CN106317021A - Arylamino alkylamine compound and preparation method thereof - Google Patents
Arylamino alkylamine compound and preparation method thereof Download PDFInfo
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Abstract
The invention provides an arylamino alkylamine compound. The compound is obtained in the steps that Ar-X, a compound of the general formula III and R1-Y1 can also be added into solvent under alkaline conditions, and synthesis is conducted according to the following reaction formula. Operation is simple and efficient, reaction conditions are mild, reagents in use are low in price and easy to obtain, safety is high, and the compound is suitable for industrial mass production. Please see the formula in the description.
Description
Technical field
The invention belongs to technical field of medical chemistry, be specifically related to a kind of aryl amine alkyl amine compound and preparation side thereof
Method.
Background technology
Aryl amine alkyl amine derivant is the compound that a class is important, and the derivant of these structures many has drug effect and lives
Property.As, cis-N-[4-[4-(1,2-benzisothiazole-3-base)-1-piperazinyl] butyl] hexamethylene-1,2-dicarboximide, main
Suppress to D2 receptor with to 5-HT2A receptor, effect in terms for the treatment of psychosis (champion Li. Shanghai Spirit medical science, 2001,
13(3):163-165)；1-[2-[4-[3-(trifluoromethyl) phenyl] piperazine-1-base] ethyl]-1H-2-ketone benzimidaozole, fluorine
Ban Selin has good curative effect in terms of suppression libido, is cerebral cortex postsynaptic 5-HT1A agonist and 5-HT2A antagonist
(Invernizzi R.W.,Sacchetti G.,Parini S.,etal.Br.J.Pharmacol.,2003,139(7):
1281-1288.), Ziprasidone can be combined with α 1 adrenoceptor, and has faint affinity with H1 mono-histamine receptor,
Having good curative effect, Ziprasidone chemical formula structure in terms of psychosis is 5-[2-[4-(1,2-benzisothiazole-3-base)-1-
Piperazinyl]-ethyl]-6-chloro-1,3-dihydro-indol-2-one monohydrate (Schmidt A.W., Lebel L.A., Howard
Jr.H.R., eta1.Eur.J.Pharmacol., 2001,425 (3): 197), therefore, aryl amine alkyl amine derivant has
Wide application prospect.But, the traditional synthesis technique of this compounds relates to multistep synthesis and converts, traditional synthesis technique
Using protection group strategy, add synthesis step, do not only result in combined coefficient low, and cause the waste of resource, this is just
Cause process costs high, complex operation, and the use of transition metal, may result in heavy metal in the product of synthesis residual
Stay.
Summary of the invention
It is an object of the invention to, for above-mentioned the deficiencies in the prior art, it is provided that a kind of aryl amine alkyl amine compound and
Its preparation method, the method process route is brief, is not required to transition-metal catalyst, reduces the wasting of resources, meets promotion at present
Efficiently, green syt, simple to operate efficiently agents useful for same is cheap and easy to get, and production cost is low, be suitable for industrialized production.
For reaching above-mentioned purpose, the technical solution used in the present invention is: have the compound of following formula
Wherein, " ┄ " is expressed as a chemical bond or does not has chemical bond；
Ar is the group represented by formula A or Formula B,
In formula A: " _ " represent the chemical bond being connected with parent；
When Q is atom N, and Z, M are the C atomic time, and R ' is in 3,4,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo
Methyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl,
Ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is that fluorine atom, chlorine atom, bromine atoms or iodine are former
Son；
When Q, M are atom N, and Z is the C atomic time, R ' is in 4,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, second
Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, R ' is in 3,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, second
Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Z, Q, M are all the C atomic time, R ' is in 1,3,4,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, second
Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In Formula B: " _ " represent the chemical bond being connected with parent；
When Q is atom N, and Z, M are the C atomic time, R ' in 3,4,5,6,7 or 8 positions, R ' be trifluoromethyl, trichloromethyl,
Trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, second
Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, R ' in 4,5,6,7 or 8 positions, R ' be trifluoromethyl, trichloromethyl, three
Bromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, R ' in 3,5,6,7 or 8 positions, R ' be trifluoromethyl, trichloromethyl, three
Bromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
R is selected from C1～C5Alkyl or C1～C10The substituted alkyl of aryl；
Y is selected from carbon atom or oxygen atom, and N is nitrogen-atoms；n1It it is the positive integer of 0～5；
R1For following formula C, general formula D, general formula E or the group represented by formula F:
In above-mentioned formula C, " _ " represent the chemical bond being connected with parent；O is oxygen atom, and N is nitrogen-atoms；
" ┄ " is expressed as a chemical bond or does not has chemical bond；In the presence of " ┄ ", Q1At 3,4,5 or 6 positions, Q1
For trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group,
Hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine
Atom, bromine atoms or atomic iodine；When " ┄ " not in the presence of, then Q1Do not exist；
In general formula D: " _ " represent the chemical bond being connected with parent；N is nitrogen-atoms；When n is 0～5；Q2For fluoroform
Base, trichloromethyl, trisbromomethyl, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, first
Base, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Q2' it is hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl
Base, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In general formula E: " _ " represent the chemical bond being connected with parent；Q3For methyl, ethyl, n-pro-pyl, isopropyl, just
Butyl, isobutyl group, the tert-butyl group, phenyl；Q3' it is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group；
In formula F: " _ " represent the chemical bond being connected with parent；O is oxygen atom, and C is carbon atom, and N is nitrogen-atoms；
R " be hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, benzyl, three
Methyl fluoride, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, ester group, sulfonate group, halogen, methoxyl group or hydroxyl, R " '
For hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, benzyl, trifluoromethyl, acetyl
Base, nitro, cyano group, ester group, sulfonate group, halogen, methoxyl group or hydroxyl.
The compound of the present invention is by Ar-X, the compound of general formula III and R1-Y1Join in solvent, by following reaction equation
Synthesize；
Wherein, the monocyclic aromatic compounds that Ar-X is following formula I in above-mentioned reaction equation or the condensed ring for formula II
Aromatic,
In above-mentioned formula I:
When Q is atom N, and Z, M are the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
3,4,5 or 6 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl
Base, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein
Halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
4,5 or 6 position, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group,
Halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen
For fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
3,5 or 6 position, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group,
Halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen
For fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z, M are the C atomic time, X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' 1,3,5 or
6 positions, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen,
Methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine
Atom, chlorine atom, bromine atoms or atomic iodine；
In formula II:
When Q is atom N, and Z, M are the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
3,4,5,6,7 or 8 position, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group,
Ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth
Base；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
4,5,6,7 or 8 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, second
Oxygen acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；
Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' exists
3,5,6,7 or 8 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, second
Oxygen acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；
Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
Compound shown in reaction equation formula of III, wherein, n1Being the positive integer of 0～5, Y is selected from carbon atom or oxygen atom,
N is nitrogen-atoms, and R is selected from C1～C5Alkyl or C1～C10The substituted alkyl of aryl；
R in reaction equation1-Y1For the group with imine moiety of following general formulae IV, the secondary amine compound of formula V, the primary amine of formula VI
Compound or be the amide compound of formula VII；
In general formulae IV: " ┄ " is expressed as a chemical bond or does not has chemical bond；In the presence of " ┄ ", Q1For acetyl group,
Nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl,
Normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；When " ┄ " not in the presence of, then
Q1Do not exist；Y1Selected from hydrogen atom, lithium atom, sodium atom or potassium atom；O is oxygen atom；N is nitrogen-atoms；
In formula V: Y1Representing hydrogen atom, N is nitrogen-atoms；N represents 0～5 carbon；Q2For trifluoromethyl, trichloromethyl, three
Bromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Q2' be hydrogen atom, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In formula VI: Q3For methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl；Q3' it is first
Base, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group；Y1Represent hydrogen atom；N is nitrogen-atoms；
In formula VII: R " it is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, benzyl
Base, R " ' it is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Y1Represent hydrogen atom；O is that oxygen is former
Son；C is carbon atom；N is nitrogen-atoms.
The above-mentioned reaction equation mentioned can also react under conditions of having alkali, and the formula of alkali is MOH, MOR or MY2, wherein,
M is selected from lithium atom, sodium atom, potassium atom or Cs atom；R selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group,
The tert-butyl group or carbonyl；Y2Selected from carbonate, phosphate radical, acetate, propionate, n-butyric acie root, methacrylate, positive pentanoate, different
Pentanoate or neopentanoic acid root；O is oxygen atom；H is hydrogen atom.
The solvent mentioned in above-mentioned reaction equation is selected from toluene, dimethylbenzene, trimethylbenzene, dichloromethane, chloroform, tetrahydrochysene furan
Mutter, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, normal propyl alcohol, isopropanol, ether, ethyl methyl ether, methyl tertiary butyl ether(MTBE), dimethyl sulfoxide,
N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or acetonitrile.
In the above-mentioned reaction equation mentioned, represented by Ar-X and general formula III, the mol ratio of compound is 1:10～10:1, Ar-X
With R1-Y1Mol ratio 1:10～10:1.Under the conditions of having alkali, Ar-X is 1:10～10:1 with the mol ratio of alkali.Reaction temperature is
0-200℃。
Concrete operating process is: take each reaction raw materials by above-mentioned mol ratio, joins in dry reactor；Solvent is pressed
1mmolAr-X raw material takes measuring of 1-10ml solvent, and joins in reactor, is placed in by reactor in 0-200 DEG C of oil bath and adds
Thermal response (also can add alkali in reactor, synthesize under conditions of having alkali, the mol ratio of Ar-X and alkali be 1:10～
10:1).After question response is complete, by reactor cooled to room temperature, the reaction system in reactor adds water, aqueous phase acetic acid
Ethyl ester extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography for separation obtains target product.
Present invention simultaneously provides the application in preparing antipsychotic drug of the aryl amine aminated compounds.
Present invention have the advantage that
1, process route is short, reduces the cost of synthesis technique.
2, need not use catalyst, reduce the cost of synthesis technique, and avoid heavy-metal residual in pharmaceutical synthesis
Etc. problem.
3, alkali used in reaction is some alkali cheap and easy to get.
4, simple to operate efficiently reaction condition is gentle, and reagent used is cheap and easy to get, low cost, high safety, is suitable for work
Industry metaplasia is produced.
Detailed description of the invention
Now it is further illustrated by the examples that follow the present invention, but and non-limiting the scope of the present invention.
Embodiment 1:2-2-(4-(5-chloropyridine base) 1-piperazinyl) ethyl) iso-indoles-1, the synthesis of 3-diketone
By bromo-for 2-5-chloropyridine (190mg, 1mmol), triethylene diamine (224mg, 2mmol), potassium phthalimide
(368mg, 2mmol), DMF (2ml) join in dry reaction tube, are suspended in 120 DEG C of oil baths reaction
24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies, evaporated under reduced pressure
Solvent, column chromatography obtains 329mg colorless solid i.e. 2-2-(4-(5-chloropyridine base) 1-piperazinyl) ethyl) iso-indoles-1,3-bis-
Ketone, yield is 89%.
Embodiment 2:2-(2-(4-(6-acetylpyridine base) 1-piperazinyl) ethyl) iso-indoles-1, the synthesis of 3-diketone
By bromo-for 1-6-acetylpyridine (198mg, 1mmol), triethylene diamine (224mg, 2mmol), phthalyl Asia
Amine (294mg, 2mmol), potassium hydroxide (112mg, 2mmol), oxolane (2ml) join in dry reaction tube, suspension
24h is reacted in 120 DEG C of oil baths.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, closes
And organic facies, evaporated under reduced pressure solvent, column chromatography obtains 348mg colorless solid i.e. 2-(2-(4-(6-acetylpyridine base) 1-piperazine
Base) ethyl) iso-indoles-1,3-diketone, yield is 92%.
Embodiment 3:5-acetyl group-2-(2-(4-(5-picolyl) 2-piperazinyl) 1-ethyl) iso-indoles-1,3-bis-
The synthesis of ketone
By 2-trifluoromethanesulfonic acid ester group-5-picoline (241mg, 1mmol), triethylene diamine (224mg, 2mmol), 5-
Acetyl group phthalimide (378mg, 2mmol), potassium hydroxide (112mg, 2mmol), oxolane (2ml) join dry
In dry reaction tube, it is suspended in 120 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase acetic acid
Ethyl ester 30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography obtains 334mg colorless solid i.e. 5-acetyl group-2-
(2-(4-(5-picolyl) 2-piperazinyl) 1-ethyl) iso-indoles-1,3-diketone, yield is 85%.
Embodiment 4:5-methoxyl group-2-(2-(4-(5-trifluoromethyl pyridine base) 2-piperazinyl) 1-ethyl) iso-indoles-1,
The synthesis of 3-diketone
By bromo-for 2-5-trifluoromethyl pyridine (224mg, 1mmol), triethylene diamine (224mg, 2mmol), 4-methoxyl group neighbour
Phthalimide (354mg, 2mmol), potassium phosphate (434mg, 2mmol), DMAC N,N' dimethyl acetamide (2ml) join dry
Reaction tube in, be suspended in 120 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase acetic acid second
Ester 30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography obtains 338mg colorless solid i.e. 5-methoxyl group-2-(2-
(4-(5-trifluoromethyl pyridine base) 2-piperazinyl) 1-ethyl) iso-indoles-1,3-diketone, yield is 78%.
Embodiment 5:5-trifluoromethyl-2-(2-(4-(6-methyl acetate yl pyridines base) 2-piperazinyl) 1-ethyl) different Yin
Diindyl-1, the synthesis of 3-diketone
By bromo-for 2-6-methyl acetate pyridine (214mg, 1mmol), triethylene diamine (224mg, 2mmol), 5-trifluoromethyl
Phthalimide (430mg, 2mmol), potassium carbonate (276mg, 2mmol), N,N-dimethylformamide (2ml) join dry
In dry reaction tube, it is suspended in 120 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase acetic acid
Ethyl ester 30ml extract 3 times, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtain 323mg colorless solid i.e. 5-trifluoromethyl-
2-(2-(4-(6-methyl acetate yl pyridines base) 2-piperazinyl) 1-ethyl) iso-indoles-1,3-diketone, yield is 70%.
Embodiment 6:2-(2-(4-(5-methylpyrazine base) 2-piperazinyl) 1-ethyl)-4-methyl iso-indoles-1,3-diketone
Synthesis
By bromo-for 2-6-methyl acetate pyridine (171mg, 1mmol), triethylene diamine (224mg, 2mmol), 4-methyl neighbour's benzene
Dicarboximide (322mg, 2mmol), potassium carbonate (276mg, 2mmol), N,N-dimethylformamide (2ml) join dry
In reaction tube, it is suspended in 120 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase ethyl acetate
30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography obtains 263mg colorless solid i.e. 2-(2-(4-(5-methyl
Pyrazinyl) 2-piperazinyl) 1-ethyl)-4-methyl iso-indoles-1,3-diketone, yield is 72%.
Embodiment 7:2-(2-(4-(6-bromoquinoline base) 2-piperazinyl) 1-ethyl)-5-chlorine iso-indoles-1, the conjunction of 3-diketone
Become
By chloro-for 2-6-bromoquinoline (240mg, 1mmol), triethylene diamine (224mg, 2mmol), 5-chlore O-phthalic acid acyl Asia
Amine (360mg, 2mmol), sodium carbonate (210mg, 2mmol), acetonitrile (2ml) join in dry reaction tube, are suspended in 120 DEG C
Oil bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic
Phase, evaporated under reduced pressure solvent, column chromatography obtains 378mg colorless solid i.e. 2-(2-(4-(6-bromoquinoline base) 2-piperazinyl) 1-second
Base)-5-chlorine iso-indoles-1,3-diketone, yield is 76%.
Embodiment 8:2-(2-(4-(8-methylquinoline base) 2-piperazinyl) 1-ethyl)-iso-indoles-1, the synthesis of 3-diketone
By bromo-for 2-8-methylquinoline (220mg, 1mmol), triethylene diamine (224mg, 2mmol), phthalimide
(294mg, 2mmol), sodium carbonate (210mg, 2mmol), acetonitrile (2ml) join in dry reaction tube, are suspended in 120 DEG C of oil
Bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies,
Evaporated under reduced pressure solvent, column chromatography obtain 336mg colorless solid i.e. 2-(2-(4-(8-methylquinoline base) 2-piperazinyl) 1-ethyl)-
Iso-indoles-1,3-diketone, yield is 84%.
Embodiment 9:2-(2-(4-(3-cyanophenyl) 1-piperazinyl) ethyl) iso-indoles-1, the synthesis of 3-diketone
Will to Brominal (180mg, 1mmol), triethylene diamine (224mg, 2mmol), phthalimide (294mg,
2mmol), sodium carbonate (210mg, 2mmol), N,N-dimethylacetamide (2ml) join in dry reaction tube, be suspended in
180 DEG C of oil baths are reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges
Organic facies, evaporated under reduced pressure solvent, column chromatography obtains 315mg brown solid i.e. 2-(2-(4-(3-cyanophenyl) 1-piperazinyl) second
Base) iso-indoles-1,3-diketone, yield is 87%.
Embodiment 10:2-(2-(4-(4-acetyl group pyrimidine radicals) 1-piperazinyl) ethyl) iso-indoles-1, the synthesis of 3-diketone
By bromo-for 2-6-acetyl group pyrazine (199mg, 1mmol), triethylene diamine (224mg, 2mmol), phthalyl Asia
Amine (294mg, 2mmol), Lithium hydrate (96mg, 2mmol), acetonitrile (2ml) join in dry reaction tube, are suspended in 120
DEG C oil bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, is associated with
Machine phase, evaporated under reduced pressure solvent, column chromatography obtains 314mg colorless solid i.e. 2-(2-(4-(4-acetyl group pyrimidine radicals) 1-piperazinyl) second
Base) iso-indoles-1,3-diketone, yield is 83%.
Embodiment 11:5-methoxyl group-2-(2-(4-(2-nitrobenzophenone) 1-piperazinyl) ethyl) iso-indoles-1,3-diketone
Synthesis
By 2-Nitrobromobenzene (200mg, 1mmol), triethylene diamine (224mg, 2mmol), 4-methoxyl group-phthalyl
Imines (354mg, 2mmol), Feldalat NM (108mg, 2mmol), toluene (2ml) join in dry reaction tube, are suspended in 80
DEG C oil bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, is associated with
Machine phase, evaporated under reduced pressure solvent, column chromatography obtains 369mg faint yellow solid i.e. 5-methoxyl group-2-(2-(4-(2-nitrobenzophenone) 1-
Piperazinyl) ethyl) iso-indoles-1,3-diketone, yield is 90%.
Embodiment 12:2-(4-(5-methoxypyridine (2-methyl) amino) butyl) iso-indoles-1, the synthesis of 3-diketone
By 2-chloro-5-methoxyl pyrimidine (144mg, 1mmol), N-methyl nafoxidine (170mg, 2mmol), O-phthalic
Acid imide (294mg, 2mmol), potassium carbonate (276mg, 2mmol), dimethyl sulfoxide (2ml) join in dry reaction tube,
It is suspended in 160 DEG C of oil baths reaction 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3
Secondary, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtains colorless solid i.e. 2-(4-(5-methoxypyridine) 2-(methyl) ammonia
Base) butyl) iso-indoles-1,3-diketone 286mg, yield is 85%.
Embodiment 13:2-(4-(isopropyl-(2-pyrimidine radicals) amino) butyl) iso-indoles-1, the synthesis of 3-diketone
By 2-chloropyrimide (113mg, 1mmol), N-isopropyl nafoxidine (226mg, 2mmol), phthalimide
(294mg, 2mmol), cesium carbonate (270mg, 2mmol), methanol (2ml) join in dry reaction tube, are suspended in 160 DEG C of oil
Bath is reacted 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies,
Evaporated under reduced pressure solvent, column chromatography obtains colorless solid i.e. 2-(4-(isopropyl-(2-pyrimidine radicals) amino) butyl) iso-indoles-1,3-
Diketone 243mg, yield is 72%.
Embodiment 14:2-(4-(benzyl-(2-pyrimidine radicals) amino) butyl) iso-indoles-1, the synthesis of 3-diketone
By 2-chloropyrimide (113mg, 1mmol), N-benzyl tetrahydro pyrroles (322mg, 2mmol), phthalimide
(294mg, 2mmol), potassium carbonate (276mg, 2mmol), methanol (2ml) join in dry reaction tube, are suspended in 160 DEG C of oil
Bath is reacted 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies,
Evaporated under reduced pressure solvent, column chromatography obtains colorless solid i.e. 2-(4-(benzyl-(2-pyrimidine radicals) amino) butyl) iso-indoles-1,3-bis-
Ketone 262mg, yield is 68%.
Embodiment 15:2-(2-(2-(ethyl (2-pyrimidine radicals) amino) ethyoxyl) ethyl) iso-indoles-1, the conjunction of 3-diketone
Become
By 2-chloropyrimide (114mg, 1mmol), N-ethylmorpholine (228mg, 2mmol), phthalimide (294mg,
2mmol), potassium phosphate (434mg, 2mmol), dimethyl sulfoxide (2ml) join in dry reaction tube, be suspended in 60 DEG C of oil baths
Middle reaction 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies, subtracts
Pressure solvent evaporated, column chromatography obtains colorless solid i.e. 2-(2-(2-(ethyl (2-pyrimidine radicals) amino) ethyoxyl) ethyl) different Yin
Diindyl-1,3-diketone 228mg, yield is 66%.
Embodiment 16:2-(2-(2-(methyl (2-quinoxalinyl) amino) methoxyl group) ethyl) iso-indoles-1,3-diketone
Synthesis
By 2-bromine quinoxaline (207mg, 1mmol), N-methyl nafoxidine (170mg, 2mmol), phthalimide
(294mg, 2mmol), sodium carbonate (210mg, 2mmol) oxolane (2ml) join in dry reaction tube, are suspended in 60 DEG C
Oil bath is reacted 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic
Phase, evaporated under reduced pressure solvent, column chromatography obtains colorless solid i.e. 2-(2-(2-(methyl (2-quinoxalinyl) amino) methoxyl group) second
Base) iso-indoles-1,3-diketone 281mg, yield is 75%.
Embodiment 17:2-(2-(2-((4-acetylphenyl) (methyl) amino) methoxyl group) ethyl) iso-indoles-1,3-bis-
The synthesis of ketone
By 4-fluoro acetophenone (147mg, 1mmol), N-methylmorpholine (228mg, 2mmol), phthalimide
(294mg, 2mmol), sodium carbonate (210mg, 2mmol), DMF (2ml) join in dry reaction tube,
It is suspended in 120 DEG C of oil baths reaction 12h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3
Secondary, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtains colorless solid i.e. 2-(2-(2-((4-acetylphenyl) (methyl)
Amino) methoxyl group) ethyl) iso-indoles-1,3-diketone 265mg, yield is 72%.
Embodiment 18:1-(2-(4-(4-acetylphenylhydrazine) piperazinyl) 1-ethyl) pyrrolidine-2, the synthesis of 5-diketone
By 4-p-methyl benzenesulfonic acid ester group-1-Phenylethanone. (290mg, 1mmol), triethylene diamine (224mg, 2mmol), succinyl
Imines (198mg, 2mmol), Lithium hydrate (48mg, 2mmol), N,N-dimethylformamide (2ml) (2ml) join dry
In reaction tube, it is suspended in 120 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase ethyl acetate
30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography obtains 224mg light tan solid i.e. 1-(2-(4-(4-second
Acyl phenylhydrazine) piperazinyl) 1-ethyl) pyrrolidine-2,5-diketone, yield is 68%.
Embodiment 19:1-(2-(4-(5-picolyl) 2-piperazinyl) 1-ethyl) pyrrolidine-2, the synthesis of 5-diketone
By chloro-for 2-4-picoline (127mg, 1mmol), triethylene diamine (224mg, 2mmol), butanimide
(198mg, 2mmol), potassium phosphate (434mg, 2mmol), oxolane (2ml) join in dry reaction tube, are suspended in 120
DEG C oil bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, is associated with
Machine phase, evaporated under reduced pressure solvent, column chromatography obtains 276mg colorless solid i.e. 1-(2-(4-(5-picolyl) 2-piperazinyl) 1-
Ethyl) pyrrolidine-2,5-diketone, yield is 91%.
The synthesis of embodiment 20:N-methyl-N-(2-(4-(5-picolyl) 2-piperazinyl) 1-ethyl) aniline
By chloro--methylpyridine (127mg, 1mmol), triethylene diamine (224mg, 2mmol), methylphenylamine
(214mg, 2mmol), potassium tert-butoxide (224mg, 2mmol), DMAC N,N' dimethyl acetamide (2ml) (2ml) join dry anti-
Ying Guanzhong, is suspended in 100 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase ethyl acetate
30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure solvent, column chromatography obtains 221mg colourless oil liquid i.e. N-methyl-N-(2-
(4-(5-picolyl) 2-piperazinyl) 1-ethyl) aniline, yield is 71%.
Embodiment 21:N, the synthesis of 3-dimethyl-N-(2-(4-(quinolyl) 2-piperazinyl) 1-ethyl) aniline
By 2-bromoquinoline (208mg, 1mmol), triethylene diamine (224mg, 2mmol), N-methyl open-chain crown ether
(242mg, 2mmol), sodium carbonate (210mg, 2mmol)), N,N-dimethylformamide (2ml) (2ml) join dry reaction
Guan Zhong, is suspended in 160 DEG C of oil baths reaction 24h.After reaction system being cooled down, add 15ml water, aqueous phase ethyl acetate 30ml
Extracting 3 times, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtains 278mg colorless solid i.e. N, 3-dimethyl-N-(2-(4-
(quinolyl) 2-piperazinyl) 1-ethyl) aniline, yield is 77%.
Embodiment 22:N-Benzyl-N-methyl-(4-group-4 ethyl formate-2-(4-(pyrimidine radicals) 2-piperazinyl) 1-ethyl) benzene
The synthesis of amine
By 2-chloropyrimide (114mg, 1mmol), triethylene diamine (224mg, 2mmol), N-methyl-4-Ethyl formate benzylamine
(258mg, 2mmol), potassium carbonate (276mg, 2mmol), DMF (2ml) join in dry reaction tube,
It is suspended in 160 DEG C of oil baths reaction 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3
Secondary, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtains 247mg colourless oil liquid i.e. N-Benzyl-N-methyl-(4-formic acid
Ethoxycarbonyl-2-(4-(pyrimidine radicals) 2-piperazinyl) 1-ethyl) aniline, yield is 67%.
Embodiment 23:N-(2-(4-pyridine radicals-2-piperazinyl)-1-ethyl)-N-(4-(trifluoromethyl) phenyl) propane-2
The synthesis of amine
By 2-chloropyrimide (114mg, 1mmol), triethylene diamine (224mg, 2mmol), N-isopropyl-4-trifluoromethylbenzene
Amine (350mg, 2mmol), cesium carbonate (650mg, 2mmol), acetonitrile (2ml) join in dry reaction tube, are suspended in 180 DEG C
Oil bath is reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic
Phase, evaporated under reduced pressure solvent, column chromatography obtains 253mg colorless solid i.e. N-(2-(4-pyridine radicals-2-piperazinyl)-1-ethyl)-N-
(4-(trifluoromethyl) phenyl) propane-2 amine, yield is 62%.
The synthesis of embodiment 24:2-methyl-N-(2-(4-(pyridine radicals)-2-piperazinyl) 1-ethyl)-3-propane-2 amine
By 2-bromopyridine (156mg, 1mmol), triethylene diamine (224mg, 2mmol), tert-butylamine (146mg,
2mmol), potassium tert-butoxide (224mg, 2mmol), DMF (2ml) join in dry reaction tube, be suspended in
180 DEG C of oil baths are reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges
Organic facies, evaporated under reduced pressure solvent, column chromatography obtains 157mg brown oil liquid i.e. 2-methyl-N-(2-(4-(pyridine radicals)-2-piperazine
Piperazine base) 1-ethyl)-3-propane-2 amine, yield is 60%.
The embodiment 25:N-methyl-N-(synthesis of 2-(4-(Phenylpiperazinyl) 1-ethyl)-3-propane-2 amine
By bromobenzene (155mg, 1mmol), triethylene diamine (224mg, 2mmol), isopropyl methyl amine (146mg,
2mmol), sodium carbonate (210mg, 2mmol), toluene (2ml) join in dry reaction tube, be suspended in 180 DEG C of oil baths anti-
Answer 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies, and decompression is steamed
Dry solvent, column chromatography obtains the 152mg i.e. N-of brown oil liquid, and (2-(4-(Phenylpiperazinyl) 1-ethyl)-3-propane-2 amine is received
Rate is 62%.
The synthesis of embodiment 26:N-(2-(4-pyridine radicals-2-piperazinyl) 1-ethyl) acetamide
By 2-bromopyridine (156mg, 1mmol), triethylene diamine (224mg, 2mmol), acetamide (118mg, 2mmol),
Potassium tert-butoxide (224mg, 2mmol), acetonitrile (2ml) join in dry reaction tube, are suspended in 160 DEG C of oil baths reaction 24h.
After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges organic facies, and evaporated under reduced pressure is molten
Agent, column chromatography obtains the 158mg i.e. N-of white oil liquid (2-(4-pyridine radicals-2-piperazinyl) 1-ethyl) acetamide, and yield is
64%.
The synthesis of embodiment 27:N-(2-(4-(3-methoxyphenyl)-2-piperazinyl) 1-ethyl) Benzoylamide
By bromo-for 1-3-methoxybenzene (185mg, 1mmol), triethylene diamine (224mg, 2mmol), Benzoylamide
(224mg, 2mmol), potassium tert-butoxide (224mg, 2mmol), DMAC N,N' dimethyl acetamide (2ml) join dry reaction tube
In, it is suspended in 160 DEG C of oil baths reaction 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts
Taking 3 times, merge organic facies, evaporated under reduced pressure solvent, column chromatography obtains the 231mg i.e. N-of white oil liquid (2-(4-(3-methoxyl group
Phenyl)-2-piperazinyl) 1-ethyl) Benzoylamide, yield is 68%.
The synthesis of embodiment 28:N-methyl-N-(2-(4-pyridine radicals-2-piperazinyl) 1-ethyl) Benzoylamide
By 2-chloropyridine (113mg, 1mmol), triethylene diamine (224mg, 2mmol), N-methyl-benzamide (270mg,
2mmol), potassium carbonate (276mg, 2mmol), DMF (2ml) join in dry reaction tube, be suspended in
160 DEG C of oil baths are reacted 24h.After reaction system being cooled down, adding 15ml water, aqueous phase ethyl acetate 30ml extracts 3 times, merges
Organic facies, evaporated under reduced pressure solvent, column chromatography obtains 211mg white oil liquid i.e. N-methyl-N-(2-(4-pyridine radicals-2-piperazine
Base) 1-ethyl) Benzoylamide, yield is 65%.
The structural formula such as table 1 below of corresponding synthesis compound in the various embodiments described above.
The structural formula of corresponding compound in each embodiment of table 1
Embodiment 29: the antipsychotic activity experiment of aryl amine alkyl amine compound, shock reflecting experimental:
Experimentation:
(1) the psychosis experimental mouse model of apomorphine induction is set up: 10 female male inbreeding C57BL/6 Mus are according to body weight
Standard is arbitrarily divided into 2 groups: the matched group of a black, a pattern collation group, and experimental mouse is carried out lumbar injection apo-
Coffee solution, the psychosis experimental mouse model of apomorphine induction is set up.
(2) the regulation behavioral activity of observation experiment Mus:
The pattern collation group experimental mouse that injection apomorphine is later is carried out the compound of lumbar injection above-described embodiment
(0.025mg/mL) (0.050mg/mL) (0.075mg/mL), starts prepulse inhibition test program and carries out after being administered 10min
Observing, before design prepulse inhibition experimental program, we carry out input and output survey firstly the need of C57BL/6 Strains of Mouse
Examination, can produce the audio intensity threshold of notable shock reflection with clearly this Strains of Mouse.Mice be positioned over gravity sensor it
On fixing cage in, adapt to after 2min in the environment of background noise 65dB, listen the sound of 65～130dB to sting the most continuously
Swashing, its shock reflection amplitudes is gathered by gravity sensor.According to 30 seconds started, 6-10,11-15,16-20,21-25,26-
30,31-35,36-40,41-45,46-50,51-55, and within 56-60 minute, carry out the regulation behavioral activity picture of observation experiment Mus
Tail is holded up activities such as also climbing wall and records.
(3) ED is calculated50:
(4) data statistics: experimental data is carried out mathematical statistics, by linear regression, determines 50% effective dose: experiment
Result: experimental result is as shown in table 2, and determines ED50.Test result indicate that, compound synthesized by each embodiment has anti-spirit
Sick activity.
The antipsychotic activity of synthesized compound in each embodiment of table 2
Claims (8)
1. there is the compound of following formula
Wherein, " ┄ " is expressed as a chemical bond or does not has chemical bond；
Ar is the group represented by formula A or Formula B,
In formula A:Represent the chemical bond being connected with parent；
When Q is atom N, and Z, M are the C atomic time, R ' is in 3,4,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, second
Base, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, R ' in 4,5 or 6 positions, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl,
Acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, R ' in 3,5 or 6 positions, R ' be trifluoromethyl, trichloromethyl, trisbromomethyl,
Acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Z, Q, M are all the C atomic time, R ' is in 1,3,4,5 or 6 positions, and R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, second
Acyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, ethyoxyl, hydroxyl, hydrogen atom, methyl, ethyl, just
Propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In Formula B:Represent the chemical bond being connected with parent；
When Q is atom N, and Z, M are the C atomic time, and R ' is in 3,4,5,6,7 or 8 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo
Methyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, just
Propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, R ' is in 4,5,6,7 or 8 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, R ' is in 3,5,6,7 or 8 positions, and R ' is trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
R is selected from C1～C5Alkyl or C1～C10The substituted alkyl of aryl；
Y is selected from carbon atom or oxygen atom, and N is nitrogen-atoms；n1It it is the positive integer of 0～5；
R1For following formula C, general formula D, general formula E or the group represented by formula F:
In above-mentioned formula C,Represent the chemical bond being connected with parent；O is oxygen atom, and N is nitrogen-atoms；
" ┄ " is expressed as a chemical bond or does not has chemical bond；In the presence of " ┄ ", Q1At 3,4,5 or 6 positions, Q1It is three
Methyl fluoride, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl,
Hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen be fluorine atom, chlorine atom,
Bromine atoms or atomic iodine；When " ┄ " not in the presence of, then Q1Do not exist；
In general formula D:Represent the chemical bond being connected with parent；N is nitrogen-atoms；When n is 0～5；
Q2For trifluoromethyl, trichloromethyl, trisbromomethyl, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl
Base, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Q2' be hydrogen atom, methyl, ethyl,
N-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In general formula E:Represent the chemical bond being connected with parent；Q3For methyl, ethyl, n-pro-pyl, isopropyl, positive fourth
Base, isobutyl group, the tert-butyl group, phenyl；Q3' it is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group；
In formula F:Represent the chemical bond being connected with parent；O is oxygen atom, and C is carbon atom, and N is nitrogen-atoms；
R " it is hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, benzyl, R " ' it is hydrogen
Atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group.
2. the method for compound described in preparation claim 1, it is characterised in that the method is by Ar-X, the compound of general formula III
And R1-Y1Join in solvent, synthesize by following reaction equation；
Wherein, the monocyclic aromatic compounds that Ar-X is following formula I in above-mentioned reaction equation or the polycyclic aromatic for formula II
Compound,
In above-mentioned formula I:
When Q is atom N, and Z, M are the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' 3,4,
5 or 6 positions, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen
Element, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is
Fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' is 4,5
Or 6 positions, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen
Element, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is
Fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' is 3,5
Or 6 positions, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen
Element, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is
Fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z, M are the C atomic time, X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' is at 1,3,5 or 6
Putting, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, first
Epoxide, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is that fluorine is former
Son, chlorine atom, bromine atoms or atomic iodine；
In formula II:
When Q is atom N, and Z, M are the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' 3,4,
5,6,7 or 8 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy
Acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Its
Middle halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, M are atom N, and Z is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' 4,5,
6,7 or 8 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl
Base, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein
Halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
When Q, Z are atom N, and M is the C atomic time, and X is halogen, trifluoromethanesulfonic acid ester group or p-methyl benzenesulfonic acid ester group；R ' 3,5,
6,7 or 8 position, R ' is trifluoromethyl, trichloromethyl, trisbromomethyl, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl
Base, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein
Halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
Compound shown in reaction equation formula of III, wherein, n1Being the positive integer of 0～5, Y is selected from carbon atom or oxygen atom, and N is nitrogen
Atom, R is selected from C1～C5Alkyl or C1～C10The substituted alkyl of aryl；
R in reaction equation1-Y1For the group with imine moiety of following general formulae IV, the secondary amine compound of formula V, the primary amine chemical combination of formula VI
Thing or be the amide compound of formula VII；
In general formulae IV: " ┄ " is expressed as a chemical bond or does not has chemical bond；In the presence of " ┄ ", Q1For acetyl group, nitro,
Cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, n-pro-pyl, isopropyl, positive fourth
Base, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；When " ┄ " not in the presence of, then Q1No
Exist；Y1Selected from hydrogen atom, lithium atom, sodium atom or potassium atom；O is oxygen atom；N is nitrogen-atoms；
In formula V: Y1Representing hydrogen atom, N is nitrogen-atoms；N represents 0～5 carbon；Q2For trifluoromethyl, trichloromethyl, tribromo first
Base, acetyl group, nitro, cyano group, methoxy acyl group, ethoxy acyl group, halogen, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Q2' be hydrogen atom, methoxyl group, hydroxyl, hydrogen atom, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Wherein halogen is fluorine atom, chlorine atom, bromine atoms or atomic iodine；
In formula VI: Q3For methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl；Q3' be methyl,
Ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group；Y1Represent hydrogen atom；N is nitrogen-atoms；
In formula VII: R " it is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl, benzyl,
R " ' it is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group；Y1Represent hydrogen atom；O is oxygen atom；C
For carbon atom；N is nitrogen-atoms.
3. method as claimed in claim 2, it is characterised in that described reaction equation can react under conditions of having alkali, leading to of alkali
Formula is MOH, MOR or MY2, wherein, M is selected from lithium atom, sodium atom, potassium atom or Cs atom；R selected from methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, the tert-butyl group or carbonyl；Y2Selected from carbonate, phosphate radical, acetate, propionate, n-butyric acie
Root, methacrylate, positive pentanoate, isovalerate or neopentanoic acid root；O is oxygen atom；H is hydrogen atom.
4. method as claimed in claim 2 or claim 3, it is characterised in that described solvent is selected from toluene, dimethylbenzene, trimethylbenzene, dichloro
Methane, chloroform, oxolane, Isosorbide-5-Nitrae-dioxane, methanol, ethanol, normal propyl alcohol, isopropanol, ether, ethyl methyl ether, methyl
Tertbutyl ether, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or acetonitrile.
5. method as claimed in claim 2, it is characterised in that compound represented by Ar-X and general formula III in described reaction equation
Mol ratio is 1:10～10:1, Ar-X and R1-Y1Mol ratio 1:10～10:1, it is molten that solvent takes 1-10ml by 1mmolAr-X raw material
The ratio of agent measures.
6. method as claimed in claim 3, it is characterised in that described reaction equation under the conditions of having alkali, Ar-X and alkali mole
Ratio is 1:10～10:1.
7. method as claimed in claim 2, it is characterised in that the reaction temperature of described reaction equation is 0-200 DEG C.
8. the application in preparing antipsychotic drug of the compound described in claim 1.
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| CN112225732A (en) * | 2019-07-15 | 2021-01-15 | 四川科瑞德制药股份有限公司 | Novel perospirone hydrochloride hydrate crystal form and preparation method thereof |
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| CN105541702A (en) * | 2016-01-27 | 2016-05-04 | 宜春学院 | Arylamine alkyl sulfide compound with structure similar to ruzadolane and preparation method of compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009594A1 (en) * | 1989-12-28 | 1991-07-11 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
| CN105541702A (en) * | 2016-01-27 | 2016-05-04 | 宜春学院 | Arylamine alkyl sulfide compound with structure similar to ruzadolane and preparation method of compound |
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Cited By (2)
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|---|---|---|---|---|
| CN112225732A (en) * | 2019-07-15 | 2021-01-15 | 四川科瑞德制药股份有限公司 | Novel perospirone hydrochloride hydrate crystal form and preparation method thereof |
| CN112225732B (en) * | 2019-07-15 | 2024-01-09 | 四川科瑞德制药股份有限公司 | Crystal form of pirone hydrochloride hydrate and preparation method thereof |
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