CN109692708A - A kind of asymmetry ciprofloxacin eye drops catalyst and its application - Google Patents
A kind of asymmetry ciprofloxacin eye drops catalyst and its application Download PDFInfo
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- CN109692708A CN109692708A CN201711001443.2A CN201711001443A CN109692708A CN 109692708 A CN109692708 A CN 109692708A CN 201711001443 A CN201711001443 A CN 201711001443A CN 109692708 A CN109692708 A CN 109692708A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
- B01J2231/52—Isomerisation reactions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
- B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
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Abstract
The invention belongs to organic synthesis fields, and in particular to a kind of asymmetry ciprofloxacin eye drops catalyst and its application.Catalyst chiral ligand as shown in formula I mixes gained, or the complex that cooperation generates with the original position of metal copper complexes, and the metal copper complexes are copper triflate benzene or copper triflate toluene.Ligand of the present invention is easy to largely prepare, easy to operate；The catalyst is suitable for large scale preparation chiral cyclopropane carboxylate, the chiral intermediate of particularly suitable preparation pesticide D V- pyrethroids.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of asymmetry ciprofloxacin eye drops catalyst and its application.
Background technique
It is the important method of synthesis of chiral cyclopropane-carboxylic acid that the asymmetry catalysis of alkene is Cyclopropanated, has many catalyst
Available (Xu Minghua, Lin Guoqiang, organic chemistry, 2000,20 (4), 475-485.).For asymmetric cyclopropane catalyst
Selection and use are that reaction is successfully crucial, at present these catalyst otherwise to obtain with good product enantioselectivity and
It needs using special diazotate, and then loses practical utility value；The synthetic intermediate of these catalyst is difficult to obtain
, similarly lose use value.Such case is particularly true to the conjugated alkene for having steric hindrance.Since conjugated alkene is Cyclopropanated
It is required that take into account chemo-selective and stereoselectivity, catalysis reaction tends to complicate, especially to bis- chloro-2-methyl 2 of such as 5,5-,
4- pentadiene this kind alkene.But, document (R.E.Lowenthal and S.Masamune, Tetrahedron
Letters, 1991,32 (50), 7373-7376) it discloses, using the double oxazoline ligands of two chiral carbons, with copper complex original position
Catalyst precarsor is formed, reusing diazoacetic acid menthol ester is reagent, can obtain high chemo-selective and high mapping selection
The cyclopropyl acid esters of property.However, since ligand intermediate is tool there are two the non-natural of chiral carbon and is not easy to obtain product, agents useful for same
Expensive, therefore, existing catalyst is difficult to meet the purpose largely manufactured and used.
Summary of the invention
The purpose of the present invention is to provide a kind of asymmetric ciprofloxacin eye drops catalyst and its applications.
To achieve the above object, the invention adopts a technical scheme as:
A kind of asymmetry ciprofloxacin eye drops catalyst: as the original of the catalyst chiral ligand as shown in formula I and metal copper complexes
Position mixing gained；Or, the complex that cooperation generates；
In formula: R is Bz (benzyl)；The metal copper complexes are copper triflate benzene or copper triflate
Toluene.
Chiral ligand shown in the formula I is (R)-configuration I.
Chiral ligand shown in the formula I and metal copper complexes mass ratio are 1:1-1.5, are still optionally further 1:1-
1.1。
A kind of preparation method of asymmetry ciprofloxacin eye drops catalyst, chiral ligand and metal copper complexes shown in formula I are in pole
Property solvent in situ mixing obtain catalyst；Wherein, chiral ligand shown in formula I and metal copper complexes mass ratio are 1:1-
1.5, preferably 1:1-1.1；
Or, chiral ligand shown in formula I and metal copper complexes are generated novel complexes as catalysis by complex reaction
Agent；The metal copper complexes are copper triflate benzene or copper triflate toluene.
The metal copper complexes are copper triflate benzene or copper triflate toluene.
Chiral ligand shown in the formula I:
Triethylamine, 2,2- methyl-prop two are added Step 1: (R) -1,2- ethamine alcohol is completely dissolved in methylene chloride
Acyl chlorides mixes under ice-water bath, warms naturally to room temperature, for use；
Step 2: above-mentioned acquisition reactant is dissolved in methylene chloride, triethylamine is added, is added dropwise under ice bath stirring
Mesyl chloride mixes, for use；
Step 3: above-mentioned acquisition product is dissolved in methanol, KOH is added, is warming up to reflux, obtains chirality shown in formula I
Ligand.
It is further:
(1) by (R) -1,2- ethamine alcohol dissolves solid with methylene chloride mixing, after dissolution under ice-water bath, is added
2,2- methyl malonyl chloride is then added dropwise in triethylamine, and material is stirred under ice-water bath, room temperature is warmed naturally to after stirring, and in room
The lower stirring of temperature, then washes, is dry, for use；
(2) above-mentioned acquisition reactant is dissolved in methylene chloride, adds triethylamine, dripped under ice bath and with stirring
Add mesyl chloride, is stirred under ice-water bath after addition, then at continuing to stir at room temperature after stirring, then washing, dry solid, to
With；
(3) above-mentioned acquisition solid is dissolved in methanol, KOH is being added, reflux is warming up under stirring, is flowing back 3-8 hours
Stop heating afterwards, cooled to room temperature obtains chiral ligand shown in formula I.
A kind of application of asymmetry ciprofloxacin eye drops catalyst, the catalyst are preparing answering in chiral cyclopropane carboxylate
With.
The catalyst prepares the application in DV- chrysanthemumic acid in hydrolysis.
A kind of method that hydrolysis prepares chiral cyclopropane carboxylate, reaction equation are
In formula: R1、R2What be may be the same or different is selected from methyl, Cl or Br；R3For ethyl or tert-butyl；
It is described to react for Cyclopropanated conjugated diene using the commodity being easy to get or by wittig by corresponding triphenyl
Alkylphosphines are synthesized with olefine aldehydr, and operation condition is that those skilled in the art are grasped.Ethyl diazoacetate or diazoacetic acid
The tert-butyl ester has commodity selling.Specifically: using Cyclopropanated conjugated diene as raw material and ethyl diazoacetate or the tertiary fourth of diazoacetic acid
It is Cyclopropanated right that ester reacts acquisition in 1-9 hours using the asymmetric ciprofloxacin eye drops catalyst in polar solvent at 0-60 DEG C
Carboxylate is answered, then obtains corresponding chrysanthemumic acid through basic hydrolysis；Wherein, catalyst charge is the 0.1-20.0mol% of raw material.
It is further: described using Cyclopropanated conjugated diene as raw material and ethyl diazoacetate or the tertiary fourth of diazoacetic acid
It is Cyclopropanated right that ester reacts acquisition in 6-8 hours using the asymmetric ciprofloxacin eye drops catalyst in polar solvent at 0-40 DEG C
Carboxylate is answered, then obtains corresponding chrysanthemumic acid through basic hydrolysis；Wherein, catalyst charge is the 0.5-5.0mol% of raw material.
The polar solvent is polar non-solute, such as ethyl acetate, tetrahydrofuran, toluene, methylene chloride；It is preferred that
Ethyl acetate.
The alkali that the hydrolysis uses is preferably potassium hydroxide or sodium hydroxide.
The catalyst is preferred for 5,5-, bis- chloro-2-methyl -2- pentadiene and the diazoacetic acid tert-butyl ester, further water
Solve the dichlor chrysanthemic acid generated:
Concrete operations are listed below:
1, in the there-necked flask of suitable volumes, under nitrogen protection by the copper triflate benzene or fluoroform of catalytic amount
Chiral ligand shown in base sulfonic acid copper toluene and formula I is mixed in ethyl acetate, and 5,5-, bis- chloro-2-methyl -2- penta 2 is added
Raw material 1.5-2.0 equivalent diazonium acetate, preferably diazonium second is added dropwise under stirring at 0 DEG C or 40 DEG C in alkene (raw material) in 4 hours
Tert-butyl acrylate stirs 2 hours at stirring 5 hours or 40 DEG C at room temperature after addition.Material depressurizes prolapse solvent, chromatography
Analysis.
2, above-mentioned material is added in Yu Qianshu there-necked flask, is added certain volume ethanol/water (1/1, v/v), 1.5-2.0 is added
Equivalent KOH or NaOH, and it is warming up to reflux with stirring, reaction was completed after 8 hours, removal ethyl alcohol is concentrated under reduced pressure, raffinate is with two
The dilution of times water, ethyl acetate extraction, organic layer discard, and water layer is neutralized to pH=3 with hydrochloric acid, with petroleum ether extraction heat, merge extraction
Liquid is taken, 1/3 volume is concentrated into, is placed, separation crystallization；Gas chromatographic analysis content, liquid phase (having chiral column) analysis product e.e
It is worth (enantiomeric excess value).
Experiment shows using catalyst of the invention, at 0 DEG C or 40 DEG C, with 5,5-, bis- chloro-2-methyl -2- pentadiene/
The ratio of catalyst is 200-20, raw material 1.5-2.0 equivalent diazonium acetate, preferably the diazoacetic acid tert-butyl ester, hydrolysate e.e
Value up to 99% or more.
Advantage for present invention:
The catalyst is simultaneously applied to that alkene asymmetry catalysis is Cyclopropanated to prepare hand by oxazoline/copper catalyst of the invention double
Property pesticide intermediate, the ligand of catalyst is easy to get, convenient for a large amount of preparations；It is easy to operate, it is suitable for large-scale and prepares chiral D V- chrysanthemum
Ester, the e.e value of product are higher than the best level of the prior art, fully meet the requirement as pesticide intermediate.
Catalyst of the present invention is reacted with copper complex by ligand and is prepared in situ acquisition, is directly used in Asymmetric cyclopropanation
It is used as good Asymmetric cyclopropanation catalyst in reaction, there is good practicability, is catalyzed obtained chiral ester and reaches 70%
Obtained acid is further purified after hydrolysis and reaches 99% or more, fully meets preparation by e.e or more, up to 80%e.e or more
Product meets extensive asymmetry and prepares Chiral pesticide intermediate, especially meets wanting for large scale preparation chiral dichloro chrysanthemic acid
It asks.
Catalyst of the present invention utilizes the new ligand of the synthesis such as the raw material benzyl chloride that is easy to get, the chiral phenyl amine yl acetate being easy to get,
Good catalytic effect is not only obtained, and reduces production cost and simplifies post processor.
Specific embodiment
Embodiment described below is for present invention be described in more detail.In these embodiments, unless specifically stated otherwise,
Reaction mass addition sequence can be optionally combined in storeroom, and diene used is with 5,5-, bis- chloro-2-methyl -2- pentadiene, and again
Nitrogen acetic acid esters, preferably the diazoacetic acid tert-butyl ester are matched with gram (g) (mole (mol)) metering, catalyst with copper triflate benzene
For the mixture of conjunction object or copper triflate toluene complex and double oxazoline ligands (R=Bz) (abbreviation ligand),
With gram (g) (mM (mmol)) metering, solvent for use is by taking ethyl acetate as an example and with milliliter (mL) metering, Cyclopropanated product
Content is examined with efficient liquid phase chromatographic analysis, condition: chromatographic column: Eclipse XDB-C18 150mm × 4.6mm (i.d.), 5-
Micron stainless steel column；Column temperature: 30 DEG C；Mobile phase: acetonitrile: water 70:30 (V/V)；Flow: 0.6ml/min；Detection wavelength:
254nm；Sample volume: 20 μ l；Or completed by GC, analysis condition are as follows: use Hp-5 gas chromatographic column, 60 DEG C of initial temperature
(hold3min), 160 DEG C are warming up to the rate of 20 DEG C/min, then 220 DEG C of (hold is warming up to the rate of 5 DEG C/min
30min)；Hydrolysate e.e value is completed by HPLC (Agilent 1200), analysis condition are as follows: uses AD-H chirality liquid phase column, flowing
Phase n-hexane: isopropanol 95:5, flow velocity: ν=1.0, Detection wavelength λ=220nm.Or hydrolysate e.e value is with high-efficient liquid phase color
Spectrum analysis is examined, condition: chromatographic column: CHIRALPAK OD-H 250mm × 4.6mm (i.d.) stainless steel column；Column temperature: 30 DEG C；Stream
Dynamic phase: n-hexane: isopropanol 99.8:0.2 (V/V)；Flow: 0.8ml/min；Detection wavelength: 254nm；Sample volume: 1 μ l；Unless
Special Statement, gained chrysanthemum monocarboxylate are trans-, 1R configuration；After hydrolysis gained chrysanthemumic acid by comparing standard items determine be configured as (it is trans-,
1R) configuration.
Embodiment 1
9.03g (31.25mmol) (R) -1,2- ethamine alcoholic compound is added in 250mL there-necked flask, 150mL dichloro is added
Methane, stirring dissolve solid.Under ice-water bath, 9.49g (93.75mmol) triethylamine is added, quickly stirs and in this bath temperature
Under, 2.64g (15.62mmol) 2,2- methyl malonyl chloride is added dropwise in 10 minutes, material stirs 4 hours under ice-water bath,
Room temperature is warmed naturally to, and is stirred at room temperature 4 hours, next day is stirred for 8 hours.Material washes (3 × 80mL), methylene chloride
Layer is dry with magnesium sulfate, and methylene chloride is recycled in air-distillation, and residue is directly used in lower step synthesis without isolation.
Preceding step product is dissolved in 150mL methylene chloride, addition 12.65g (125.00mmol) triethylamine, under ice bath simultaneously
10.74g (93.75mmol) mesyl chloride is added dropwise in 15 minutes with stirring.After being stirred 4 hours under ice-water bath, continue at room temperature
Stirring 4 hours.Material is transferred in 250mL separatory funnel, is washed (3 × 50mL), and magnesium sulfate is dry, and normal pressure recycles dichloromethane
Alkane obtains 17.58g solid.This solid is dissolved in 150mL methanol, 22.75g KOH is added, reflux is warming up under stirring, 3 is small
When after stop heating, cooled to room temperature.It should be decompressor, and recycle about 2/3 volumes methanol, residue adds water 100mL dilute
Release, with methylene chloride (3 × 80mL) extraction, combining extraction liquid, magnesium sulfate is dry, and normal pressure recycles methylene chloride, surplus material with
Silica gel column chromatography separation, obtains chiral ligand 7.90g shown in formula I, yield 72.60%.
Embodiment 2
Copper benzene compound (copper triflate benzene) 0.01g (0.04mmol) is added in 100mL there-necked flask, is added
3mL ethyl acetate is added with stirring 0.03g (0.044mmol) ligand, is passed through nitrogen under stirring；0.61g is added after 15 minutes
Bis- chloro-2-methyl -2,4- pentadiene of (4mmol) 5,5-；0.86g (6mmol) diazoacetic acid uncle is added dropwise down toward 40 DEG C in material stirring
Butyl ester adds for 4 hours；After stirring 2 hours at 40 DEG C, cooled to room temperature, decompression steams ethyl acetate, and 10mL ethyl alcohol is added
Aqueous solution (1/1, v/v) is added with stirring 0.48g (12mmol) sodium hydroxide, is heated to reflux 8 hours, stops.Vacuum distillation is steamed
Ethyl alcohol out adds water 20mL, ethyl acetate 10mL to extract 2 times, discards organic layer, water layer is neutralized with hydrochloric acid, pH=3.0, with dichloro
Methane 20mL is extracted 3 times, merges dichloromethane solution, dry with sodium sulphate, vacuum distillation recovered solvent, is tied in residue petroleum ether
Crystalline substance obtains dichlor chrysanthemic acid 0.47g, yield 56.22%, e.e > 99%.
Embodiment 3
Copper benzene compound 0.07g (0.26mmol) is added in 100mL there-necked flask, 20mL ethyl acetate is added, under stirring
0.20g (0.70mmol) ligand is added, is passed through nitrogen under stirring；2.91g (26.46mmol) 2,5- diformazan is added after 15 minutes
Base -2,4- pentadiene；Material stirring is added dropwise 5.66g (39.69mmol) diazoacetic acid tert-butyl ester, adds within 6 hours down toward 40 DEG C；
After stirring 2 hours at 40 DEG C, cooled to room temperature, decompression steams ethyl acetate, and 100mL ethanol water (1/1, v/ is added
V), it is added with stirring 4.45g (79.38mmol) potassium hydroxide, is heated to reflux 8 hours, is stopped.Ethyl alcohol is steamed, is added
Water 40mL, ethyl acetate 30mL are extracted 3 times, discard organic layer, and water layer is neutralized with hydrochloric acid, pH=3.0, with methylene chloride 30mL extraction
It taking 3 times, merges dichloromethane solution, vacuum distillation recovered solvent dry with sodium sulphate obtains chrysanthemumic acid 2.79g, yield 62.69%,
E.e=74.15%.
Embodiment 4
Copper toluene compound (copper triflate toluene) 0.01g (0.04mmol) is added in 100mL there-necked flask, is added
Enter 3mL ethyl acetate, is added with stirring 0.03g (0.044mmol) ligand, is passed through nitrogen under stirring；0.61g is added after 15 minutes
Bis- chloro-2-methyl -2,4- pentadiene of (4mmol) 5,5-；0.86g (6mmol) diazoacetic acid uncle is added dropwise down toward 40 DEG C in material stirring
Butyl ester adds for 4 hours；After stirring 2 hours at 40 DEG C, cooled to room temperature, decompression steams ethyl acetate, and 10mL ethyl alcohol is added
Aqueous solution (1/1, v/v) is added with stirring 0.48g (12mmol) sodium hydroxide, is heated to reflux 8 hours, stops.Vacuum distillation is steamed
Ethyl alcohol out adds water 20mL, ethyl acetate 10mL to extract 2 times, discards organic layer, water layer is neutralized with hydrochloric acid, pH=3.0, with dichloro
Methane 20mL is extracted 3 times, merges dichloromethane solution, and dry with sodium sulphate, vacuum distillation recovered solvent, residue is with petroleum ether knot
Crystalline substance obtains dichlor chrysanthemic acid 0.45g, yield 54.37%, e.e > 99%.
Embodiment 5
Copper toluene compound 0.07g (0.26mmol) is added in 100mL there-necked flask, 20mL ethyl acetate, stirring is added
Lower addition 0.21g (0.70mmol) ligand, is passed through nitrogen under stirring；2.91g (26.46mmol) 2,5- diformazan is added after 15 minutes
Base -2,4- pentadiene；Material stirring is added dropwise 5.66g (39.69mmol) diazoacetic acid tert-butyl ester, adds within 6 hours down toward 40 DEG C；
After stirring 2 hours at 40 DEG C, cooled to room temperature, decompression steams ethyl acetate, and 100mL ethanol water (1/1, v/ is added
V), it is added with stirring 4.45g (79.38mmol) potassium hydroxide, is heated to reflux 8 hours, is stopped.Ethyl alcohol is steamed, is added
Water 40mL, ethyl acetate 30mL are extracted 3 times, discard organic layer, and water layer is neutralized with hydrochloric acid, pH=3.0, with methylene chloride 30mL extraction
It taking 3 times, merges dichloromethane solution, vacuum distillation recovered solvent dry with sodium sulphate obtains chrysanthemumic acid 2.84g, yield 63.82%,
E.e=75.32%.
Embodiment 6
Copper benzene compound 0.01g (0.04mmol) is added in 100mL there-necked flask, 3mL ethyl acetate is added, stirring is lower to be added
Enter 0.03g (0.044mmol) ligand, is passed through nitrogen under stirring；The chloro- 2- first of 0.61g (4mmol) 5,5- bis- is added after 15 minutes
Base -2,4- pentadiene；Material stirring is added dropwise 0.68g (6mmol) ethyl diazoacetate, adds within 4 hours down toward 40 DEG C；At 40 DEG C
After stirring 2 hours, cooled to room temperature, decompression steams ethyl acetate, is added 10mL ethanol water (1/1, v/v), stirring
Lower addition 0.48g (12mmol) sodium hydroxide, is heated to reflux 8 hours, stops.Ethyl alcohol is steamed, water 20mL, acetic acid are added
Ethyl ester 10mL is extracted 2 times, discards organic layer, and water layer is neutralized with hydrochloric acid, pH=3.0, with methylene chloride 20mL extraction 3 times, is merged
Dichloromethane solution, dry with sodium sulphate, vacuum distillation obtains dichlor chrysanthemic acid 0.31g, yield 35.89%, e.e > 99%.
Embodiment 7
Copper toluene compound 0.01g (0.04mmol) is added in 100mL there-necked flask, 3mL ethyl acetate is added, under stirring
0.03g (0.044mmol) ligand is added, is passed through nitrogen under stirring；The chloro- 2- first of 0.61g (4mmol) 5,5- bis- is added after 15 minutes
Base -2,4- pentadiene；Material stirring is added dropwise 0.68g (6mmol) ethyl diazoacetate, adds within 4 hours down toward 40 DEG C；At 40 DEG C
After stirring 2 hours, cooled to room temperature, decompression steams ethyl acetate, is added 10mL ethanol water (1/1, v/v), stirring
Lower addition 0.48g (12mmol) sodium hydroxide, is heated to reflux 8 hours, stops.Ethyl alcohol is steamed, water 20mL, acetic acid are added
Ethyl ester 10mL is extracted 2 times, discards organic layer, and water layer is neutralized with hydrochloric acid, pH=3.0, with methylene chloride 20mL extraction 3 times, is merged
Dichloromethane solution, dry with sodium sulphate, vacuum distillation recovered solvent, residue is crystallized with petroleum ether, obtains dichlor chrysanthemic acid 0.34g,
Yield 40.66%, e.e > 99%.
Embodiment 8
Copper toluene compound 0.01g (0.04mmol) is added in 100mL there-necked flask, 3mL ethyl acetate is added, under stirring
0.03g (0.044mmol) ligand is added, is passed through nitrogen under stirring；The chloro- 2- first of 0.61g (4mmol) 5,5- bis- is added after 15 minutes
Base -2,4- pentadiene；Material stirring is added dropwise 0.86g (6mmol) diazoacetic acid tert-butyl ester, adds within 3 hours down toward 0 DEG C；At room temperature
After stirring 15 hours, decompression steams ethyl acetate, is added 10mL ethanol water (1/1, v/v), is added with stirring 0.48g
(12mmol) sodium hydroxide is heated to reflux 8 hours, is stopped.Ethyl alcohol is steamed, water 20mL, ethyl acetate 10mL extraction are added
It taking 2 times, discards organic layer, water layer is neutralized with hydrochloric acid, pH=3.0, with methylene chloride 20mL extraction 3 times, merge dichloromethane solution,
Dry with sodium sulphate, vacuum distillation, residue is crystallized with petroleum ether, obtains dichlor chrysanthemic acid 0.49g, yield 58.61%, and e.e >
99%.
Claims (10)
1. a kind of asymmetry ciprofloxacin eye drops catalyst, it is characterised in that: with catalyst chiral ligand shown in formula I and metallic copper
The mixing gained in situ of object, or the complex that cooperation generates, the metal copper complexes are copper triflate benzene or three
Methyl fluoride sulfonic acid copper toluene；
In formula: R is Bz (benzyl).
2. asymmetry ciprofloxacin eye drops catalyst according to claim 1, it is characterised in that: chiral ligand shown in the formula I is
(R)-configuration I.
3. asymmetry ciprofloxacin eye drops catalyst according to claim 1, it is characterised in that: chiral ligand shown in the formula I with
Metal copper complexes mass ratio is 1:1-1.5.
4. a kind of preparation method of asymmetric ciprofloxacin eye drops catalyst described in claim 1, it is characterised in that: hand shown in formula I
Property ligand mixes in situ in polar solvent with metal copper complexes or product is cooperated to be catalyst.
5. the preparation method of Asymmetric cyclopropanation catalyst according to claim 4, it is characterised in that: the metallic copper is matched
Closing object is copper triflate benzene or copper triflate toluene.
6. the preparation method of Asymmetric cyclopropanation catalyst according to claim 4, it is characterised in that: shown in the formula I
Chiral ligand:
Step 1: 2- ethamine alcohol, which is dissolved in methylene chloride, adds triethylamine, 2,2- methyl malonyl chloride, ice water by (R) -1
Bath is lower to be mixed, and warms naturally to room temperature, for use；
Step 2: above-mentioned acquisition reactant is dissolved in methylene chloride, triethylamine is added, methylsulphur is added dropwise under ice bath stirring
Acyl chlorides mixes, for use；
Step 3: the acquisition product of above-mentioned steps two is dissolved in methanol, KOH is added, is warming up to the chirality shown in formula I that flows back to obtain
Ligand.
7. a kind of application of asymmetric ciprofloxacin eye drops catalyst described in claim 1, it is characterised in that: prepared by the catalyst
Application in chiral cyclopropane carboxylate.
8. the application of asymmetry ciprofloxacin eye drops catalyst according to claim 7, it is characterised in that: the catalyst is made in hydrolysis
Application in standby DV- chrysanthemumic acid.
9. a kind of method that hydrolysis prepares chiral cyclopropane carboxylate, it is characterised in that: reaction equation is
In formula: R1、R2What be may be the same or different is selected from methyl, Cl or Br；R3For ethyl or tert-butyl；
Specifically: it using Cyclopropanated conjugated diene is raw material and ethyl diazoacetate or the diazoacetic acid tert-butyl ester in polar solvent
1-9 hours acquisition cyclopropyls are reacted at 0-60 DEG C using the asymmetric ciprofloxacin eye drops catalyst of the claim 1-3 any one
Alkanisation corresponds to carboxylate, then obtains corresponding chrysanthemumic acid through basic hydrolysis；Wherein, catalyst charge is the 0.1-20.0mol% of raw material.
10. the method that hydrolysis according to claim 9 prepares chiral cyclopropane carboxylate, it is characterised in that: described with cyclopropyl
Alkanisation conjugated diene is that raw material and ethyl diazoacetate or the diazoacetic acid tert-butyl ester use the asymmetry in polar solvent
Ciprofloxacin eye drops catalyst reacts at 0-40 DEG C obtains Cyclopropanated corresponding carboxylate for 6-8 hours, then obtains corresponding chrysanthemum through basic hydrolysis
Acid；Wherein, catalyst charge is the 0.5-5.0mol% of raw material.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112824372A (en) * | 2019-11-21 | 2021-05-21 | 中国科学院大连化学物理研究所 | Copper-catalyzed asymmetric cyclopropanation method of olefin and application thereof |
| CN114426485A (en) * | 2020-10-28 | 2022-05-03 | 中国科学院大连化学物理研究所 | Method for synthesizing dichlorochrysanthemic acid compound |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205326A (en) * | 1997-07-14 | 1999-01-20 | 住友化学工业株式会社 | Process for producing opitically active cyclopropanecaboxylic acid esters |
| CN1373116A (en) * | 2001-02-28 | 2002-10-09 | 住友化学工业株式会社 | Process for preparing optical active chrysanthemic acid |
| CN1384105A (en) * | 2001-04-27 | 2002-12-11 | 住友化学工业株式会社 | Asymmetric copper compound and cyclopropanation reaction with it |
| JP2005041786A (en) * | 2003-07-23 | 2005-02-17 | Sumitomo Chemical Co Ltd | Method for producing optically active cyclopropane compound |
| CN1771236A (en) * | 2003-02-07 | 2006-05-10 | 住友化学株式会社 | Optical activity bisoxazoline compound, method for producing the same and use of the same |
| WO2006100606B1 (en) * | 2005-03-24 | 2007-04-12 | Warner Lambert Co | Preparation of beta-amino acid precursors via indium (iii) mediated markovnikov addition and knoevenagel condensation |
| CN1988954A (en) * | 2004-06-16 | 2007-06-27 | 恩德拉（共同）股份公司 | Catalysts based on metal complexes for the synthesis of optically active chrysanthemic acid |
| CN101370812A (en) * | 2005-12-02 | 2009-02-18 | 武田药品工业株式会社 | Fused heterocyclic compound |
-
2017
- 2017-10-24 CN CN201711001443.2A patent/CN109692708A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205326A (en) * | 1997-07-14 | 1999-01-20 | 住友化学工业株式会社 | Process for producing opitically active cyclopropanecaboxylic acid esters |
| CN1373116A (en) * | 2001-02-28 | 2002-10-09 | 住友化学工业株式会社 | Process for preparing optical active chrysanthemic acid |
| CN1384105A (en) * | 2001-04-27 | 2002-12-11 | 住友化学工业株式会社 | Asymmetric copper compound and cyclopropanation reaction with it |
| CN1771236A (en) * | 2003-02-07 | 2006-05-10 | 住友化学株式会社 | Optical activity bisoxazoline compound, method for producing the same and use of the same |
| JP2005041786A (en) * | 2003-07-23 | 2005-02-17 | Sumitomo Chemical Co Ltd | Method for producing optically active cyclopropane compound |
| CN1988954A (en) * | 2004-06-16 | 2007-06-27 | 恩德拉（共同）股份公司 | Catalysts based on metal complexes for the synthesis of optically active chrysanthemic acid |
| WO2006100606B1 (en) * | 2005-03-24 | 2007-04-12 | Warner Lambert Co | Preparation of beta-amino acid precursors via indium (iii) mediated markovnikov addition and knoevenagel condensation |
| CN101370812A (en) * | 2005-12-02 | 2009-02-18 | 武田药品工业株式会社 | Fused heterocyclic compound |
Non-Patent Citations (1)
| Title |
|---|
| 边庆花: "环丙烷类双噁唑啉手性配体的合成及不对称诱导性能研究", 《中国博士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112824372A (en) * | 2019-11-21 | 2021-05-21 | 中国科学院大连化学物理研究所 | Copper-catalyzed asymmetric cyclopropanation method of olefin and application thereof |
| CN114426485A (en) * | 2020-10-28 | 2022-05-03 | 中国科学院大连化学物理研究所 | Method for synthesizing dichlorochrysanthemic acid compound |
| CN114426485B (en) * | 2020-10-28 | 2023-06-13 | 中国科学院大连化学物理研究所 | Synthetic method of dichlorochrysanthemic acid compound |
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