CN107602559A - A kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition - Google Patents
A kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition Download PDFInfo
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Abstract
The invention discloses a kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition, the asymmetric syntheses field belonged in organic chemistry.Using the acrylate and Bromo-t-butylacetate of α purine substitution as raw material, chiral cyclopropane carbocyclic purine nucleosides are obtained after Chiral Amine catalytic reaction derived from quinine, reaction enantioselectivity is good, and yield is medium to outstanding.
Description
Technical field
The present invention relates to the synthetic method of chiral carbocyclic ring purine nucleosides, and in particular to it is a kind of by Michael's addition trigger
The method of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside, the asymmetric syntheses field belonged in organic chemistry.
Background technology
Chiral cyclopropane carbocyclic purine nucleosides class compound has extensive physiologically active, such as Besifovir,
MBX1616 and A5021 shows the (reference of very high pharmaceutical activity：Boutureira,O.；Matheu,M.I.；Díaz,
Y.；Castillón,S.Chem.Soc.Rev.2013,42,5056).For example, LB80317, LB80380 and A- for being currently known
5021, all it is by a cyclopropane and one.Base is connected, 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 produce medicinal effects (ginseng
Examine：Vince,R.；Hua, M.J.Med.Chem.1990,33,17 and Oh, C.H.；Hong,J.H.,Nucleosides
Nucleotides.2007,26,403).This constructs the cyclopropane purine nucleoside analogs with chirality with very extensive research
Prospect and meaning.
The approach that tradition constructs chiral cyclopropane has two kinds.The first approach is by well-designed synthesis of chiral ternary carbon
Ring, amino is introduced on ternary carbocyclic ring, purine bases or pyrimidine bases are constructed from amino, so as to form the ternary of chirality
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 approaches construct cyclopropane nucleoside derivates is excessively numerous
Trivial, synthesis cost is higher.Comparatively, from low cost, raw material cheap and easy to get prepares chiral cyclopropane carbocyclic nucleoside
Method, there is very high value.
The content of the invention
In order to overcome drawbacks described above, the present invention use the acrylate 1 that α-purine substitutes and monobromo-acetic acid ester 2 as raw material,
The synthesis of chiral cyclopropane homocyclic nucleus glycosides compound in the presence of chiral 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 asymmetric cyclization synthesis of chiral cyclopropane carbocyclic purine nucleosides, it is characterised in that including such as
Lower step：It is raw material with the acrylate 1 and monobromo-acetic acid ester 2 of α-purine substitution, solvent and alkali is added, in hand derived from quinine
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 kind in following groups：Cl, dimethylamino, diethylin, methoxyl group, ethyoxyl, H, Ph,
Rosickyite base, piperidines, morpholine, pyrroles；R2Represent one kind in following groups：Cl、H；R3Represent one kind in following groups：Methyl,
Ethyl, isopropyl, the tert-butyl group, benzyl；R4Represent one kind in following groups：Methyl, ethyl, isopropyl, the tert-butyl group, benzyl；
Further, in the above-mentioned technical solutions, chiral amine catalyst precursor structure is derived from chirality derived from the quinine
Quinine, every kind of catalyst all include two kinds of R types and S types, and catalyst concrete structure is as follows：
Further, in the above-mentioned technical solutions, the acrylate 1 of the α-purine substitution, Bromo-t-butylacetate 2,
The mol 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 mol ratio of alkali and the acrylate 1 of α-purine substitution 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, dichloromethane, ether or chloroform are one or more of.It is preferred that acetonitrile, tetrahydrofuran, 1,
The mixed solvent of 2- dichloroethanes, dichloromethane or dichloromethane 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, whole course of reaction under inert gas shielding without operating.
Further, in such scheme, product 3ac can further pass through NaBH4Reduction obtains monohydroxy chemical combination
Thing 4ac, reduce to obtain dihydroxyl compound 5ac by DIBAL-H.
Research finds, under the above-described reaction conditions, by after purification, for different substrate separation yield 72%-98%.
Invention beneficial effect：
The present invention provides a kind of simplicity for the method for synthesis of chiral cyclopropane carbocyclic purine nucleosides, inexpensively, efficiently closed
Into method, reaction raw materials are easy to get, and product structure enriches, 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.
Embodiment
Embodiment 1
aUnless otherwise indicated, reaction condition is as follows：The acrylate 1a (0.1mmol) of α-purine substitution, the tertiary fourth of bromoacetic acid
Ester 2c (0.11mmol), quinine class catalyst (10mol%) and alkali (1.1 equivalent) 1mL solvents are in 0 DEG C of reaction.bSeparation yield.c
Determined by chiral HPLC.dReact at room temperature.eIncrease the amount of alkali to 2 equivalents, yield is improved to 52%, ee=92%
。fCatalyst 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
By compareing influence of the different catalysts to reaction, it is determined that catalyst 4f optimum catalysts.
The investigation of reaction condition：In 10mL vacuum tube, the 6-Cl ethyl acrylates 1a of α-purine substitution 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 0.66mL dichloromethane and 0.34mL acetonitriles is added.Reaction tube is sealed, will be reacted
Pipe, which is placed in 0 DEG C of cryogenic pump, to react 2 days.Tracked and reacted with TLC, after terminating reaction, reaction solution is concentrated in vacuo, then through post layer
Analysis obtains target compound 3ac yields 95%, 97%ee values.
In the case where other conditions are fixed, influence of the dosage of catalyst to reaction is only investigated, with 1a and 2a reaction lifes
Into exemplified by 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 of Different Alkali to reaction is only examined or check, reaction equation is as follows：
aUnless otherwise indicated, reaction condition is as follows：The acrylate 1a (0.1mmol) of α-purine substitution, the tertiary fourth of bromoacetic acid
Ester 2 (0.11mmol), quinine class catalyst (10mol%) and alkali (1.1 equivalent) 1mL solvents are in 0 DEG C of reaction.bSeparation yield.cIt is logical
Cross chiral HPLC measure.
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) of α-purine substitution, 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 solvents
In 0 DEG C of reaction.bSeparation yield.cDetermined by chiral HPLC.
Embodiment 2：
In 10mL vacuum tube, the 6- dimethylamino acrylates (26.1mg, 0.1mmol) of α-purine substitution,
(DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then 0.66mL dichloro is added
Methane and 0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, eventually
After only reacting, reaction solution is concentrated in vacuo, then obtains target compound 3fc yields 84%, 97%ee through column chromatography.
Embodiment 3：
In 10mL vacuum tube, the 6- lignocaines acrylate (28.9mg, 0.1mmol) of α-purine substitution,
(DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then 0.66mL dichloro is added
Methane and 0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, eventually
After only reacting, reaction solution is concentrated in vacuo, then obtains target compound 3gc yields 87%, 94%ee through column chromatography.
Representative compound characterize data is as follows：
3gc colourless oil liquids, 87%yield, 94%ee. [α]25 D=-80.1 (c=1.2, CH2Cl2)；Ee values pass through
Chiral HPLC detects (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 10mL vacuum tube, 6- pyrroles's acrylate (28.7mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3hc yields 87%, 97%ee through column chromatography.
Embodiment 5：
In 10mL vacuum tube, the 6- morpholines acrylate (30.3mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mmol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then 0.66mL dichloromethane is added
With 0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminated anti-
Ying Hou, reaction solution is concentrated in vacuo, then obtains target compound 3jc yields 98%, 96%ee through column chromatography.
Embodiment 6：
In 10mL vacuum tube, the 6- methoxy acrylates (24.8mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3kc yields 94%, 96%ee through column chromatography.
Representative compound characterize data is as follows：
3kc Colorless oil, 92%yield, 96%ee. [α]25 D=-98.7 (c=1.4, CH2Cl2)；
Ee values detect (mobile phase, n-hexane/2-propanol=80/20, flow velocity by chiral HPLC:0.6mL/
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 10mL vacuum tube, the 6- ethoxy acrylates (26.2mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3lc yields 86%, 95%ee through column chromatography.
Embodiment 8：
In 10mL vacuum tube, the 6- rosickyite base acrylate (29.2mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3mc yields 92%, 96%ee through column chromatography.
Representative compound characterize data is as follows：
3mc colourless oil liquids, 92%yield, 96%ee. [α]25 D=-84.4 (c=1.2, CH2Cl2)；Ee values pass through
Chiral HPLC detects (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 10mL vacuum tube, the 6- phenyl acrylates (29.4mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3nc yields 90%, 97%ee through column chromatography.
Embodiment 10：
In 10mL vacuum tube, the 6- hydracrylic acids ester (29.4mg, 0.1mmol) of α-purine substitution, (DHQD)2AQN
(8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L, 0.11mmol).Then add 0.66mL dichloromethane and
0.34mL acetonitriles.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.Tracked and reacted with TLC, terminating reaction
Afterwards, reaction solution is concentrated in vacuo, then obtains target compound 3oc yields 72%, 96%ee through column chromatography.
Embodiment 11
According to the reaction condition of embodiment, in 10mL vacuum tube, chemical combination derived from the acrylate of α-purine substitution
Thing (1ac-1rc, 1ag-1ad, 0.1mmol), (DHQD)2AQN (8.6mg, 10mol%) and Bromo-t-butylacetate (17 μ L,
0.11mmol).Then 1mL solvents are added.Reaction tube is sealed, reaction tube is placed in 0 DEG C of cryogenic pump and reacted 2 days.With TLC with
Track reacts, and after terminating reaction, is concentrated in vacuo reaction solution, then obtains target compound through column chromatography.Only reaction substrate is entered
Row changes, and obtains following reaction result：
aReaction 3 days.bSolvent is tetrahydrofuran.
Embodiment 12：
In 10mL reaction tube, cyclopropane Carbocyclic nucleoside analogues 3ac (36.6mg, 0.1mmol) is added, and add first
Alcohol, react as -10 DEG C, and add NaBH4(11.7mg, 0.3mmol) is detected with TLC, after complete reaction, with saturation
NH4Reactions CH is quenched in Cl2Cl2(3 × 10mL) is extracted, and is merged organic phase and is spin-dried for products and crosses post (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 values detect (mobile phase, n-hexane/2-propanol=80/20, flow velocity by chiral HPLC:0.6mL/
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 10mL vacuum tube, cyclopropane carbocyclic purine nucleosides 3ac (36.6mg, 0.1mmol) is added.Put by nitrogen
Change 3 times so that nitrogen is full of in reaction tube, then under nitrogen flowing, adds 1mL dichloromethane.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).Tracked and reacted with TLC, terminated anti-
Ying Hou, the ammonium chloride solution of saturation is added, dichloromethane extraction, anhydrous sodium sulfate drying organic phase, is concentrated in vacuo organic phase, so
Target compound 5ac, yield 42%, ee values 97% are obtained by column chromatography.
Representative compound characterize data is as follows：
5ac Colorless oil, 42%yield, 97%ee. [α]25 D=-60.6 (c=1.0, MeOH)；
Ee values detect (mobile phase, n-hexane/2-propanol=80/20, flow velocity by chiral HPLC:0.6mL/
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 10mL pressure pipe, the double hydroxyl carbocyclic purine nucleosides 5ac (25.4mg, 0.1mmol) of cyclopropane are added.Then
Methanolic ammonia solution 2mL sealing reaction tubes are added, reaction tube is placed in 110 DEG C.Tracked and reacted with TLC, after 24h terminating reactions, very
Empty concentration of reaction solution, then obtain target compound 6ac, yield 52%, 95%ee through column chromatography.
Representative compound characterize data is as follows：
6ac White soild, 52%yield, 95%ee. [α]25 D=-60.6 (c=0.9, MeOH)；
Ee values detect (mobile phase, n-hexane/2-propanol=70/30, flow velocity by chiral HPLC:0.8mL/
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 the general principle of the present invention, main features and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
1. a kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition, its feature exist
In：Comprise the following steps：The acrylate 1 and monobromo-acetic acid ester 2 of α-purine substitution add alkali and solvent, in hand derived from quinine
Property amine catalyst in the presence of, reaction obtain chiral ternary carbocyclic purine nucleosides 3 or its enantiomter, reaction equation is as follows：
A kind of 2. method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition：R1 is selected from：
Chlorine, dimethylamino, diethylin, methoxyl group, ethyoxyl, hydrogen, phenyl, rosickyite base, piperidines, morpholine or pyrroles；R2 is selected from：Chlorine,
Hydrogen；R3 is selected from：Methyl, ethyl, isopropyl, the tert-butyl group or benzyl；R4It is selected from：Methyl, ethyl, isopropyl, the tert-butyl group or benzyl.
3. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：Chiral amine catalyst derived from the quinine is selected from (DHQD)2PYR、(DQHD)2PHAL or
(DHQD)2AQN。
4. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：The solvent is selected from acetonitrile, tetrahydrofuran, 1,2- dichloroethanes, toluene, chlorobenzene, dioxanes, two
Chloromethanes, ether or chloroform are one or more of.
5. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic ring triggered by Michael's addition in claim 1 or 4
The method of nucleosides, it is characterised in that：The solvent is selected from acetonitrile, tetrahydrofuran, 1,2- dichloroethanes, dichloromethane or dichloromethane
The mixed solvent of alkane and acetonitrile.
6. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：The alkali is selected from potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, silver carbonate.
7. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：The acrylate 1 of the α-purine substitution, Bromo-t-butylacetate 2, chiral amines catalyst with
The mol ratio of cesium carbonate is 1:1-2:0.05-0.20:1-2.
8. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：Reaction temperature is -10 DEG C to 30 DEG C.
9. according to a kind of asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition in claim 1
Method, it is characterised in that：Product chirality ternary carbocyclic purine nucleosides 3ac and NaBH4Reduction obtains monohydroxy compound 4ac,
Reduce to obtain dihydroxyl compound 5ac with DIBAL-H.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774229A (en) * | 2018-07-18 | 2018-11-09 | 河南师范大学 | A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center |
| CN110015996A (en) * | 2019-05-07 | 2019-07-16 | 河南师范大学 | A method of 2 '-loop coil bases of synthesis replace ternary carbocyclic nucleoside |
| CN111646948A (en) * | 2020-07-03 | 2020-09-11 | 河南师范大学 | Method for synthesizing chiral pyrimidine substituted diester cyclopropane by asymmetric cyclopropanation |
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| CN104447749A (en) * | 2014-11-21 | 2015-03-25 | 河南师范大学 | Method for establishing non-cyclic nucleoside through selective ring opening of purine to vinylcyclopropane |
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| CN104447749A (en) * | 2014-11-21 | 2015-03-25 | 河南师范大学 | Method for establishing non-cyclic nucleoside through selective ring opening of purine to vinylcyclopropane |
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| PAVEL IVASHKIN ET AL.: "One-Step Synthesis of Highly Functionalized Monofluorinated Cyclopropanes from Electron-Deficient Alkenes", 《ORG. LETT.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774229A (en) * | 2018-07-18 | 2018-11-09 | 河南师范大学 | A kind of synthetic method of the pyrazoline nucleoside analog with quaternary carbon center |
| CN110015996A (en) * | 2019-05-07 | 2019-07-16 | 河南师范大学 | A method of 2 '-loop coil bases of synthesis replace ternary carbocyclic nucleoside |
| CN111646948A (en) * | 2020-07-03 | 2020-09-11 | 河南师范大学 | Method for synthesizing chiral pyrimidine substituted diester cyclopropane by asymmetric cyclopropanation |
| CN111646948B (en) * | 2020-07-03 | 2021-08-27 | 河南师范大学 | Method for synthesizing chiral pyrimidine substituted diester cyclopropane by asymmetric cyclopropanation |
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| CN107602559B (en) | 2019-10-18 |
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