CN103553968A - Cinnamic hydroxamic acid compounds and preparation method thereof - Google Patents
Cinnamic hydroxamic acid compounds and preparation method thereof Download PDFInfo
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Abstract
The invention discloses cinnamic hydroxamic acid compounds and a preparation method thereof, belonging to the field of drug synthesis. A series of cinnamic hydroxamic acid compounds with novel structures are synthesized, and a preparation method for the compounds is provided; the compounds exert a substantial inhibitory effect on Gram negative bacterium escherichia coli and Gram-positive bacterium staphylococcus aureus and can be developed into a novel broad-spectrum antiseptic. The compounds may exert an antibacterial effect by inhibiting the effects of Mur enzyme (MurA and MurZ).
Description
The application is dividing an application of Chinese invention patent, and the applying date of original application is: on June 29th, 2012, application number is: 201210222626.8, and denomination of invention is: antibacterial agent acyl group phenoxy acetic acid, acyl group styracin and preparation method thereof.
Technical field
The present invention relates to a series of acyl group phenoxy carboxylic acid derivatives herbicides, acyl group cinnamic acid compound and Chinese cassia tree hydroximic acid compound as antibacterial agent, belong to the synthetic field of medicine.
Background technology
Abuse of antibiotics makes bacterial drug resistance problem day by day serious, so find new antibiotic, seems particularly urgent.Mur enzyme (MurA and MurZ) is a kind of very important enzyme being present in gram-positive microorganism and negative bacterium, and it brings into play keying action in the biosynthetic the first step of bacteria cell wall, promotes the synthetic of mucopeptide, thereby further causes the formation of cell walls.Therefore, Mur enzyme inhibitors provides effective way for antibacterial treatment.
The mechanism of action of Mur enzyme: cell walls is one deck rigid structure that is wrapped in bacterium outside, protects it not because inner high osmotic pressure breaks, and also protects bacterium to avoid the attack of the foreign matters such as microbiotic.Cell walls is that bacterial cell is peculiar, and the acellular wall of mammalian cell.The main component of bacteria cell wall is mucopeptide, is to have cancellated sugary polypeptide, and by-acetylmuramic acid (MurNAc), N-Acetyl-D-glucosamine (GlcNAc) and polypeptide linear high polymer form through crosslinked.In biosynthetic the first committed step of mucopeptide, by phosphorylation enol pyruvic acid (PEP), the 3-hydroxyl to UDP-N-acetylglucosamine (UDP-GlcNAc) shifts Mur enzyme (MurA/MurZ) catalysis enol pyruvic acid, forms enol pyruvic acid UDP-N-acetylglucosamine (EP-UDP-GlcNAc) (reaction formula 1).
Summary of the invention
Main purpose of the present invention is to provide serial acyl group phenoxy carboxylic acid derivatives herbicide, acyl group cinnamic acid compound and Chinese cassia tree hydroximic acid compound and preparation method thereof; and these compounds are carried out to preliminary bioactivity research, find active good antibacterial agent.
Acyl group phenoxy carboxylic acid derivatives herbicide of the present invention, its general structure as shown in structural formula I, described acyl group cinnamic acid compound, its general structure is as shown in formula II:
Wherein in structural formula I and II class, R
1for hydrogen, straight chain or C
1-C
13branched-chain alkyl; R
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.
The general structure of Chinese cassia tree hydroximic acid compound of the present invention is as follows:
Wherein in formula II IA, R
3for hydrogen, straight chain or C
1-C
14branched-chain alkyl; R
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.
In formula II IB, R
4hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), C
1-C
10straight or branched alkane, methoxyl group, sulfonic group, sulfoamido, amide group, hydroxyl, nitro, amino or substituted-amino etc.
The present invention also provides the synthetic method of above-mentioned three compounds:
One, the synthetic method of acyl group phenoxy carboxylic acid derivatives herbicide
The synthetic method of acyl group phenoxy carboxylic acid derivatives herbicide, specifically according to following step, carry out:
(1) exist
time, fortified phenol (1) reacts under trifluoromethayl sulfonic acid effect with substituted alkyl acyl chlorides, generates 4-substituted acyl fortified phenol (2), and its structural formula is
wherein said fortified phenol: replace acyl chlorides: the mol ratio of trifluoromethayl sulfonic acid is 1:1-5:1-200, preferably 1:1.1:12; Wherein said temperature of reaction is-40 ℃-80 ℃, preferably 0 ℃-25 ℃; Reaction times is 1-24 hour, preferably 2 hours; The substituent R that wherein replaces described fortified phenol
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.; The substituent R of wherein said replacement acyl chlorides
1for hydrogen atom, straight chain or C
1-C
13branched-chain alkyl.
(2) 4-substituted acyl fortified phenol (2), under the condition of DMF and Anhydrous potassium carbonate, obtains the tertiary butyric ester of 4-substituted acyl phenoxy acetic acid (3) with bromo-acetic acid tert-butyl generation alkylated reaction, and its structural formula is
wherein said 4-substituted acyl fortified phenol: bromo-acetic acid tert-butyl: the mol ratio of salt of wormwood is 1:1-5:1-5, preferably 1:1.5:2; Wherein said alkali is salt of wormwood, sodium carbonate, sodium hydride, potassium tert.-butoxide, preferably salt of wormwood; Wherein said solvent is DMF, acetone, butanone, preferably DMF; Wherein said temperature of reaction is 20 ℃-120 ℃, preferably 85 ℃; Reaction times is 2-24 hour, preferably 6 hours.
(3) under diacetyl oxide exists, the tertiary butyric ester of 4-substituted acyl phenoxy acetic acid and N, N, N, N-tetramethyl-methylene diamines carries out Mannich reaction, obtains [4-(2-methylene radical) substituted acyl] phenoxy acetic acid tert-butyl ester (4), and its structural formula is
the tertiary butyric ester of wherein said 4-substituted acyl phenoxy acetic acid: N, N, N, N-tetramethyl-methylene diamines: the mol ratio of diacetyl oxide is 1:1-5:1-10, preferably 1:2:4; Wherein said temperature of reaction is 20 ℃-120 ℃, preferably 85 ℃; Reaction times is 2-24 hour, preferably 9 hours.
(4) [4-(2-methylene radical) substituted acyl] phenoxy acetic acid tert-butyl ester, through trifluoroacetic acid Deprotection, produces [4-(2-methylene radical) substituted acyl] phenoxy acetic acid (5), and its structural formula is
wherein said [4-(2-methylene radical) substituted acyl] phenoxy acetic acid tert-butyl ester: the mol ratio of trifluoroacetic acid is 1:10-100, preferably 1:30; Wherein said temperature of reaction is-20 ℃-80 ℃, preferably 0 ℃-25 ℃; Reaction times is 2-24 hour, preferably 8 hours.
Two, the synthetic method of acyl group cinnamic acid compound
The synthetic method of acyl group cinnamic acid compound, specifically according to following step, carry out:
(1) there is Friedel-Crafts acylation reaction with replacement acyl chlorides in substituted phenyl-bromide (6), generates 4-substituted acyl bromobenzene (7), and its structural formula is
wherein said substituted phenyl-bromide: replace acyl chlorides: the mol ratio of aluminum chloride is 1:1-5:1-10, preferably 1:1.5:6; Wherein said temperature of reaction is-40 ℃-80 ℃, preferably 0 ℃-25 ℃; Reaction times is 1-24 hour, preferably 6 hours; Wherein said reaction solvent is Nitromethane 99Min., oil of mirbane, methylene dichloride, preferably Nitromethane 99Min.; The substituent R of institute's substituted phenyl-bromide wherein
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.; The substituent R of wherein said replacement acyl chlorides
1for hydrogen atom, straight chain or C
1-C
13branched-chain alkyl.
(2) under palladium catalysis, 4-substituted acyl bromobenzene (7) carries out Heck reaction with tert-butyl acrylate, obtains the tertiary butyric ester of 4-substituted acyl styracin (8), and its structural formula is
wherein said 4-substituted acyl bromobenzene: the mol ratio of tert-butyl acrylate is 1:1-3, preferably 1:1.5; The consumption of catalyst acetic acid palladium is 0%-5% mole, preferably 0.02% mole; Wherein said reaction solvent is N-first class pyrrolidone (NMP), oil of mirbane, DMF, preferably N-first class pyrrolidone (NMP); Wherein said temperature of reaction is 60 ℃-180 ℃, preferably 120 ℃; Reaction times is 1-24 hour, preferably 12 hours.
(3) the tertiary butyric ester of 4-substituted acyl styracin (8) in diacetyl oxide with N, N, N, N-tetramethyl-methylene diamines reacting by heating, produces [4-(2-methylene radical) substituted acyl] tertiary butyric ester of styracin (9), its structural formula is
the tertiary butyric ester of wherein said 4-substituted acyl styracin: N, N, N, N-tetramethyl-methylene diamines: the mol ratio of diacetyl oxide is 1:1-5:1-10, preferably 1:2:4; Wherein said temperature of reaction is 20 ℃-120 ℃, preferably 85 ℃; Reaction times is 1-24 hour, preferably 2 hours.
(4) acidolysis reaction of Deprotection, under trifluoroacetic acid effect, [4-(2-methylene radical) substituted acyl] tertiary butyric ester of styracin (9) is converted into [4-(2-methylene radical) substituted acyl] styracin (10), and its structural formula is
wherein said [4-(2-methylene radical) substituted acyl] tertiary butyric ester of styracin: the mol ratio of trifluoroacetic acid is 1:10-100, preferably 1:30; Wherein said temperature of reaction is-20 ℃-80 ℃, preferably 0 ℃-25 ℃; Reaction times is 2-24 hour, preferably 5 hours.
Three, the synthetic method of Chinese cassia tree hydroximic acid compound
The synthetic method of Chinese cassia tree hydroximic acid compound, specifically according to following step, carry out:
(1) the tertiary butyric ester of 4-substituted acyl styracin (8), through trifluoroacetic acid deprotection, generates 4-substituted acyl styracin (11), and its structural formula is
the tertiary butyric ester of wherein said 4-substituted acyl styracin: the mol ratio of trifluoroacetic acid is 1:10-100, preferably 1:30; Wherein said temperature of reaction is-20 ℃-80 ℃, preferably 0 ℃-25 ℃; Reaction times is 2-24 hour, preferably 5 hours; The substituent R of wherein said substituted acyl side chain
1for hydrogen atom, straight chain or C
1-C
13branched-chain alkyl; The substituent R of institute's phenyl ring wherein
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.
(2) under coupling agent and alkali existence, 4-substituted acyl styracin (11), with oxammonium hydrochloride coupling, obtains 4-substituted acyl Chinese cassia tree hydroximic acid (12), and its structural formula is
wherein said 4-substituted acyl styracin: oxammonium hydrochloride: the mol ratio of coupling agent is 1:1-5:1-3, preferably 1:2:1.1; Wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC), preferably HBTU; Wherein said alkali is triethylamine, N, N'-diisopropyl ethyl amine (DIEA), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), pyridine, preferably DIEA and DBU; Wherein said reaction solvent is DMF, second eyeball, tetrahydrofuran (THF) and methylene dichloride, preferably DMF; Wherein said temperature of reaction is-20 ℃-80 ℃, preferably 0 ℃-25 ℃; The wherein said reaction times is 1-24 hour, preferably 2 hours.
(3) similarly, under coupling agent and alkali existence, substituted acyl styracin (13), with oxammonium hydrochloride coupling, obtains substituted acyl Chinese cassia tree hydroximic acid (14), and its structural formula is
wherein said substituted acyl styracin: oxammonium hydrochloride: the mol ratio of coupling agent is 1:1-5:1-3, preferably 1:2:1.1; Wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC), preferably HBTU; Wherein said alkali is triethylamine, N, N'-diisopropyl ethyl amine (DIEA), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), pyridine, preferably DIEA and DBU; Wherein said reaction solvent is DMF, second eyeball, tetrahydrofuran (THF) and methylene dichloride, preferably DMF; Wherein said temperature of reaction is-20 ℃-80 ℃, preferably 0 ℃-25 ℃; The wherein said reaction times is 1-24 hour, preferably 2 hours; The substituent R of institute's phenyl ring wherein
2for hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine), methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino etc.
Advantage of the present invention: the acyl group phenoxy carboxylic acid derivatives herbicide, acyl group cinnamic acid compound and the Chinese cassia tree hydroximic acid compound that have synthesized a series of novel structures by short-cut method; these compounds have shown obvious restraining effect to gram negative bacterium intestinal bacteria and gram positive bacterium streptococcus aureus, can be developed as the antibacterial agent of wide spectrum.These compounds may be to produce antibacterial effect by suppressing the effect of Mur enzyme (MurA and MurZ).
Accompanying drawing explanation
Fig. 1: II compounds when different amounts to colibacillary inhibition;
Caption: No. 1 scraps of paper are compound 10c, No. 2 scraps of paper are compound 10a, and No. 3 scraps of paper are compound 10b, and No. 4 scraps of paper are compound 10d, and No. 5 scraps of paper are phosphonomycin, No. 6 scraps of paper are CHIR-090.
Fig. 2: II compounds is the inhibition to streptococcus aureus when different amounts;
Caption: No. 1 scraps of paper are compound 10c, No. 2 scraps of paper are compound 10a, and No. 3 scraps of paper are compound 10b, and No. 4 scraps of paper are compound 10d, and No. 5 scraps of paper are phosphonomycin, No. 6 scraps of paper are CHIR-090.
Fig. 3: III compounds when different amounts to colibacillary inhibition;
Caption: No. 1 scraps of paper are compound 11a, No. 2 scraps of paper are compound 12a, and No. 3 scraps of paper are compound 14b, and No. 4 scraps of paper are compound 14a, and No. 5 scraps of paper are DMSO (blank).
Fig. 4: III compounds is the inhibition to streptococcus aureus when different amounts;
Caption: No. 1 scraps of paper are compound 11a, No. 2 scraps of paper are compound 12a, and No. 3 scraps of paper are compound 14b, and No. 4 scraps of paper are compound 14a, and No. 5 scraps of paper are DMSO (blank).
Embodiment
Below in conjunction with embodiment, describe the present invention, but the present invention is not limited to these embodiment.
Embodiment 1
[4-(2-methylene radical) propionyl] phenoxy acetic acid (5a; R
1=Me, R
2=H) preparation
Step 1:4-propionyl phenol (2a; R
1=Me, R
2=H) preparation
Embodiment 1: get phenol (0.94g, 10mmol) and be added in 50mL there-necked flask, ice bath to 0 ℃, at N
2under condition, add trifluoromethayl sulfonic acid 10mL(114mmol), propionyl chloride (0.95mL, 10.9mmol), in 0 ℃ of reaction 1 hour, remove ice bath, normal-temperature reaction is after 1 hour again, add frozen water, be extracted with ethyl acetate (40mL * 3), merge organic phase, with 1N hydrochloric acid soln, wash (30mL * 2), saturated sodium bicarbonate is washed (30mL * 3), saturated common salt washing (30mL * 3), with anhydrous magnesium sulfate drying, filter, with Rotary Evaporators, remove desolventizing, column chromatography purification (sherwood oil: ethyl acetate=5:1), obtain white solid 2a(1.13g), productive rate 76%.
1H NMR(300MHz,DMSO-d
6):δ1.21(t,J=7.23Hz,3H),2.93(m,2H),3.34(s,1H),6.84(d,J=4.71Hz,2H),7.84(d,J=4.74Hz,2H)。
The step 2:4-propionyl phenoxy acetic acid tert-butyl ester (3a; R
1=Me, R
2=H) preparation
Embodiment 1: get 2a(1.02g, 6.7mmol) join in 100mL there-necked flask, at N
2under condition, add anhydrous N, dinethylformamide (7mL), Anhydrous potassium carbonate (1.92g, 13.2mmol), bromo-acetic acid tert-butyl (1.35mL, 8.2mmol), in 85 ℃, reflux 6 hours, thing to be mixed is cooled to after room temperature, add frozen water (12mL), be extracted with ethyl acetate (20mL * 3), merge organic phase, wash (10mL * 2) with water, saturated common salt washing (10mL * 2), and add anhydrous sodium sulfate drying, filter, with Rotary Evaporators, remove desolventizing, column chromatography purification (sherwood oil: ethyl acetate=10:1), obtain white solid 3a(1.72g), productive rate 96%.
1H NMR(300MHz,CDCl
3):δ1.21(t,J=7.26Hz,3H),1.49(s,9H),2.96(m,2H),4.58(s,2H),6.92(d,J=8.67Hz,2H),7.95(d,J=8.73Hz,2H)。
Step 3:[4-(2-methylene radical) propionyl] the phenoxy acetic acid tert-butyl ester (4a; R
1=Me, R
2=H) preparation
Embodiment 1: get 3a(1.7g, 6.44mmol) be added in 100mL there-necked flask, add diacetyl oxide (2.2mL, 23.5mmol), and at N
2under condition, drip N, N, N, N-tetramethyl-methylene diamines (2mL, 14.2mmol), 85 ℃ are refluxed 9 hours, and thing to be mixed is cooled to after room temperature, adds saturated sodium bicarbonate solution 30mL, be extracted with ethyl acetate (30mL * 3), merge organic phase, with saturated sodium bicarbonate solution, wash, 1N hydrochloric acid soln is washed (20mL * 2) and saturated common salt washing (20mL * 2), and add anhydrous sodium sulfate drying, filter, with Rotary Evaporators, remove desolventizing, column chromatography purification (sherwood oil: ethyl acetate=20:1), obtain white solid 4a(0.69g), productive rate 40%.
1H NMR(300MHz,CDCl
3):δ1.49(s,9H),2.06(s,3H),4.58(s,2H),5.55(s,1H),5.82(s,1H),6.91(d,J=6.84Hz,2H),7.78(d,J=6.84Hz,2H)。
Step 4:[4-(2-methylene radical) propionyl] phenoxy acetic acid (5a; R
1=Me, R
2=H) preparation
Embodiment 1: get 4a(0.67g, 2.4mmol) be added in tri-mouthfuls of round-bottomed flasks of dry 50mL, ice bath to 0 ℃, at N
2under condition, add methylene dichloride (9mL), trifluoroacetic acid (3mL), in 0 ℃ of reaction 1 hour, remove ice bath, then normal-temperature reaction is after 7 hours, with Rotary Evaporators, removes desolventizing, column chromatography purification (methylene dichloride: methyl alcohol=20:1), obtain micro-yellow solid 5a(0.34g), productive rate 65%.
1H NMR(300MHz,DMSO-d
6):δ1.91(s,3H),4.79(s,2H),5.49(s,1H),5.90(s,1H),7.02(d,J=6.84Hz,2H),7.72(d,J=6.84Hz,2H),13.16(s,1H)；MS(ESI,negative):m/z219(M-1)。
Embodiment 2
[4-(2-methylene radical) pentanoyl] phenoxy acetic acid (5b; R
1=n-Pr, R
2=H) preparation
The positive pentanoyl phenol of step 1:4-(2b; R
1=n-Pr, R
2=H) preparation
Embodiment 2: take n-amyl chloride as raw material, press the method preparation of embodiment 1 step 1, obtain micro-yellow solid 2b(1.75g), productive rate 98%.
1H NMR(300MHz,CDCl
3):δ0.94(t,J=7.32Hz,3H),1.37(s,2H),1.73(m,2H),2.93(t,J=7.29Hz,2H),6.91(d,J=6.78Hz,2H),7.91(d,J=6.78Hz,2H)。
The positive pentanoyl phenoxy acetic acid of the step 2:4-tert-butyl ester (3b; R
1=n-Pr, R
2=H) preparation
Embodiment 2: take compound 2b as raw material, press the method preparation of embodiment 1 step 2, obtain white solid 3b(2.56g), productive rate 97%.
1H NMR(300MHz,CDCl
3):δ0.95(t,J=7.32Hz,3H),1.39(m,2H),1.49(s,9H),1.71(m,2H),2.91(t,J=7.59Hz,2H),4.58(s,2H),6.92(d,J=6.87Hz,2H),7.94(d,J=6.87Hz,2H)。
The positive pentanoyl of step 3:[4-(2-methylene radical)] the phenoxy acetic acid tert-butyl ester (4b; R
1=n-Pr, R
2=H) preparation
Embodiment 2: take compound 3b(1.48g, 5.1mmol) be raw material, press the method preparation of embodiment 1 step 3, obtain transparent oily liquid 4b(0.39g), productive rate 26%.
1H NMR(300MHz,CDCl
3):δ0.96(t,J=7.38Hz,3H),1.49(s,9H),2.44(t,J=7.32Hz,2H),4.58(s,2H),5.50(s,1H),5.73(s,1H),6.92(d,J=6.84Hz,2H),7.81(d,J=6.06Hz,2H)。
The positive pentanoyl of step 4:[4-(2-methylene radical)] phenoxy acetic acid (5b; R
1=n-Pr, R
2=H) preparation
Embodiment 2: take compound 4b(0.3g, 1mmol)) be raw material, press the method preparation of embodiment 1 step 4, obtain micro-yellow solid 5b(0.19g), productive rate 80%.
1H NMR(300MHz,DMSO-d6):δ0.90(t,J=7.40Hz,3H),1.44(m,2H),2.36(t,J=7.35Hz,2H),4.80(s,2H),5.45(s,1H),5.80(s,1H),7.03(d,J=6.90Hz,2H),7.74(d,J=6.87Hz,2H),13.15(s,1H).MS(ESI,negative):m/z247(M-1).
Embodiment 3
[4-(2-methylene radical) propionyl] styracin (10a; R
1=Me, R
2=H) preparation method
Step 1:4-propionyl bromobenzene (7a; R
1=Me, R
2=H) preparation
Embodiment 3: choose the there-necked flask of a 100mL, add magneton, the oven drying of putting into 120 ℃ took out after 30 minutes, and bottle stopper is beyond the Great Wall cooled to room temperature under nitrogen protection immediately.Measure solvent Nitromethane 99Min. (33mL), ice bath to 0 ℃, add pressed powder aluminum chloride (16g, 120mmol), then with syringe, dropwise add propionyl chloride (2.86mL), said mixture drops into bromobenzene (3.14g stir 5min at 0 ℃ after, 20mmol), this mixed solution stirring reaction 1 hour at 0 ℃, then returns to room temperature and continues to stir, coreaction 6 hours, reacting complete is yellow liquid.Reaction mixture is poured in the frozen water that is mixed with concentrated hydrochloric acid (16mL), be extracted with ethyl acetate (60mL * 3), organic phase is used respectively 1M NaOH solution (50mL * 2), water (60mL * 2) and saturated aqueous common salt (60mL) washing, and use anhydrous sodium sulfate drying.Column chromatography purification (eluent, sherwood oil: ethyl acetate=35:1 → sherwood oil: ethyl acetate=30:1), obtain yellow liquid 7a(2.38g), productive rate 87%.
1H NMR(400MHz,CDCl
3):δ1.22(t,J=7.2Hz,2H),2.97(q,J=7.2Hz,1H),7.6(d,J=8.8Hz,2H),7.83(d,J=8.4Hz,2H)。
The step 2:4-propionyl styracin tert-butyl ester (8a; R
1=Me, R
2=H) preparation
Embodiment 3: choose three mouthfuls of round-bottomed flasks of a 250mL, the oven drying of putting into 120 ℃ took out after 30 minutes, immediately bottle stopper beyond the Great Wall; condenser and stirrer in configuration, inflated with nitrogen protection, drains air by air-discharging method; under room temperature, start to feed intake; add compound 7a(2.5g, 11.74mmol), sodium acetate (1.16g; 14.14mmol); tert-butyl acrylate (2.05mL), solvent nitrogen methyl-2-pyrrolidone (15mL), dropwise adds 0.02mol%Pd (OAc) with syringe
2nmp solution (3mL), 135 ℃ of reflux, react 11 hours, reaction finish after, solution is brownish black.By reactant cool to room temperature, add water (87mL), cancellation reaction, solution becomes taupe.Be extracted with ethyl acetate (45mL * 3), organic phase water (45mL * 2) and saturated aqueous common salt (45mL) washing, and use anhydrous sodium sulfate drying organic phase.With diatomite suction filtration, remove catalyst particle Pd (OAc)
2, column chromatography purification (eluent, sherwood oil: ethyl acetate=40:1), obtain light green solid 8a(2.75g), productive rate 90%.
1H NMR(400MHz,CDCl
3):δ1.23(t,J=7.2Hz,2H),1.56(s,9H),3.01(q,J=7.2Hz,3H),6.43(s,1H),6.47(d,J=16Hz,2H),7.62(d,J=16.4Hz,2H),7.60(d,J=8.8Hz,2H),7.96(d,J=8.4Hz,2H)。
Step 3:[4-(2-methylene radical) propionyl] the styracin tert-butyl ester (9a; R
1=Me, R
2=H) preparation
Embodiment 3: select the there-necked flask of a 100mL, add stirrer, the oven drying of putting into 120 ℃ took out after 30 minutes; bottle stopper beyond the Great Wall immediately, inflated with nitrogen protection, device water of condensation; under room temperature, feed intake, compound 8a(1.5g, 5.8mmol); diacetyl oxide (1.6mL), solvent N, N; N, N-tetramethyl-methylene diamines (2mL), opens water of condensation; oil bath set temperature is 85 ℃, reacts end in 2 hours.After stopped reaction, add NaHCO
3(25mL), and diacetyl oxide.With ethyl acetate (15mL * 3) extraction, organic phase is used respectively NaHCO
3(12mL), 1M hydrochloric acid (12mL * 2), saturated aqueous common salt (12mL * 2) wash, and use anhydrous sodium sulfate drying organic phase.After filtering and concentrating, column chromatography purification (eluent, sherwood oil: ethyl acetate=30:1), obtain light yellow liquid 9a(0.86g), crystallization obtains pale yellow crystals, productive rate 54%.
1H NMR(400MHz,CDCl
3):δ1.25(s,1H),1.54(s,9H),5.63(s,1H),5.94(s,1H),6.44(d,J=16Hz,2H),7.56(d,J=8.4Hz,2H),7.60(d,J=16.4Hz,2H),7.74(d,J=8Hz,2H)。
Step 4:[4-(2-methylene radical) propionyl] styracin (10a; R
1=Me, R
2=H) preparation
Embodiment 3: the there-necked flask of selecting a 100mL; the suitable stirrer of size, the oven drying of putting into 120 ℃ took out after 30 minutes, immediately bottle stopper beyond the Great Wall; nitrogen protection; add compound 9a(0.6g, 2.2mmol), add methylene chloride (8mL); add again trifluoroacetic acid (2.5mL); under ice bath, react after 1 hour, remove ice bath and continue at room temperature reaction, coreaction 4.5 hours.After reaction finishes, reaction soln is transferred in the single port flask of a 50mL, Rotary drying, vacuum filtration is also used ether rinse, upper strata solid collection is air-dry, lower floor's filtrate, by sherwood oil and re-crystallizing in ethyl acetate, obtains white solid 10a(0.44g), productive rate 93%.
1H NMR(400MHz,DMSO-d
6):δ1.99(s,3H),5.59(s,1H),6.04(s,1H),6.65(d,J=16Hz,1H),7.65(d,J=16Hz,1H),7.70(d,J=8.4Hz,2H),7.82(d,J=8Hz,2H),12.56(s,1H);MS(ESI,positive):m/z217(M+1)。
Embodiment 4
[4-(2-methylene radical) butyryl radicals] styracin (10b; R
1=Et, R
2=H) preparation method
Step 1:4-butyryl radicals bromobenzene (7b; R
1=Et, R
2=H) preparation
Embodiment 4: take bromobenzene (1.57g, 10mmol) and butyryl chloride (1.43mL) is raw material, press the method preparation of embodiment 3 steps 1, obtain yellow oily liquid 7b(0.69g), easily crystallization obtains yellow crystals, productive rate 30%.
1H NMR(400MHz,CDCl
3):δ1.00(t,J=8.0Hz,3H),1.76(m,J=7.2Hz,2H),2.91(t,J=7.2Hz,2H),7.6(d,J=8.4Hz,2H),7.82(d,J=8.4Hz,2H)。
The step 2:4-butyryl radicals styracin tert-butyl ester (8b; R
1=Et, R
2=H) preparation
Embodiment 4: take compound 7b as raw material, press the method preparation of embodiment 3 steps 2, obtain white solid 8b(0.52g), productive rate 87%.
1H NMR(400MHz,CDCl
3):δ1.01(t,J=7.6Hz,3H),1.54(s,9H),1.78(m,J=7.2Hz,2H),2.94(t,J=7.2Hz,2H),6.45(d,J=16Hz,1H),7.45(d,J=16Hz,1H),7.58(d,J=8Hz,2H),7.96(d,J=8.4Hz,2H)。
Step 3:[4-(2-methylene radical) butyryl radicals] the styracin tert-butyl ester (9b; R
1=Et, R
2=H) preparation
Embodiment 4: take compound 8b as raw material, press the method preparation of embodiment 3 steps 3, obtain light green solid 9b(0.11g), productive rate 49%.
1H NMR(400MHz,CDCl
3):δ1.13(t,J=7.6Hz,2H),1.54(s,9H),2.49(q,J=7.6Hz,2H),5.58(s,1H),5.84(s,1H),6.44(d,J=16Hz,1H),7.45(d,J=16Hz,1H),7.56(d,J=8.4Hz,2H),7.6(d,J=16Hz,2H),7.76(d,J=8Hz,2H)。
Step 4:[4-(2-methylene radical) butyryl radicals] styracin (10b; R
1=Et, R
2=H) preparation
Embodiment 4: take compound 9b as raw material, press the method preparation of embodiment 3 steps 4, obtain pale solid thing 10b(80mg), productive rate 90%.
1H NMR(300MHz,DMSO-d
6):δ1.06(t,J=7.2Hz,3H),2.40(q,J=7.5Hz,2H),5.55(s,1H),5.94(s,1H),6.67(d,J=16.2Hz,1H),7.65(d,J=15.9Hz,1H),7.72(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H),12.66(s,1H)；MS(ESI,negative):m/z229(M-1)。
Embodiment 5
[the positive pentanoyl of 4-(2-methylene radical)] styracin (10c; R
1=n-Pr, R
2=H) preparation method
The positive pentanoyl bromobenzene of step 1:4-(7c; R
1=n-Pr, R
2=H) preparation
Embodiment 5: take bromobenzene (1.57g, 10mmol) and n-amyl chloride (1.5mL) is raw material, press the method preparation of embodiment 3 steps 1, obtain light yellow oily liquid 7c(0.69g), crystallization obtains yellow crystals, productive rate 80%.
1H NMR(300MHz,CDCl
3):δ1.29(t,J=7.2Hz,2H),1.35(m,J=7.2Hz,2H),1.35(m,J=7.2Hz,2H),1.43(m,J=7.2Hz,2H),2.93(t,J=7.5Hz,3H),7.72(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H)。
The positive pentanoyl styracin of the step 2:4-tert-butyl ester (8c; R
1=n-Pr, R
2=H) preparation
Embodiment 5: take compound 7c as raw material, press the method preparation of embodiment 3 steps 2, obtain light green solid 8c(0.7g), productive rate 49%.
1H NMR(300MHz,CDCl
3):δ1.29(t,J=7.2Hz,2H),1.35(m,J=7.2Hz,2H),1.35(m,J=7.2Hz,2H),1.43(m,J=7.2Hz,2H),2.93(t,J=7.5Hz,3H),6.45(d,J=16Hz,2H),7.56(d,J=16Hz,2H),7.72(d,J=8.4Hz,2H),7.84(d,J=8.4Hz,2H)。
The positive pentanoyl of step 3:[4-(2-methylene radical)] the styracin tert-butyl ester (9c; R
1=n-Pr, R
2=H) preparation
Embodiment 5: take compound 8c as raw material, press the method preparation of embodiment 3 steps 3, obtain oyster white or faint yellow solid 9c approximately (0.3g) slightly, productive rate 94%.
1H NMR(400MHz,CDCl
3):δ0.97(t,J=7.6Hz,2H),1.52(m,J=7.2Hz,2H),1.56(s,9H),2.45(t,J=7.6Hz,2H),5.58(s,1H),5.84(s,1H),6.44(d,J=15.6Hz,2H),7.56(d,J=8Hz,2H),7.60(d,J=16Hz,2H),7.76(d,J=8.4Hz,2H)。
The positive pentanoyl of step 4:[4-(2-methylene radical)] styracin (10c; R
1=n-Pr, R
2=H) preparation
Embodiment 5: take compound 9c as raw material, press the method preparation of embodiment 3 steps 4, obtain white or slightly lurid solid 10c(188mg), productive rate 94%.
1H NMR(300MHz,DMSO-d
6):δ1.40(t,J=7.38Hz,3H),1.50(m,H),2.50(t,J=1.71Hz,2H),5.57(s,1H),5.95(s,1H),6.66(d,J=16.05Hz,1H),7.65(d,J=16.02Hz,1H),7.72(d,J=8.25Hz,2H),7.83(d,J=8.31Hz,2H),12.60(s,1H)；MS(ESI,negative):m/z243(M-1)。
Embodiment 6
[the positive caproyl of 4-(2-methylene radical)] styracin (10d; R
1=n-Bu, R
2=H) preparation method
The positive caproyl bromobenzene of step 1:4-(7d; R
1=n-Bu, R
2=H) preparation
Embodiment 6: with bromobenzene (1.57g, 10mmol) and positive caproyl chloride (1.6mL), press the method preparation of embodiment 3 steps 1, obtain light yellow or light green crystal 7d(0.88g), productive rate 35%.
1H NMR(300MHz,CDCl3):δ0.91(t,J=7.2Hz,2H),1.26(t,J=7.77Hz,2H),1.75(m,J=7.0Hz,2H),2.93(t,J=7.38Hz,2H),7.60(d,J=8.19Hz,2H),7.82(d,J=8.12Hz,2H)。
The positive caproyl styracin of the step 2:4-tert-butyl ester (8d; R
1=n-Bu, R
2=H) preparation
Embodiment 6: take compound 7d as raw material, press the method preparation of embodiment 3 steps 2, obtain white or micro-light green solid 8d(0.6g), productive rate 85%.
1H NMR(300MHz,CDCl
3):δ0.91(t,J=2.49Hz,2H),1.35(m,J=3.63Hz,2H),1.38(m,J=3.66Hz,2H),1.75(m,J=2.67Hz,2H),2.96(t,J=7.29Hz,2H),6.45(d,J=16.05Hz,2H),7.60(d,J=16.23Hz,2H),7.61(d,J=8.01Hz,2H),7.96(d,J=8.4Hz,2H)。
The positive caproyl of step 3:[4-(2-methylene radical)] the styracin tert-butyl ester (9d; R
1=n-Bu, R
2=H) preparation
Embodiment 6: take compound 8d as raw material, press the method preparation of embodiment 3 steps 3, obtain faint yellow solid 9d(0.3g), productive rate 94%.
1H NMR(300MHz,CDCl
3):δ0.95(t,J=7.17Hz,2H),1.43(m,J=2.76Hz,2H),1.48(m,J=3.87Hz,2H),5.30(s,2H),5.58(s,1H),6.45(d,J=15.99Hz,2H),7.6(d,J=15.81Hz,2H)，7.56(d,J=8.22Hz,2H),7.75(d,J=8.34Hz,2H).
The positive caproyl of step 4:[4-(2-methylene radical)] styracin (10d; R
1=n-Bu, R
2=H) preparation
Embodiment 6: take compound 9d as raw material, press the method preparation of embodiment 3 steps 4, obtain the solid 10d(119mg of white or rice white), productive rate 99%.
1H NMR(300MHz,DMSO-d
6):δ0.89(t,J=9.48Hz,3H),1.35(m,J=7.2Hz,2H),1.40(m,J=1.1Hz,2H),2.40(t,J=9.2Hz,2H),5.55(s,1H),5.95(s,1H),6.66(d,J=16.05Hz,1H),7.65(d,J=16.02Hz,1H),7.72(d,J=8.31Hz,2H),7.83(d,J=8.28Hz,2H),12.60(s,1H)；MS(ESI,negative):m/z257(M-1)。
Embodiment 7
(4-propionyl) Chinese cassia tree hydroximic acid (12a; R
1=Me, R
2=H) preparation
The step 1:4-propionyl styracin tert-butyl ester (8a; R
1=Me, R
2=H) preparation
Embodiment 7: with the step 2 in embodiment 3
Step 2:(4-propionyl) styracin (11a; R
1=Me, R
2=H) preparation
Embodiment 7: by needed instrument 50mL there-necked flask, and magneton, the oven drying of putting into 120 ℃ took out after 30 minutes, under nitrogen protection, was cooled to room temperature.In there-necked flask, add anhydrous methylene chloride (4mL), ice bath is cooled to 0 ℃, add compound 8a(0.3g, 1.15mmol) be dissolved in wherein, in 0 ℃ of stirring, add once trifluoroacetic acid (TFA) (1.2mL), reaction mixture stirs 1h in 0 ℃, then be warming up to room temperature, continue to stir 1h left and right.Solvent is concentrated.Column chromatography purification product (eluent: DCM:MeOH=40:1), obtain white powder solid 11a(0.2g), productive rate 93%.
1H NMR(400MHz,DMSO-d
6):δ1.09(t,J=7.2Hz,3H),3.06(m,J=7.2Hz,2H),6.66(d,J=16Hz,1H),7.64(d,J=16.4Hz,1H),7.83(d,J=8Hz,2H),7.98(d,J=8Hz,2H),12.55(s,1H)。
Step 3:(4-propionyl) Chinese cassia tree hydroximic acid (12a; R
1=Me, R
2=H) preparation
Embodiment 7: by two 50mL there-necked flasks of needed instrument, and magneton, the oven drying of putting into 120 ℃ took out after 30 minutes, under nitrogen protection, was cooled to room temperature.Under room temperature in the there-necked flask of a 50mL disposable compound 11a(0.1g, the 0.49mmol of adding), DIEA(0.18mL, 0.98mmol, 2equiv.), DMF(1mL), add HBTU(0.21g, 0.54mmol, 1.1equiv.).Mixture at room temperature stirs 5-10min.In another 50mL there-necked flask, under room temperature, add H
2nOH.HCl(0.07g, 0.98mmol, 2equiv.), DMF(0.5mL), DBU(0.15mL, 0.98mmol, 2equiv.), stir, obtain the solution of a character homogeneous.Under the homogeneity solution room temperature obtaining, be added in first there-necked flask, then whole reaction mixture at room temperature stirs one hour.Concentrated, remove as far as possible a large amount of DMF, add ethyl acetate (11mL) to dissolve, water (4mL) and saturated aqueous common salt (4mL * 2) washing, anhydrous Na SO
4dry.Filter, concentrated, and column chromatography purification crude product (eluent: DCM:MeOH=20:1), obtain reddish-brown pressed powder 12a(0.05g), productive rate 46%.
1H NMR(300MHz,DMSO-d
6):δ1.17(t,J=7.5Hz,3H),3.04(m,2H),6.59(d,J=15.3Hz,1H),7.51(d,J=15Hz,1H),7.70(d,J=7.0Hz,2H),7.99(d,J=7.4Hz,2H),9.15(s,1H),10.87(s,1H)；MS(EI,negative):m/z218(M-1)。
Embodiment 8
(the positive pentanoyl of 4-) Chinese cassia tree hydroximic acid (12c; R
1=n-Pr, R
2=H) preparation
The positive pentanoyl styracin of the step 1:4-tert-butyl ester (8c; R
1=n-Pr, R
2=H) preparation
Embodiment 8: with the step 2 of example 5
The positive pentanoyl of step 2:(4-) styracin (11c; R
1=n-Pr, R
2=H) preparation
Embodiment 8: with compound 8c(0.4g), press the method for embodiment 7 steps 3 and prepare, obtain white powder solid 11c(0.4g), productive rate 98%.
1H NMR(300MHz,DMSO-d
6):δ0.92(t,J=7.3Hz,3H),1.34(m,J=5.5Hz,2H),1.60(m,J=4.9Hz,2H),3.02(m,J=7.3Hz,2H),6.67(d,J=16.1Hz,1H),7.64(d,J=16.1Hz,1H),7.83(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,2H),12.66(s,1H)。
The positive pentanoyl of step 3:(4-) Chinese cassia tree hydroximic acid (12c; R
1=n-Pr, R
2=H) preparation
Embodiment 8: take compound 11c(0.2g, 0.87mmol) be raw material, press the method preparation of embodiment 7 steps 4, obtain reddish-brown pressed powder 12c(0.08g), productive rate 32%.
Embodiment 9
(4-fluorine) Chinese cassia tree hydroximic acid (14a; R
3=4-F) preparation
By two 50mL there-necked flasks of needed instrument, magneton, the oven drying of putting into 120 ℃ took out after 30 minutes, under nitrogen protection, was cooled to room temperature.Under room temperature in the there-necked flask of a 50mL disposable adding (4-fluorine) styracin 13a(0.5g, 3mmol), DIEA(1.05mL, 6mmol, 2equiv.), DMF(6mL), add HBTU(1.25g, 3.3mmol, 1.1equiv.).Mixture at room temperature stirs 5-10min.In another 50mL there-necked flask, under room temperature, add H
2nOH.HCl(0.42g, 6mmol, 2equiv.), DMF(3mL), DBU(0.9mL, 6mmol, 2equiv.), stir, obtain the solution of a character homogeneous.Under the homogeneity solution room temperature obtaining, be added in first there-necked flask, then whole reaction mixture at room temperature stirs one hour.Concentrated, remove as far as possible DMF, add ethyl acetate (65mL) to dissolve, water (25mL * 2) and saturated aqueous common salt (25mL * 2) washing, anhydrous Na SO
4dry.Filter, concentrated, column chromatography purification crude product (eluent: DCM:MeOH=40:1), obtain reddish-brown pressed powder 14a(0.052g), productive rate 20%.
1H NMR(300MHz,DMSO-d
6):δ6.41(d,J=15.5Hz,1H),7.25(t,J=7.85Hz,2H),7.46(d,J=15.5Hz,1H),7.63(t,J=7.3Hz,2H)，9.07(s,1H),10.78(s,1H)。
Embodiment 10
(4-chlorine) Chinese cassia tree hydroximic acid (14b; R
3=4-Cl) preparation
(4-chlorine) the styracin 13b (0.5g, 2.74mmol) of take is raw material, presses the method preparation of embodiment 9, obtains rose pink pressed powder 14b(0.48g), productive rate 88%.
Embodiment 11
(4-bromine) Chinese cassia tree hydroximic acid (14c; R
3=4-Br) preparation
Take (4-bromine) styracin 13c(0.5g, 2.2mmol) be raw material, press the method preparation of embodiment 9, obtain white solid powder 14c(0.26g), productive rate 50%.
1H NMR(300MHz，DMSO-d
6):δ6.48(d,J=15.8Hz,1H),7.43(t,J=15.9Hz,1H),7.52(d,J=8.5Hz,2H),7.61(t,J=8.4Hz,2H),9.09(s,1H),10.80(s,1H)。
Embodiment 12
Determination of Antibacterial Activity
Choosing gram negative bacterium intestinal bacteria and gram positive bacterium streptococcus aureus is bacteria tested.LB solid medium after sterilizing is poured in culture dish while hot, after culture medium solidifying, the bacterium liquid that adds 0.1mL, with glass spatula, smoothen, after 5-10min, the filter paper that contains Different Weight (10 μ g, 50 μ g, 100 μ g, 200 μ g) test compound is placed on the substratum that contains bacterium liquid, is then placed on overnight incubation in the biochemical cultivation case of 30 ℃, finally observe inhibition zone size.Parallel testing is carried out in every group of experiment 3 times.
By the method, 12 compounds in embodiment have been measured, with phosphonomycin and the known positive contrast of Gram-negative antiseptic-germicide CHIR-090.Wherein I compounds only demonstrates faint restraining effect to intestinal bacteria (No. 1 filter paper of Fig. 1) and streptococcus aureus (No. 2 filter papers of Fig. 2); II compounds all has obvious restraining effect to intestinal bacteria (table 1) and streptococcus aureus (table 2), and particularly compound 10b, has demonstrated broad spectrum; III compounds has good anti-microbial activity to intestinal bacteria (table 3) and streptococcus aureus (table 4).Fig. 3: III compounds when different amounts to colibacillary inhibition; Caption: No. 1 scraps of paper are compound 11a, No. 2 scraps of paper are compound 12a, and No. 3 scraps of paper are compound 14b, and No. 4 scraps of paper are compound 14a, and No. 5 scraps of paper are DMSO (blank).Fig. 4: III compounds is the inhibition to streptococcus aureus when different amounts; Caption: No. 1 scraps of paper are compound 11a, No. 2 scraps of paper are compound 12a, and No. 3 scraps of paper are compound 14b, and No. 4 scraps of paper are compound 14a, and No. 5 scraps of paper are DMSO (blank).
Table 1. II compounds is to colibacillary restraining effect
The restraining effect of table 2. II compounds to streptococcus aureus
Annotation: (1) phosphonomycin is marketed drug; CHIR-090 is for there being the known compound of inhibition to Gram-negative bacteria;
(2) anti-microbial activity: "-" represents to no effect, below antibacterial circle diameter 16mm; A little less than "+" represents that bacteriostatic activity, antibacterial circle diameter is 16-22mm; " ++ " represents that bacteriostatic activity is better, and antibacterial circle diameter is 22-28mm; " +++ " represents that bacteriostatic activity is fine, and antibacterial circle diameter is 28-32mm.
Table 3. III compounds is to colibacillary restraining effect
The restraining effect of table 4. III compounds to streptococcus aureus
Annotation: (1) DMSO is blank group; (2) anti-microbial activity: "-" represents to no effect; "+" represents bacteriostatic activity weak (antibacterial circle diameter is 12-14mm); " ++ " represents bacteriostatic activity strong (antibacterial circle diameter is 14-18mm); " +++ " represents bacteriostatic activity strong (antibacterial circle diameter is more than 18mm).
Claims (3)
1. Chinese cassia tree hydroximic acid compound, its general structure is as follows:
（
IIIA） （
IIIB）
Wherein in formula II IA, R
3for hydrogen, straight chain or C
1-C
14branched-chain alkyl; R
2for hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino;
In formula II IB, R
4hydrogen atom, fluorine, chlorine, bromine, iodine, C
1-C
10straight or branched alkane, methoxyl group, sulfonic group, sulfoamido, amide group, hydroxyl, nitro, amino or substituted-amino.
2. the synthetic method of Chinese cassia tree hydroximic acid compound claimed in claim 1, is characterized in that carrying out according to following step:
(1) the tertiary butyric ester of 4-substituted acyl styracin, through trifluoroacetic acid deprotection, generates 4-substituted acyl styracin, and its structural formula is
; The tertiary butyric ester of wherein said 4-substituted acyl styracin: the mol ratio of trifluoroacetic acid is 1:10-100, wherein said temperature of reaction is-20
0c-80
0c, the reaction times is 2-24 hour; The substituent R of wherein said substituted acyl side chain
1for hydrogen atom, straight chain or C
1-C
13branched-chain alkyl; The substituent R of institute's phenyl ring wherein
2for hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino;
(2) under coupling agent and alkali existence, 4-substituted acyl styracin, with oxammonium hydrochloride coupling, obtains 4-substituted acyl Chinese cassia tree hydroximic acid, and its structural formula is
; Wherein said 4-substituted acyl styracin: oxammonium hydrochloride: the mol ratio of coupling agent is 1:1-5:1-3, wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC); Wherein said alkali is triethylamine, N, N'-diisopropyl ethyl amine (DIEA), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), pyridine; Wherein said reaction solvent is DMF, second eyeball, tetrahydrofuran (THF) or methylene dichloride; Wherein said temperature of reaction is-20
0c-80
0c, the wherein said reaction times is 1-24 hour,
(3) under coupling agent and alkali existence, substituted acyl styracin, with oxammonium hydrochloride coupling, obtains substituted acyl Chinese cassia tree hydroximic acid, and its structural formula is
, wherein said substituted acyl styracin: oxammonium hydrochloride: the mol ratio of coupling agent is 1:1-5:1-3, wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC), wherein said alkali is triethylamine, N, N'-diisopropyl ethyl amine (DIEA), 1, 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), pyridine, wherein said reaction solvent is N, dinethylformamide, second eyeball, tetrahydrofuran (THF) and methylene dichloride, wherein said temperature of reaction is-20
0c-80
0c, the wherein said reaction times is 1-24 hour, wherein the substituent R of institute's phenyl ring
2for hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, methoxyl group, hydroxyl, nitro, amino or substituted-amino.
3. the synthetic method of Chinese cassia tree hydroximic acid compound according to claim 2, is characterized in that
Wherein described in step (1), the reaction times is 5 hours;
4-substituted acyl styracin described in step (2) wherein: oxammonium hydrochloride: the mol ratio of coupling agent is 1:2:1.1; Wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester; Wherein said alkali is N, N'-diisopropyl ethyl amine (DIEA), and 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), pyridine, wherein said reaction solvent is DMF; Wherein said temperature of reaction is 0
0c-25
0c; The wherein said reaction times is 2 hours;
Substituted acyl styracin described in step (3) wherein: oxammonium hydrochloride: the mol ratio of coupling agent is preferred 1:2:1.1; Wherein said coupling agent is benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU); Wherein said alkali is N, N'-diisopropyl ethyl amine (DIEA), 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU); Wherein said reaction solvent is DMF; Wherein said temperature of reaction is 0
0c-25
0c; The wherein said reaction times is 2 hours.
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| CN108456153A (en) * | 2018-03-26 | 2018-08-28 | 江西理工大学 | Cinnamyl group hydroximic acid and preparation method thereof and the application in floatation of tungsten mineral |
| CN109734831A (en) * | 2018-12-28 | 2019-05-10 | 广东工业大学 | A kind of polyacrylamide polymer and preparation method thereof |
| CN112209852A (en) * | 2020-11-03 | 2021-01-12 | 湖南中医药大学 | Method for preparing hydroxamic acid compound by peroxide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108456153A (en) * | 2018-03-26 | 2018-08-28 | 江西理工大学 | Cinnamyl group hydroximic acid and preparation method thereof and the application in floatation of tungsten mineral |
| CN108456153B (en) * | 2018-03-26 | 2020-11-24 | 江西理工大学 | Phenylpropanoid hydroximic acid, preparation method thereof and application thereof in tungsten ore flotation |
| CN109734831A (en) * | 2018-12-28 | 2019-05-10 | 广东工业大学 | A kind of polyacrylamide polymer and preparation method thereof |
| CN112209852A (en) * | 2020-11-03 | 2021-01-12 | 湖南中医药大学 | Method for preparing hydroxamic acid compound by peroxide |
| CN113318000A (en) * | 2021-05-28 | 2021-08-31 | 福建莲珂科技有限公司 | Cosmetic preservatives and their use as ingredients in cosmetic formulations |
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