CN108264488A - A kind of preparation method for replacing phthalazone class compound - Google Patents
A kind of preparation method for replacing phthalazone class compound Download PDFInfo
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- CN108264488A CN108264488A CN201810150518.1A CN201810150518A CN108264488A CN 108264488 A CN108264488 A CN 108264488A CN 201810150518 A CN201810150518 A CN 201810150518A CN 108264488 A CN108264488 A CN 108264488A
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- hydrazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- 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
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention provides a kind of preparation method for replacing 2,3 benzodiazine ketone compounds, step is：(1) substitution hydrazine and substitution 2-carboxybenzaldehyde are added in reaction vessel, reaction temperature control carries out insulation reaction under 50 DEG C 150 DEG C, mechanical mixture；(2) TLC or gas phase monitoring reaction, after reaction, into reaction system plus precipitation agent, stirring 0.5 1.0 hours are stood, and filtering obtains solid crystal, as replaces 2,3 benzodiazine ketone compounds；The preparation method is from raw material cheap and easy to get, a series of substitutions 2 with high bioactivity are efficiently prepared with 90% 99% yield by one kettle way in the molten state, 3 benzodiazine ketone compounds, this method wide application range of substrates, catalyst is not added, without using solvent, mild condition, reaction time shortens more than 95% compared with catalysis preparation method under the conditions of conventional solvent, and product purity is high.
Description
Technical field
The present invention relates to a kind of preparation method of compound, especially a kind of substitution 2,3- benzodiazine ketone compounds
Preparation method.
Background technology
Substitution 2,3- benzodiazine ketone compounds are a kind of heterocycle structures with important biomolecule medicinal activity, be can be used for
The treatment of the diseases such as diabetes, hepatitis B, hypertension, asthma, cardiac arrhythmia and the anticancer drug vascular endothelial cell factor
(VEGF), the Medicines material such as antiseptic Poly adenosine diphosphate-ribose polymerase-1 inhibitor, inhibitors of phosphodiesterase-4
Core active segment, product antiallergy, antihistamine drug " azelastine " have been enter into finished medicines market, sale in 2008 downstream
Volume has huge basic research and industrialization value up to 2.4 hundred million dollars.
Preparation method is mainly [4+2] or [3+2+1] cyclic condensation under catalytic condition in solvent in document and patent at present
Reaction, used catalyst include nano-TiO2, palladium catalyst, platinum catalyst, heteropoly acid, HClO4-SiO2, solid acid, montmorillonite
K-10 etc., for these methods using a large amount of organic solvents and all kinds of expensive and severe toxicity catalyst, it is small that the reaction time is up to 16~24
When more than, need the extreme reaction condition such as highly acid, strong basicity, high temperature, byproduct of reaction is more, and post processing is complicated, product purity
It is low, cause great environmental pollution, energy consumption and chemical resource waste.More seriously, made due to metallic catalyst
With even across stringent post processing, micro hypertoxic heavy metal pollution can be still contained in product, significantly impact it active former
Expect the application of the preparation fields such as medicine (API) and biological agent.
Patent CN102485721A reports a kind of preparation method of substituted 2,3- benzodiazine ketone compounds, this method
To replace phthalic anhydride as raw material, sodium borohydride, organic phosphorus catalyst, organic base etc. are added in DMF solvent, through 4 steps
Phthalazone nuclear structure is obtained by the reaction, reaction condition and post processing are extremely complex, and manufacturing cost is high, without practical valency
Value, patent CN1538960A (WO2003/014090), CN1555366A (WO2003/024938), CN103709162A are also used
Similar approach.Patent CN103910726A is using 4- amino -3- haloperidids as raw material, in alcohols or benzene kind solvent, in palladium
Under the conditions of catalyst, one kind 1,6- bis- is prepared for by series reactions such as iodo, heck couplings, intramolecular amine transesterifications
Azanaphthalene -2 (1H) -one isomers, solvent used in this method and catalyst can cause great environmental pollution, and prepare
Complicated condition.Patent CN101027290A (WO2006/032518), CN101163681A (WO2006/115221),
CN101410391A (WO2007/107298), CN102731782A, CN103172619A etc. are with existing phthalazone
Parent nucleus is completed derivatization for raw material and is prepared, and object construction is used to active medicaments compound, but for the side of mother nucleus structure preparation
Method is inquired into less.
Based on many defects and problem present in preparation process in existing patent and document, exploitation it is a kind of it is environmentally protective,
It is prepared by the green of the strong substitution phthalazone class compound of high-efficient simple, the pollution of product heavy metal free, Atom economy
Method has highly important production practices meaning.
Invention content
The technical problems to be solved by the invention are to provide a kind of preparation for replacing phthalazone class compound
Method.
In order to solve the above technical problems, the technical scheme is that：
A kind of preparation method for replacing 2,3- benzodiazine ketone compounds, is as follows：
(1) substitution hydrazine and substitution 2-carboxybenzaldehyde are added in reaction vessel, reaction temperature control is at 50 DEG C -150 DEG C, machine
Tool mixing is lower to carry out insulation reaction；
(2) TLC or gas phase monitoring reaction, after reaction, precipitation agent are added into reaction system, stirred 0.5-1.0 hours,
It stands, filtering obtains solid crystal, as replaces 2,3- benzodiazine ketone compounds；The substitution phthalazone has
Formula (I) described structural formula,
Wherein, R1For hydrogen, C1-C12 alkyl, hydroxy alkyl, phenyl, halogenophenyl, nitrobenzophenone, alkyl phenyl, alcoxyl
Base phenyl, pyridyl group, pyrazinyl, pyridazinyl, pyrimidine radicals, furyl, thienyl, pyrrole radicals, thiazolyl, imidazole radicals；
R2For hydrogen, halogen, C1-C12 alkyl, C1-C12 alkoxies, nitro.
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, substitution 2, the 3- benzodiazines
Ketone compounds are following compound：
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, the middle substitution hydrazine of the step (1) are
Phenylhydrazine, hydrazine, methyl hydrazine, ethyl hydrazine, isopropyl hydrazine, tertiary butyl hydrazine, hydroxymethyl hydrazine, hydroxyethyl hydrazine, adjacent chlorophenyl hydrazine, chlorobenzene
Hydrazine, to chlorophenyl hydrazine, adjacent fluorine phenylhydrazine, fluorine phenylhydrazine, to fluorine phenylhydrazine, bromophenyl hydrazine, bromophenyl-hydrazine, para-bromophenyl-hydrazine, O-Nitrophenylfluorone,
M-nitro base, paranitrophenylhydrazine, O-methoxy phenylhydrazine, meta-methoxy phenylhydrazine, to methoxyl group phenylhydrazine, o-methyl-benzene hydrazine, first
Base phenylhydrazine, to procarbazine, diethyl phenylhydrazine, pyridyl group hydrazine, pyrazinyl hydrazine, thienyl hydrazine, furyl hydrazine or thiazolyl hydrazine.
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, the adjacent carboxylic of the middle substitution of the step (1)
Benzaldehyde for 2-carboxybenzaldehyde, 3- methoxyl group -2- carboxyl benzaldehydes, 4- methoxyl group -2- carboxyl benzaldehydes, 5- methoxyl groups -
2- carboxyl benzaldehydes, 6- methoxyl group -2- carboxyl benzaldehydes, 3,4- dimethoxy -2- carboxyl benzaldehydes, 3- methyl -2- carboxyl benzene
Formaldehyde, 4- methyl -2- carboxyl benzaldehydes, 5- methyl -2- carboxyl benzaldehydes, 6- methyl -2- carboxyl benzaldehydes, 5,6- dimethyl -
2- carboxyl benzaldehydes, 3- ethyl -2- carboxyl benzaldehydes, 4- ethyl -2- carboxyl benzaldehydes, 5- ethyl -2- carboxyl benzaldehydes, 6- second
Base -2- carboxyl benzaldehydes, 3- propyl -2- carboxyl benzaldehydes, 4- propyl -2- carboxyl benzaldehydes, 5- propyl -2- carboxyl benzaldehydes,
6- propyl -2- carboxyl benzaldehydes, 3- butyl -2- carboxyl benzaldehydes, 4- butyl -2- carboxyl benzaldehydes, 5- butyl -2- carboxyl benzene first
Aldehyde, 6- butyl -2- carboxyl benzaldehydes, the chloro- 2- carboxyl benzaldehydes of 3-, the chloro- 2- carboxyl benzaldehydes of 4-, the chloro- 2- carboxyl benzaldehydes of 5-,
The chloro- 2- carboxyl benzaldehydes of 6-, the fluoro- 2- carboxyl benzaldehydes of 3-, the fluoro- 2- carboxyl benzaldehydes of 4-, the fluoro- 2- carboxyl benzaldehydes of 5-, 6- are fluoro-
The bromo- 2- carboxyl benzaldehydes of 2- carboxyl benzaldehydes, 3-, the bromo- 2- carboxyl benzaldehydes of 4-, the bromo- 2- carboxyl benzaldehydes of 5-, the bromo- 2- carboxylics of 6-
Benzaldehyde, 3- nitro -2- carboxyl benzaldehydes, 4- nitro -2- carboxyl benzaldehydes, 5- nitro -2- carboxyl benzaldehydes or 6- nitros -
2- carboxyl benzaldehydes.
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, in the step (1) substitution hydrazine with
The molar ratio for replacing 2-carboxybenzaldehyde is 0.6-1.5:1.
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, reaction vessel in the step (1)
It is reaction kettle, mill, round-bottomed flask, mortar etc. according to substrate state and quantity, mechanical mixture is according to substrate state and quantity
For mechanical agitation, grinding etc..
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, soaking time in the step (1)
It is 10-300 minutes.
Preferably, above-mentioned substitution 2, the preparation method of 3- benzodiazine ketone compounds, precipitation agent is in the step (2)
Water, methanol, ethyl alcohol, isopropanol, ethylene glycol one or more combination.
The process route of the preparation method of above-mentioned substitution phthalazone class compound is as follows：
The beneficial effects of the invention are as follows：
The preparation method of substitution 2, the 3- benzodiazine ketone compounds, the green preparation side for no catalyst or solvent
From raw material cheap and easy to get, a system is efficiently prepared by one kettle way with the yield of 90%-99% in the molten state for method
Substitution 2 of the row with high bioactivity, 3- benzodiazine ketone compounds, this method wide application range of substrates do not add catalysis
Agent, without using solvent, mild condition, the reaction time shortens more than 95% compared with preparation method is catalyzed under the conditions of conventional solvent, production
Product very high purity is all kinds of reaction shapes such as " Liquid-liquids ", " liquid-solid " and " solid phase-solid phase " suitable for substrate state
State has the advantages such as easy to operate, clean and effective, chemical specialty are strong, post processing is convenient, product is completely eliminated from root
Middle heavy metal pollution problem, Atom economy is strong, especially suitable for preparations such as activated feedstock medicine (API) and biological agents, has
Extremely strong pollution-free industryization value.
Description of the drawings
Fig. 1-1 is the nuclear magnetic resonance of target compound 11H spectrograms.
Fig. 1-2 is the nuclear magnetic resonance of target compound 113C spectrograms.
Fig. 2-1 is the nuclear magnetic resonance of target compound 21H spectrograms.
Fig. 2-2 is the nuclear magnetic resonance of target compound 213C spectrograms.
Fig. 3-1 is the nuclear magnetic resonance of target compound 31H spectrograms.
Fig. 3-2 is the nuclear magnetic resonance of target compound 313C spectrograms.
Fig. 4-1 is the nuclear magnetic resonance of target compound 41H spectrograms.
Fig. 4-2 is the nuclear magnetic resonance of target compound 413C spectrograms.
Fig. 5-1 is the nuclear magnetic resonance of target compound 51H spectrograms.
Fig. 5-2 is the nuclear magnetic resonance of target compound 513C spectrograms.
Fig. 6-1 is the nuclear magnetic resonance of target compound 61H spectrograms.
Fig. 6-2 is the nuclear magnetic resonance of target compound 613C spectrograms.
Fig. 7-1 is the nuclear magnetic resonance of target compound 71H spectrograms.
Fig. 7-2 is the nuclear magnetic resonance of target compound 713C spectrograms.
Fig. 8-1 is the nuclear magnetic resonance of target compound 81H spectrograms.
Fig. 8-2 is the nuclear magnetic resonance of target compound 813C spectrograms.
Fig. 9-1 is the nuclear magnetic resonance of target compound 91H spectrograms.
Fig. 9-2 is the nuclear magnetic resonance of target compound 913C spectrograms.
Figure 10-1 is the nuclear magnetic resonance of target compound 101H spectrograms.
Figure 10-2 is the nuclear magnetic resonance of target compound 1013C spectrograms.
Figure 11-1 is the nuclear magnetic resonance of target compound 111H spectrograms.
Figure 11-2 is the nuclear magnetic resonance of target compound 1113C spectrograms.
Figure 12-1 is the nuclear magnetic resonance of target compound 121H spectrograms.
Figure 12-2 is the nuclear magnetic resonance of target compound 1213C spectrograms.
Figure 13-1 is the nuclear magnetic resonance of target compound 131H spectrograms.
Figure 13-2 is the nuclear magnetic resonance of target compound 1313C spectrograms.
Figure 14-1 is the nuclear magnetic resonance of target compound 141H spectrograms.
Figure 14-2 is the nuclear magnetic resonance of target compound 1413C spectrograms.
Specific embodiment
With reference to embodiment, the present invention is further described, but embodiment does not limit the scope of the invention.
Embodiment 1
1.08kg (10mol) phenylhydrazine, 1.5kg (10mol) 2-carboxybenzaldehyde are added in 5L reaction kettles, are heated to 80
DEG C, insulation reaction 25 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, and after reaction, 1L first are added in into reaction system
Alcohol and 0.5L ethylene glycol stir 0.5 hour, stand, and filtering obtains 2.13kg pale-orange crystals, i.e. target compound 1, yield
It is 95.76%.As shown in Fig. 1-1 and 1-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,ppm)δ:8.52
(dd, J=7.6,0.9Hz, 1H, ArH), 8.30 (s, 1H, CH=N), 7.89-7.78 (m, 2H, ArH), 7.78-7.72 (m, 1H,
ArH),7.70–7.63(m,2H,ArH),7.54–7.48(m,2HArH),7.45–7.36(m,1H,ArH)；13C NMR
(100MHz,CDCl3-d1,ppm):δ:159.17,141.95,138.50,133.51,131.99,129.50,128.78,
128.55,127.76,127.25,127.21,126.18,125.75.Mass spectrometric data is：HRMS(ESI-MS)calcd for
C14H11N2O[M+H]+223.0871,found 223.0879。
Embodiment 2
625g (10mol) hydrazine, 1.88kg (12.5mol) 2-carboxybenzaldehyde are added in 5L reaction kettles, are heated to 95
DEG C, insulation reaction 40 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, and after reaction, 0.5L are added in into reaction system
Ethyl alcohol and 0.5L ethylene glycol stir 0.5 hour, stand, and filtering obtains 1.41kg light yellow crystals, i.e. target compound 2, receives
Rate is 96.36%.As shown in Fig. 2-1 and 2-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,ppm)δ:
11.33 (s, 1H, NH), 8.47 (d, J=7.8Hz, 1H, ArH), 8.23 (s, 1H, CH=N), 7.91-7.78 (m, 2H, ArH),
7.75 (d, J=7.6Hz, 1H, ArH)；13C NMR(100MHz,DMSO-d6,ppm)δ:160.10,138.69,134.08,
132.23,130.39,128.01,127.19,125.82.Mass spectrometric data is：HRMS(ESI-MS)calcd for C8H7N2O[M+
H]+147.0558,found 147.0562。
Embodiment 3
1.15kg (10mol) methyl hydrazine, 1.5kg (10mol) 2-carboxybenzaldehyde are added in 5L reaction kettles, are heated to
110 DEG C, insulation reaction 150 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, and after reaction, are added in into reaction system
1L isopropanols stir 0.8 hour, stand, and filtering obtains 1.52kg light yellow crystals, i.e. target compound 3, yield is
95.13%.As shown in Fig. 3-1 and 3-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,ppm)δ:8.46–
8.41 (m, 1H), 8.15 (s, 1H), 7.79 (pd, J=7.2,1.5Hz, 2H), 7.72-7.68 (m, 1H), 3.87 (s, 3H)；13C
NMR(100MHz,CDCl3-d1,ppm)δ:159.63,137.55,132.93,131.59,129.76,127.72,126.46,
125.96,39.39.Mass spectrometric data is：HRMS(ESI-MS)calcd for C9H9N2O[M+H]+161.0715,found
161.0723。
Embodiment 4
750g (10mol) isopropyls hydrazine, 2.25kg (15mol) 2-carboxybenzaldehyde are added in 5L reaction kettles, heated
To 70 DEG C, insulation reaction 60 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, and after reaction, are added in into reaction system
0.5L ethyl alcohol and 0.5L isopropanols stir 0.5 hour, stand, and extraction obtains the orange oily liquids of 1.87kg, i.e. target chemical combination
Object 4, yield 98.76%.As shown in Fig. 4-1 and 4-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,
ppm)δ:8.45 (d, J=7.7Hz, 1H, PhH), 8.22 (s, 1H, N=CH), 7.78 (tt, J=15.2,3.7Hz, 2H, PhH),
7.69 (d, J=8.0Hz, 1H, PhH), 5.45 (dt, J=13.3,6.6Hz, 1H, PhH), 1.41 (d, J=6.7Hz, 6H,
CH3)；13C NMR(101MHz,CDCl3-d1,ppm)δ:158.89,137.54,137.51,132.88,131.36,129.29,
127.85,126.80,125.76,48.41,21.05.Mass spectrometric data is：HRMS(ESI-MS)calcd for C11H13N2O[M+
H]+189.1028,found 189.1029。
Embodiment 5
890g (10mol) tertiary butyl hydrazine, 1.95kg (13mol) 2-carboxybenzaldehyde are added in 5L reaction kettles, heated
To 110 DEG C, insulation reaction 30 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, and after reaction, are added into reaction system
Enter 1L methanol and 0.5L isopropanols, stir 0.6 hour, stand, extraction obtains the orange oily liquids of 1.98kg, i.e. target chemical combination
Object 5, yield 97.25%.As shown in Fig. 5-1 and 5-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,
ppm)δ:8.41 (d, J=7.7Hz, 1H, PhH), 8.11 (s, 1H, N=CH), 7.75 (ddd, J=17.4,11.1,4.1Hz,
2H, PhH), 7.65 (d, J=7.7Hz, 1H, PhH), 1.72 (s, 9H, CH3)；13C NMR(100MHz,CDCl3-d1,ppm)δ:
160.01,135.62,132.69,131.04,129.37,129.28,126.57,125.23,64.19,28.31.Mass spectrometric data
For：HRMS(ESI-MS)calcd for C12H15N2O[M+H]+203.1184,found 203.1187。
Embodiment 6
1.52g (20mmol) hydroxyethyls hydrazine, 3.15g (21mmol) 2-carboxybenzaldehyde are added to 10mL single neck round bottom
In flask, 125 DEG C are heated to, insulation reaction 80 minutes under mechanical agitation, TLC or gas phase monitoring reaction, after reaction, to anti-
It answers and 1mL ethyl alcohol and 2mL ethylene glycol is added in system, stir 0.5 hour, stand, filtering obtains 3.67g white solids, i.e. target
Compound 6, yield 96.71%.As shown in Fig. 6-1 and 6-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-
d1,ppm)δ:8.43 (dd, J=7.6,1.0Hz, 1H, PhH), 8.21 (s, 1H, N=CH), 7.87-7.77 (m, 2H, PhH),
7.74–7.70(m,1H,PhH),4.50–4.43(m,2H,CH2),4.10–4.05(m,2H,CH2),3.26(s,1H,OH)；13C
NMR(100MHz,CDCl3-d1,ppm)δ:160.42,138.31,133.32,131.89,129.56,127.70,126.67,
126.10,61.68,53.93.Mass spectrometric data is：HRMS(ESI-MS)calcd for C10H11N2O2[M+H]+191.0821,
found 198.0823。
Embodiment 7
The adjacent chlorophenyl hydrazines of 2.85g (20mmol), 3.00g (20mmol) 2-carboxybenzaldehyde are added to 10mL single neck round bottom and burnt
In bottle, 85 DEG C are heated to, insulation reaction 55 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, after reaction, to reaction
3mL methanol and 1mL ethyl alcohol are added in system, is stirred 0.7 hour, is stood, filtering obtains 4.23g orange solids, i.e. target chemical combination
Object 7, yield 82.42%.As shown in Fig. 7-1 and 7-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,
ppm)δ:8.85 (s, 1H, N=CH), 8.37 (s, 1H, PhH), 8.27 (d, J=7.9Hz, 1H, PhH), 8.13 (d, J=
7.9Hz, 1H, PhH), 7.64 (dd, J=15.4,8.1Hz, 2H, PhH), 7.45 (dd, J=11.1,4.2Hz, 1H, PhH),
7.36-7.30 (m, 1H, PhH), 6.85 (dd, J=10.9,4.4Hz, 1H, PhH)；13C NMR(100MHz,CDCl3-d1,ppm)
δ:171.97,140.31,138.01,136.77,133.15,131.68,129.23,128.27,127.95,127.15,
126.47,120.41,117.20,114.30.Mass spectrometric data is：HRMS(ESI-MS)calcd for C14H10ClN2O[M+H]+
257.0482,found 257.0494。
Embodiment 8
Chlorophenyl hydrazine, 3.00g (20mmol) 2-carboxybenzaldehyde between 2.85g (20mmol) are added to 10mL single neck round bottom to burn
In bottle, 105 DEG C are heated to, insulation reaction 75 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, after reaction, to reaction
3mL ethyl alcohol is added in system, is stirred 0.5 hour, is stood, filtering obtains 4.69g orange solids, i.e. target compound 8, yield
It is 91.53%.As shown in Fig. 8-1 and 8-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,ppm)δ:8.51
(d, J=7.6Hz, 1H, PhH), 8.30 (s, 1H, N=CH), 7.92-7.81 (m, 2H, PhH), 7.80-7.71 (m, 2H, PhH),
7.63 (d, J=7.9Hz, 1H, PhH), 7.43 (t, J=8.0Hz, 1H, PhH), 7.36 (d, J=8.0Hz, 1H, PhH)；13C
NMR(100MHz,CDCl3-d1,ppm)δ:159.09,142.82,138.85,134.30,133.75,132.22,129.65,
129.41,128.46,127.82,127.35,126.27,126.00,123.83.Mass spectrometric data is：HRMS(ESI-MS)
calcdfor C14H10ClN2O[M+H]+257.0482,found 257.0483。
Embodiment 9
2.99g (21mmol) is added to chlorophenyl hydrazine, 2.40g (16mmol) 2-carboxybenzaldehyde to 10mL single neck round bottom burning
In bottle, 88 DEG C are heated to, insulation reaction 20 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, after reaction, to reaction
1mL ethyl alcohol and 1mL isopropanols are added in system, is stirred 0.7 hour, is stood, filtering obtains 4.79g orange solids, i.e. targeted
Close object 9, yield 93.45%.As shown in figs. 9-1 and 9-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,
ppm)δ:8.56-8.47 (m, 1H, PhH), 8.30 (s, 1H, CH=N), 7.86 (dqd, J=14.8,7.3,1.4Hz, 2H,
), PhH 7.79-7.71 (m, 2H, PhH), 7.63 (ddd, J=8.0,1.9,1.2Hz, 1H, PhH), 7.43 (t, J=8.0Hz,
1H, PhH), 7.36 (ddd, J=8.0,1.8,1.2Hz, 1H, PhH)；13C NMR(100MHz,CDCl3-d1)δ:159.08,
142.83,138.84,134.28,133.75,132.21,129.64,129.40,128.45,127.80,127.33,126.27,
125.98,123.82.Mass spectrometric data is：HRMS(ESI-MS)calcd for C14H10ClN2O[M+H]+257.0482,found
257.0485。
Embodiment 10
2.52g (20mmol) is added to fluorine phenylhydrazine, 2.70g (18mmol) 2-carboxybenzaldehyde to 10mL single neck round bottom burning
In bottle, 126 DEG C are heated to, insulation reaction 15 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, after reaction, to reaction
2mL ethyl alcohol and 2mL ethylene glycol are added in system, is stirred 0.5 hour, is stood, filtering obtains 4.43g white solids, i.e. targeted
Close object 10, yield 92.27%.As shown in figs. 10-1 and 10-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-
d1,ppm)δ:8.53-8.49 (m, 1H, PhH), 8.29 (s, 1H, N=CH), 7.85 (dqd, J=14.8,7.3,1.4Hz, 2H,
), PhH 7.77 (dd, J=7.6,1.0Hz, 1H, PhH), 7.68-7.61 (m, 2H, PhH), 7.22-7.14 (m, 2H, PhH)；13C
NMR(100MHz,CDCl3-d1,ppm)δ:162.92,160.46,159.22,138.64,137.91,137.88,133.64,
132.14,129.49,128.45,127.60,127.51,127.26,126.24,115.74,115.51.Mass spectrometric data is：
HRMS(ESI-MS)calcd for C14H9FN2O[M+H]+=241.07717, found=241.07714.
Embodiment 11
3.06g (20mmol) paranitrophenylhydrazine, 2.85g (19mmol) 2-carboxybenzaldehyde are added to 10mL single neck round bottom
In flask, 75 DEG C are heated to, insulation reaction 85 minutes under mechanical agitation, TLC or gas phase monitoring reaction, after reaction, to anti-
It answers and 1mL methanol and 2mL ethylene glycol is added in system, stir 0.6 hour, stand, filtering obtains 4.71g white solids, i.e. target
Compound 11, yield 88.32%.As shown in Figure 11-1 and 11-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,
CDCl3-d1,ppm)δ:8.53 (d, J=7.7Hz, 1H, ArH), 8.39-8.36 (m, 1H, CH=N), 8.35 (t, J=2.3Hz,
2H, ArH), 8.06-8.03 (m, 1H, ArH), 8.02-8.00 (m, 1H, ArH), 7.89 (dqd, J=14.9,7.4,1.4Hz,
2H,ArH),7.81–7.78(m,1H,ArH)；13C NMR(100MHz,CDCl3-d1,ppm)δ:159.17,146.93,
146.15,139.54,134.13,132.53,129.26,128.36,127.51,126.43,125.78,124.07.Spectra count
According to for：HRMS(ESI-MS)calcd for C10H10N3O3[M+H]+268.0722,found 268.0723。
Embodiment 12
3.17g (20mmol) is added to procarbazine, 3.23g (21.5mmol) 2-carboxybenzaldehyde to 10mL single port circle
In the flask of bottom, 80 DEG C are heated to, insulation reaction 240 minutes under mechanical agitation, TLC or gas phase monitoring are reacted, after reaction, to
3mL methanol and 1mL ethyl alcohol are added in reaction system, is stirred 0.5 hour, is stood, filtering obtains 5.45g orange solids, i.e. target
Compound 12, yield 88.32%.As shown in Figure 12-1 and 12-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,
CDCl3-d1,ppm)δ:8.54-8.47 (m, 1H, ArH), 8.28 (s, 1H, CH=N), 7.88-7.77 (m, 2H, ArH), 7.76-
7.71 (m, 1H, ArH), 7.56-7.48 (m, 2H, ArH), 7.30 (d, J=8.2Hz, 2H, ArH), 2.41 (s, 3H, CH3)；13C
NMR(100MHz,CDCl3-d1,ppm)δ:159.09,142.82,138.85,134.29,133.75,132.21,129.64,
129.41,128.45,127.81,127.34,126.27,125.99,123.82,20.08.Mass spectrometric data is：HRMS(ESI-
MS)calcd for C15H13N2O[M+H]+237.1028,found 237.1031。
Embodiment 13
2.40g (22mmol) pyridyl groups hydrazine, 3.00g (20mmol) 2-carboxybenzaldehyde are added in mortar, are heated to
115 DEG C, grind lower insulation reaction 65 minutes, TLC or gas phase monitoring reaction after reaction, it is different that 2mL are added in into reaction system
Propyl alcohol stirs 0.5 hour, stands, and filtering obtains 4.05g white solids, i.e. target compound 13, yield 90.76%.Such as
Shown in Figure 13-1 and 13-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,DMSO-d6,ppm)δ:8.75 (s, 1H, N=
), CH 8.15-8.04 (m, 2H, PhH), 7.86-7.80 (m, 1H, PhH), 7.68-7.61 (m, 1H, PhH), 7.58 (t, J=
7.3Hz, 1H, PhH), 7.41 (dd, J=10.9,4.2Hz, 1H, PhH), 7.26 (d, J=8.4Hz, 1H, PhH), 6.78 (dd, J
=6.4,5.1Hz, 1H, PhH)；13C NMR(100MHz,DMSO-d6,ppm)δ:168.98,157.46,148.20,138.39,
138.03,135.93,132.07,130.55,130.09,128.44,126.39,115.60,107.01.Mass spectrometric data is：
HRMS(ESI-MS)calcd for C13H10N3O[M+H]+224.0824,found 224.0826。
Embodiment 14
1.15kg (10.5mol) phenylhydrazine, 2.21kg (10.5mmol) 3,4- dimethoxy -2- carboxyl benzaldehydes are added to
In 5L mills, it is heated to 80 DEG C, grinds lower insulation reaction 250 minutes, TLC or gas phase monitoring reaction, after reaction, to anti-
Addition 1L ethyl alcohol in system to be answered, is stirred 0.6 hour, is stood, filtering obtains the orange-yellow crystal of 2.42kg, i.e. target compound 14,
Yield is 85.76%.As shown in Figure 14-1 and 14-2, nuclear magnetic resonance modal data is：1H NMR(400MHz,CDCl3-d1,ppm)
δ:8.11 (s, 1H, N=CH), 7.63 (d, J=7.7Hz, 2H, PhH), 7.52-7.43 (m, 4H, PhH), 7.36 (t, J=
7.4Hz, 1H, PhH), 4.00 (d, J=6.1Hz, 6H, OCH3)；13C NMR(100MHz,CDCl3-d1,ppm)δ:157.45,
155.91,149.12,142.14,137.97,128.70,127.56,126.09,124.73,123.14,122.72,118.40,
61.92,56.55.Mass spectrometric data is：HRMS(ESI-MS)calcd for C16H15N2O3[M+H]+283.1083,found
283.1085。
Each target compound corresponds to structural formula of compound and see the table below 1 in above-described embodiment 1-14.
Table 1
Above-mentioned reference embodiment carries out a kind of preparation method of substitution phthalazone class compound detailed
Description, is illustrative rather than limited, several embodiments can be enumerated according to limited range, therefore do not departing from
Change and modification under present general inventive concept should belong within protection scope of the present invention.
Claims (8)
1. a kind of preparation method for replacing 2,3- benzodiazine ketone compounds, it is characterised in that：It is as follows：
(1) substitution hydrazine and substitution 2-carboxybenzaldehyde are added in reaction vessel, reaction temperature is controlled at 50 DEG C -150 DEG C, and machinery is mixed
Close lower progress insulation reaction；
(2) TLC or gas phase monitoring reaction, after reaction, into reaction system plus precipitation agent, stirring 0.5-1.0 hours are quiet
It puts, filters, obtain solid crystal, as replace 2,3- benzodiazine ketone compounds；The substitution phthalazone has formula
(I) structural formula,
Wherein, R1For hydrogen, C1-C12 alkyl, hydroxy alkyl, phenyl, halogenophenyl, nitrobenzophenone, alkyl phenyl, alkoxy benzene
Base, pyridyl group, pyrazinyl, pyridazinyl, pyrimidine radicals, furyl, thienyl, pyrrole radicals, thiazolyl, imidazole radicals；
R2For hydrogen, halogen, C1-C12 alkyl, C1-C12 alkoxies, nitro.
2. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
It is following compound to replace phthalazone class compound：
3. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Substitution hydrazine is phenylhydrazine, hydrazine, methyl hydrazine, ethyl hydrazine, isopropyl hydrazine, tertiary butyl hydrazine, hydroxymethyl hydrazine, hydroxyethyl in step (1)
Hydrazine, adjacent chlorophenyl hydrazine, chlorophenyl hydrazine, to chlorophenyl hydrazine, adjacent fluorine phenylhydrazine, fluorine phenylhydrazine, to fluorine phenylhydrazine, bromophenyl hydrazine, bromophenyl-hydrazine, right
Bromophenyl-hydrazine, O-Nitrophenylfluorone, m-nitro base, paranitrophenylhydrazine, O-methoxy phenylhydrazine, meta-methoxy phenylhydrazine, to methoxybenzene
Hydrazine, o-methyl-benzene hydrazine, procarbazine, to procarbazine, diethyl phenylhydrazine, pyridyl group hydrazine, pyrazinyl hydrazine, thienyl hydrazine,
Furyl hydrazine or thiazolyl hydrazine.
4. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Substitution 2-carboxybenzaldehyde is 2-carboxybenzaldehyde, 3- methoxyl group -2- carboxyl benzaldehydes, 4- methoxyl group -2- carboxyls in step (1)
Benzaldehyde, 5- methoxyl group -2- carboxyl benzaldehydes, 6- methoxyl group -2- carboxyl benzaldehydes, 3,4- dimethoxy -2- carboxyl benzaldehydes,
3- methyl -2- carboxyl benzaldehydes, 4- methyl -2- carboxyl benzaldehydes, 5- methyl -2- carboxyl benzaldehydes, 6- methyl -2- carboxyl benzene first
Aldehyde, 5,6- dimethyl -2- carboxyl benzaldehydes, 3- ethyl -2- carboxyl benzaldehydes, 4- ethyl -2- carboxyl benzaldehydes, 5- ethyls -2-
Carboxyl benzaldehyde, 6- ethyl -2- carboxyl benzaldehydes, 3- propyl -2- carboxyl benzaldehydes, 4- propyl -2- carboxyl benzaldehydes, 5- third
Base -2- carboxyl benzaldehydes, 6- propyl -2- carboxyl benzaldehydes, 3- butyl -2- carboxyl benzaldehydes, 4- butyl -2- carboxyl benzaldehydes,
5- butyl -2- carboxyl benzaldehydes, 6- butyl -2- carboxyl benzaldehydes, the chloro- 2- carboxyl benzaldehydes of 3-, the chloro- 2- carboxyl benzaldehydes of 4-,
The chloro- 2- carboxyl benzaldehydes of 5-, the chloro- 2- carboxyl benzaldehydes of 6-, the fluoro- 2- carboxyl benzaldehydes of 3-, the fluoro- 2- carboxyl benzaldehydes of 4-, 5- are fluoro-
The fluoro- 2- carboxyl benzaldehydes of 2- carboxyl benzaldehydes, 6-, the bromo- 2- carboxyl benzaldehydes of 3-, the bromo- 2- carboxyl benzaldehydes of 4-, the bromo- 2- carboxylics of 5-
The bromo- 2- carboxyl benzaldehydes of benzaldehyde, 6-, 3- nitro -2- carboxyl benzaldehydes, 4- nitro -2- carboxyl benzaldehydes, 5- nitros -2-
Carboxyl benzaldehyde or 6- nitro -2- carboxyl benzaldehydes.
5. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Substitution hydrazine is with replacing the molar ratio of 2-carboxybenzaldehyde to be 0.6-1.5 in step (1):1.
6. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Soaking time is 10-300 minutes in step (1).
7. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Mechanical mixture is mechanical agitation or grinding stirring.
8. the preparation method of substitution 2,3- benzodiazine ketone compounds according to claim 1, it is characterised in that：It is described
Precipitation agent is the one or more combination of water, methanol, ethyl alcohol, isopropanol, ethylene glycol in step (2).
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| CN111825620A (en) * | 2020-07-17 | 2020-10-27 | 河南科技大学 | Carbamate derivative and preparation method and application thereof |
| CN114560814A (en) * | 2022-03-02 | 2022-05-31 | 天津理工大学 | Synthesis method of substituted 2, 3-phthalazinone compound |
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| CN101522638A (en) * | 2006-07-25 | 2009-09-02 | 赛福伦公司 | Pyridizinone derivatives |
| CN105601577A (en) * | 2014-10-24 | 2016-05-25 | 沈阳中化农药化工研发有限公司 | Phenylthioether compound and use thereof |
| WO2017160670A1 (en) * | 2016-03-16 | 2017-09-21 | Merck Sharp & Dohme Corp. | M1 receptor positive allosteric modulators and methods of use thereof |
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| CN105601577A (en) * | 2014-10-24 | 2016-05-25 | 沈阳中化农药化工研发有限公司 | Phenylthioether compound and use thereof |
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| CN111825620A (en) * | 2020-07-17 | 2020-10-27 | 河南科技大学 | Carbamate derivative and preparation method and application thereof |
| CN111825620B (en) * | 2020-07-17 | 2022-02-15 | 河南科技大学 | Carbamate derivative and preparation method and application thereof |
| CN114560814A (en) * | 2022-03-02 | 2022-05-31 | 天津理工大学 | Synthesis method of substituted 2, 3-phthalazinone compound |
| CN114560814B (en) * | 2022-03-02 | 2023-10-20 | 天津理工大学 | Synthesis method of substituted 2, 3-naphthyridine ketone compound |
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