CN107602559B - A method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition - Google Patents
A method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition Download PDFInfo
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Abstract
The invention discloses a kind of methods of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition, belong to the field of asymmetric synthesis in organic chemistry.The acrylate and Bromo-t-butylacetate replaced using α-purine obtains chiral cyclopropane carbocyclic purine nucleosides after the catalysis reaction of the Chiral Amine derived from quinine, reaction enantioselectivity is good, and yield is medium to outstanding as raw material.
Description
Technical field
The present invention relates to the synthetic methods of chiral carbocyclic ring purine nucleosides, and in particular to it is a kind of by Michael's addition cause
The method of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside, belongs to the field of asymmetric synthesis in organic chemistry.
Background technique
Chiral cyclopropane carbocyclic purine nucleosides class compound has extensive physiological activity, such as Besifovir,
MBX1616 and A5021 shows the (reference: Boutureira, O. of very high pharmaceutical activity；Matheu,M.I.；Díaz,
Y.；Castillón,S.Chem.Soc.Rev.2013,42,5056).For example, LB80317, LB80380 and A- for being currently known
5021, it is all by a cyclopropane and one.Base phase connects, and shows good antiviral activity, has been respectively used to two
Clinical trial phase treats hepatitis B and herpes simplex virus, while the compound of various configuration can also generate medicinal effects (ginseng
It examines: Vince, R.；Hua, M.J.Med.Chem.1990,33,17 and Oh, C.H.；Hong,J.H.,Nucleosides
Nucleotides.2007,26,403).This, which is constructed, has very extensive research with chiral cyclopropane purine nucleoside analogs
Prospect and meaning.
Tradition is constructed there are two types of the approach of chiral cyclopropane.The first approach is by well-designed synthesis of chiral ternary carbon
Ring introduces amino on ternary carbocyclic ring, constructs purine bases or pyrimidine bases from amino, to form chiral ternary
Carbocyclic nucleoside.Second of approach is designed by multistep, multistep synthesis is carried out in purine bases, then in chiral rhodium catalyst
The cyclopropanization reaction of intramolecular is formed under effect.But the method that both methods constructs cyclopropane nucleoside derivates is excessively numerous
Trivial, synthesis cost is higher.Comparatively, low cost is selected, raw material cheap and easy to get prepares chiral cyclopropane carbocyclic nucleoside
Method, have very high value.
Summary of the invention
In order to overcome drawbacks described above, the present invention uses α-purine substitution acrylate 1 and monobromo-acetic acid ester 2 for raw material,
Synthesis of chiral cyclopropane homocyclic nucleus glycosides compound under the action of chirality amines catalyst derived from quinine.This method is synthesis
Chiral cyclopropane homocyclic nucleus glycosides compound provides a kind of easy, cheap, efficient approach.
A kind of method of asymmetry cyclization synthesis of chiral cyclopropane carbocyclic purine nucleosides, which is characterized in that including such as
Lower step: the acrylate 1 and monobromo-acetic acid ester 2 replaced with α-purine is raw material, and solvent and alkali, the hand derived from quinine is added
Property amine catalyst in the presence of, reaction obtain chiral ternary carbocyclic purine nucleosides 3 or its enantiomter, reaction equation is as follows:
Wherein, R1Represent one of following groups: Cl, dimethylamino, diethylin, methoxyl group, ethyoxyl, H, Ph,
Rosickyite base, piperidines, morpholine, pyrroles；R2Represent one of following groups: Cl, H；R3Represent one of following groups: methyl,
Ethyl, isopropyl, tert-butyl, benzyl；R4Represent one of following groups: methyl, ethyl, isopropyl, tert-butyl, benzyl；
Further, in the above-mentioned technical solutions, chiral amine catalyst precursor structure derived from the quinine is derived from chirality
Quinine, every kind of catalyst all include R type and two kinds of S type, and catalyst specific structure is as follows:
Further, in the above-mentioned technical solutions, the α-purine replaces acrylate 1, Bromo-t-butylacetate 2,
The molar ratio of chiral amines catalyst is 1:1-2:0.05-0.20.
Further, in the above-mentioned technical solutions, reaction base is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, carbon
Sour silver.The molar ratio for the acrylate 1 that alkali and α-purine replace is 1:1-2.
Further, in the above-mentioned technical solutions, reaction dissolvent is selected from the solvent and is selected from acetonitrile, tetrahydrofuran, 1,2-
Dichloroethanes, toluene, chlorobenzene, dioxanes, methylene chloride, ether or chloroform are one or more of.It is preferred that acetonitrile, tetrahydrofuran, 1,
The mixed solvent of 2- dichloroethanes, methylene chloride or methylene chloride and acetonitrile.
Further, in the above-mentioned technical solutions, reaction temperature is selected from -10 DEG C to 30 DEG C.
Further, in the above-mentioned technical solutions, entire reaction process without operating under inert gas protection.
Further, in the above scheme, product 3ac can further pass through NaBH4Reduction obtains monohydroxy chemical combination
Object 4ac restores to obtain dihydroxyl compound 5ac by DIBAL-H.
The study found that under the above-described reaction conditions, by after purification, for different substrate separation yield 72%-98%.
Invention the utility model has the advantages that
The present invention provides a kind of easy, cheap, efficient conjunction for the method for synthesis of chiral cyclopropane carbocyclic purine nucleosides
At method, reaction raw materials are easy to get, and product structure is abundant, and product stereoselectivity is high, and it is fast that chiral cyclopropane carbocyclic ring is obtained after reaction
Purine nucleoside compound, yield are medium to outstanding.
Specific embodiment
Embodiment 1
aUnless otherwise indicated, reaction condition is as follows: the acrylate 1a (0.1mmol) that α-purine replaces, the tertiary fourth of bromoacetic acid
Ester 2c (0.11mmol), quinine class catalyst (10mol%) and alkali (1.1 equivalent) 1mL solvent are reacted at 0 DEG C.bSeparation yield.c
It is measured by chiral HPLC.dIt reacts at room temperature.eIncrease the amount of alkali to 2 equivalents, yield is improved to 52%, ee=92%.f
Catalyst amount is 5mol%.gAt -10 DEG C.hAt -20 DEG C.
In the screening process of reaction condition, influence (label 1-6) of the amines catalyst to reaction has been primarily looked at.Simultaneously
Influence by control different catalysts to reaction, it is determined that catalyst 4f optimum catalyst.
The investigation of reaction condition: in the vacuum tube of 10mL, the 6-Cl ethyl acrylate 1a that α-purine replaces is added
(25.2mg,0.1mmol),(DHQD)2AQN (8.6mg, 10mol%), cesium carbonate (36mg, 0.11mmol) and monobromo-acetic acid uncle
Butyl ester 2a (17 μ L, 0.11mmol).Then the methylene chloride and 0.34mL acetonitrile of 0.66mL is added.Reaction tube is sealed, will be reacted
Pipe, which is placed in 0 DEG C of cryogenic pump, to react 2 days.It is tracked and is reacted with TLC, after terminating reaction, reaction solution is concentrated in vacuo, then through column layer
Analysis obtains target compound 3ac yield 95%, 97%ee value.
In the case where other conditions are fixed, influence of the dosage of catalyst to reaction is only investigated, with 1a and 2a reaction life
For 3ac, reaction equation is as follows:
5%mmol (DHQD)2AQN yield:30%-40%；Ee:94%-98%；
15%mmol (DHQD)2AQN yield:80%-90%；Ee:94%-98%；
20%mmol (DHQD)2AQN yield:90%-98%；Ee:94%-98%；
In the case where other conditions are fixed, influence of the effect to reaction of different alkali is only examined or check, reaction equation is as follows:
aUnless otherwise indicated, reaction condition is as follows: the acrylate 1a (0.1mmol) that α-purine replaces, the tertiary fourth of bromoacetic acid
Ester 2 (0.11mmol), quinine class catalyst (10mol%) and alkali (1.1 equivalent) 1mL solvent are reacted at 0 DEG C.bSeparation yield.cIt is logical
Cross chiral HPLC measurement.
In the case where other conditions are fixed, influence of the effect of different solvents to reaction is only examined or check, reaction equation is such as
Under:
aUnless otherwise indicated, reaction condition is as follows: the acrylate 1a (0.1mmol) that α-purine replaces, the tertiary fourth of bromoacetic acid
Ester 2c (0.11mmol), quinine class catalyst (10mol%) and alkali (1.1 equivalents, entry 1-4 alkali are 2 equivalents), 1mL solvent
It is reacted at 0 DEG C.bSeparation yield.cIt is measured by chiral HPLC.
Embodiment 2:
In the vacuum tube of 10mL, the 6- dimethylamino acrylate (26.1mg, 0.1mmol) that α-purine replaces,
(DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then the dichloro of 0.66mL is added
Methane and 0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, eventually
After only reacting, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3fc yield 84%, 97%ee.
Embodiment 3:
In the vacuum tube of 10mL, the 6- lignocaine acrylate (28.9mg, 0.1mmol) that α-purine replaces,
(DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then the dichloro of 0.66mL is added
Methane and 0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, eventually
After only reacting, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3gc yield 87%, 94%ee.
Representative compound characterize data is as follows:
3gc colourless oil liquid, 87%yield, 94%ee. [α]25 D=-80.1 (c=1.2, CH2Cl2)；Ee value passes through
Chiral HPLC detection (mobile phase, n-hexane/2-propanol=80/20, flow velocity: 0.6mL/min, Detection wavelength: 250nm,
Retention time: 13.924min, 18.512min.)；1H NMR(600MHz,CDCl3):8.30(s,1H),7.66(s,1H),
4.13-4.16 (m, 2H), 3.96 (br, 4H), 2.98 (br, 1H), 2.05-2.45 (m, 2H), 1.26 (t, J=6.6Hz, 6H),
1.18 (s, 9H), 1.15 (t, J=6.6Hz, 3H)；13C NMR(150 MHz,CDCl3):168.6,166.5,153.9,152.9,
151.9,139.0,119.2,82.3,62.8,43.1,41.3,28.1,27.6,20.5,14.1,13.6；HRMS calcd for
C20H29N5NaO4[M+Na]+426.2112,found 426.2113.
Embodiment 4:
In the vacuum tube of 10mL, 6- pyrroles's acrylate (28.7mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3hc yield 87%, 97%ee.
Embodiment 5:
In the vacuum tube of 10mL, the 6- morpholine acrylate (30.3mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mmol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then the methylene chloride of 0.66mL is added
With 0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminated anti-
Ying Hou is concentrated in vacuo reaction solution, then chromatographs through column and obtains target compound 3jc yield 98%, 96%ee.
Embodiment 6:
In the vacuum tube of 10mL, the 6- methoxy acrylate (24.8mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3kc yield 94%, 96%ee.
Representative compound characterize data is as follows:
3kc Colorless oil, 92%yield, 96%ee. [α]25 D=-98.7 (c=1.4, CH2Cl2)；
Ee value detects (mobile phase, n-hexane/2-propanol=80/20, flow velocity: 0.6mL/ by chirality HPLC
Min, Detection wavelength: 250nm, retention time: 11.557min, 16.991min.)；1H NMR(600 MHz,CDCl3):8.53
(s,1H),7.87(s,1H),4.18(s,3H),4.10-4.18(m,2H),2.96(br,1H),2.10-2.50(m,2H),1.18
(s, 9H), 1.129 (t, J=6.6Hz, 3H)；13C NMR(150MHz,CDCl3):168.2,166.2,161.2,153.3,
152.5,143.3,121.3,82.6,63.0,54.3,41.4,27.7,20.5,14.0；HRMS calcd for
C17H22N4NaO5[M+Na]+385.1482,found 385.1486.
Embodiment 7:
In the vacuum tube of 10mL, the 6- ethoxy acrylate (26.2mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3lc yield 86%, 95%ee.
Embodiment 8:
In the vacuum tube of 10mL, the 6- rosickyite base acrylate (29.2mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3mc yield 92%, 96%ee.
Representative compound characterize data is as follows:
3mc colourless oil liquid, 92%yield, 96%ee. [α]25 D=-84.4 (c=1.2, CH2Cl2)；Ee value passes through
Chiral HPLC detection (mobile phase, n-hexane/2-propanol=80/20, flow velocity: 0.6mL/min, Detection wavelength: 250nm,
Retention time: 12.683min, 23.804min.)；1H NMR(600MHz,CDCl3):8.66(s,1H),7.88(s,1H),
4.09-4.17(m,2H),3.29-3.37(m,2H),2.93,(br,1H),2.07-2.5(m,2H),1.76-1.82(m,2H),
1.15 (s, 9H), 1.11 (t, J=7.2Hz, 3H), 1.05 (t, J=7.2Hz, 3H)；13C NMR(150MHz,CDCl3):
168.1,166.2,161.9,152.2,149.6,143.6,131.2,82.6,63.1,41.3,30.7,27.6,22.9,20.5,
14.0,13.5；HRMS calcd for C19H26N4NaO4S[M+Na]+429.1567,found 429.1573.
Embodiment 9:
In the vacuum tube of 10mL, the 6- phenyl acrylate (29.4mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3nc yield 90%, 97%ee.
Embodiment 10:
In the vacuum tube of 10mL, the 6- hydracrylic acid ester (29.4mg, 0.1mmol) that α-purine replaces, (DHQD)2AQN
(8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then be added 0.66mL methylene chloride and
0.34mL acetonitrile.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.It is tracked and is reacted with TLC, terminate reaction
Afterwards, it is concentrated in vacuo reaction solution, is then chromatographed through column and obtains target compound 3oc yield 72%, 96%ee.
Embodiment 11
Reaction condition according to the embodiment, in the vacuum tube of 10mL, chemical combination derived from the acrylate that α-purine replaces
Object (1ac-1rc, 1ag-1ad, 0.1mmol), (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L,
0.11mmol).Then 1mL solvent is added.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and is reacted 2 days.With TLC with
Track reaction after terminating reaction, is concentrated in vacuo reaction solution, then chromatographs through column and obtain target compound.Only by reaction substrate into
Row changes, and obtains following reaction result:
aReaction 3 days.bSolvent is tetrahydrofuran.
Embodiment 12:
In the reaction tube of 10mL, it is added cyclopropane Carbocyclic nucleoside analogues 3ac (36.6mg, 0.1mmol), and first is added
Alcohol reacts as -10 DEG C, and NaBH is added4(11.7mg, 0.3mmol) is detected with TLC, after reacting completely, with saturation
NH4Cl is quenched reaction and uses CH2Cl2(3 × 10mL) extraction merges organic phase and is spin-dried for product and crosses column (CH2Cl2/ MeOH=50:
1) product 4ac (yield 92%, 97%ee) is obtained
Representative compound characterize data is as follows:
4ac White solid, 92%yield, 97%ee. [α]25 D=-73.0 (c=2.4, CH2Cl2)；
Ee value detects (mobile phase, n-hexane/2-propanol=80/20, flow velocity: 0.6mL/ by chirality HPLC
Min, Detection wavelength: 250nm, retention time: 10.636min, 13.960min.)；1H NMR(600 MHz,CDCl3):8.69
(s, 1H), 8.12 (s, 1H), 4.04 (d, J=11.4Hz, 1H), 3.83 (d, J=12Hz, 1H), 3.74 (s, 1H), 2.35 (q,
1H) 2.07 (t, J=6Hz, 1H), 1.72 (q, 1H), 1.14 (s, 9H)；13C NMR(150MHz,CDCl3):167.8,152.5,
152.1,150.9,146.9,131.4,82.2,67.0,45.2,27.7,25.0,17.3；HRMS calcd for
C14H17ClN4NaO3[M+Na]+347.0881,found 347.0872.
Embodiment 13:
In the vacuum tube of 10mL, it is added cyclopropane carbocyclic purine nucleosides 3ac (36.6mg, 0.1mmol).It is set by nitrogen
It changes 3 times, so that the methylene chloride of 1mL then under nitrogen flowing is added full of nitrogen in reaction tube.Reaction tube is sealed, will be reacted
Pipe is placed in -40 DEG C.It is slowly added to DIBAL-H (7equiv, 1.0M in cyclohexane).It is tracked and is reacted with TLC, terminated anti-
Ying Hou, is added the ammonium chloride solution of saturation, methylene chloride extraction, and the dry organic phase of anhydrous sodium sulfate is concentrated in vacuo organic phase, so
It is chromatographed by column and obtains target compound 5ac, yield 42%, ee value 97%.
Representative compound characterize data is as follows:
5ac Colorless oil, 42%yield, 97%ee. [α]25 D=-60.6 (c=1.0, MeOH)；
Ee value detects (mobile phase, n-hexane/2-propanol=80/20, flow velocity: 0.6mL/ by chirality HPLC
Min, Detection wavelength: 250nm, retention time: 22.917min, 29.932min.)；1H NMR(600 MHz,CD3OD):8.75
(s, 1H), 8.61 (s, 1H), 8.34 (d, J=9.6Hz, 1H), 3.63 (d, J=10.8Hz, 1H), 3.56 (d, J=6.0Hz,
1H), 3.23 (t, J=9.6Hz, 1H), 1.74-1.79 (m, 1H), 1.48 (t, J=6.6 Hz, 1H), 1.44 (t, J=6.6Hz,
1H)；13C NMR(150MHz,CD3OD):152.8,151.5,150.0,149.2,131.3,66.1,60.0,47.2,23.7,
12.8；HRMS calcd for C10H11ClN4NaO2[M+Na]+277.0463,found 277.0471.
Embodiment 14:
In the pressure pipe of 10mL, the double hydroxyl carbocyclic purine nucleosides 5ac (25.4mg, 0.1mmol) of cyclopropane are added.Then
Methanolic ammonia solution 2mL is added and seals reaction tube, reaction tube is placed in 110 DEG C.It is tracked and is reacted with TLC, after terminating reaction for 24 hours, very
Then empty concentration of reaction solution chromatographs through column and obtains target compound 6ac, yield 52%, 95%ee.
Representative compound characterize data is as follows:
6ac White soild, 52%yield, 95%ee. [α]25 D=-60.6 (c=0.9, MeOH)；
Ee value detects (mobile phase, n-hexane/2-propanol=70/30, flow velocity: 0.8mL/ by chirality HPLC
Min, Detection wavelength: 250nm, retention time: 19.895min, 38.407min.)；1H NMR(600 MHz,CD3OD):8.75
(s, 1H), 8.62 (s, 1H), 3.84 (d, J=9.6Hz, 1H), 3.62 (d, J=12.0Hz, 1H), 3.56 (d, J=6.6Hz,
1H), 3.23 (d, J=8.4Hz, 1H), 1.74-1.79 (m, 1H), 1.48 (t, J=6.6Hz, 1H), 1.44 (t, J=6.6Hz,
1H)；13C NMR(150MHz,CD3OD):157.5,153.7,151.3,145.1,120.4,67.6,61.7,44.1,25.1,
14.2；HRMS calcd for C10H13N5NaO2[M+Na]+258.0961,found 258.0967.
Embodiment above describes basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (7)
1. a kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition, feature exist
In: include the following steps: that alkali and solvent, the hand derived from quinine is added in α-purine substitution acrylate 1 and monobromo-acetic acid ester 2
Property amine catalyst in the presence of, reaction obtain chiral ternary carbocyclic purine nucleosides 3 or its enantiomter, reaction equation is as follows:
Wherein, R1Be selected from: chlorine, dimethylamino, diethylin, methoxyl group, ethyoxyl, hydrogen, phenyl, rosickyite base, piperidines, morpholine or
Pyrroles；R2It is selected from: chlorine, hydrogen；R3It is selected from: methyl, ethyl, isopropyl, tert-butyl or benzyl；R4It is selected from: methyl, ethyl, isopropyl
Base, tert-butyl or benzyl；Chiral amine catalyst derived from the quinine is selected from (DHQD)2PYR、(DQHD)2PHAL or (DHQD)2AQN。
2. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition according to claim 1
Method, it is characterised in that: the solvent be selected from acetonitrile, tetrahydrofuran, 1,2- dichloroethanes, toluene, chlorobenzene, dioxanes, two
Chloromethanes, ether or chloroform are one or more of.
3. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic ring caused by Michael's addition according to claim 1 or in 2
The method of nucleosides, it is characterised in that: the solvent is selected from acetonitrile, tetrahydrofuran, 1,2- dichloroethanes, methylene chloride or dichloromethane
The mixed solvent of alkane and acetonitrile.
4. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition according to claim 1
Method, it is characterised in that: the alkali be selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, silver carbonate.
5. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition according to claim 1
Method, it is characterised in that: acrylate 1 that the α-purine replaces, Bromo-t-butylacetate 2, chiral amines catalyst with
The molar ratio of alkali is 1:1-2:0.05-0.20:1-2.
6. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition according to claim 1
Method, it is characterised in that: reaction temperature be -10 DEG C to 30 DEG C.
7. a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition according to claim 1
Method, it is characterised in that: product chirality ternary carbocyclic purine nucleosides 3acWith NaBH4Reduction obtains single hydroxyl
Based compound 4acIt restores to obtain dihydroxyl compound 5ac with DIBAL-H
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