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.