CN108864088B - The preparation method of novel isoquinoline drug molecule with antibacterial activity - Google Patents
The preparation method of novel isoquinoline drug molecule with antibacterial activity Download PDFInfo
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Abstract
The preparation method of the invention discloses a kind of novel isoquinoline drug molecule with antibacterial activity, belongs to medical synthesis technical field.Technical key point of the present invention are as follows:
Description
Technical field
The invention belongs to the synthesis technical fields of antibacterials, and in particular to a kind of novel isoquinoline with antibacterial activity
The preparation method of quinoline drug molecule.
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..
6-membered heterocyclic compound is the nitrogenous hexa-member heterocycle such as most important part, especially quinoline in heterocyclic compound.Quinoline
Quinoline and its derivative, medicine aspect quinoline play an important role, it can be used as fungicide, herbicide in terms of pesticide, in material
It can be used as organic fluorescence agent to aspect, can use ortho-aminobenzoic acid, anthranilamide, adjacent amino aromatic ketone, adjacent halogen fragrance
Ketone or o-amino-benzylamine etc. are Material synthesis quinoline.For example, quinoline derivatives can anticancer, antibacterial, anti-malarial agents, anti-spasm, resist
The scorching medical value as glucocerebroside inhibitor, isoquinolin and quinazoline urea analog are as mankind's A3 gland acid anhydride receptor antagonist
Agent, methoxy quinazoline amide have very strong immune suppression as many cells cycle kinase inhibitors, the derivative of this kind of compound
Function processed, the fluorescence probe based on quinazoline can be used as adrenergic receptor, have the anticancer activity having good prospects.
We are modified in the structure basis of isoquinolin, have synthesized a kind of isoquinolin drug point of structure novel
Son, the drug molecule have significant antibacterial action to human normal cell line nontoxicity.
Summary of the invention
Simple, low in raw material price that the technical problem to be solved by the present invention is to provide a kind of synthetic methods, structure novel
The preparation method of novel isoquinoline drug molecule with antibacterial activity.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of novel isoquinoline with antibacterial activity
The preparation method of quinoline drug molecule, it is characterised in that specific steps are as follows:
(1), dimethyl malenate and N,N-dimethylformamide dimethylacetal first occur after condensation reaction again with benzylamine
Substitution reaction occurs and obtains 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene；
(2), 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene obtains 2,3- through itself cyclization under calcium hydride effect
Dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester；
(3), 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester sloughs a molecule formic acid first under copper catalyst effect
Ester obtains 1,2- dihydro-isoquinoline -4- methyl formate；
(4), 1,2- dihydro-isoquinoline -4- methyl formate occurs under chlorination reagent effect with n,N-Dimethylformamide
Substitution reaction obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate；
(5), 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate obtains 1,2- dihydro-isoquinoline -3- formaldehyde through hydrolysis
Base -4- formic acid；
(6), 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid and carbamide compounds generation annulation obtain targeted
Close object.
Further preferably, the detailed process of step (1) are as follows: N, N- dimethyl formyl under room temperature and inert gas shielding
Amine dimethylacetal is added drop-wise in dimethyl malenate, keeps being stirred at room temperature reaction after dripping to raw material disappearance；In being cooled to
A certain amount of benzylamine is added dropwise in 10~15 DEG C of temperature, and solution can be observed during being added dropwise and heat up, and temperature is added dropwise at 30 DEG C or less and adds in holding
It is complete；It is cooled to 10~15 DEG C again, visible a large amount of solids are precipitated after stirring a period of time, and methyl tertiary butyl ether(MTBE) is added, slowly stirs
Mixing makes solid suspend, and filter cake is washed after filtering with methyl tertiary butyl ether(MTBE), obtains solid 1,1- dicarboxylic acid methyl ester base vinyl amido
Methylbenzene；Solid is precipitated in mother liquor concentrations again, and filtering, filter cake is washed three times with methyl tertiary butyl ether(MTBE) again, obtains solid 1,1-
Dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene；The N,N-dimethylformamide dimethylacetal and dimethyl malenate
Inventory molar ratio is 1:1；The reaction temperature of the N,N-dimethylformamide dimethylacetal and dimethyl malenate is
15~30 DEG C, preferably 25 DEG C；The inventory molar ratio of the N,N-dimethylformamide dimethylacetal and benzylamine is 1:0.8
~1.1, preferably 1:1.0.
Further preferably, the detailed process of step (2) are as follows: 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene and hydrogen
Change calcium to be added in the methylene chloride of Non-aqueous processing, is heated to flowing back under nitrogen protection, after TLC monitors raw material fully reacting,
Filtering reacting liquid is concentrated after filtrate through silica gel column chromatography (V petroleum ether: V ethyl acetate is 2:1) isolated 2,3- dihydro isoquinoline
Quinoline -4,4 (1H)-dicarboxylic acid methyl ester；The inventory of 1,1- dicarboxylic acid methyl ester base the vinyl amine ylmethyl benzene and calcium hydride
Molar ratio is 1:3~5, preferably 1:4.
Further preferably, the detailed process of step (3) are as follows: 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester is added
Enter in dimethyl sulfoxide, add copper catalyst, in 120 DEG C of heating reactions to raw material fully reacting, filtering reacting liquid is added
Methylene chloride extraction reaction solution is multiple, is concentrated after being washed with water after merging organic phase, then in the mixed liquor of acetone and n-hexane
In be recrystallized to give 1,2- dihydro-isoquinoline -4- methyl formate in (V acetone: V n-hexane=3:1)；The copper catalyst is
Copper bromide, cupric iodide, copper sulphate, preferably cupric iodide；2,3- dihydro-isoquinoline -4,4 (the 1H)-dicarboxylic acid methyl ester is urged with copper
The inventory molar ratio of agent is 1:0.1~0.3, preferably 1:0.15.
Further preferably, the detailed process of step (4) are as follows: 1,2- dihydro-isoquinoline -4- methyl formate is added to dichloro
In methane and n,N-Dimethylformamide, chlorinated compound is added at room temperature, is heated to back flow reaction to raw material and reacts
After completely, it is down to room temperature, filtering reacting liquid, filtrate is added the sodium acetate solution of saturation, filtering reacting liquid is stirred evenly, after washing
Concentration of reaction solution obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate；1,2- dihydro-isoquinoline -4- the formic acid
The inventory molar ratio of methyl esters and N,N-dimethylformamide and chlorinated compound is 1:2~5:2~5；The chloro chemical combination
Object is phosphorus oxychloride, phosphorus tribromide, hydrobromic acid.
Further preferably, the detailed process of step (5) are as follows: 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate is added
Enter in tetrahydrofuran, add lithium hydroxide, be heated to flowing back, be down to room temperature after reacting a period of time, is adjusted with dilute hydrochloric acid anti-
Answering liquid pH is 3~4, has a large amount of solids to be precipitated in whipping process, filters reaction solution, obtains 1,2- dihydro isoquinoline after filter cake drying
Quinoline -3- carboxaldehyde radicals -4- formic acid.
Further preferably, the detailed process of step (6) are as follows: N is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid,
In dinethylformamide, potassium carbonate and urea or thiocarbamide are added, heating reaction at a certain temperature to raw material fully reacting, mistake
Filter reaction solution, it is multiple to add methylene chloride extraction reaction solution, merge and be concentrated after being washed with water after organic phase, then in acetone and
It is recrystallized to give in (V acetone: V n-hexane=3:1) in the mixed liquor of n-hexane
The reaction temperature is 80~150 DEG C, preferably 120 DEG C.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of novel isoquinoline with antibacterial activity
The preparation method of quinoline drug molecule, it is characterised in that specific steps are as follows:
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 reaction flask, under argon gas protection, cooling, 15~25 DEG C of interior temperature, n,N-Dimethylformamide dimethyl are started
Acetal 120g (1.0mol) is slowly dropped in dimethyl malenate 135g (1.0mol), and 20min is added dropwise, it is seen that solution face
Color blacks；Temperature 25 DEG C of stirrings 1.5h, TLC show that raw material disappears in keeping；It is cooled to 10~15 DEG C of interior temperature again, benzylamine is added dropwise
Solution heating can be observed in 110g (1.0mol) during being added dropwise, keep interior temperature to be added dropwise at 30 DEG C or less, 1.5h is added；System
10~15 DEG C are maintained at, visible a large amount of solids are precipitated after stirring 30min；Methyl tertiary butyl ether(MTBE) 1000mL is added, is slowly stirred
15min makes solid suspend, blowing, and filtering, filter cake is washed twice with methyl tertiary butyl ether(MTBE) (0~5 DEG C) 500mL, obtains solid
210g, liquid phase purity are 99.84%；Solid is precipitated in mother liquor concentrations again, and filtering, filter cake uses methyl tertiary butyl ether(MTBE) (0~5 again
DEG C) 500mL washing three times, obtain solid 16g, purity 98.83%, combining solid stands overnight naturally and dries, be obtained about 1,
1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 226g, total recovery 90.7%；1HNMR(600MHz,CDCl3):δ9.57(s,
1H), 7.49-7.48 (m, 2H), 7.35 (d, J=12.0Hz, 1H), 7.17-7.15 (m, 2H), 4.77 (s, 2H), 3.74-3.72
(m,6H)。
Embodiment 2
In reaction flask, under argon gas protection, cooling, 15~25 DEG C of interior temperature, n,N-Dimethylformamide dimethyl are started
Acetal 120g (1.0mol) is slowly dropped in dimethyl malenate 135g (1.0mol), and 20min is added dropwise, it is seen that solution face
Color blacks；Temperature 25 DEG C of stirrings 1.5h, TLC show that raw material disappears in keeping；It is cooled to 10~15 DEG C of interior temperature again, benzylamine is added dropwise
Solution heating can be observed in 88g (0.8mol) during being added dropwise, keep interior temperature to be added dropwise at 30 DEG C or less, 1.5h is added；System is protected
It holds at 10~15 DEG C, visible a large amount of solids are precipitated after stirring 30min；Methyl tertiary butyl ether(MTBE) 1000mL is added, is slowly stirred 15min
Solid is set to suspend, blowing filters, and filter cake obtains solid 138g, liquid with (0~5 DEG C) washing (500mL × 2) of methyl tertiary butyl ether(MTBE)
Phase purity is 99.61%；Solid is precipitated in mother liquor concentrations again, and filtering, filter cake uses methyl tertiary butyl ether(MTBE) (0~5 DEG C) again
500mL is washed three times, obtains solid 24g, purity 98.43%, combining solid stands overnight naturally and dries, and is obtained about 1,1-
Dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 162g, total recovery 65%；1H NMR(600MHz,CDCl3):δ9.57(s,
1H), 7.49-7.48 (m, 2H), 7.35 (d, J=12.0Hz, 1H), 7.17-7.15 (m, 2H), 4.77 (s, 2H), 3.74-3.72
(m,6H)。
Embodiment 3
In reaction flask, under argon gas protection, cooling, 15~25 DEG C of interior temperature, n,N-Dimethylformamide dimethyl are started
Acetal 120g (1.0mol) is slowly dropped in dimethyl malenate 135g (1.0mol), and 20min is added dropwise, it is seen that solution face
Color blacks；Temperature 25 DEG C of stirrings 1.5h, TLC show that raw material disappears in keeping；It is cooled to 10~15 DEG C of interior temperature again, benzylamine is added dropwise
Solution heating can be observed in 120g (1.1mol) during being added dropwise, keep interior temperature to be added dropwise at 30 DEG C or less, 1.5h is added；System
10~15 DEG C are maintained at, visible a large amount of solids are precipitated after stirring 30min；Methyl tertiary butyl ether(MTBE) 1000mL is added, is slowly stirred
15min makes solid suspend, blowing, and filtering, filter cake obtains solid with (0~5 DEG C) washing (500mL × 2) of methyl tertiary butyl ether(MTBE)
188g, liquid phase purity are 99.76%；Solid is precipitated in mother liquor concentrations again, and filtering, filter cake uses methyl tertiary butyl ether(MTBE) (0~5 again
DEG C) 500mL washing three times, obtain solid 25g, purity 99.02%, combining solid stands overnight naturally and dries, be obtained about 1,
1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 213g, total recovery 85.2%；1H NMR(600MHz,CDCl3):δ9.57
(s, 1H), 7.49-7.48 (m, 2H), 7.35 (d, J=12.0Hz, 1H), 7.17-7.15 (m, 2H), 4.77 (s, 2H), 3.74-
3.72(m,6H)。
Embodiment 4
In reaction flask, 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 25g (0.1mol) and calcium hydride 12.6g
(0.3mol) is added in the methylene chloride 100mL of Non-aqueous processing, is heated to flowing back under nitrogen protection, and it is anti-that TLC monitors raw material
Should completely after, filtering reacting liquid is concentrated after filtrate through silica gel column chromatography (V petroleum ether: V ethyl acetate be 5:1) isolated 2,
3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 19.2g, yield 77%；1H NMR(600MHz,CDCl3):δ9.34(s,
1H),7.55-7.54(m,2H),7.17-7.15(m,2H),3.35-3.24(m,2H),3.15(s,2H),3.06-3.04(m,
6H),HRMS(ESI):250.2623[M+H]+。
Embodiment 5
In reaction flask, 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 25g (0.1mol) and calcium hydride 17g
(0.4mol) is added in the methylene chloride 100mL of Non-aqueous processing, is heated to flowing back under nitrogen protection, and it is anti-that TLC monitors raw material
Should completely after, filtering reacting liquid is concentrated after filtrate through silica gel column chromatography (V petroleum ether: V ethyl acetate be 5:1) isolated 2,
3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 23.6g, yield 95%；1H NMR(600MHz,CDCl3):δ9.34(s,
1H),7.55-7.54(m,2H),7.17-7.15(m,2H),3.35-3.24(m,2H),3.15(s,2H),3.06-3.04(m,
6H),HRMS(ESI):250.2623[M+H]+。
Embodiment 6
In reaction flask, 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene 25g (0.1mol) and calcium hydride 21g
(0.5mol) is added in the methylene chloride 100mL of Non-aqueous processing, is heated to flowing back under nitrogen protection, and it is anti-that TLC monitors raw material
Should completely after, filtering reacting liquid is concentrated after filtrate through silica gel column chromatography (V petroleum ether: V ethyl acetate be 5:1) isolated 2,
3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 21g, yield 84%；1H NMR(600MHz,CDCl3):δ9.34(s,
1H),7.55-7.54(m,2H),7.17-7.15(m,2H),3.35-3.24(m,2H),3.15(s,2H),3.06-3.04(m,
6H),HRMS(ESI):250.2623[M+H]+。
Embodiment 7
In reaction flask, quinoline is added in 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 25g (0.1mol)
In 150mL, copper bromide 3.3g (0.015mol) is added, reacts 1h in 170 DEG C of heating, TLC monitors raw material fully reacting, filtering
Reaction solution adds methylene chloride 200mL extraction reaction solution three times, is concentrated after being washed after merging organic phase with water 200mL, then
1,2- dihydro-isoquinoline-is recrystallized to give in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
4- methyl formate 14g, yield 74%；1H NMR(600MHz,CDCl3):δ7.38(s,1H),7.21(dd,J1=6.0Hz, J2
=6.0Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=6.0Hz, 1H), 6.96 (s, 1H), 3.67-3.66 (m, 2H), 3.65 (s,
3H)；HRMS(ESI):190.2115[M+H]+。
Embodiment 8
In reaction flask, quinoline is added in 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 25g (0.1mol)
In 150mL, cupric iodide 4.8g (0.015mol) is added, reacts 1h in 170 DEG C of heating, TLC monitors raw material fully reacting, filtering
Reaction solution adds methylene chloride 200mL extraction reaction solution three times, is concentrated after being washed after merging organic phase with water 200mL, then
1,2- dihydro-isoquinoline-is recrystallized to give in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
4- methyl formate 17g, yield 90%；1H NMR(600MHz,CDCl3):δ7.38(s,1H),7.21(dd,J1=6.0Hz, J2
=6.0Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=6.0Hz, 1H), 6.96 (s, 1H), 3.67-3.66 (m, 2H), 3.65 (s,
3H)；HRMS(ESI):190.2115[M+H]+。
Embodiment 9
In reaction flask, quinoline is added in 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester 25g (0.1mol)
In 150mL, anhydrous cupric sulfate 2.4g (0.015mol) is added, reacts 1h in 170 DEG C of heating, TLC monitors raw material fully reacting,
Filtering reacting liquid adds methylene chloride 200mL extraction reaction solution three times, is concentrated after being washed after merging organic phase with water 200mL,
Then 1,2- dihydro isoquinoline is recrystallized to give in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
Quinoline -4- methyl formate 13g, yield 68%；1H NMR(600MHz,CDCl3):δ7.38(s,1H),7.21(dd,J1=
6.0Hz,J2=6.0Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=6.0Hz, 1H), 6.96 (s, 1H), 3.67-3.66 (m,
2H),3.65(s,3H)；HRMS(ESI):190.2115[M+H]+。
Embodiment 10
In reaction flask, 1,2- dihydro-isoquinoline -4- methyl formate 19g (0.1mol) is added to methylene chloride 100mL
In n,N-Dimethylformamide 14g (0.2mol), phosphorus oxychloride 30g (0.2mol) is added at room temperature, is heated to back
Stream reaction 2.5h after TLC monitors raw material fully reacting, is down to room temperature, filtering reacting liquid, and the sodium acetate solution of saturation is added in filtrate
450mL stirs 30min, again filtering reacting liquid, and concentration of reaction solution obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- after washing
Methyl formate 17.4g, yield 80%；H NMR(600MHz,CDCl3):δ9.58(s,1H),8.05(s,1H),7.77(s,
1H),7.66-7.64(m,2H),4.39(s,2H),3.55-3.54(m,3H)；HRMS(ESI):218.1966[M+H]+。
Embodiment 11
In reaction flask, 1,2- dihydro-isoquinoline -4- methyl formate 19g (0.1mol) is added to methylene chloride 100mL
In n,N-Dimethylformamide 14g (0.2mol), tribromo oxygen phosphorus 86g (0.3mol) is added at room temperature, is heated to back
Stream reaction 2.5h after TLC monitors raw material fully reacting, is down to room temperature, filtering reacting liquid, and the sodium acetate solution of saturation is added in filtrate
500mL stirs 30min, again filtering reacting liquid, and concentration of reaction solution obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- after washing
Methyl formate 18.6g, yield 86%；H NMR(600MHz,CDCl3):δ9.58(s,1H),8.05(s,1H),7.77(s,
1H),7.66-7.64(m,2H),4.39(s,2H),3.55-3.54(m,3H)；HRMS(ESI):218.1966[M+H]+。
Embodiment 12
In reaction flask, 1,2- dihydro-isoquinoline -4- methyl formate 19g (0.1mol) is added to methylene chloride 100mL
In n,N-Dimethylformamide 14g (0.2mol), hydrobromic acid 40g (0.5mol) is added at room temperature, is heated to flowing back
2.5h is reacted, after TLC monitors raw material fully reacting, is down to room temperature, filtering reacting liquid, the sodium acetate solution of saturation is added in filtrate
300mL stirs 30min, again filtering reacting liquid, and concentration of reaction solution obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- after washing
Methyl formate 13.5g, yield 62%；1H NMR(600MHz,CDCl3):δ9.58(s,1H),8.05(s,1H),7.77(s,
1H),7.66-7.64(m,2H),4.39(s,2H),3.55-3.54(m,3H)；HRMS(ESI):218.1966[M+H]+。
Embodiment 13
In reaction flask, tetrahydro furan is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate 22g (0.1mol)
It mutters in 300mL, adds lithium hydroxide 4.8g (0.2mol), be heated to flowing back, room temperature is down to after reacting 4h, with dilute hydrochloric acid tune
Saving reaction solution pH is 3~4, has a large amount of solids to be precipitated in whipping process, filters reaction solution, and it is different to obtain 1,2- dihydro after filter cake drying
Quinoline-3-formaldehyde base -4- formic acid 17g, yield 85%.
Embodiment 14
In reaction flask, N, N- dimethyl is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid 20g (0.1mol)
In formamide 150mL, potassium carbonate 40g (0.3mol) and urea 6.6g (0.11mol) are added, reacts 1h, TLC in 120 DEG C of heating
Raw material fully reacting is monitored, filtering reacting liquid adds methylene chloride 200mL extraction reaction solution three times, uses after merging organic phase
It is concentrated after water 200mL washing, is then tied again in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
Crystalline substance obtains17g, HPLC purity are 99%, yield 75%；1H NMR(400MHz,CDCl3):δ7.56-
7.55 (m, 1H), 7.49-7.48 (m, 1H), 7.42 (s, 1H), 7.35 (d, J=6.0Hz, 1H), 7.11 (s, 1H), 3.97 (s,
2H)；HRMS(ESI):228.0725[M+H]+；Anal.Calcd for C12H9N3O2:C,63.43；H,3.99；N,
18.49.Found:C,63.55；H,4.07；N,18.30.
Embodiment 15
In reaction flask, N, N- dimethyl is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid 20g (0.1mol)
In formamide 150mL, potassium carbonate 40g (0.3mol) and urea 6.6g (0.11mol) are added, reacts 1h, TLC prison in 80 DEG C of heating
Raw material fully reacting is controlled, filtering reacting liquid adds methylene chloride 200mL extraction reaction solution three times, uses water after merging organic phase
It is concentrated after 200mL washing, is then recrystallized in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
It obtains11g, HPLC purity are 99%, yield 48%；1H NMR(400MHz,CDCl3):δ7.56-7.55
(m, 1H), 7.49-7.48 (m, 1H), 7.42 (s, 1H), 7.35 (d, J=6.0Hz, 1H), 7.11 (s, 1H), 3.97 (s, 2H)；
HRMS(ESI):228.0725[M+H]+；Anal.Calcd for C12H9N3O2:C,63.43；H,3.99；N,18.49.Found:
C,63.55；H,4.07；N,18.30.
Embodiment 16
In reaction flask, N, N- dimethyl is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid 20g (0.1mol)
In formamide 150mL, potassium carbonate 40g (0.3mol) and urea 6.6g (0.11mol) are added, reacts 1h, TLC in 150 DEG C of heating
Raw material fully reacting is monitored, filtering reacting liquid adds methylene chloride 200mL extraction reaction solution three times, uses after merging organic phase
It is concentrated after water 200mL washing, is then tied again in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
Crystalline substance obtains16g, HPLC purity are 98.5%, yield 70%；1H NMR(400MHz,CDCl3):δ7.56-
7.55 (m, 1H), 7.49-7.48 (m, 1H), 7.42 (s, 1H), 7.35 (d, J=6.0Hz, 1H), 7.11 (s, 1H), 3.97 (s,
2H)；HRMS(ESI):228.0725[M+H]+；Anal.Calcd for C12H9N3O2:C,63.43；H,3.99；N,
18.49.Found:C,63.55；H,4.07；N,18.30.
Embodiment 17
In reaction flask, N, N- dimethyl is added in 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid 19g (0.1mol)
In formamide 150mL, potassium carbonate 40g (0.3mol) and thiocarbamide 8.5g (0.11mol) are added, reacts 1h in 120 DEG C of heating,
TLC monitors raw material fully reacting, and filtering reacting liquid adds methylene chloride 200mL extraction reaction solution three times, after merging organic phase
It is concentrated after being washed with water 200mL, it is then heavy in (V acetone: V n-hexane=3:1) 100mL in the mixed liquor of acetone and n-hexane
Crystallization obtains21g, HPLC purity are 99%, yield 87%；1H NMR(400MHz,CDCl3):δ7.51
(s, 1H), 7.45-7.43 (m, 2H), 7.39 (d, J=6.0Hz, 1H), 7.19-7.18 (m, 1H), 3.85 (s, 2H)；HRMS
(ESI):244.0587[M+H]+；Anal.Calcd for C12H9N3OS:C,59.24；H,3.73；N,17.27.Found:C,
59.41；H,3.62；N,17.33.
Embodiment 18
Biological activity determination
We select Escherichia coli (Gram-negative brevibacterium) and golden yellow glucose coccus (gram-positive bacteria) conduct
Antibacterial activity test object.It is to prepare fluid nutrient medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g, distilled water first
100mL is placed in 250mL conical flask, is placed on electric furnace and is heated while stirring, it is to be mixed clarification it is uniform when, stop heating, by bottle
Mouthful successively sealed for use with gauze and brown paper) and solid medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g, agar
2g, distilled water 100mL are placed in 250mL conical flask, are placed on electric furnace and are heated while stirring, it is to be mixed clarification it is uniform when, stop
Heating, bottleneck gauze and brown paper are successively sealed for use)；Then culture medium is carried out at sterilizing by high-pressure sterilizing pot
Reason.It is living to pipette 100 μ L with liquid-transfering gun after Escherichia coli and golden yellow glucose coccus actication of culture for the followed by preparation of bacterium solution
Bacterium solution after change is placed in sterilized 100mL distilled water and is uniformly mixed.It sterilizes finally by ultraviolet lamp to plate, so
Culture medium is quickly poured into plate while hot afterwards, thickness about 0.15cm is uniformly paved, and is stood, is allowed its slow solidification, puts after solidification
Enter to cultivate one day in 37 DEG C of incubator and does no Detection.
Synthesized target compound and control compound solution are respectively configured with DMF, is placed in volumetric flask stand-by.With beating
Hole device punches on filter paper, aperture 5mm, be immersed in after then filter paper sterilizes concentration be 1mg/mL sample solution in
With.
On superclean bench, alcolhol burner is lighted, takes the 10 diluted culture solutions of μ L to be added to solid culture base table with liquid-transfering gun
Face, and be coated with uniform.The garden filter paper impregnated is taken to be taped against media surface with aseptic nipper.Each plate puts 4, carries out 3
Secondary parallel laboratory test, wherein a piece of carry out blank control.The plate for being placed with tablet is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, observation
Phenomenon.It, can by measurement antibacterial circle diameter by occurring different size of transparent ring-inhibition zone on agar medium respectively
To find out the bacteriostatic activity size of each sample.
Embodiment 19
Cytotoxicity detection
Influence of the target compound of various concentration to human fibroblasts survival rate is detected by CCK-8 method, as a result table
Bright, the target compound of various concentration is respectively with cell co-culture, and each concentration group is compared with negative control group compared with difference is without system
Meter learns meaning, and target compound has safety to human fibroblasts.
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 (8)
1. a kind of preparation method of the isoquinolin drug molecule with antibacterial activity, it is characterised in that specific steps are as follows:
Step (1), dimethyl malenate and N,N-dimethylformamide dimethylacetal first occur after condensation reaction again with benzylamine
Substitution reaction occurs and obtains 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene；
Step (2), 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene obtain 2,3- through itself cyclization under calcium hydride effect
Dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester；
Step (3), 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester slough a molecule formic acid first under copper catalyst effect
Ester obtains 1,2- dihydro-isoquinoline -4- methyl formate；
Step (4), 1,2- dihydro-isoquinoline -4- methyl formate take under chlorination reagent effect with N,N-dimethylformamide
Generation reaction obtains 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate；
Step (5), 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate obtain 1,2- dihydro-isoquinoline -3- formaldehyde through hydrolysis
Base -4- formic acid；
Step (6), 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid and carbamide compounds occur annulation and obtain targeted
Close object；
In step (6): carbamide compounds are urea or thiocarbamide.
2. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (1) are as follows: N,N-dimethylformamide dimethylacetal is added drop-wise under room temperature and inert gas shielding
Keep being stirred at room temperature reaction in dimethyl malenate, after dripping to raw material disappearance；It is cooled to 10~15 DEG C of interior temperature, is added dropwise certain
Benzylamine is measured, solution heating can be observed during being added dropwise, temperature is added at 30 DEG C or less in holding；It is cooled to 10~15 again
DEG C, visible a large amount of solids are precipitated after stirring a period of time, methyl tertiary butyl ether(MTBE) are added, being slowly stirred makes solid suspend, after filtering
Filter cake is washed with methyl tertiary butyl ether(MTBE), obtains solid 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene；Mother liquor concentrations, again
Solid, filtering is precipitated, filter cake is washed three times with methyl tertiary butyl ether(MTBE) again, obtains solid 1,1- dicarboxylic acid methyl ester base vinyl amine
Ylmethyl benzene；The inventory molar ratio of the N,N-dimethylformamide dimethylacetal and dimethyl malenate is 1:1；Institute
The reaction temperature of the N,N-dimethylformamide dimethylacetal and dimethyl malenate stated is 15~30 DEG C；The N, N- bis-
The inventory molar ratio of methylformamide dimethylacetal and benzylamine is 1:0.8~1.1.
3. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (2) are as follows: 1,1- dicarboxylic acid methyl ester base vinyl amine ylmethyl benzene and calcium hydride are added to Non-aqueous processing
Methylene chloride in, be heated to flowing back under nitrogen protection, TLC monitor raw material fully reacting after, filtering reacting liquid, be concentrated filtrate
By isolated 2,3- dihydro-isoquinoline -4,4 (the 1H)-dicarboxylic acid methyl ester of silica gel column chromatography, column chromatographic eluate is V petroleum
Ether: V ethyl acetate is 2:1；The inventory mole of 1,1- dicarboxylic acid methyl ester base the vinyl amine ylmethyl benzene and calcium hydride
Than for 1:3~5.
4. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (3) are as follows: 2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester is added in dimethyl sulfoxide, then plus
Enter copper catalyst, in 120 DEG C of heating reactions to raw material fully reacting, filtering reacting liquid adds methylene chloride extraction reaction solution
Repeatedly, merge organic phase after be washed with water after be concentrated, then in the mixed liquor of acetone and n-hexane in be recrystallized to give 1,2-
V acetone in the mixed liquor of dihydro-isoquinoline -4- methyl formate, acetone and n-hexane: V n-hexane=3:1；The copper catalyst
For copper bromide, cupric iodide, copper sulphate；2,3- dihydro-isoquinoline -4,4 (1H)-dicarboxylic acid methyl ester and copper catalyst throwing
Doses molar ratio is 1:0.1~0.3.
5. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (4) are as follows: 1,2- dihydro-isoquinoline -4- methyl formate is added to methylene chloride and N, N- dimethyl formyl
In amine, chlorinated compound is added at room temperature, after being heated to back flow reaction to raw material fully reacting, is down to room temperature, filters
Reaction solution, filtrate are added the sodium acetate solution of saturation, stir evenly filtering reacting liquid, concentration of reaction solution obtains 1,2- bis- after washing
Hydrogen isoquinoline -3- carboxaldehyde radicals -4- methyl formate；1,2- dihydro-isoquinoline -4- the methyl formate and N, N- dimethyl formyl
The inventory molar ratio of amine and chlorinated compound is 1:2~5:2~5；The chlorinated compound is phosphorus oxychloride, tribromide
Phosphorus, hydrobromic acid.
6. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (5) are as follows: 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- methyl formate is added in tetrahydrofuran, is added
Lithium hydroxide is heated to flowing back, and is down to room temperature after reacting a period of time, and adjusting reaction solution pH with dilute hydrochloric acid is 3~4, stirred
The a large amount of solids of Cheng Zhongyou are precipitated, and filter reaction solution, obtain 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid after filter cake drying.
7. the preparation method of the isoquinolin drug molecule according to claim 1 with antibacterial activity, it is characterised in that:
The detailed process of step (6) are as follows: 1,2- dihydro-isoquinoline -3- carboxaldehyde radicals -4- formic acid is added in n,N-Dimethylformamide, then
Potassium carbonate and urea or thiocarbamide is added, to raw material fully reacting, filtering reacting liquid adds dichloro for heating reaction at a certain temperature
Methane extract reaction solution it is multiple, merge organic phase after be washed with water after be concentrated, then in the mixed liquor of acetone and n-hexane in
V acetone in the mixed liquor of recrystallization, acetone and n-hexane: V n-hexane=3:1 obtainsInstitute
The reaction temperature stated is 80~150 DEG C.
8. a kind of isoquinolin drug molecule with antibacterial activity as described in claim 1 is in preparing anti-bacterial drug
Using.
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