CN103880789B - Furans lactonic ring analog derivative and uses thereof - Google Patents

Furans lactonic ring analog derivative and uses thereof Download PDF

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Publication number
CN103880789B
CN103880789B CN201410110990.4A CN201410110990A CN103880789B CN 103880789 B CN103880789 B CN 103880789B CN 201410110990 A CN201410110990 A CN 201410110990A CN 103880789 B CN103880789 B CN 103880789B
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compound
acceptable salt
reaction
pharmacy acceptable
alkyl
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CN103880789A (en
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彭成
韩波
唐正伟
黄维
冷海军
谢欣
李想
杨磊
王彪
赵倩
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Chengdu Zhongsheng Kangtai Pharmaceutical Technology Co., Ltd
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Chengdu University of Traditional Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention provides such as formula the compound shown in I or its pharmacy acceptable salt or prodrug, R1, R3 are independently selected from H, C1-4 alkyl, 1 ~ 3 halogen; R2 is selected from H, phenyl or substituted-phenyl, and its substituting group is halogen or C1-4 alkyl; Wherein, when R2 is phenyl, be H when R1 with R3 is different; Or, when R2 is H, be halogen when R1 with R3 is different.Present invention also offers its purposes.Compound provided by the invention, has certain anti-microbial activity, can it can be used as antibacterial potential drug, for clinical application provides new selection.

Description

Furans lactonic ring analog derivative and uses thereof
Technical field
The present invention relates to furans lactonic ring analog derivative and uses thereof.
Background technology
Furans lactonic ring class formation is extensively present in natural product, synthetic drugs, agricultural chemicals equimolecular, and it is applied to the synthesis aspect of biologically active substance, luminous organic material and dyestuff as raw material, intermediate or product, has certain application prospect.
Summary of the invention
The object of the present invention is to provide new furans lactonic ring analog derivative and uses thereof.
The invention provides such as formula the compound shown in I or its pharmacy acceptable salt or prodrug,
Wherein, R1, R3 are independently selected from H, C1-4 alkyl, 1 ~ 3 halogen;
R2 is selected from H, phenyl or substituted-phenyl, and its substituting group is halogen or C1-4 alkyl.
Further, described compound structure is such as formula shown in II:
Further, when R2 is phenyl, be H when R1 with R3 is different; Or, when R2 is H, be halogen when R1 with R3 is different.
Further, R1, R3 are independently selected from H, C1-4 alkyl, 1 ~ 2 halogen.
Further, described C1-4 alkyl is selected from methyl or propyl group.
Preferably, described compound is one of following:
Wherein, described pharmacy acceptable salt is the hydrochloride of compound, vitriol, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid salt, acetate, propionic salt, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
Pharmaceutically acceptable prodrug of the present invention, what refer to that described compound obtains after modifying for chemical structure discharges activeconstituents through the conversion of enzyme or non-enzymatic and plays the compound of drug effect in vivo.
Present invention also offers above-claimed cpd or its pharmacy acceptable salt or prodrug and prepare the purposes in anti-bacterial drug.
Further, described bacterium be intestinal bacteria, addicted to Fructus Hordei Germinatus Zymomonas mobilis, promise luxuriant and rich with fragrance acinetobacter calcoaceticus, Staphylococcus aureus or staphylococcus epidermidis.
Present invention also offers Compound I h or its pharmacy acceptable salt or the prodrug purposes in the medicine of the luxuriant and rich with fragrance acinetobacter calcoaceticus of the anti-promise of preparation.
Present invention also offers a kind of pharmaceutical composition, it is the preparation containing above-claimed cpd or its pharmacy acceptable salt or prodrug.
In one embodiment of the present invention, further comprises isotope-labeled above-claimed cpd or its pharmacy acceptable salt, described compound isotopically labelled refers to listed Compound Phase is same herein, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from the common atomic mass of occurring in nature or total mass number.The isotropic substance can introduced in compound comprises hydrogen, carbon, nitrogen, oxygen, sulphur, i.e. 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S.Compound containing above-mentioned isotropic substance and/or other atom isotope and steric isomer thereof, and this compound, steric isomer pharmaceutically useful salt all should be included within the scope of the invention.
The present invention can adopt preparation technique means or the pharmaceutical methods of this area routine, the compounds of this invention is prepared into suitable medicine type, comprise: tablet, injection, tincture, suppository, capsule, paste (ointment, ointment), ophthalmic preparation, pill, implant, syrup, mist agent (aerosol, powder inhalation, sprays), film, granule, oral solution (oral suspensions, Orally taken emulsion), powder, aural preparations, nasal formulations, lotion (irrigation, enema), liniment (paint, liniment), gelifying agent, patch etc., be preferably tablet, capsule, ophthalmic preparation.Wherein, described tablet is selected from lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc.; Described injection is selected from injection, transfusion, freeze-dried powder, emulsion, implant, microball preparation, pellet preparations etc.; Described capsule is selected from hard capsule, soft capsule, slow releasing capsule, controlled release capsule and enteric coated capsule etc.; Described ophthalmic preparation is selected from eye drops, eye wash, intraocular injection solution, Eye ointments, eye ointment, gel for eye, eye mask agent, eye pill, intraocular intercalating agent etc.; Described pill is selected from dripping pill, sugar-pill etc.; Described granule is selected from mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Described aural preparations is selected from ear drop, ear lotion, ear sprays, ear ointment, ear ointment, ear gelifying agent, earplug, ear powder, ear pill etc.; Described nasal formulations is selected from nasal drop, nasal douche, nasal spray, nose ointment, gel for nose, nose powder, powder nose inhalant, nose stylus etc.
Compound provided by the invention, has certain anti-microbial activity, can it can be used as antibacterial potential drug, for clinical application provides new selection.
Below by way of embodiment, the present invention is described in further detail, but do not limit the present invention, those skilled in the art can make various change and distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Embodiment
Embodiment 1
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ia compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 90% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakOD-H post records ee value, UV254nm, t minor=10.98min, t major=11.98min; Fusing point: 138 ~ 139 DEG C; Specific rotatory power [α] d 20-450 (c=0.10inEtOH).
1hNMR (400MHz, CDCl 3): δ=7.90 (d, J=7.6Hz, 2H), 7.46-7.43 (m, 1H), 7.32-7.26 (m, 2H), 7.11-7.07 (m, 8H), 6.94 (s, 2H), 4.88 (t, J=5.6Hz, 1H), 3.03 (dd, J 1=18.0Hz, J 2=8.8Hz, 1H), 2.88 (dd, J 1=18.0Hz, J 2=3.2Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=195.29,175.24,137.31,135.33,133.59,133.42,130.95,128.79,128.45,128.27,128.19,128.07,127.26,124.68,95.07,47.94,35.53ppm; ESIHRMS: calculated value C 23h 18o 3+ Na365.1154, measured value 365.1151.
Embodiment 2
Get 10mL reaction tube, add o-chlorobenzaldehyde 281mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ib compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 90% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakOD-H post records ee value, UV254nm, t minor=9.97min, t major=11.10min. fusing point: 144 ~ 145 DEG C; [α] d 20-156.3 (c=0.03inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.57 (d, J=7.2Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 7.26-7.21 (m, 1H), 7.12-6.93 (m, 10H), 5.05 (d, J=8.8Hz, 1H), 3.62 (dd, J 1=18.0Hz, J 2=9.2Hz, 1H), 2.71 (d, J=18.0Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.46,175.25,139.28,134.30,134.02,133.48,131.81,131.11,130.70,129.80,129.70,129.32,128.21,127.93,127.38,126.77,125.48,94.29,45.32,37.97ppm; ESIHRMS: calculated value C 23h 16cl 2o 3+ Na433.0374, measured value 433.0375.
Embodiment 3
Get 10mL reaction tube, add 4-chloro-benzaldehyde 281mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ic compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 92% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=9.68min, t major=12.32min. fusing point: 54 ~ 55 DEG C; [α] d 20-250 (c=0.1inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.84 (d, J=8.4Hz, 2H), 7.31-7.29 (m, 2H), 7.11-7.09 (m, 5H), 6.98-6.93 (m, 4H), 4.85 (dd, J 1=8.0Hz, J 2=5.6Hz, 1H), 3.03 (dd, J 1=18.0Hz, J 2=8.4Hz, 1H), 2.87 (dd, J 1=18.0Hz, J 2=5.6Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.84,174.65,140.29,136.89,134.49,133.76,132.27,131.61,128.79,128.76,128.63,128.35,127.62,126.07,94.48,47.75,35.38ppm; ESIHRMS: calculated value C 23h 16cl 2o 3+ Na433.0374, measured value 433.0375.
Embodiment 4
Get 10mL reaction tube, add 3-bromobenzaldehyde 370mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Id compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 92% (10%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakOD-H post records ee value, UV270nm, t minor=13.18min, t major=15.51min. fusing point: 126 ~ 127 DEG C; [α] d 20-175.0 (c=0.10inEtOH);
1hNMR (400MHz, CDCl 3): δ=8.08 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.60-7.56 (m, 1H), 7.25-7.23 (m, 1H), 7.20-7.16 (m, 2H), 7.11 (m, 3H), 7.00-6.91 (m, 4H), 4.84 (t, J=6.8Hz, 1H), 3.03 (dd, J 1=18.0Hz, J 2=8.4Hz, 1H), 2.88 (dd, J 1=18.0Hz, J 2=5.2Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.60,174.52,137.25,136.73,136.55,135.04,133.47,131.57,130.07,129.94,129.60,128.59,128.32,127.78,127.70,123.26,122.92,122.68,94.20,47.94,35.24ppm; ESIHRMS: calculated value C 23h 16br 2o 3+ Na520.9364, measured value 520.9361.
Embodiment 5
Get 10mL reaction tube, add p-bromobenzaldehyde 370mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ie compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 94% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV254nm, t minor=10.94min, t major=13.64min. fusing point: 143 ~ 144 DEG C; [α] d 20-288.5 (c=0.052inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.76 (d, J=8.4Hz2H), 7.47 (d, J=8.0Hz1H), 7.26-7.24 (m, 3H), 7.11 (s, 3H), 6.91-6.89 (m, 3H), 4.84 (t, J=6.4Hz1H), 3.03 (dd, J 1=18.0Hz, J 2=8.4Hz, 1H), 2.87 (dd, J 1=18.0Hz, J 2=5.2Hz1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.85,174.58,136.83,134.26,132.31,132.01,131.78,131.74,129.19,128.62,128.36,127.64,126.34,122.68,94.50,47.70,35.37ppm; ESIHRMS: calculated value C 23h 16br 2o 3+ Na520.9364, measured value 520.9362.
Embodiment 6
Get 10mL reaction tube, add p-Fluorobenzenecarboxaldehyde 248mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula If compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 92% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=16.58min, t major=25.25min. fusing point: 127 ~ 128 DEG C; [α] d 20-100 (c=0.1inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.95 (s, 2H), 7.10 (brs, 3H), 7.01-7.00 (m, 4H), 6.92 (m, 2H), 6.83-6.79 (m, 2H), 4.86 (t, J=6.0Hz, 1H), 3.03 (dd, J 1=18.0Hz, J 2=8.4Hz, 1H), 2.88 (dd, J 1=18.0Hz, J 2=4.8Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.59,174.82,137.10,133.82,133.73,131.12,129.70,128.65,128.27,127.50,126.58,126.49,115.70,115.49,94.57,47.81,35.38ppm; ESIHRMS: calculated value C 23h 16f 2o 3+ Na401.0965, measured value 401.0961.
Embodiment 7
Get 10mL reaction tube, add 2 successively, 4-chlorobenzaldehyde 439mg (2mmol), VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ig compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 99% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV210nm, t minor=6.84min, t major=9.13min. fusing point: 148 ~ 149 DEG C; [α] d 20-50 (c=0.10inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.49 (d, J=8.4Hz, 1H), 7.43 (s, 1H), 7.19-7.17 (m, 1H), 7.07-6.97 (m, 8H), 4.98 (d, J=8.8Hz, 1H), 3.61 (dd, J 1=18.0Hz, J 2=9.2Hz, 1H), 2.82 (d, J=18.4Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=192.09,174.73,138.86,137.85,135.08,134.85,132.83,132.17,131.36,131.33,130.30,129.68,128.73,128.46,127.75,127.25,126.03,93.71,45.39,37.76ppm; ESIHRMS: calculated value C 23h 14cl 4o 3+ Na500.9595, measured value 500.9593.
Embodiment 8
Get 10mL reaction tube, add cumic aldehyde 296mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ih compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 94% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV254nm, t minor=6.43min, t major=7.74min. fusing point: 132 ~ 133 DEG C; [α] d 20-130.2 (c=0.096inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.86 (d, J=8.4Hz, 2H), 7.17-7.15 (m, 2H), 7.04-7.03 (m, 3H), 6.96-6.88 (m, 6H), 4.83 (dd, J 1=8.4Hz, J 2=6.4Hz, 1H), 2.99 (dd, J 1=18.0Hz, J 2=8.8Hz, 1H), 2.90-2.83 (m, 2H), 2.77-2.71 (m, 1H), 1.20-1.18 (m, 6H), 1.12-1.09 (m, 6H) ppm; 13cNMR (100MHz, CDCl 3): δ=195.06,175.47,154.91,148.99,137.40,132.71,131.44,131.32,128.85,127.86,127.06,126.39,124.57,95.20,48.04,35.40,34.24,33.60,23.77,23.53,23.47ppm; ESIHRMS: calculated value C 29h 30o 3+ Na449.2093, measured value 449.2091.
Embodiment 9
Get 10mL reaction tube, add furfural 192mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ii compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 89% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=22.59min, t major=28.17min. fusing point: 126 ~ 127 DEG C; [α] d 20+ 12 (c=0.12inCH 2cl 2);
1HNMR(400MHz,CDCl 3):δ＝7.65(s,1H),7.32(d,J＝6.0Hz1H),7.18(brs,4H),7.09(brs,2H),6.49(s,1H),6.15(d,J＝8.8Hz,2H),4.70(t,J＝8.4Hz,1H),3.11-2.97(m,2H)ppm； 13CNMR(100MHz,CDCl 3):δ＝181.03,174.27,149.14,148.16,147.95,143.20,136.25,128.29,128.24,127.66,123.13,112.56,110.58,109.38,89.67,46.69,34.42ppm；ESIHRMS:calcd.ForC 19H 14O 5+Na345.0739,found345.0740.
Embodiment 10
Get 10mL reaction tube, add thiophenecarboxaldehyde 224mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add phenylacrolein 92.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ij compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 90% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=18.82min, t major=23.26min. fusing point: 90`91 DEG C; [α] d 20+ 50 (c=0.10inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.98 (d, J=3.6Hz, 1H), 7.66 (d, J=4.8Hz, 1H), 7.16-7.05 (m, 7H), 6.75-6.72 (m, 1H), 6.60-6.59 (m, 1H), (4.75 t, J=7.2Hz, 1H), (3.06-2.93 m, 2H) ppm; 13cNMR (100MHz, CDCl 3): δ=187.83,174.24,139.34,138.10,136.77,136.63,135.76,128.70,128.61,128.18,127.67,127.10,126.17,126.09,48.18,34.96ppm; ESIHRMS: calculated value C 19h 14o 3s 2+ Na377.0282, measured value 377.0280.
Embodiment 11
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add chlorocinnamaldehyde 116.6mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ik compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 95% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV254nm, t minor=12.08min, t major=16.11min. fusing point: 123 ~ 124 DEG C; [α] d 20-50 (c=0.10inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.89 (d, J=8.0Hz, 2H), 7.47-7.43 (m, 1H), 7.32-7.29 (m, 2H), 7.15 (brs, 3H), 7.06-7.04 (m, 4H), 6.86 (d, J=7.6Hz, 2H), 4.85 (t, J=7.6Hz, 1H), 3.01 (dd, J 1=18.0Hz, J 2=8.4Hz, 1H), 2.82 (dd, J 1=18.0Hz, J 2=6.4Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=194.03,173.71,134.67,134.01,132.50,132.41,132.18,129.91,129.10,127.65,127.46,127.26,127.17,123.58,93.64,46.37,34.28ppm; ESIHRMS: calculated value C 23h 17clO 3+ Na399.0764, measured value 399.0762.
Embodiment 12
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add bromocinnamaldehyde 147.7mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Il compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 95% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=12.79min, t major=17.68min. fusing point: 149 ~ 150 DEG C; [α] d 20-89.3 (c=0.12inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.89 (d, J=8.0Hz, 2H), 7.46-7.43 (m, 1H), 7.32-7.28 (m, 2H), 7.21-7.15 (m, 5H), 7.04 (brs, 2H), 6.80 (d, J=8.0Hz, 2H), 4.83 (t, J=7.6Hz, 1H), 3.01 (dd, J 1=18.0Hz, J 2=8.8Hz, 1H), 2.81 (dd, J 1=18.0Hz, J 2=6.4Hz, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=195.04,174.70,136.23,135.02,133.53,133.44,131.16,130.94,130.49,128.70,128.52,128.30,124.62,121.37,94.59,47.48,35.26ppm; ESIHRMS: calculated value C 123h 17brO 3+ Na443.0259, measured value 443.0257.
Embodiment 13
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add a fluorine phenylacrolein 105.1mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Im compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 95% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=10.57min, t major=12.96min. fusing point: 129 ~ 130 DEG C; [α] d 20-97.7 (c=0.13inEtOH);
1HNMR(400MHz,CDCl 3):δ＝7.90(d,J＝8.0Hz,2H),7.47-7.43(m,1H),7.33-7.29(m,2H),7.15-7.14(m,3H),7.07-7.02(m,3H),6.79-6.73(m,2H),6.65(d,J＝10.0Hz,1H),4.88(t,J＝7.2Hz,1H),3.03(dd,J 1＝18.0Hz,J 2＝8.8Hz,1H),2.86(dd,J 1＝18.0Hz,J 2＝6.0Hz,1H)ppm； 13CNMR(100MHz,CDCl 3):δ＝193.93,173.68,162.55,160.10,138.84,138.76,134.00,132.50,132.38,129.94,128.55,128.46,127.58,127.41,127.26,123.53,123.37,123.34,114.99,114.78,113.31,113.10,93.73,46.55,34.24ppm；ESIHRMS:calcd.ForC 23H 17FO 3+Na383.1059,found383.1057.
Embodiment 14
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add methyl cinnamic aldehyde 102.3mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula In compound.
Proterties is white solid, and productive rate 52%, dr value is 95:5, and it is 95% (5%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAmycoat post records ee value, UV270nm, t minor=11.13min, t major=12.73min. fusing point: 99 ~ 100 DEG C; [α] d 20-300.0 (c=0.10inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.90 (d, J=7.6Hz, 2H), 7.45-7.41 (m, 1H), 7.31-7.27 (m, 2H), 7.12-7.11 (m, 3H), 7.065-7.056 (m, 2H), 6.87 (d, J=8.0Hz, 2H), 6.81 (d, J=8.0Hz, 2H), 4.83 (t, J=7.2Hz, 1H), 2.99 (dd, J 1=17.6Hz, J 2=8.4Hz, 1H), 2.84 (dd, J 1=18.0Hz, J 2=6.0Hz, 1H), 2.19 (s, 3H) ppm; 13cNMR (100MHz, CDCl 3): δ=195.40,175.32,136.91,135.38,134.15,133.78,133.36,130.92,128.74,128.66,128.44,128.25,128.17,124.76,95.06,47.68,35.64,20.96ppm; ESIHRMS: calculated value C 24h 20o 3+ Na379.1310, measured value 379.1312.
Embodiment 15
Get 10mL reaction tube, add 4-chloro-benzaldehyde 281mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add propenal 39.2mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Io compound.
Proterties is white semi-solid, and productive rate 52%, dr value is 95:5, and it is 95% (2%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakAS-H post records ee value, UV254nm, t minor=18.24min, t major=20.52min. [α] d 20-83.3 (c=0.06inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.89 (d, J=8.4Hz, 2H), 7.39 (brs, 4H), 7.32 (d, J=8.4Hz, 2H), 3.46-3.39 (m, 1H), 2.61-2.56 (m, 2H), 2.32-2.25 (m, 1H) ppm; 13cNMR (100MHz, CDCl 3): δ=193.72,175.03,140.33,137.65,134.88,132.13,131.52,129.64,128.80,125.17,91.49,34.17,27.88ppm; ESIHRMS: calculated value C 17h 12cl 2o 3+ Na357.0061, measured value 357.0060.
Embodiment 16
Get 10mL reaction tube, add phenyl aldehyde 212mg (2mmol) successively, VB190mg (0.3mmol), with 2mL acetonitrile as solvents, drip aqueous sodium hydroxide solution, adjust pH to 9-10, in 60 DEG C of stirring reactions, thin layer is followed the trail of, question response reaches balance rear (about 1.5h), directly add crotonaldehyde 49.5mg (0.7mmol), diphenylprolinol silicon ether 65mg (0.2mmol), phenylformic acid 212mg (1.8mmol) and toluene 2mL, be heated to 120 DEG C and continue reaction, thin layer is followed the trail of, after reaction terminates, vacuum rotary steam removing reaction solvent---toluene and acetonitrile, silicagel column on residue, sherwood oil: ethyl acetate=15:1 wash-out, obtain the first step crude product 138mg (0.4mmol).Gained reaction product is dissolved in 2mL methylene dichloride, add pyridinium chlorochromate 172mg (0.8mmol), stirring reaction at 50 DEG C, reaction to be oxidized terminates rear filtration, be spin-dried for liquid portion methylene chloride, silicagel column on residue, sherwood oil: ethyl acetate=50:1 wash-out, obtains formula Ip compound.
Proterties is white semi-solid, and productive rate 52%, dr value is 95:5, and it is 95% (2%2-propanol/n-hexane, 1mL/min) that high performance liquid phase ChiralpakOD-H post records ee value, UV270nm, t minor=7.99min, t major=12.63min. [α] d 20+ 125 (c=0.06inEtOH);
1hNMR (400MHz, CDCl 3): δ=7.81 (d, J=8.4Hz, 2H), 7.59-7.27 (m, 8H), 3.63 (m, 1H), 2.75 (dd, J 1=17.6Hz, J 2=8.0Hz, 1H), 2.28 (dd, J 1=17.6Hz, J 2=4.8Hz, 1H), 0.77 (d, J=7.2Hz, 3H) ppm; 13cNMR (100MHz, CDCl 3): δ=194.30,174.58,140.21,134.93,133.84,132.17,131.68,129.50,128.75,125.90,93.93,36.81,36.43,16.52ppm; ESIHRMS: calculated value C 18h 16o 3+ Na303.0997, measured value 303.0995.
Beneficial effect of the present invention is illustrated below by way of test example.
Test example 1 anti-microbial activity is studied
Adopt the anti-microbial activity of each compound of equimultiple By Dilution
First dissolved by the compound 2mlDMSO of accurate weighing, do 10 concentration gradients respectively by equimultiple dilution method, each gradient adds 1ml containing drug solns in MH culture dish, and with the mixing of 14mlMH solid medium, makes the culture dish that pastille is different.Then be 10 with the punch tool in 27 holes by bacteria containing amount 6bacterium liquid be inoculated on culture dish, put into the constant incubator of 37 DEG C, cultivate 18-24h, observe inoculation position whether have bacterial growth, to judge its fungistatic effect.Result is as shown in Table 1 and Table 2:
The mensuration of the anti-microbial activity MIC (mg/ml) of table 1 Compound I a ~ Ig
Note: "-" represents when concentration is 2mg/ml, and this compound does not have anti-microbial activity to this kind of bacterial strain.The bacterial strain of above-mentioned use, except reference culture, all the other are all clinical separation strains.
The mensuration of the anti-microbial activity MIC (mg/ml) of table 2 Compound I h ~ In
Note: "-" represents when concentration is 2mg/ml, and this compound does not have anti-microbial activity to this kind of bacterial strain.The bacterial strain of above-mentioned use, except reference culture, all the other are all clinical separation strains.
From above-mentioned test, compound provided by the invention has certain anti-microbial activity, and each compound is also because of textural difference, also different to the anti-microbial activity of identical bacterial strain.Wherein, Compound I h only has anti-microbial activity to the luxuriant and rich with fragrance acinetobacter calcoaceticus of promise, and to other common bacteria if intestinal bacteria, S. aureus L-forms, form staph are without anti-microbial effect, can, using the narrow spectrum antibiotic thing of Compound I h as the luxuriant and rich with fragrance acinetobacter of exclusive treatment promise, can avoid making other bacteriums produce resistance.In addition, Compound I m all has obvious anti-microbial effect to the various bacteriums provided in the present invention, and its antimicrobial spectrum is the widest, it can be used as potential extensive pedigree antibiotic.

Claims (10)

1. such as formula the compound shown in I or its pharmacy acceptable salt,
R 1, R 3independently be selected from H, C1-4 alkyl, 1 ~ 3 halogen;
R 2be selected from phenyl or substituted-phenyl, its substituting group is halogen or C1-4 alkyl;
Wherein, R is worked as 2during for phenyl, R 1and R 3be asynchronously H.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that: described compound structure is such as formula shown in II:
3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that: R 1, R 3independently be selected from H, C1-4 alkyl, 1 ~ 2 halogen.
4. compound according to claim 3 or its pharmacy acceptable salt, is characterized in that: described C1-4 alkyl is selected from methyl or propyl group.
5. compound according to claim 4 or its pharmacy acceptable salt, is characterized in that: described compound is one of following:
6. the compound according to Claims 1 to 5 any one or its pharmacy acceptable salt, is characterized in that: described pharmacy acceptable salt is the hydrochloride of compound, vitriol, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid salt, acetate, propionic salt, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
7. compound described in claim 1 ~ 6 any one or its pharmacy acceptable salt are preparing the purposes in anti-bacterial drug.
8. purposes according to claim 7, is characterized in that: described bacterium is intestinal bacteria, addicted to Fructus Hordei Germinatus Zymomonas mobilis, promise luxuriant and rich with fragrance acinetobacter calcoaceticus, Staphylococcus aureus or staphylococcus epidermidis.
9. Compound I h described in claim 5 or its pharmacy acceptable salt purposes in the medicine of the luxuriant and rich with fragrance acinetobacter calcoaceticus of the anti-promise of preparation.
10. a pharmaceutical composition, is characterized in that: it is the preparation containing compound described in claim 1 ~ 6 any one or its pharmacy acceptable salt.
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