CN109305961A - Imatinib amine derivative with pharmaceutical activity and preparation method thereof - Google Patents
Imatinib amine derivative with pharmaceutical activity and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/14—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 three or more hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of Imatinib amine derivative and preparation method thereof with pharmaceutical activity, belongs to medical synthesis technical field.Technical solution of the present invention main points are as follows: a kind of Imatinib amine derivative with pharmaceutical activity, structural formula are as follows:The preparation method of present invention Imatinib amine derivative also with anti-tumor activity.Imatinib amine derivative produced by the present invention has preferable inhibitory activity to lung cell A549, has the potential quality as anti-tumor drug.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of Imatinib amine derivative with pharmaceutical activity and its
Preparation method.
Background technique
Heterocyclic compound is widely present in nature, and many natural heterocyclic compounds play important in animal and plant body
Physiological action.Such as the active portion of biochemical reaction is catalyzed in base, enzyme and the coenzyme in ferroheme, chlorophyll, DNA and RNA
Position and medium-height grass the effective elements of the medicine alkaloid etc., are all nitrogen-containing heterocycle compounds；Vitamin few in number, antibiotic and one
A little phytochromes and vegetable colour all contain jeterocyclic chemistry.The heterocyclic compound synthesized at present is related to medicine, pesticide, dyestuff, biology
Simulation material, molecular device.Energy storage material etc., especially in modern medicines, heterocyclic compound, which occupies, sizable specific gravity, with
People's lives are closely bound up.The heterocyclic compound of drug treatment maturation has anti-hypertension systemic drug captopril, thunder
Meter Pu Li, antianginal drug piperazine derivative Trimetazidine, lipid regulating agent Fluvastatin, cyclopyrrolones hypnotic sedative agent assistant
Clone, Imidazopyridine class somnifacient zolpidem etc..
Pyridine compounds are to be widely used in the conjunction of medicine and pesticide with the active nitrogen-containing heterocycle compound of good biological
At research.Pyridine is mainly used for synthesis medicine, pesticide and rubber chemicals, pyridine farm chemical and is referred to as forth generation pesticide, has height
The feature of effect, low toxicity has good Environmental compatibility with people and biology, meets the demand for development and trend of pesticide, contains pyridine
The compound of ring is increasingly becoming one of Main way of pesticides discovery, has very much development prospect.Such as it is used in pharmaceuticals industry
Anticancer drug Imatinib, the isoniazid etc. of antituberculosis.Promote in Rubber Chemicals Industries for synthesizing the super vulcanization of thiurams
Into agent bis-pentamethylenethiuram tetrasulfide, the super promotor pentamethylene aminodithioformic acid of dithiocarbamates
Piperidinium salt etc..In addition pyridine can also synthesize various new fine-chemical intermediate, and many products belong to small ton newly developed
Position, the medicine of high added value, pesticide and auxiliary agent intermediate, such as 2- picoline, 3- aminomethyl-pyridine, 4- pyridone.
A kind of Imatinib amine derivative with pharmaceutical activity of our development in laboratory, and carried out corresponding biology work
Property detection.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of Imatinib amines with good pharmaceutical activity of structure novel to spread out
The preparation method of biology.
The present invention adopts the following technical scheme that a kind of Imatinib amine with pharmaceutical activity is derivative to solve above-mentioned technical problem
The preparation method of object, it is characterised in that its molecular structure are as follows:
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of novel her horse with pharmaceutical activity
The preparation method of amine derivative, it is characterised in that specific steps are as follows:
(1), urea and 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone are heated to reflux and (1- are prepared in alcohol solvent
(1- (pyridyl group -3- base) -2- benzal)) urea；
(2), (1- (1- (pyridyl group -3- base) -2- benzal)) urea heats in polyphosphoric acids, and 4- (pyridyl group-is made
3- yl) pyrimidine -2 (H) -one；
(3), in toluene solvant, with phosphorus oxychloride reaction, it is chloro- that 2- is made in 4- (pyridyl group -3- base) pyrimidine -2 (H) -one
4- (pyridin-3-yl) pyridine；
(4), the chloro- 4- of 2- (pyridin-3-yl) pyridine) in cuprous iodide, Anhydrous potassium carbonate, dimethylaminoethyl second
Ester and 2- methyl-5-nitro aniline make solvent with Isosorbide-5-Nitrae-dioxane, react and N- (2- methyl-5-nitrophenyl) -4- is made
(3- pyridyl group) -2- pyrilamine；
(5), N- (2- methyl-5-nitrophenyl) -4- (3- pyridyl group) -2- pyrilamine is hydrated chlorine with six in alcohol solvent
Change iron and reduction reaction occurs for hydrazine hydrate, N- (5- amino-2-methyl phenyl) -4- (3- pyridyl group) -2- aminopyrimidine is made；
(6), benzhydryl -3- methyl azetidine is in acetonitrile solvent, in K2CO3Effect is lower and bromoacetate is sent out
Raw reaction, is made 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide；
(7), under the conditions of hydrogen atmosphere, 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza quaternary ring bromination
Amine sloughs benzhydryl protecting group in catalyst Pd/C, and 3- methyl-1-N- ethyl acetate-azepine four-membered ring is made；
(8), 3- methyl-1-N- ethyl acetate-azepine four-membered ring is in the mixed solution of acetonitrile and water, in inorganic base hydrogen-oxygen
3- methyl-1-N- acetic acid-azepine four-membered ring is made in hydrolysis under the action of changing sodium；
(9), N- (5- amino-2-methyl phenyl)-4- (3- pyridyl group)-2- aminopyrimidine and 3- methyl-1-N- acetic acid-nitrogen
Miscellaneous four-membered ring is in organic bases triethylamine and condensing agent 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid
Under the action of ester, N- (3- (4- (pyridin-3-yl) pyrimidine -2 --amino)-4- aminomethyl phenyl)-2- (3- methyl-aza-is made
1- yl) acetamide.
Further preferably, the detailed process of step (1) are as follows: urea is dissolved in dehydrated alcohol, heats 60 DEG C, is then slowly dripped
Add 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone, be heated to flowing back after dripping off, reaction has a large amount of white solid to analyse after a certain period of time
Out, white solid is filtered, and dries to obtain off-white powder (1- (1- (pyridyl group -3- base) -2- benzal)) urea；
Further preferably, the detailed process of step (2) are as follows: in polyphosphoric acids, (1- (1- (pyridyl group -3- base)-is added
2- benzal)) urea, a period of time is stirred at room temperature first, is then heated to 110 DEG C and is stirred to react to raw material fully reacting, delays
It is slow that water and active carbon is added, it filters after mixing evenly, filtrate puts refrigerator overnight, is then collected by vacuum filtration consolidating for precipitating
Body is recrystallized solid with water, and drying obtains solid 4- (pyridyl group -3- base) pyrimidine -2 (H) -one.
Further preferably, the detailed process of step (3) are as follows: in toluene solvant, it is phonetic that 4- (pyridyl group -3- base) is then added
Pyridine -2 (H) -one, be stirred at room temperature first a period of time, phosphorus oxychloride is then slowly added dropwise, is heated to flowing back, be stirred to react to
Raw material is down to room temperature after completely disappearing, reaction solution is then poured into quenching reaction in a large amount of ice water, and organic solvent dichloromethane is added
Alkane merges organic phase after extracting repeatedly, chromatographs pure 2- chloro- 4- (pyridin-3-yl) pyridine through column after being then concentrated.
Further preferably, the detailed process of step (4) are as follows: under nitrogen atmosphere, by 2- chloro- 4- (pyridin-3-yl) pyridine,
2- methyl-5-nitro aniline, cuprous iodide, anhydrous K2CO3It is molten that 1,4- dioxane is added with dimethylaminoethyl methacrylate
In liquid, 100 DEG C are heated, reaction to raw material fully reacting first at reduced pressure conditions boils off Isosorbide-5-Nitrae-dioxane of the overwhelming majority,
After being cooled to room temperature, reaction mixture is poured into ice water, has a large amount of off-white powder to be precipitated, filtering is drenched with n-hexane
It washes, N- (2- methyl-5-nitrophenyl) -4- (3- the pyridyl group) -2- pyrilamine for being dried in vacuo pure.
Further preferably, the detailed process of step (5) are as follows: by N- (2- methyl-5-nitrophenyl) -4- (3- pyridyl group) -
2- pyrilamine and ferric chloride hexahydrate are added in ethyl alcohol, and oil bath is slowly heated to 78 DEG C, are added with stirring activated carbon, by quality point
Number is slowly dropped in reaction for 85% hydrazine hydrate, is stopped reaction after the reaction was continued a period of time, is filtered, filtrate is concentrated to get
Yellow oil is added ethyl alcohol and dissolves by heating, lower dropwise addition distilled water is stirred at room temperature and obtains glassy yellow crystalline solid N- (5- amino-
2- aminomethyl phenyl) -4- (3- pyridyl group) -2- aminopyrimidine.
Further preferably, the detailed process of step (6) are as follows: by benzhydryl -3- methyl azetidine, bromoacetic acid second
Ester, potassium carbonate are added in acetonitrile, are then heated to 90 DEG C of reactions, react to raw material 1- benzhydryl -3- methyl azetidine
After completely, it is cooled to room temperature, is filtered to remove potassium carbonate, filtrate is concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl -
Azepine four-membered ring amine bromide.
Further preferably, the detailed process of step (7) are as follows: by 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-nitrogen
Miscellaneous four-membered ring amine bromide is put into methanol, and catalyst Pd/C is then added, and under hydrogen 0.2MPa pressure, is reacted complete to raw material
After disappearance, Filtration of catalyst Pd/C, filtrate is concentrated to give mixture, and 3- methyl-1-N- ethyl acetate-is obtained after column chromatographs
Azepine four-membered ring.
Further preferably, the detailed process of step (8) are as follows: 3- methyl-1-N- ethyl acetate-azepine four-membered ring is dissolved in second
Alkali sodium hydroxide is added in the in the mixed solvent of nitrile and water, is heated to 40 DEG C, is cooled to room temperature after stirring a period of time, concentration removes
Solvent acetonitrile is removed, then into remaining aqueous solution, the weak solution of hydrochloric acid is slowly added dropwise, after aqueous solution is tuned into acidity, is had white
Color solid is precipitated, and white solid is filtered, 3- methyl-1-N- acetic acid-azepine four-membered ring is dried to obtain.
Further preferably, the detailed process of step (9) are as follows: by N- (5- amino-2-methyl phenyl) -4- (3- pyridyl group) -
2- aminopyrimidine and 3- methyl-1-N- acetic acid-azepine four-membered ring are added in dichloromethane solution, and three second of organic base is then added dropwise
Amine, after stirring half an hour, addition condensing agent 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester,
At room temperature, continue to be stirred to react, after raw material completely disappears, water is added, organic solvent dichloromethane extraction is added three times, merges
Organic phase is concentrated to give oily compound, chromatographs to obtain N- (3- (4- (pyridin-3-yl) pyrimidine -2 --amino)-4- methyl through column
Phenyl) -2- (3- methyl-aza -1- base) acetamide.
The Imatinib amine derivative of new method synthesis of the present invention, has anti-tumor activity, and carried out corresponding bioactivity
Detection.
The present invention also provides application of the Imatinib amine derivative in preparation treating cancer drug, the cancer is related to lung
Cancer.
The invention has the benefit that the compound molecule can effectively enter in the target point protein of lung carcinoma cell, quilt
Target point protein includes completely, and active force corresponding with the generation of the amino acid of surrounding, and then forms highly significant with the albumen
Function and effect, are able to suppress the activity of the albumen, to inhibit the growth of tumour cell, have patent medicine potential quality.
Detailed description of the invention
Fig. 1 is the Imatinib amine drug molecule and tumor targets docking scheme of the embodiment of the present invention 9.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In the round-bottomed flask of 10000mL, urea 300g is dissolved in dehydrated alcohol 2000mL, 60 DEG C is heated, then delays
After slow dropwise addition 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone 790g is dripped off, it is heated to gentle reflux, is then reacted 5 hours, had a large amount of
White solid be precipitated, white solid filtered, and off-white powder (1- (1- (pyridyl group -3- base) -2- benzal)) is dried to obtain
Urea 810g；1H NMR(400MHz,CDCl3): 9.23 (d, J=8.0Hz, 1H), 8.83 (d, J=24.0Hz, 1H), 8.39 (d,
J=24.0Hz, 1H), 7.62 (t, J1=8.0Hz, J2=8.0Hz, 1H), 6.04 (s, 1H), 1.83 (s, 1H)
Embodiment 2
In the round-bottomed flask of 10000mL, polyphosphoric acids 1500g is added, (1- (1- (pyridyl group -3- base)-is then added
2- benzal)) urea 700g, stirs 20 minutes, is heated to 110 DEG C, stir 4 hours, be slowly added to water 2000mL and active carbon
100g is stirred 15 minutes, and filtering, filtrate puts refrigerator overnight, be then collected by vacuum filtration the solid of precipitating, with water by solid
It is recrystallized, drying obtains solid 4- (pyridyl group -3- base) (H) -one of pyrimidine -2 672g；1H NMR(400MHz,CDCl3):
9.16 (s, 1H), 8.79 (d, J=12.0Hz, 1H), 8.42 (d, J=12.0Hz, 1H), 7.67 (t, J1=8.0Hz, J2=
8.0Hz, 1H), 7.31 (d, J=24.0Hz, 1H), 4.57 (d, J=16.0Hz, 1H).
Embodiment 3
In the round-bottomed flask of 5000mL, toluene 1300mL is added, 4- (pyridyl group -3- base) pyrimidine -2 (H)-is then added
Ketone 500g is stirred at room temperature 20 minutes, and phosphorus oxychloride 532g is slowly added dropwise, and is heated to gentle reflux, stirs 5 hours, and TLC detection is former
After material completely disappears, reaction solution is cooled to room temperature, and then reaction solution is poured into ice water 3500mL, and organic solvent dichloromethane is added
Alkane, extraction three times, merge organic phase, are then concentrated, obtain pure 2- chloro- 4- (pyridin-3-yl) pyrrole by column chromatography for separation
Pyridine 520g,1H NMR(400MHz,CDCl3): 9.11 (s, 1H), 8.85-8.83 (m, 1H), 8.79 (d, J=4.0Hz, 1H),
8.55-8.54 (m, 1H), 7.92 (d, J=24.0Hz, 2H), 7.43 (d, J=8.0Hz, 1H).
Embodiment 4
Under nitrogen atmosphere, by 2- chloro- 4- (pyridin-3-yl) pyridine 190g, 2- methyl-5-nitro aniline 167g, iodate
Isosorbide-5-Nitrae-dioxane solution 2000mL is added in cuprous 47g, Anhydrous potassium carbonate 276g and dimethylaminoethyl methacrylate 22g
In, 100 DEG C are heated, 20h, TLC detection, raw material fully reacting are reacted；First at reduced pressure conditions, the solvent two of the overwhelming majority is boiled off
Six ring of oxygen, after being cooled to room temperature, reaction mixture is poured into ice water, has a large amount of off-white powder to be precipitated, filtering, is had few
Measure n-hexane elution, N- (2- methyl-5-nitrophenyl) -4- (3- the pyridyl group) -2- pyrilamine 290g for being dried in vacuo pure
；1H NMR(400MHz,CDCl3): 8.81 (s, 1H), 8.53 (d, J=24.0Hz, 1Hz), 7.97 (d, J=4.0Hz, 1H),
7.44(t,J1=12.0Hz, J1=4.0Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 6.8 (d, J=4.0Hz,
1H),2.35(s,3H).
Embodiment 5
N- (2- methyl-5-nitrophenyl) -4- (3- pyridyl group) -2- pyrilamine 300g and ferric chloride hexahydrate 50g is added
Enter in ethyl alcohol 2000mL, oil bath is slowly heated to 78 DEG C, is added with stirring activated carbon 10g, the hydration for being 85% by mass fraction
Hydrazine 600g is slowly dropped in reaction, and the reaction was continued 6 hours, stops reaction, is filtered, and filtrate is concentrated to get yellow oil, adds
Enter ethyl alcohol 500mL heating for dissolving, lower dropwise addition distilled water 150mL is stirred at room temperature and obtains glassy yellow crystalline solid N- (5- amino -2- first
Base phenyl) -4- (3- pyridyl group) -2- aminopyrimidine 267g, purity 99.9%；1H NMR(400MHz,CDCl3):8.92(s,
1H), 8.56 (d, J=4.0Hz, 1Hz), 7.87 (d, J=16.0Hz, 1H), 7.34 (t, J1=4.0Hz, J2=4.0Hz, 2H),
7.17 (s, 1H), 7.01 (d, J=8.0Hz, 1H), 6.64 (d, J=12.0Hz, 1H), 4.27 (s, 2H), 2.33 (s, 3H).
Embodiment 6
Acetonitrile is added in benzhydryl -3- methyl azetidine 120g, bromoacetate 100g and potassium carbonate 138g
In 2000mL, 90 DEG C of reactions are then heated to, after TLC detects the -3- methyl azetidine fully reacting of raw material 1- benzhydryl,
It is cooled to room temperature, is filtered to remove potassium carbonate, filtrate is concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza quaternary
Ring bromination amine 190g,1H NMR(400MHz,CDCl3): 7.94-7.23 (m, 10H), 6.4 (s, 1H), 4.23 (s, 2H), 4.12-
4.10(m,2H),3.59-3.52(m,4H),2.91(s,1H),1.34(s,3H),1.07(s,3H)。
Embodiment 7
Acetonitrile is added in benzhydryl -3- methyl azetidine 120g, bromoacetate 100g and potassium carbonate 138g
In 2000mL, 60 DEG C of reactions are then heated to, after TLC detects the -3- methyl azetidine fully reacting of raw material 1- benzhydryl,
It is cooled to room temperature, is filtered to remove potassium carbonate, filtrate is concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza quaternary
Ring bromination amine 95g,1H NMR(400MHz,CDCl3): 7.94-7.23 (m, 10H), 6.4 (s, 1H), 4.23 (s, 2H), 4.12-
4.10(m,2H),3.59-3.52(m,4H),2.91(s,1H),1.34(s,3H),1.07(s,3H)。
Embodiment 8
Acetonitrile is added in benzhydryl -3- methyl azetidine 120g, bromoacetate 100g and potassium carbonate 138g
In 2000mL, 80 DEG C of reactions are then heated to, after TLC detects the -3- methyl azetidine fully reacting of raw material 1- benzhydryl,
It is cooled to room temperature, is filtered to remove potassium carbonate, filtrate is concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza quaternary
Ring bromination amine 128g,1H NMR(400MHz,CDCl3): 7.94-7.23 (m, 10H), 6.4 (s, 1H), 4.23 (s, 2H), 4.12-
4.10(m,2H),3.59-3.52(m,4H),2.91(s,1H),1.34(s,3H),1.07(s,3H)。
Embodiment 9
Acetonitrile is added in benzhydryl -3- methyl azetidine 120g, bromoacetate 100g and potassium carbonate 138g
In 2000mL, 100 DEG C of reactions are then heated to, TLC detects the -3- methyl azetidine fully reacting of raw material 1- benzhydryl
Afterwards, it is cooled to room temperature, is filtered to remove potassium carbonate, filtrate is concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza
Four-membered ring amine bromide 149g,1H NMR(400MHz,CDCl3): 7.94-7.23 (m, 10H), 6.4 (s, 1H), 4.23 (s, 2H),
4.12-4.10(m,2H),3.59-3.52(m,4H),2.91(s,1H),1.34(s,3H),1.07(s,3H)。
Embodiment 10
1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide 125g is put into methanol 1000mL
In, catalyst Pd/C 25g is then added, under hydrogen 0.2MPa pressure, reacts 4h, TLC is detected after raw material completely disappears,
Filtration of catalyst Pd/C, filtrate are concentrated to give mixture, and pure 3- methyl-1-N- ethyl acetate-is obtained after column chromatographs
Azepine four-membered ring 43g；1H NMR(400MHz,CDCl3): 4.12 (q, 2H, J=8.0Hz), 3.38-3.12 (m, 6H), 2.40-
2.38(m,1H),1.35(t,J1=12.0Hz, J2=4.0Hz, 3H), 1.07 (t, J1=4.0Hz, J2=4.0Hz, 3H).
Embodiment 11
1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide 125g is put into methanol 1000mL
In, catalyst Pd/C 5g is then added, under hydrogen 0.2MPa pressure, reacts 4h, TLC detects the mistake after raw material completely disappears
Catalyst Pd/C is filtered out, filtrate is concentrated to give mixture, and pure 3- methyl-1-N- ethyl acetate-nitrogen is obtained after column chromatographs
Miscellaneous four-membered ring 17g；1H NMR(400MHz,CDCl3): 4.12 (q, 2H, J=8.0Hz), 3.38-3.12 (m, 6H), 2.40-2.38
(m,1H),1.35(t,J1=12.0Hz, J2=4.0Hz, 3H), 1.07 (t, J1=4.0Hz, J2=4.0Hz, 3H).
Embodiment 12
1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide 125g is put into methanol 1000mL
In, catalyst Pd/C 15g is then added, under hydrogen 0.2MPa pressure, reacts 4h, TLC is detected after raw material completely disappears,
Filtration of catalyst Pd/C, filtrate are concentrated to give mixture, and pure 3- methyl-1-N- ethyl acetate-is obtained after column chromatographs
Azepine four-membered ring 31g；1H NMR(400MHz,CDCl3): 4.12 (q, 2H, J=8.0Hz), 3.38-3.12 (m, 6H), 2.40-
2.38(m,1H),1.35(t,J1=12.0Hz, J2=4.0Hz, 3H), 1.07 (t, J1=4.0Hz, J2=4.0Hz, 3H).
Embodiment 13
1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide 125g is put into methanol 1000mL
In, catalyst Pd/C 30g is then added, under hydrogen 0.2MPa pressure, reacts 4h, TLC is detected after raw material completely disappears,
Filtration of catalyst Pd/C, filtrate are concentrated to give mixture, and pure 3- methyl-1-N- ethyl acetate-is obtained after column chromatographs
Azepine four-membered ring 37g；1H NMR(400MHz,CDCl3): 4.12 (q, 2H, J=8.0Hz), 3.38-3.12 (m, 6H), 2.40-
2.38(m,1H),1.35(t,J1=12.0Hz, J2=4.0Hz, 3H), 1.07 (t, J1=4.0Hz, J2=4.0Hz, 3H).
Embodiment 14
3- methyl-1-N- ethyl acetate-azepine four-membered ring 16g is dissolved in the in the mixed solvent of acetonitrile 200mL and water 50mL,
Sodium hydroxide 20g is added, is heated to 40 DEG C, stirs 5 hours, then cools to room temperature, concentration removes solvent acetonitrile, then toward surplus
In remaining aqueous solution, the weak solution of hydrochloric acid is slowly added dropwise, after aqueous solution is tuned into acidity, there is white solid precipitation, white is solid
Body filtering, dries to obtain 3- methyl-1-N- acetic acid-azepine four-membered ring 11g；1H NMR(400MHz,CDCl3):11.38-11.35(m,
1H), 4.12 (q, J=8.0Hz, 2H), 3.39-3.16 (m, 4H), 2.40-2.35 (m, 1H), 1.07 (t, J1=4.0Hz, J2=
4.0Hz,3H)
Embodiment 15
N- (5- amino-2-methyl phenyl)-4- (3- pyridyl group)-2- aminopyrimidine 28g and 3- methyl-1-N- acetic acid-nitrogen
Miscellaneous four-membered ring 13g is added in methylene chloride 300mL, and triethylamine 15g is then added dropwise, and after stirring half an hour, condensing agent 2- is added
(7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester 20g continue to be stirred to react, to raw material at room temperature
After completely disappearing, water is added, organic solvent dichloromethane extraction is added three times, merges organic phase, is concentrated to give oily compound, passes through
Column chromatographs to obtain pure N- (3- (4- (pyridin-3-yl) pyrimidine -2 --amino)-4- aminomethyl phenyl)-2- (3- methyl-aza-1-
Base) acetamide 31g；1H NMR(400MHz,CDCl3): δ 9.41 (s, 1H), 8.85 (d, J=4.0Hz, 1H), 8.41-8.35 (m,
2H), 7.69 (d, J=8.0Hz, 1H), 7.16-7.13 (m, 1H), 6.92-6.87 (m, 2H), 6.45 (s, 1H), 4.19 (s,
1H), 3.77 (s, 2H), 3.34-3.26 (m, 4H), 2.34 (s, 2H), 2.17 (d, J=12.0Hz, 1H), 0.88 (s, 3H)；HR
MS(ESI):389.2083[M+H]+.Anal.Calcd for C22H24N6O:C,68.02；H,6.23；N,21.63.Found:C,
68.47；H,6.14；N,21.35.
Embodiment 16
The method that we use computer drug Computer Aided Design, the target spot egg of resulting compound molecule and tumour cell
White carry out molecular docking, target spot serial number 1M17.We have found that compound can be very good to enter inside target point protein pocket, change
Adduct molecule is surrounded by target point protein residue amino acid, forms very strong function and effect with target spot, wherein compound molecule
Hydrogen bond action is formed with aspartic acid ASP831, methionine MET769 and lysine LYS721, with phenylalanine PHE699 shape
At π-πconjugation.It is specifically shown in Fig. 1, is compound molecule and tumor targets docking scheme.
Embodiment 17
Anti-tumor activity test
Growth period lung cell A549 is collected, the anticancer activity of compound is measured with MTS method, by cell with appropriate dense
(every milliliter 5 × 10 of degree4A cell) be added in 96 porocyte culture plates (containing 10% tire calf serum obtain culture solution be made into it is single thin
Born of the same parents' suspension), after culture 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound effects 72 with various concentration
Hour, then the mixture of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration) are directly added into containing thin
In the culture medium of born of the same parents, continue to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, DMSO150 μ L is added in every hole, vibrates, carefully
Born of the same parents' survival rate measures absorptivity of the metabolin of MTS effect under enzyme linked immunological monitor 490nm wavelength by it, N- (3-
(4- (pyridin-3-yl) pyrimidine -2 --amino)-4- aminomethyl phenyl)-2- (3- methyl-aza-1- base) acetamide is to the cell
Inhibiting rate IC50 is 73 μm of olL-1。
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (7)
1. the Imatinib amine derivative and preparation method thereof with pharmaceutical activity, it is characterised in that the structure of the Imatinib amine derivative
Are as follows:
2. the preparation method of the Imatinib amine derivative according to claim 1 with pharmaceutical activity, it is characterised in that specific
Step are as follows:
A, urea is dissolved in dehydrated alcohol, heats 60 DEG C, 1- (pyridin-3-yl) propyl- 2- alkynes -1- ketone is then slowly added dropwise, drips off
After be heated to flowing back, reaction has a large amount of white solid to be precipitated after a certain period of time, and white solid is filtered, dry off-white color is solid
Body (1- (1- (pyridyl group -3- base) -2- benzal)) urea；
B, in polyphosphoric acids, (1- (1- (pyridyl group -3- base) -2- benzal)) urea is added, when one section being stirred at room temperature first
Between, it is then heated to 110 DEG C and is stirred to react to raw material fully reacting, be slowly added to water and active carbon, filter after mixing evenly, filter
Liquid puts refrigerator overnight, is then collected by vacuum filtration the solid of precipitating, is recrystallized solid with water, and drying obtains solid
4- (pyridyl group -3- base) pyrimidine -2 (H) -one.
C, in toluene solvant, 4- (pyridyl group -3- base) pyrimidine -2 (H) -one is then added, when one section being stirred at room temperature first
Between, phosphorus oxychloride is then slowly added dropwise, is heated to flowing back, is stirred to react to raw material after completely disappearing and is down to room temperature, then anti-
It answers liquid to pour into quenching reaction in a large amount of ice water, organic solvent dichloromethane is added, merge organic phase after extracting repeatedly, be then concentrated
Pure 2- chloro- 4- (pyridin-3-yl) pyridine is chromatographed by column.
D, under nitrogen atmosphere, by 2- chloro- 4- (pyridin-3-yl) pyridine, 2- methyl-5-nitro aniline, cuprous iodide, anhydrous carbon
Sour potassium and dimethylaminoethyl methacrylate are added in Isosorbide-5-Nitrae-dioxane solution, heat 100 DEG C, reaction to raw material has been reacted
Entirely, first at reduced pressure conditions, the Isosorbide-5-Nitrae-dioxane for boiling off the overwhelming majority, after being cooled to room temperature, pours into reaction mixture
In ice water, there is a large amount of off-white powder to be precipitated, filtering is eluted, the N- (2- methyl -5- for being dried in vacuo pure with n-hexane
Nitrobenzophenone) -4- (3- pyridyl group) -2- pyrilamine.
E, N- (2- methyl-5-nitrophenyl) -4- (3- pyridyl group) -2- pyrilamine and ferric chloride hexahydrate are added in ethyl alcohol,
Oil bath is slowly heated to 78 DEG C, is added with stirring activated carbon, and the hydrazine hydrate that mass fraction is 85% is slowly dropped in reaction,
Stopping reaction after the reaction was continued a period of time, filters, filtrate is concentrated to get yellow oil, and ethyl alcohol is added and dissolves by heating, room temperature
It is phonetic that the lower dropwise addition distilled water of stirring obtains glassy yellow crystalline solid N- (5- amino-2-methyl phenyl) -4- (3- pyridyl group) -2- amino
Pyridine.
F, by benzhydryl -3- methyl azetidine, bromoacetate, potassium carbonate is added in acetonitrile, is then heated to certain
Thermotonus is cooled to room temperature after raw material 1- benzhydryl -3- methyl azetidine fully reacting, is filtered to remove carbonic acid
Potassium, filtrate are concentrated to give 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide.
G, 1-N- benzhydryl -1-N- ethyl acetate -3- methyl-aza four-membered ring amine bromide is put into methanol, is then added
Catalyst Pd/C reacts after completely disappearing to raw material, Filtration of catalyst Pd/C under hydrogen 0.2MPa pressure, and filtrate is dense
Contract to obtain mixture, and 3- methyl-1-N- ethyl acetate-azepine four-membered ring is obtained after column chromatographs.
H, 3- methyl-1-N- ethyl acetate-azepine four-membered ring is dissolved in the mixed solvent, alkali sodium hydroxide is added, is heated to 40
DEG C, it is cooled to room temperature after stirring a period of time, after concentration of reaction solution, the weak solution of hydrochloric acid is slowly added dropwise, is tuned into acid to aqueous solution
After property, there is white solid precipitation, white solid is filtered, dry to obtain 3- methyl-1-N- acetic acid-azepine four-membered ring.
I, by N- (5- amino-2-methyl phenyl)-4- (3- pyridyl group)-2- aminopyrimidine and 3- methyl-1-N- acetic acid-azepine four
Member ring is added in dichloromethane solution, and organic bases triethylamine is then added dropwise, and after stirring half an hour, condensing agent 2- (7- oxygen is added
Change benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester continues to be stirred to react, completely disappear to raw material at room temperature
Afterwards, water is added, organic solvent dichloromethane extraction is added three times, merges organic phase, is concentrated to give oily compound, is chromatographed through column
To N- (3- (4- (pyridin-3-yl) pyrimidine -2 --amino)-4- aminomethyl phenyl)-2- (3- methyl-aza-1- base) acetamide.
3. the preparation method of the Imatinib amine derivative according to claim 2 with pharmaceutical activity, it is characterised in that: step
The inventory molar ratio of the chloro- 4- of 2- described in D (pyridin-3-yl) pyridine and cuprous iodide and Anhydrous potassium carbonate is 4:1:8.
4. the preparation method of the Imatinib amine derivative according to claim 2 with pharmaceutical activity, it is characterised in that: step
N- described in E (2- methyl-5-nitrophenyl) -4- (3- pyridyl group) -2- pyrilamine and ferric chloride hexahydrate and active carbon
Inventory mass ratio is 30:5:1.
5. the preparation method of the Imatinib amine derivative according to claim 2 with pharmaceutical activity, it is characterised in that: step
The inventory molar ratio of benzhydryl -3- methyl azetidine described in F and bromoacetate and potassium carbonate is 5:6:10；
The reaction temperature is 60~100 DEG C.
6. the preparation method of the Imatinib amine derivative according to claim 2 with pharmaceutical activity, it is characterised in that: step
Ethyl acetate -3- methyl-aza four-membered ring the amine bromide of 1-N- benzhydryl -1-N- described in G feeds intake with catalyst Pd/C's
Amount mass ratio is 25:1~6.
7. the preparation method of the Imatinib amine derivative according to claim 2 with pharmaceutical activity, it is characterised in that: step
Mixed solvent described in H is acetonitrile and water, volume ratio 4:1.
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| CN110078706A (en) * | 2019-05-31 | 2019-08-02 | 浙江师范大学 | A kind of Imatinib derivative and its preparation method and application |
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| WO2006021458A2 (en) * | 2004-08-27 | 2006-03-02 | Gpc Biotech Ag | Pyrimidine derivatives |
| KR20120052095A (en) * | 2010-11-15 | 2012-05-23 | 일양약품주식회사 | ??-phenyl-2-pyrimidine isothiocyanate derivatives and preparation process thereof |
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| WO2006021458A2 (en) * | 2004-08-27 | 2006-03-02 | Gpc Biotech Ag | Pyrimidine derivatives |
| KR20120052095A (en) * | 2010-11-15 | 2012-05-23 | 일양약품주식회사 | ??-phenyl-2-pyrimidine isothiocyanate derivatives and preparation process thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110078706A (en) * | 2019-05-31 | 2019-08-02 | 浙江师范大学 | A kind of Imatinib derivative and its preparation method and application |
| CN110078706B (en) * | 2019-05-31 | 2022-02-01 | 浙江师范大学 | Imatinib derivative and preparation method and application thereof |
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