CN103333122A - Pinanyl-2-aminopyrimidine compounds as well as synthesis and application thereof - Google Patents
Pinanyl-2-aminopyrimidine compounds as well as synthesis and application thereof Download PDFInfo
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Abstract
The invention relates to pinanyl-2-aminopyrimidine compounds with the structural formula shown in the specification, wherein in the structural formula, Ar is phenyl, p-chlorphenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and furyl aromatic base. The synthesizing method comprises the following technical steps of: (1) using (-)-alpha-pinene as a raw material and selectively oxidizing to obtain (+)-2-hydroxyl-3-pinone; (2) under the effect of a catalyst, performing condensation on (+)-2-hydroxyl-3-pinone and aromatic aldehyde to prepare a series of 4-aryl methylene-2-hydroxyl-3-pinone compounds; and (3) in sodium hydroxide liquor or potassium tert-butoxide, performing cyclization reaction on 4-aryl methylene-2-hydroxyl-3-pinone compounds and guanidine hydrochloride to obtain the pinanyl-2-aminopyrimidine compounds. The compounds have the advantages that the compounds have good bactericidal activity and bacteriostatic activity to fungus and bacteria and are antifungal and antibacterial compounds with great potential.
Description
Technical field
The present invention relates to the novel pinane base of a class-2-amino-metadiazine compound and synthetic and application thereof.With (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation; Under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again; In sodium hydroxide solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain novel pinane base-2-amino-metadiazine compound.Belong to Minute Organic Synthesis technology and technical field of medicine synthesis.
Background technology
Pyrimidines is typical nitrogen-containing heterocycle compound, extensively is present in human body and the organism, all contains the pyrimidine ring structure as the uridylic in the nucleic acid component (Uracil), cytosine(Cyt) (Cytosine) and thymus pyrimidine (Thymine).Because its particular structure and character, has biological activity preferably mostly, as antitumor, anti-inflammatory, desinsection, sterilization, antibiotic, plant growth regulating etc.The present invention is intended to development of new turpentine oil base fine chemicals, and the pyrimidines of research, screening biologically active is further developing
α-firpene utilizes frontier to lay the foundation.
2-sulfonyloxy methyl-4,6-dimethoxypyridin (1) effect is the especially necessary intermediate of weedicide of synthesizing fungicide, plant-growth regulator significantly.
The pyribenzoxim (Pyribenzoxim, 2) of Korea S LG chemical company exploitation can suppress acetolactate synthestase (ALS), is optionally post-emergence herbicide of a wide spectrum.The mepanipyrim (Mepanipyrim, 3) of combinatorial chemistry company development is to apple brown rot, and black spot etc. have distinguished prevention effect.Cyprodinil (Cyprodinil, 4) is the miazines product of Switzerland Novartis Co.,Ltd exploitation, is used for preventing and treating gray mold, Powdery Mildew, black spot, is full of rot and wheat eyeprint disease etc.
L á szl ó Varga in 2003 etc. by cinnamophenone and guanidine derivatives generation addition cyclization, make 4 through the hydrogen peroxide dehydroaromatizationof, 6-diaryl-2-amino-metadiazine compound, productive rate 40%～70% under the catalysis of alkali.
Shigeru Takagi in 2002 etc. are with 1, and 3-two-(2'-pyridine)-2-propylene-1-ketone is raw material, and sodium methylate is catalyzer and Guanidinium nitrate reaction, has synthesized 4, and 6-two-(2'-pyridine)-2-aminopyrimidine has studied the fluorescent characteristic of this compound in solution.
N. Ingarsal etc. is raw material with the naphthalene, makes 2-amino-4-(1'-naphthyl)-6-substituted-phenyl pyrimidine through replacement, aldol condensation and cyclization, and this compounds has good restraining and sterilizing bacteria effect to pneumonia Ke Laibo chamber bacillus and Pseudomonas aeruginosa.
Charles Q. Huang etc. are from substituted acetophenone, with
N,
N-dimethyl formamide dimethylacetal or diethyl acetal reaction obtain corresponding enamine.2-dialkylamino-4-Arylpyrimidines that enamine and Guanidinium hydrochloride reaction generate is good corticotropin-releasing factor receptor body antagonist, can be used for treating mental disorder.
Summary of the invention
The object of the present invention is to provide the novel pinane base of a class-2-amino-metadiazine compound, make it have the restraining and sterilizing bacteria activity of wide spectrum; Another purpose of the present invention provides the method for preparing above-claimed cpd; The present invention also has a purpose to provide the application of above-claimed cpd, and is significant to widening the terebinthine field that utilizes of China.
Technical solution of the present invention: the structural formula of pinane base-2-amino-metadiazine compound
In the formula, Ar is phenyl, rubigan, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and furyl aryl radical.
The synthetic method of pinane base-2-amino-metadiazine compound comprises following processing step:
(1), with (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation;
(2), under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again;
(3), in NaOH solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain pinane base-2-amino-metadiazine compound.
Processing step 1:
Processing step 2:
Processing step 3:
Synthetic following compound formula (1), formula (2), formula (3), formula (4), formula (5), formula (6) are new compound.
Advantage of the present invention:
1)
α-firpene is the main component in the turps, is the abundant bicyclic diterpene vinyl compound of a class.Utilize its specific space structure synthesizing new pinane base-2-amino-metadiazine compound, screening has a compound of restraining and sterilizing bacteria activity efficiently, with overcome natural disinfection, the existing source of fungistat less, shortcoming that price is high;
2) provide a kind of method of screening novel pinane base-2-amino-metadiazine compound, namely by oxidation (-)-
α-firpene obtains (+)-2-hydroxyl-3-pinone, and (+)-2-hydroxyl-3-pinone and aromatic aldehyde reaction generate 4-aryl methylene-2-hydroxyl-3-pinone compounds, carry out cyclisation with Guanidinium hydrochloride again and obtain chirality pinane base-2-amino-metadiazine compound.Compound of the present invention has good bacteriostatic activity to Candida albicans, aspergillus niger, candida tropicalis, intestinal bacteria, streptococcus aureus, subtilis and Pseudomonas fluorescens, is antimycotic, the antibacterium compound that has potentiality;
3) for the analysis of design novel azaheterocyclic compound and structure activity relationship, provide certain reference value, significant to widening the terebinthine field that utilizes of China.
Embodiment
Pinane base-2-amino-metadiazine compound, the structural formula of this compounds is:
In the formula, Ar is phenyl, rubigan, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and furyl aryl radical.
The synthetic method of pinane base-2-amino-metadiazine compound comprises following processing step:
(1) with (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation;
(2) under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again;
(3) in sodium hydroxide solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain pinane base-2-amino-metadiazine compound.
Described processing step (1) with (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation; Concrete preparation method comprises
1) in the there-necked flask of being furnished with agitator, thermometer and feed hopper;
2) adding (-) successively-
α-firpene, acetone and deionized water;
3) ice bath is cooled to 0～5 ℃;
4) add potassium permanganate in batches, at room temperature continue reaction 5～6 h;
5) after reaction finishes, filter, use the washing with acetone solid residue;
6) reclaim acetone, add ethyl acetate in the residuum, extremely neutral with the saturated common salt water washing;
7) organic layer is removed moisture, removes by filter siccative, is concentrated and reclaim ethyl acetate through anhydrous sodium sulfate drying;
8) 120～122 ℃/2.66 kPa cuts are collected in underpressure distillation again, obtain (+)-2-hydroxyl-3-pinone.
Described processing step (2), under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again; Concrete preparation method comprises
1) in the there-necked flask of being furnished with thermometer, agitator, reflux exchanger;
2) add (+)-2-hydroxyl-3-pinone, aromatic aldehyde, solvent and basic catalyst successively.The mol ratio of 2-hydroxyl-3-pinone and aromatic aldehyde is 1: 1～1.5 (mol/mol); The catalyzer add-on is 5%～20% of aldehyde and ketone total mass, and solvent is 1～1.5: 1 (L/mol) with the ratio of 2-hydroxyl-3-pinone;
3) temperature control reacts 1～12 h down for 20～85 ℃;
4) after the cooling, ethyl acetate extraction for several times;
5) organic phase of He Binging is washed to neutrality with deionized water and saturated common salt;
6) organic layer is removed moisture, removes by filter siccative, is concentrated and reclaim ethyl acetate through anhydrous sodium sulfate drying, and recrystallization obtains 4-aryl methylene-2-hydroxyl-3-pinone compounds.
Described aromatic aldehyde comprises phenyl aldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, aubepine, paranitrobenzaldehyde and furfural, and the mol ratio of 2-hydroxyl-3-pinone and aromatic aldehyde is 1: 1～1.5 (mol/mol).
Described processing step (3), in sodium hydroxide solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain pinane base-2-amino-metadiazine compound; Concrete preparation method comprises
1) in the there-necked flask of being furnished with thermometer, agitator, reflux exchanger;
2) add 4-aryl methylene-2-hydroxyl-3-pinone compounds, Guanidinium hydrochloride, solvent and basic catalyst successively.The mol ratio of 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride is 1: 3.0～5.0 (mol/mol); Catalyzer is 30% sodium hydroxide solution, sodium hydroxide solution is 2～4: 1 (L/mol) with the ratio of 4-aryl methylene-2-hydroxyl-3-pinone, or adopting potassium tert.-butoxide to make catalyzer, the consumption of potassium tert.-butoxide is 60%～90% of 4-aryl methylene-2-hydroxyl-3-pinone and Guanidinium hydrochloride total mass; Solvent is 4～6: 1 (L/mol) with the ratio of 4-aryl methylene-2-hydroxyl-3-pinone;
3) temperature control reacts 8～16 h down for 60～70 ℃;
4) after the cooling, ethyl acetate extraction for several times;
5) organic phase that merges is washed with deionized water and saturated common salt;
6) remove moisture, remove by filter siccative, concentrate the recovery ethyl acetate solvent, obtain pinane base-2-amino-metadiazine compound through glacial acetic acid/dehydrated alcohol (1: 5 mL/mL) mixed solvent recrystallization through anhydrous sodium sulfate drying again.
The application of pinane base-2-amino-metadiazine compound is for the preparation of sterilant and the fungistat of fungi and bacterium.
In order to explain the present invention, provide a series of examples below, these examples are illustrative fully, they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
General rule:Intermediate and degree of purity of production adopt Agilent 7890A gas chromatograph for determination; EI-MS adopts U.S. Agilent 5975C mass spectrograph to measure; Infrared spectra (IR) adopts U.S. Nicolet 380 FT-IR determination of infrared spectroscopy; Nuclear magnetic resonance spectrum (NMR) adopts Bruker AV 500 Hz nmr determinations; Ultimate analysis adopts German Elementar Vario EL cube elemental analyser to measure; Specific rotation adopts exact science WZZ-2S type automatic polarimeter in Shanghai to measure; Fusing point adopts Tyke, Beijing X-6 micro melting point apparatus to measure.
The preparation of (one) (+)-2-hydroxyl-3-pinone
In following examples, the preparation of (+)-2-hydroxyl-3-pinone, reference literature [(-)-
α-firpene selective oxidation synthesizes the research of (+)-2-hydroxyl-3-pinone. biomass chemical engineering, 2012,46 (6): 30～34] in disclosed method carry out.In being furnished with 500 mL there-necked flasks of agitator, thermometer and feed hopper, add successively (-)-
α-firpene 13.60 g (0.10 mol), acetone 110 mL and deionized water 12 mL, ice bath is cooled to 0～5 ℃, add the abundant fine ground potassium permanganate of 31.61 g (0.20 mol) (adds in 1.5～2 h in batches, the control temperature of reaction system, prevent the too high material that dashes of temperature), at room temperature continue reaction 6 h (GC tracking monitor).After reaction finishes, filter with sand core funnel, use acetone (10 mL * 3) washing solid residue again.Reclaim acetone with the rotation concentrating instrument, add 30 mL ethyl acetate in the residuum, extremely neutral with the saturated common salt water washing, after anhydrous sodium sulfate drying, filtration, concentrating, 120～122 ℃/2.66 kPa cuts are collected in underpressure distillation again, obtain 12.72 g colorless solids, productive rate 75.6%, purity are 98.3% (GC).m.?p.?38.1～39.0℃；
＋37.5?(
c?0.5,?CHCl
3)。
(2) preparation of 4-aryl methylene-2-hydroxyl-3-pinone compounds
The preparation of 4-aryl methylene-2-hydroxyl-3-pinone compounds, reference literature [the synthetic and characteristic ultraviolet absorption research of 4-aryl methylene-2-hydroxyl-3-pinone compounds. organic chemistry, 2012,32 (12): 2287～2293] disclosed method is carried out in.
At NaOH, under the katalysis such as sodium ethylate or potassium tert.-butoxide, get (+)-2-hydroxyl-3-pinone of embodiment 1 preparation, respectively with phenyl aldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, aubepine, paranitrobenzaldehyde and furfural carry out aldol reaction, obtain 4-Ben Yajiaji-2-hydroxyl-3-pinone, 4-(4'-chlorobenzene methylene radical)-2-hydroxyl-3-pinone, 4-(4'-methylbenzene methylene radical)-2-hydroxyl-3-pinone, 4-(4'-anisole methylene radical)-2-hydroxyl-3-pinone, 4-(4'-oil of mirbane methylene radical)-2-hydroxyl-3-pinone, 4-(furans-2'-methylene radical)-2-hydroxyl-3-pinone, structural formula is as follows:
1, the preparation of 4-Ben Yajiaji-2-hydroxyl-3-pinone
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.27 g (12.0 mmol) phenyl aldehyde, the 10 mL trimethyl carbinols, after adding 0.44 g (aldehyde ketone total mass 15%) potassium tert.-butoxide under the induction stirring, be warming up to 70 ℃ of reaction 4 h, 2-hydroxyl-3-pinone transformation efficiency reaches 97.9%, and reaction preference reaches 97.5% (GC tracking monitor).After the cooling, add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 1.88 g colourless transparent crystals through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 73.4%, and purity is 99.5% (GC).m.p.?103.5～104.5?℃；[
α]
＋18.4?(
c?0.5,?CH
3OH)。
2,4-(4 '-chlorobenzene methylene radical)-2-hydroxyl-3-pinone is synthetic
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.69 g (12.0 mmol) 4-chloro-benzaldehyde, 10 mL, 20% NaOH solution, following 70 ℃ of reaction 3 h of induction stirring, 2-hydroxyl-3-pinone transformation efficiency reaches 98.9%, and reaction preference reaches 97.8% (GC tracking monitor).After the cooling, add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 2.17 g colourless transparent crystals through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 74.6%, and purity is 99.7% (GC).m.p.?103.9～105.0?℃；[
α]
＋11.6?(
c?0.5,?CH
3OH)。
3,4-(4 '-methylbenzene methylene radical)-2-hydroxyl-3-pinone is synthetic
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.44 g (12.0 mmol) p-tolyl aldehyde, the 10 mL trimethyl carbinols, after adding 0.31 g (aldehyde ketone total mass 10%) potassium tert.-butoxide under the induction stirring, be warming up to 70 ℃ of reaction 3 h, 2-hydroxyl-3-pinone transformation efficiency reaches 99.3%, and reaction preference reaches 98.2% (GC tracking monitor).After the cooling, add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 2.12 g colourless transparent crystals through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 78.4%, and purity is 99.0% (GC).m.p.?125.8～126.3?℃；[
α]
＋18.0?(
c?0.5,?CH
3OH)。
4,4-(the anisole methylene radical of 4'-)-2-hydroxyl-3-pinone is synthetic
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.63 g (12.0 mmol) aubepine, the 10 mL trimethyl carbinols, after adding 0.33 g (aldehyde ketone total mass 10%) potassium tert.-butoxide under the induction stirring, be warming up to 70 ℃ of reaction 3 h, 2-hydroxyl-3-pinone transformation efficiency reaches 98.9%, and reaction preference reaches 97.6% (GC tracking monitor).After the cooling, add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 1.76 g colourless transparent crystals through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 61.3%, and purity is 99.8% (GC).m.p.?89.2～90.1?℃；[
α]
－17.6?(
c?0.5,?CH
3OH)。
5,4-(4'-oil of mirbane methylene radical)-2-hydroxyl-3-pinone is synthetic
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.81 g (12.0 mmol) paranitrobenzaldehyde, 15 mL dehydrated alcohols, after adding 0.31 g (aldehyde ketone total mass 9%) sodium ethylate under the induction stirring, normal temperature (20 ± 5 ℃) is reaction 2 h down, and 2-hydroxyl-3-pinone transformation efficiency reaches 99.5%, and reaction preference reaches 98.7% (GC tracking monitor).Add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets the light yellow needle-like crystal of 2.51 g through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 83.3%, and purity is 99.1% (GC).m.p.?164.6～166.1℃；[
α]
－57.8?(
c?0.5,?CH
3OH)。
6,4-(furans-2'-methylene radical)-2-hydroxyl-3-pinone is synthetic
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 1.68 g (10.0 mmol) 2-hydroxyl-3-pinone successively, 1.06 g (11.0 mmol) furfural, 10 mL dehydrated alcohols, after adding 0.27 g (aldehyde ketone total mass 10%) sodium ethylate under the induction stirring, normal temperature (20 ± 5 ℃) is reaction 1 h down, and 2-hydroxyl-3-pinone transformation efficiency reaches 99.8%, and reaction preference reaches 97.2% (GC tracking monitor).After the cooling, add 30 mL saturated aqueous common salts in the reaction solution, divide 3 extractions with 60 mL ethyl acetate, the organic phase of merging is washed to neutrality with saturated common salt, obtains the reddish-brown dope through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 1.04 g light red transparent crystalss through 5 mL ethyl acetate/10 mL sherwood oil crystallizations, productive rate 42.3%, and purity is 100.0% (GC).m.p.?97.3～97.5?℃；[
α]
－16.6?(
c?0.5,?CH
3OH)。
(3) preparation of novel pinane base-2-amino-metadiazine compound
The precursor skeleton carbon atoms numbered of synthetic novel pinane base-2-amino-metadiazine compound is shown below.
Embodiment 1
5,6,7,8-tetrahydrochysene-4-phenyl-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (1):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.64 g (2.5 mmol) 4-Ben Yajiaji-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, 10 mL dehydrated alcohols behind the adding 5 mL 30% NaOH solution, are warming up to 70 ℃ of reaction 16 h under the induction stirring, raw material rate of decomposition 9.1%, transformation efficiency 94.8%, reaction preference 94.7% (GC tracking monitor) has solid to separate out in the reaction process.After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets 0.62 g colourless transparent crystal through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 80.2%, and purity is 99.8% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.75 (s, 3H, 11-CH
3), 1.38 (s, 3H, 10-CH
3), 1.55 (s, 3H, 12-CH
3), 1.76 (d,
J=9.7 Hz, 1H, 9
α-CH), 2.10 (t,
J=6.0 Hz, 1H, 9
β-CH), 2.43～2.47 (m, 1H, 7-CH), 2.83 (t,
J=5.8 Hz, 1H, 5-CH), 5.01 (s, 1H, O-H), 6.38 (s, 2H, N-H); Phenyl: 7.38 (t,
J=6.6 Hz, 2H, 2', 6'-CH), 7.42～7.48 (m, 3H, 3', 4', 5'-CH);
13C NMR (DMSO, 500 MHz)
δ: 23.74,26.24,27.02,30.98,41.64,43.65,52.83,73.27,122.69,127.96,128.38,128.63,138.01,161.83,162.23,169.98; IR (KBr)
ν: 3407 (
ν O-H), 3311,3178 (
ν N-H), 2981 (
ν As C-H, CH
3), 2930 (
ν As C-H, CH
2), 2866 (
ν S C-H, CH
2), 1642 (
ν C=N), 1572,1549 (
δ N-H), 1469,1440 (
ν C=C, phenyl ring C=C encircles stretching vibration), 1098,822,819 (
τ N-H), 704 (
τ C-H, phenyl ring C-H out-of-plane deformation vibration) and cm
-1; MS (70 eV)
M/z(%): 295 (M
+, 10), 226 (100), 115 (10); Anal. calcd for C
18H
21N
3O:C 73.19, and H 7.17, and N 14.23; Found C 73.31, H 7.25, and N 14.30.
Embodiment 2
5,6,7,8-tetrahydrochysene-4-(4'-chloro-phenyl-)-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (2):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.73 g (2.5 mmol) 4-(4'-chlorobenzene methylene radical)-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, 10 mL dehydrated alcohols behind adding 5 mL 30% NaOH, are warming up to 60 ℃ of reaction 12 h under the induction stirring, raw material rate of decomposition 7.9%, transformation efficiency 95.8%, reaction preference 94.4% (GC tracking monitor) has solid to separate out in the reaction process.After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets colourless transparent crystal through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 81.5%, and purity is 99.7% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.71 (s, 3H, 11-CH
3), 1.36 (s, 3H, 10-CH
3), 1.52 (s, 3H, 12-CH
3), 1.73 (d,
J=9.8 Hz, 1H, 9
α-CH), 2.07 (t,
J=5.95 Hz, 1H, 9
β-CH), 2.41～2.45 (m, 1H, 7-CH), 2.77 (t,
J=5.8 Hz, 1H, 5-CH), 4.99 (s, 1H, O-H), 6.41 (s, 2H, N-H); Phenyl: 7.37 (d,
J=8.4 Hz, 2H, 3', 5'-CH), 7.51 (d,
J=8.4 Hz, 2H, 2', 6'-CH);
13C NMR (DMSO, 500 MHz)
δ: 23.68,26.21,26.95,30.92,41.58,43.65,52.78,73.22,122.64,128.08,130.48,133.22,136.78,160.48,162.23,170.26; IR (KBr)
ν: 3416 (
ν O-H), 3301,3186 (
ν N-H), 2978 (
ν As C-H, CH
3), 2911 (
ν As C-H, CH
2), 2869 (
ν S C-H, CH
2), 1639 (
ν C=N), 1562,1551 (
δ N-H), 1492,1466 (
ν C=C, phenyl ring C=C encircles stretching vibration), 1085,841,816 (
τ N-H), 726 cm
-1; MS (70 eV)
M/z(%): 329 (M
+, 5), 260 (100), 115 (3); Anal. calcd for C
18H
20N
3OCl:C 65.55, and H 6.11, and N 12.74; Found C 65.70, H 6.20, and N 12.85.
Embodiment 3
5,6,7,8-tetrahydrochysene-4-(4'-aminomethyl phenyl)-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (3):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.68 g (2.5 mmol) 4-(4'-methylbenzene methylene radical)-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, 10 mL dehydrated alcohols behind adding 5 mL 30% NaOH, are warming up to 70 ℃ of reaction 16 h under the induction stirring, raw material rate of decomposition 12.7%, transformation efficiency 91.5%, reaction preference 92.7% (GC tracking monitor) has solid to separate out in the reaction process.After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets colourless transparent crystal through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 75.7%, and purity is 99.5% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.71 (s, 3H, 11-CH
3), 1.35 (s, 3H, 10-CH
3), 1.51 (s, 3H, 12-CH
3), 1.71 (d,
J=9.7 Hz, 1H, 9
α-CH), 2.06 (t,
J=5.95 Hz, 1H, 9
β-CH), 2.41～2.43 (m, 1H, 7-CH), 2.81 (t,
J=5.75 Hz, 1H, 5-CH), 4.94 (s, 1H, O-H), 6.30 (s, 2H, N-H); Phenyl: 2.34 (s, 3H, Ar-CH
3), 7.24 (s, 4H, 2', 3', 5', 6'-CH);
13C NMR (DMSO, 500 MHz)
δ: 20.78,23.73,26.23,27.01,30.95,41.65,43.62,52.83,73.24,122.61,128.50,128.59,135.18,137.80,161.79,162.20,169.82; IR (KBr)
ν: 3436 (
ν O-H), 3317,3176 (
ν N-H), 2978 (
ν As C-H, CH
3), 2955 (
ν As C-H, CH
2), 2920 (
ν S C-H, CH
3), 2866 (
ν S C-H, CH
2), 1645 (
ν C=N), 1565,1553 (
δ N-H), 1476,1450 (
ν C=C, phenyl ring C=C encircles stretching vibration), 1095,829,813 (
τ N-H), 771 cm
-1; MS (70 eV)
M/z(%): 309 (M
+, 3), 240 (100), 115 (6); Anal. calcd for C
19H
23N
3O:C 73.76, and H 7.49, and N 13.58; Found C 73.85, H 7.54, and N 13.49.
Embodiment 4
5,6,7,8-tetrahydrochysene-4-(4'-p-methoxy-phenyl)-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (4):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.72 g (2.5 mmol) 4-(4'-anisole methylene radical)-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, 10 mL dehydrated alcohols behind adding 5 mL 30% NaOH, are warming up to 70 ℃ of reaction 16 h under the induction stirring, raw material rate of decomposition 2.6%, transformation efficiency 93.7%, reaction preference 95.5% (GC tracking monitor) has solid to separate out in the reaction process.After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets white cotton shape solid through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 84.8%, and purity is 100% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.71 (s, 3H, 11-CH
3), 1.36 (s, 3H, 10-CH
3), 1.51 (s, 3H, 12-CH
3), 1.72 (d,
J=9.7 Hz, 1H, 9
α-CH), 2.06 (t,
J=5.95 Hz, 1H, 9
β-CH), 2.42～2.43 (m, 1H, 7-CH), 2.85 (t,
J=5.8 Hz, 1H, 5-CH), 4.93 (s, 1H, O-H), 6.28 (s, 2H, N-H); Phenyl: 3.79 (s, 3H, Ar-OCH
3), 7.00 (d,
J=8.7 Hz, 2H, 3', 5'-CH), 7.31 (d,
J=8.7 Hz, 2H, 2', 6'-CH);
13C NMR (DMSO, 500 MHz)
δ: 23.73,26.25,27.05,31.00,41.70,43.63,52.84,55.12,73.27,113.38,122.47,130.12,130.34,159.44,161.43,162.16,169.80; IR (KBr)
ν: 3442 (
ν O-H), 3308,3186 (
ν N-H), 2991 (
ν As C-H, CH
3), 2939 (
ν As C-H, CH
2), 2866 (
ν S C-H, CH
2), 1610 (
ν C=N), 1561,1549 (
δ N-H), 1511 (
ν As C-O-C), 1466,1440 (
ν C=C, phenyl ring C=C encircles stretching vibration), 1248 (
ν S C-O-C), 1098,841,822 (
τ N-H) cm
-1; MS (70 eV)
M/z(%): 325 (M
+, 4), 256 (100), 115 (4); Anal. calcd for C
19H
23N
3O
2: C 70.13, and H 7.12, and N 12.91; Found C 70.26, H 7.18, and N 13.02.
Embodiment 5
5,6,7,8-tetrahydrochysene-4-(4'-nitrophenyl)-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (5):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.75 g (2.5 mmol) 4-(4'-oil of mirbane methylene radical)-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, the 20 mL trimethyl carbinols, after adding 1.03 g (raw material total mass 60%) potassium tert.-butoxide under the induction stirring, be warming up to 70 ℃ of reaction 8 h, raw material rate of decomposition 1.2%, transformation efficiency 94.1%, reaction preference 97.4% (GC tracking monitor).After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets buff powder through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 77.6%, and purity is 99.5% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.72 (s, 3H, 11-CH
3), 1.35 (s, 3H, 10-CH
3), 1.52 (s, 3H, 12-CH
3), 1.75 (d,
J=9.75 Hz, 1H, 9
α-CH), 2.08 (t,
J=5.9 Hz, 1H, 9
β-CH), 2.41～2.46 (m, 1H, 7-CH), 2.73 (t,
J=5.75 Hz, 1H, 5-CH), 5.03 (s, 1H, O-H), 6.51 (s, 2H, N-H); Phenyl: 7.62 (d,
J=8.75 Hz, 2H, 3', 5'-CH), 8.30 (d,
J=8.75 Hz, 2H, 2', 6'-CH);
13C NMR (DMSO, 500 MHz)
δ: 23.64,26.18,26.87,30.86,41.55,43.70,52.74,73.22,122.94,123.28,130.02,144.30,147.25,159.56,162.28,170.72; IR (KBr)
ν: 3426 (
ν O-H), 3314,3195 (
ν N-H), 2977 (
ν As C-H, CH
3), 2907 (
ν S C-H, CH
3), 2869 (
ν S C-H, CH
2), 1632 (
ν C=N), 1574,1549 (
δ N-H), 1517 (
ν As NO2), 1469,1454 (
ν C=C, phenyl ring C=C encircles stretching vibration), 1344 (
ν S NO2), 1097,823,806 (
τ N-H), 757 cm
-1; MS (70 eV)
M/z(%): 340 (M
+, 5), 271 (100), 115 (3); Anal. calcd for C
18H
20N
4O
3: C 63.52, and H 5.92, and N 16.46; Found C 63.64, H 6.02, and N 16.52.
Embodiment 6
5,6,7,8-tetrahydrochysene-4-(2'-furyl)-6,6,8-trimethylammonium-8-hydroxyl-5, the preparation of 7-methylene bridge-2-quinazoline amine (6):
In being furnished with 50 mL there-necked flasks of thermometer and condenser, add 0.62 g (2.5 mmol) 4-(furans-2'-methylene radical)-2-hydroxyl-3-pinone successively, 0.96 g (10 mmol) Guanidinium hydrochloride, the 20 mL trimethyl carbinols, after adding 1.41 g (raw material total mass 90%) potassium tert.-butoxide under the induction stirring, be warming up to 70 ℃ of reaction 8 h, raw material rate of decomposition 3.6%, transformation efficiency 94.3%, reaction preference 95.3% (GC tracking monitor).After the cooling, add 50 mL deionized waters in the reaction solution, divide 3 extractions with 180 mL ethyl acetate, the organic phase of merging is washed with saturated common salt, obtains yellow solid through anhydrous sodium sulfate drying, filtration, after concentrated.Crude product gets white powder through 3 mL glacial acetic acids/15 mL dehydrated alcohol recrystallizations, productive rate 76.2%, and purity is 99.6% (GC).
1H NMR (DMSO, 500 MHz)
δ: pinane base: 0.65 (s, 3H, 11-CH
3), 1.42 (s, 3H, 10-CH
3), 1.50 (s, 3H, 12-CH
3), 1.72 (d,
J=9.85 Hz, 1H, 9
α-CH), 2.07 (t,
J=6.0 Hz, 1H, 9
β-CH), 2.46～2.50 (m, 1H, 7-CH), 3.47 (t,
J=5.8 Hz, 1H, 5-CH), 4.95 (s, 1H, O-H), 6.33 (s, 2H, N-H); Furyl: 6.60 (dd,
J=3.3,1.8 Hz, 1H, 4'-CH), 6.94 (d,
J=3.35 Hz, 1H, 5'-CH), 7.81 (d,
J=0.85 Hz, 1H, 3'-CH);
13C NMR (DMSO, 500 MHz)
δ: 23.71,26.31,27.20,30.52,41.07,43.37,52.60,73.33,111.58,112.29,121.40,144.20,150.13,152.59,162.08,171.10; IR (KBr)
ν: 3423 (
ν O-H), 3314,3192 (
ν N-H), 2975 (
ν As C-H, CH
3), 2927 (
ν As C-H, CH
2), 2866 (
ν S C-H, CH
2), 1636 (
ν C=N), 1569,1546 (
δ N-H), 1492,1453 (
ν C=C, furan nucleus C=C encircles stretching vibration), 1101,1014 (
τ C-H, furan nucleus C-H in-plane bending vibration), 809,781 (
τ N-H), 749 (
τ C-H, furan nucleus C-H out-of-plane deformation vibration) and cm
-1; MS (70 eV)
M/z(%): 285 (M
+, 6), 216 (100), 115 (3); Anal. calcd for C
16H
19N
3O
2: C 67.35, and H 6.71, and N 14.73; Found C 67.50, H 6.80, and N 14.84.
The physical properties of 6 novel pinane base-2-amino-metadiazine compounds of the present invention's preparation, as shown in table 1.
The physical properties of table 1 compound (1)～(6)
The bacteriostatic activity test of The compounds of this invention
1, for the examination bacterial classification
Candida albicans (
C.albicans), aspergillus niger (
A.niger), candida tropicalis (
G.tropicalis), intestinal bacteria (
E.coli), streptococcus aureus (
S.aureus), subtilis (
B.subtilis), Pseudomonas fluorescens (
P.fluorescens), provide by Microbiological Lab of chemical engineering institute of Nanjing Forestry University.
2, the preparation of substratum
Substratum is a kind of suitable microorganism growth breeding by artificial preparation and the mixing nutriment of accumulative total meta-bolites.According to characteristics and the experiment purpose of fungi and bacterium, need two kinds of substratum of preparation.
Potato glucose agar medium (fungi is used), be called for short the PDA substratum, its composition and making:
Potato 200 g, glucose 20 g, agar 18 g, distilled water 1000 mL.With the potato cutting of cleaning after removing the peel, add that water 1000 mL are well-done (to boil 30 min, can be poked by glass stick and get final product), with 4 layers of filtered through gauze, add glucose and agar again, supply water to 1000 mL after the heating and melting again, the pH nature, be sub-packed in the triangular flask, difference is cotton plug beyond the Great Wall, at 1.05 kgcm
-2, 121 ℃ of sterilization 20 min down, standby.
Beef-protein medium (bacterium is used), be called for short the NA substratum, its composition and making:
Take by weighing extractum carnis 5 g, peptone 10 g, glucose 1 g, NaCl 5 g, agar 18 g, distilled water 1000 mL, heating for dissolving is transferred pH to 7.0～7.2 with 10% NaOH solution, this experiment is omitted and is filtered, and is sub-packed in the triangular flask, and difference is cotton plug beyond the Great Wall, at 1.05 kgcm
-2, 121 ℃ of sterilization 20 min down, standby.
3, for the activation of examination bacterial classification and the preparation of bacteria suspension
With transfering loop picking Candida albicans, aspergillus niger, candida tropicalis bacterium bacterial classification from the PDA substratum of 4 ℃ of preservations, the method of in Bechtop, inoculating according to the inclined-plane, be inoculated into aseptic technique on the PDA slant medium of sterilization, in 28 ℃ of thermostat containers, cultivate 72 h.
With transfering loop picking intestinal bacteria, streptococcus aureus, subtilis, Pseudomonas fluorescens bacterial classification from the NA substratum of 4 ℃ of preservations, the method of in Bechtop, inoculating according to the inclined-plane, be inoculated into aseptic technique on the NA slant medium of sterilization, in 37 ℃ of thermostat containers, cultivate 24 h.
Picking 2 encircles the bacterial classification that has activated and puts into the test tube that 10 mL PDA or NA liquid nutrient medium are housed respectively, and vibration shakes up, and makes a series of 10
6～10
7CFUmL
-1Bacteria suspension, standby.
4, the mensuration of minimum inhibitory concentration (MIC)
(Minimum Inhibitory Concentration MIC) adopts doubling dilution to measure to minimum inhibitory concentration.Concrete operations: earlier 12 holes, the 2nd hole to the are added 75 μ L sterilized waters, again testing compound, positive reference substance KETOKONAZOL and kantlex are made into 500 μ gmL with DMSO respectively
-1Solution 150 μ L add the 1st hole, compound and positive control solution are carried out doubling dilution in 96 hole analysis plates respectively, the from the 1st to the 12nd hole is made into a series of concentration gradient (500 μ gmL
-1～0.244 μ gmL
-1), every hole contains 75 μ L solution, as reference, adds the bacteria suspension that 75 μ L prepare in advance then in each hole, fully mixing with pure DMSO.At last 96 hole analysis plates are placed 30 ℃ of incubators, microbial culture 24 h observe behind fungus culture 48 h, with the concentration of the hole correspondence that do not produce muddy minimum concentration as the minimum inhibitory concentration of this sample to this test bacterium.
Each sample is to every kind of test bacterium triplicate, results averaged.
5, bacteriostatic activity test-results
The present invention adopts the minimum inhibitory concentration experiment that the bacteriostatic activity of novel pinane base-2-amino-metadiazine compound is estimated, and experimental result sees Table 2.
The minimum inhibitory concentration (MIC) of table 2 compound (1)～(5)
a Positive control (Positive control): fungi is KETOKONAZOL, and bacterium is kantlex.
Claims (7)
1. pinane base-2-amino-metadiazine compound is characterized in that the structural formula of this compounds is:
In the formula, Ar is phenyl, rubigan, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl and furyl aryl radical.
2. the synthetic method of pinane base-2-amino-metadiazine compound is characterized in that this method comprises following processing step:
(1) with (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation;
(2) under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again;
(3) in sodium hydroxide solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain pinane base-2-amino-metadiazine compound.
3. the synthetic method of pinane base according to claim 2-2-amino-metadiazine compound, it is characterized in that described processing step (1) with (-)-
α-firpene is raw material, obtains (+)-2-hydroxyl-3-pinone through selective oxidation; Concrete preparation method comprises
1) in the there-necked flask of being furnished with agitator, thermometer and feed hopper;
2) adding (-) successively-
α-firpene, acetone and deionized water;
3) ice bath is cooled to 0～5 ℃;
4) add potassium permanganate in batches, at room temperature continue reaction 5～6 h;
5) after reaction finishes, filter, use the washing with acetone solid residue;
6) reclaim acetone, add ethyl acetate in the residuum, extremely neutral with the saturated common salt water washing;
7) organic layer is removed moisture, removes by filter siccative, is concentrated and reclaim ethyl acetate through anhydrous sodium sulfate drying,
8) 120～122 ℃/2.66 kPa cuts are collected in underpressure distillation again, obtain (+)-2-hydroxyl-3-pinone.
4. the synthetic method of pinane base according to claim 2-2-amino-metadiazine compound, it is characterized in that described processing step (2), under catalyst action, (+)-2-hydroxyl-3-pinone makes serial 4-aryl methylene-2-hydroxyl-3-pinone compounds with the aromatic aldehyde condensation again; Concrete preparation method comprises
1) in the there-necked flask of being furnished with thermometer, agitator, reflux exchanger;
2) add (+)-2-hydroxyl-3-pinone, aromatic aldehyde, solvent and basic catalyst successively; The mol ratio of 2-hydroxyl-3-pinone and aromatic aldehyde is 1: 1～1.5 (mol/mol); The catalyzer add-on is 5%～20% of aldehyde and ketone total mass, and solvent is 1～1.5: 1 (L/mol) with the ratio of 2-hydroxyl-3-pinone;
3) temperature control reacts 1～12 h down for 20～85 ℃;
4) after the cooling, ethyl acetate extraction for several times;
5) organic phase of He Binging is washed to neutrality with deionized water and saturated common salt;
6) again through anhydrous sodium sulfate drying remove moisture, remove by filter siccative, concentrate reclaim ethyl acetate solvent, recrystallization obtains 4-aryl methylene-2-hydroxyl-3-pinone compounds.
5. the synthetic method of pinane base according to claim 4-2-amino-metadiazine compound, it is characterized in that described aromatic aldehyde comprises phenyl aldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, aubepine, paranitrobenzaldehyde and furfural, the mol ratio of 2-hydroxyl-3-pinone and aromatic aldehyde is 1: 1～1.5 (mol/mol).
6. the synthetic method of pinane base according to claim 2-2-amino-metadiazine compound, it is characterized in that described processing step (3), in sodium hydroxide solution or potassium tert.-butoxide, 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride carry out cyclization, obtain pinane base-2-amino-metadiazine compound; Concrete preparation method comprises
1) in the there-necked flask of being furnished with thermometer, agitator, reflux exchanger;
2) add 4-aryl methylene-2-hydroxyl-3-pinone compounds, Guanidinium hydrochloride, solvent and basic catalyst successively; The mol ratio of 4-aryl methylene-2-hydroxyl-3-pinone compounds and Guanidinium hydrochloride is 1: 3.0～5.0 (mol/mol); Catalyzer is 30% sodium hydroxide solution, sodium hydroxide solution is 2～4: 1 (L/mol) with the ratio of 4-aryl methylene-2-hydroxyl-3-pinone, or adopting potassium tert.-butoxide to make catalyzer, the consumption of potassium tert.-butoxide is 60%～90% of 4-aryl methylene-2-hydroxyl-3-pinone and Guanidinium hydrochloride total mass; Solvent is 4～6: 1 (L/mol) with the ratio of 4-aryl methylene-2-hydroxyl-3-pinone;
3) temperature control reacts 8～16 h down for 60～70 ℃;
4) after the cooling, ethyl acetate extraction for several times;
5) organic phase that merges is washed with deionized water and saturated common salt;
6) remove moisture, remove by filter siccative, concentrate the recovery ethyl acetate solvent, obtain pinane base-2-amino-metadiazine compound through glacial acetic acid/dehydrated alcohol (1: 5 mL/mL) mixed solvent recrystallization through anhydrous sodium sulfate drying again.
7. the application of pinane base-2-amino-metadiazine compound is characterized in that sterilant and fungistat for the preparation of fungi and bacterium.
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| CN103965118B (en) * | 2014-05-26 | 2015-12-09 | 南京林业大学 | One class pinane base-2-amino-metadiazine compound and synthetic method thereof and application |
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Application publication date: 20131002 |