate 11 and the reaction of intermediate 5 obtain deuterated pimozide,
The reaction dissolvent of step (1) is ether, toluene or tetrahydrofuran；4- bromofluorobenzene-d4 and 2 mol ratio of intermediate are 1：0.8
～1：1.2；
The anti-solvent-applied of step (2) is toluene, benzene or dichloromethane；
The reagent of step (3) hydrogenation is methanol, ethanol or isopropanol；
The mol ratio of intermediate 6 and intermediate 7 described in step (4) is 1：0.8～1：2；The alkali of reaction is triethylamine, carbonic acid
Potassium, sodium carbonate, it is DMF, acetonitrile, ethanol or isopropanol to react the solvent used；Described catalyst is potassium iodide or sodium iodide；
Reaction dissolvent described in step (5) be methanol, ethanol, isopropanol；Reaction temperature is 60～80 DEG C, and the response time is 1～2
Hour；
Step (6) reaction alkali used is triethylamine, pyridine or 2-aminopropane.；It is triphosgene or carbon-based diimidazole into cyclization reagent；
Step (7) intermediate 10 is reacted at room temperature 1 hour with trifluoroacetic acid and prepares intermediate with dichloromethane as solvent
11；
Step (8) takes intermediate 11 and intermediate 5, adds potassium carbonate, is flowed back overnight in glycerol formal, and reaction is obtained
Deuterated pimozide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352811A (en) * | 1981-11-12 | 1982-10-05 | Hoechst-Roussel Pharmaceuticals Inc. | 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles |
| WO2006135826A1 (en) * | 2005-06-10 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
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| ES2387793T3 (en) * | 2006-12-28 | 2012-10-01 | Institut Univ. De Ciència I Tecnologia, S.A. | Process for the preparation of loperamide |
| US20080312318A1 (en) * | 2007-06-14 | 2008-12-18 | Protia, Llc | Deuterium-enriched escitalopram |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352811A (en) * | 1981-11-12 | 1982-10-05 | Hoechst-Roussel Pharmaceuticals Inc. | 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles |
| WO2006135826A1 (en) * | 2005-06-10 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| Concise and Simple Synthesis of M1 Allosteric Agonist TBPB;Mohammed Abdul Rasheed,et al.;《Synthetic Communications》;20131231;1796-1801 * |
| Synthesis of (1-Substituted Piperidin-4-yl)-1H-benzimidazoles and (1-Substituted Piperidin-4-yl)-3,4-dihydroquinazolines as Possible Antihypertensive Agents;Hiroyuki Obase, et al.;《J.Heterocyclic Chem.》;19831231;565-573 * |
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