CN108383806A - A kind of preparation method of dimerization fluostatins class antibiotic - Google Patents
A kind of preparation method of dimerization fluostatins class antibiotic Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
- C07D303/06—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms in which the oxirane rings are condensed with a carbocyclic ring system having three or more relevant rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
The invention discloses a kind of preparation methods of dimerization fluostatins class antibiotic.It is using acyl group fluostatins as raw material; the reaction overnight in the proton solvents such as water or methanol; acyl group fluostatins forms a paraquinones ketone methide intermediate by non-enzymatic deacylation; again through 1; 6 nucleophilic additions obtain the dimerization fluostatins crude products of C C/C N couplings, and the dimerization fluostatins class antibiotic for obtaining high-purity is isolated and purified through half preparative high-performance liquid chromatographic.Its dimerization of the preparation method of the present invention is not necessarily to catalyst, and normal temperature and pressure, the time is relatively short, easy to operate, and product yield is high, stable quality, feature at low cost, is effective way prepared by high-purity dimerization fluostatins.
Description
Technical field：
The invention belongs to aromatic polyketones chemical industrial fields, and in particular to a kind of dimerization fluostatins class antibiotic
Preparation method.
Background technology：
Fluostatins (FSTs) is comprising plain (angucycline) aromatic polyketones of the fluorene structured atypia square ring of benzo
There is good antibacterial, antitumor and dipeptidase to inhibit isoreactivity for class compound, structure novel.
Invention content：
The object of the present invention is to provide a kind of environmentally protective, easy to operate, at low cost, product yield is high, stable quality
The preparation method of dimerization fluostatins class antibiotic.
The preparation method of the dimerization fluostatins class antibiotic of the present invention includes the following steps：
Using acyl group fluostatins classes compound as raw material, paraquinones ketone methide intermediate is formed in proton solvent,
With nucleopilic reagent dimerization fluostatins class antibiotic is obtained through 1,6- nucleophilic additions.
The acyl group fluostatins classes compound can be fluostatin D, fluostatin G/H,
The acyl groups fluostatins class compounds such as fluostatin J or fluostatin L.
The proton solvent is preferably the proton solvents such as water or methanol.
The nucleopilic reagent can be for acyl group fluostatins classes combound itself or with each of preferable nucleophilic reactivity
Kind nucleopilic reagent.
Dimerization fluostatins class antibiotic, generally crude product are obtained through 1,6- nucleophilic additions, if it is desired to obtaining pure change
Object is closed, is needed by isolating and purifying, described isolating and purifying is by dimerization fluostatins class antibiotic crude product ethyl acetate
Extraction is concentrated under reduced pressure removal organic solvent and obtains ethyl acetate portion, i.e. dimerization fluostatins crude products, uses Hitachi-
L2130 (two level array detector, Hitachi L-2455) half preparative high-performance liquid chromatographic (semi-HPLC) isolates and purifies, color
Spectrum column is Phenomenex C18 (250mm × 10mm, 2.5mL min-1), mobile phase includes A phases and B phases, mobile phase A phase：
The formic acid of the acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction), solvent are water, Mobile phase B phase：90% (volume fraction)
Acetonitrile, solvent is water；Injection procedure：0-20 minute, mobile phase ratio was A phases/B phases (volume ratio)：95:5-20:80,20-
21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：20:80-0:100,21-24 minutes, mobile phase ratio was A phases/B phases
(volume ratio)：0:100,24-25 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:100-95:5,25-30min, flowing
Phase Proportion is A phases/B phases (volume ratio)：95:5, flow velocity 2.5mL min-1, obtain the dimerization fluostatins class antibiosis of high-purity
Element.
It is preferred that when raw material is fluostatin D, when proton solvent is water, the dimerization fluostatins class antibiosis
Element is compound 6；
Or when raw material is fluostatin J, and proton solvent is water, the dimerization fluostatins class antibiotic is
Compound 6 and 7；
Or when raw material is fluostatin D, and proton solvent is methanol, the dimerization fluostatins class antibiotic
For compound 8；
Or when raw material is fluostatin D, proton solvent is water, and when nucleopilic reagent is 2- amino-5-methylphenols, institute
The dimerization fluostatins class antibiotic stated is compound 9；
Or when raw material is fluostatin D, proton solvent is water, described when nucleopilic reagent is trimethoxy benzyl Aminometradine
Dimerization fluostatins class antibiotic be compound 10 and 11；
The compound 6,7,8,9,10 and 11 structures is as follows：
The present invention is incubated overnight using acyl group fluostatins classes compound as raw material in the proton solvents such as water or methanol,
Acyl group fluostatins forms a paraquinones ketone methide intermediate by non-enzymatic deacylation, then is obtained through 1,6- nucleophilic additions
The dimerization fluostatins crude products of C-C/C-N couplings, the dimerization for obtaining high-purity is isolated and purified through half preparative high-performance liquid chromatographic
Fluostatins class antibiotic.Preparation method its dimerization of the present invention is not necessarily to catalyst, normal temperature and pressure, and the time is opposite
Shorter, easy to operate, product yield is high, and stable quality, feature at low cost is prepared by high-purity dimerization fluostatins
Effective way
Description of the drawings：
Fig. 1 is two steps that acyl group fluostatins classes compound non-enzymatic catalysis deacylation is formed and proposed along with dimer
Method Forming Mechanism.
(a) de-acyl reaction of HPLC analyses：(i) FST D (1) standard items；(ii) FST D (1) are incubated overnight in water；
(iii) FST D (1) are incubated overnight in methyl alcohol；(iv) FST J (2) standard items；(v) FST J (2) are incubated overnight in water.
(b) the spontaneous deacylation and adjoint dimerization Forming Mechanism proposed, 1,2,3,4,5,6,7,8 respectively representing in Fig. 1 a
Object 1,2,3,4,5,6,7,8 is closed, it is corresponding with the compound in Fig. 1 b.
Fig. 2 is the structure of compound 5~11.
Fig. 3 be the key that compound 6~11 HMBC,1H-1H COSY are related to NOESY.
Fig. 4 is to co-culture FST D (1) and 2- amino-5-methylphenols synthesis compound 9.(a) HPLC analyses coupling is anti-
It answers：(i) FST D (1) standard items；(ii) 2- amino-5-methylphenols standard items；(iii) FST D (1) and 2- amino -5- methyl
Phenol co-cultures overnight in water.(b) Forming Mechanism of the coupling product proposed, in Fig. 4 a 1,6,9 respectively represent compound 1,
6,9, it is corresponding with the compound in Fig. 4 b.
Fig. 5 is to co-culture FST D (1) and trimethoxy benzyl Aminometradine.(a) HPLC analyzes coupled reaction：(i)FST D(1)
Standard items；(ii) trimethoxy benzyl Aminometradine standard items；(iii) FST D (1) and trimethoxy benzyl Aminometradine co-culture in water
Overnight.(b) what is proposed couples the Forming Mechanism of product, and 1,5,10,11 respectively represent compound 1,5,10,11 in Fig. 5 a, with figure
Compound in 5b is corresponding.
Specific implementation mode：
The following examples are further illustrations of the invention, rather than limiting the invention.
Embodiment 1：
By 16.0mg fluostatin D (the FST D in 1, i.e. Fig. 1 b) soluble in water, ambient temperature overnight culture (Fig. 1).Instead
It answers liquid to be extracted with isometric ethyl acetate, removal organic solvent is concentrated under reduced pressure and obtains ethyl acetate portion, i.e. dimerization
Fluostatins crude products prepare efficient liquid phase with Hitachi-L2130 (two level array detector, Hitachi L-2455) half
Chromatography (semi-HPLC) isolates and purifies, and chromatographic column is Phenomenex C18 (250mm × 10mm, 2.5mLmin-1), mobile phase
Including A phases and B phases, mobile phase A phase：The formic acid of the acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction), solvent is water, stream
Dynamic phase B phases：The acetonitrile of 90% (volume fraction), solvent are water；Injection procedure：0-20 minute, mobile phase ratio was A phases/B phases
(volume ratio)：95:5-20:80,20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：20:80-0:100,21-24 points
Clock, mobile phase ratio are A phases/B phases (volume ratio)：0:100,24-25 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:
100-95:5,25-30min, mobile phase ratio is A phases/B phases (volume ratio)：95:5, flow velocity 2.5mL min-1, isolate and purify
To compound 6 (retention time 18.0min).By structural analysis, the compound 6 (Fig. 2) that the present invention is prepared is carried out
Identification, qualification result are as follows：
The negative source high-resolution electrospray ionization mass spectrum figure of compound 6 shows that its quasi-molecular ion peak is m/z [M-H]-629.1093
Speculate that its molecular formula is C36H22O11.Nuclear-magnetism (NMR) data (table 1) for carefully analyzing compound 6 show that the compound is to pass through C-
Fluostatin C (Zhang, the W.J. of 1/C-10 ' couplings；Liu,Z.；Li,S.M.；et al.,J.Nat.Prod.2012,
75,1937-1943) dimer.From H-1 to C-9 '/C-10 '/C-10a ' and H-9 ' to the HMBC of C-1 related (Fig. 3) further
Confirm above-mentioned supposition.Because compound 6 is from fluostatin D (1) spontaneous generation, its absolute configuration is speculated as 1R,
2S, 3S, 1 ' R, 2 ' S ' and 3 ' S.
According to information above, the structure of compound 6 is determined as shown in Fig. 2, being named as：difluostatin F.
Embodiment 2：
By 16.0mg fluostatin J (the FST J in 2, i.e. Fig. 1 b) soluble in water, ambient temperature overnight culture (Fig. 1).Instead
It answers liquid to be extracted with isometric ethyl acetate, removal organic solvent is concentrated under reduced pressure and obtains ethyl acetate portion, i.e. dimerization
Fluostatins crude products prepare efficient liquid phase with Hitachi-L2130 (two level array detector, Hitachi L-2455) half
Chromatography (semi-HPLC) isolates and purifies, and chromatographic column is Phenomenex C18 (250mm × 10mm, 2.5mLmin-1), mobile phase
Including A phases and B phases, mobile phase A phase：The formic acid of the acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction), solvent is water, stream
Dynamic phase B phases：The acetonitrile of 90% (volume fraction), solvent are water；Injection procedure：0-20 minute, mobile phase ratio was A phases/B phases
(volume ratio)：95:5-20:80,20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：20:80-0:100,21-24 points
Clock, mobile phase ratio are A phases/B phases (volume ratio)：0:100,24-25 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:
100-95:5,25-30min, mobile phase ratio is A phases/B phases (volume ratio)：95:5, flow velocity 2.5mL min-1, isolate and purify
To compound 6 (retention time 18.0min) and 7 (retention time 24.2min).By structural analysis, prepared by the present invention
Obtained compound 7 (Fig. 2) is identified that qualification result is as follows：
The negative source high-resolution electrospray ionization mass spectrum figure of compound 7 shows that its quasi-molecular ion peak is m/z [M-H]-713.1662
Speculate that its molecular formula is C41H30O12.Carefully analyze compound 71H and13C nuclear-magnetisms (NMR) data (table 1) show the compound
It is a dimer, and similar to 6 height of compound.The middle positions C-1 ' of compound 7 unlike unique are 2- methylbutyryls.
Spin System H3-17′/H14′/H2-15′/H3- 16 ' COSY related (Fig. 3) and from H-1 ' (δH7.00) C-13 ' (δ are arrivedC
175.1) HMBC related (Fig. 3) further demonstrates above-mentioned supposition.In addition, NOESY correlations show 7 chiral centre of compound
Configuration is consistent with compound 6.Therefore the absolute configuration of compound 7 is speculated as 1R, 2S, 3S, 1 ' R, 2 ' S ' and 3 ' S.
According to information above, the structure of compound 7 is determined as shown in Fig. 2, being named as：difluostatin G.
Embodiment 3：
16.0mg fluostatin D (1) are dissolved in methanol, ambient temperature overnight culture (Fig. 1).The isometric second of reaction solution
Acetoacetic ester extracts, and removal organic solvent is concentrated under reduced pressure and obtains ethyl acetate portion, i.e. dimerization fluostatins crude products, uses
Hitachi-L2130 (two level array detector, Hitachi L-2455) half preparative high-performance liquid chromatographic (semi-HPLC) detaches
Purifying, chromatographic column are Phenomenex C18 (250mm × 10mm, 2.5mL min-1), mobile phase includes A phases and B phases, mobile phase
A phases：The formic acid of the acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction), solvent are water, Mobile phase B phase：90% (volume point
Number) acetonitrile, solvent is water；Injection procedure：0-20 minute, mobile phase ratio was A phases/B phases (volume ratio)：95:5-20:80,
20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：20:80-0:100,21-24 minutes, mobile phase ratio was A phases/B
Phase (volume ratio)：0:100,24-25 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:100-95:5,25-30min, stream
Dynamic Phase Proportion is A phases/B phases (volume ratio)：95:5, flow velocity 2.5mL min-1, isolating and purifying to obtain compound 8, (retention time is
20.5min).By structural analysis, the compound 8 (Fig. 2) that the present invention is prepared identifies that qualification result is as follows：
The negative source high-resolution electrospray ionization mass spectrum figure of compound 8 shows that its quasi-molecular ion peak is m/z [M-H]-643.1239
Speculate that its molecular formula is C37H24O11.Nuclear-magnetism (NMR) data (table 1) of compound 8 show that the compound is also a dimer,
Including two fluostatin C samples monomer A units and unit B.From H-1 to C-9 '/C-10 '/C-10a ' and H-9 ' arrive C-1's
HMBC correlations (Fig. 3) confirm that A units and unit B are by C-1/C-10 ' connections.
According to information above, the structure of Compound Compound 8 is determined as shown in Fig. 2, being named as：difluostatin H.
Embodiment 4：
By compound 2- amino-5-methylphenols (0.16mmol, 20.0mg) and fluostatin D (0.04mmol,
It is 16.0mg) soluble in water, ambient temperature overnight culture (Fig. 4).Reaction solution is extracted with isometric ethyl acetate, and it is organic that removal is concentrated under reduced pressure
Solvent obtains ethyl acetate portion.It is prepared with Hitachi-L2130 (two level array detector, Hitachi L-2455) half efficient
Liquid chromatogram (semi-HPLC) isolates and purifies, and chromatographic column is Phenomenex C18 (250mm × 10mm, 2.5mL min-1), stream
Dynamic includes mutually A phases and B phases, mobile phase A phase：The formic acid of the acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction), solvent are
Water, Mobile phase B phase：The acetonitrile of 90% (volume fraction), solvent are water；Injection procedure：0-20 minute, mobile phase ratio be A phases/
B phases (volume ratio)：95:5-20:80,20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：20:80-0:100,21-
24 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:100,24-25 minutes, mobile phase ratio was A phases/B phase (volumes
Than)：0:100-95:5,25-30min, mobile phase ratio is A phases/B phases (volume ratio)：95:5, flow velocity 2.5mL min-1, separation
Purifying obtains compound 9 (retention time 15.5min).By structural analysis, the compound 9 that the present invention is prepared (figure
2) it is identified, qualification result is as follows：
The negative source high-resolution electrospray ionization mass spectrum figure of compound 9 shows that its quasi-molecular ion peak is m/z [M-H]-428.1148
Speculate that its molecular formula is C25H19NO6.1D and 2D nuclear-magnetisms (NMR) data (table 2) for carefully analyzing compound 9 show the compound packet
Containing a fluostatin C samples unit and 2- amino-5-methylphenol units.From H-1 (δH5.01) C-2 ' (δ are arrivedC
137.1), NH (δH5.05) C-1/C-2/C-1 '/C-2 '/C-3 ' and H is arrived3-12(δH1.49) C-1 ' (δ are arrivedC144.7)
HMBC correlations (Fig. 3) confirm that two units are by C-1-N-C-2 ' and C-3-O-C-1 ' connections.According to H-1's and H-2
Coupling constant (3JH1-H22.8Hz) and H-2 (δHAnd NH (δ 4.13)H5.05) NOESY related (Fig. 3) determines the H- of compound 9
1 and H-2 is anti-configuration.Finally, it is contemplated that compound 9 is generated by fluostatin D chemical derivatizations, determines it absolutely
It is configured as 1R, 2S and 3R.
According to information above, determine the structure of compound 9 as shown in 9 in Fig. 2.
Embodiment 5：
By compound trimethoxy benzyl Aminometradine (trimethoprim, 0.16mmol, 47.0mg) and fluostatin D
(0.04mmol, 16.0mg) is soluble in water, ambient temperature overnight culture (Fig. 5).Reaction solution is extracted with isometric ethyl acetate, and decompression is dense
Contracting removal organic solvent obtains ethyl acetate portion.With Hitachi-L2130 (two level array detector, Hitachi L-2455)
Half preparative high-performance liquid chromatographic (semi-HPLC) isolates and purifies, chromatographic column be Phenomenex C18 (250mm × 10mm,
2.5mL min-1), mobile phase includes A phases and B phases, mobile phase A phase：The acetonitrile+0.8 ‰ (volume fraction) of 10% (volume fraction)
Formic acid, solvent is water, Mobile phase B phase：The acetonitrile of 90% (volume fraction), solvent are water；Injection procedure：0-20 minute, stream
Dynamic Phase Proportion is A phases/B phases (volume ratio)：95:5-20:80,20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：
20:80-0:100,21-24 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:100,24-25 minutes, mobile phase ratio
For A phases/B phases (volume ratio)：0:100-95:5,25-30min, mobile phase ratio is A phases/B phases (volume ratio)：95:5, flow velocity
2.5mLmin-1, isolate and purify to obtain compound 10 (retention time 12min) and 11 (retention time 16.5min).Pass through knot
Structure is analyzed, and the compound 10 and 11 (Fig. 2) be prepared to the present invention identifies that qualification result is as follows：
The negative source high-resolution electrospray ionization mass spectrum figure of compound 10 shows that its quasi-molecular ion peak is m/z [M-H]-
595.1833, thus it is speculated that its molecular formula is C32H28N4O8.Carefully analyzing nuclear-magnetism (NMR) data (table 2) of compound 10 can determine
There are the trimethoxy benzyl Aminometradine unit Bs of the A units and a rearrangement of a fluostatin C sample for the compound.From H-1/
NH-3 ' arrives C-2 ' (δC149.4), H-6 ' (δH7.80) C-3 (δ are arrivedCAnd H 64.5)3-12(δH1.75) C-6 ' (δ are arrivedC
138.1) HMBC related (Fig. 3) confirms that A units and unit B are by C-1-N-C-2 ' connections.It is possible thereby to determinization
Close the planar structure of object 10.H-1/12-CH3(Fig. 3) related to the NOESY of H-2/H-6 ' determines the three-dimensional structure of compound 10
Type.Finally, it is contemplated that compound 10 is generated by fluostatin D chemical derivatizations, determine its absolute configuration be 1R, 2S and
3R。
According to information above, determine the structure of compound 10 as shown in 10 in Fig. 2.
The negative source high-resolution electrospray ionization mass spectrum figure of compound 11 shows that its quasi-molecular ion peak is m/z [M-H]-
901.2354, thus it is speculated that its molecular formula is C50H38N4O13.Comprehensive analysis compound 111H and13C nuclear-magnetisms (NMR) data (table 2) table
There are the unit Bs of the A units and 10 sample of compound of a fluostatin C sample for the bright compound.From H-1 (δH 6.29)
To C-9 '/C-10 '/C-10a ' and H-9 ' (δH5.87) C-1 (δ are arrivedC34.1) HMBC related (Fig. 3) confirms the two lists
Member is by C-1-C-10 ' connections.It is possible thereby to determine the planar structure of compound 11.Finally, it is contemplated that compound 11 is
It is generated by fluostatin D chemical derivatizations, determines that its absolute configuration is 1R, 2S, 3S, 1 ' R, 2 ' S and 3 ' R.
According to information above, determine the structure of compound 11 as shown in 11 in Fig. 2.
The NMR nuclear magnetic datas ownership (δ inppm) of 1. compound 6~8 of table
a1H and 13C NMR were recorded at 700 and 176 MHz,respectively；b1H and13C NMR were recorded at 500 and 125 MHz,respectively；cMeasured in DMSO-d6；dMeasured in acetone-d6；The NMR nuclear magnetic datas of 2. compound 9~11 of N=no signal. tables belong to (DMSO-d6)
1H and 13C NMR were recorded at 700 and 176 MHz,respectively；Chemical
shift can be exchanged；N=no signal.
Claims (6)
1. a kind of preparation method of dimerization fluostatins class antibiotic, which is characterized in that include the following steps：
Using acyl group fluostatins classes compound as raw material, paraquinones ketone methide intermediate is formed in proton solvent, with parent
Core reagent obtains dimerization fluostatins class antibiotic through 1,6- nucleophilic additions.
2. preparation method according to claim 1, which is characterized in that the acyl group fluostatins class compounds are
Fluostatin D, fluostatin G, H, fluostatin J or fluostatin L.
3. preparation method according to claim 1 or 2, which is characterized in that the proton solvent is water or methanol.
4. preparation method according to claim 1 or 2, which is characterized in that the nucleopilic reagent is acyl group
Fluostatins classes combound itself, 2- amino-5-methylphenols or trimethoxy benzyl Aminometradine.
5. preparation method according to claim 1, which is characterized in that when raw material is fluostatin D, proton solvent is
When water, the dimerization fluostatins class antibiotic is compound 6；
Or when raw material is fluostatin J, and proton solvent is water, the dimerization fluostatins class antibiotic is chemical combination
Object 6 and 7；
Or when raw material is fluostatin D, and proton solvent is methanol, the dimerization fluostatins class antibiotic is to change
Close object 8；
Or when raw material is fluostatin D, proton solvent is water, described when nucleopilic reagent is 2- amino-5-methylphenols
Dimerization fluostatins class antibiotic is compound 9；
Or when raw material is fluostatin D, proton solvent is water, and when nucleopilic reagent is trimethoxy benzyl Aminometradine, described two
Poly- fluostatins classes antibiotic is compound 10 and 11；
The compound 6,7,8,9,10 and 11 structures is as follows：
6. preparation method according to claim 1, which is characterized in that obtain dimerization through 1,6- nucleophilic additions
Fluostatins class antibiotic, is crude product, is needed by isolating and purifying, and described isolating and purifying is by dimerization
Fluostatins class antibiotic crude products are extracted with ethyl acetate, and removal organic solvent is concentrated under reduced pressure and obtains ethyl acetate portion, i.e.,
Dimerization fluostatins crude products are isolated and purified with half preparative high-performance liquid chromatographics of Hitachi-L2130, and chromatographic column is
Phenomenex C18, mobile phase include A phases and B phases, mobile phase A phase：(the volume point of acetonitrile+0.8 ‰ of 10% (volume fraction)
Number) formic acid, solvent is water, Mobile phase B phase：The acetonitrile of 90% (volume fraction), solvent are water；Injection procedure：0-20 minute,
Mobile phase ratio is A phases/B phases (volume ratio)：95:5-20:80,20-21 minutes, mobile phase ratio was A phases/B phases (volume ratio)：
20:80-0:100,21-24 minutes, mobile phase ratio was A phases/B phases (volume ratio)：0:100,24-25 minutes, mobile phase ratio
For A phases/B phases (volume ratio)：0:100-95:5,25-30min, mobile phase ratio is A phases/B phases (volume ratio)：95:5, flow velocity
2.5mL min-1, thus isolate and purify to obtain dimerization fluostatins class antibiotic.
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