CN104557936A - Synthetic method of novel chiral non-cycle purine nucleoside analogue - Google Patents
Synthetic method of novel chiral non-cycle purine nucleoside analogue Download PDFInfo
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- CN104557936A CN104557936A CN201510021934.8A CN201510021934A CN104557936A CN 104557936 A CN104557936 A CN 104557936A CN 201510021934 A CN201510021934 A CN 201510021934A CN 104557936 A CN104557936 A CN 104557936A
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- 0 *c(nc(*=I)nc1NC=C)c1N Chemical compound *c(nc(*=I)nc1NC=C)c1N 0.000 description 5
- ZHRSJLIUHYMYHD-WDEREUQCSA-N C[C@@H]([C@@H](CO)O)[n]1c(ncnc2N3CCCCC3)c2nc1 Chemical compound C[C@@H]([C@@H](CO)O)[n]1c(ncnc2N3CCCCC3)c2nc1 ZHRSJLIUHYMYHD-WDEREUQCSA-N 0.000 description 1
- IGKKMKUDKPIMKA-VGOFRKELSA-N C[C@H](CO)[C@H](c1cc(cccc2)c2cc1)[n]1c2ncnc(N3CCCCC3)c2nc1 Chemical compound C[C@H](CO)[C@H](c1cc(cccc2)c2cc1)[n]1c2ncnc(N3CCCCC3)c2nc1 IGKKMKUDKPIMKA-VGOFRKELSA-N 0.000 description 1
- ZSMUSCZJXKYQAN-PWSUYJOCSA-N NC(C=CN1[C@H]([C@@H](CO)O)c2ccccc2)=NC1=O Chemical compound NC(C=CN1[C@H]([C@@H](CO)O)c2ccccc2)=NC1=O ZSMUSCZJXKYQAN-PWSUYJOCSA-N 0.000 description 1
- JZSHSHCURXPXEX-WUJWULDRSA-N Nc1nc(N2CCOCC2)c2nc[n]([C@H](C(CO)O)c3ccccc3)c2n1 Chemical compound Nc1nc(N2CCOCC2)c2nc[n]([C@H](C(CO)O)c3ccccc3)c2n1 JZSHSHCURXPXEX-WUJWULDRSA-N 0.000 description 1
- OOCCDEMITAIZTP-QPJJXVBHSA-N OC/C=C/c1ccccc1 Chemical compound OC/C=C/c1ccccc1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 1
- NYILKWGTXMMLEH-KRWDZBQOSA-N OCC([C@H](c1ccccc1)[n]1c2ncnc(N3CCCCC3)c2nc1)=O Chemical compound OCC([C@H](c1ccccc1)[n]1c2ncnc(N3CCCCC3)c2nc1)=O NYILKWGTXMMLEH-KRWDZBQOSA-N 0.000 description 1
- HTBIRPMAEQSPBM-GGAORHGYSA-N OC[C@H]([C@H](c(cc1)ccc1-c1ccccc1)[n]1c2ncnc(N3CCCCC3)c2nc1)O Chemical compound OC[C@H]([C@H](c(cc1)ccc1-c1ccccc1)[n]1c2ncnc(N3CCCCC3)c2nc1)O HTBIRPMAEQSPBM-GGAORHGYSA-N 0.000 description 1
- QFJBXVZMWQDION-CTNGQTDRSA-N OC[C@H]([C@H](c1cccc2ccccc12)[n]1c2ncnc(N3CCCCC3)c2nc1)O Chemical compound OC[C@H]([C@H](c1cccc2ccccc12)[n]1c2ncnc(N3CCCCC3)c2nc1)O QFJBXVZMWQDION-CTNGQTDRSA-N 0.000 description 1
- HKAOPRUDMQSEJX-ZBFHGGJFSA-N OC[C@H]([C@H](c1ccccc1)[n]1c2ncnc(N3CCCC3)c2nc1)O Chemical compound OC[C@H]([C@H](c1ccccc1)[n]1c2ncnc(N3CCCC3)c2nc1)O HKAOPRUDMQSEJX-ZBFHGGJFSA-N 0.000 description 1
- OIRMUYSGQZXAET-ZBFHGGJFSA-N OC[C@H]([C@H](c1ccccc1)[n]1c2ncnc(N3CCOCC3)c2nc1)O Chemical compound OC[C@H]([C@H](c1ccccc1)[n]1c2ncnc(N3CCOCC3)c2nc1)O OIRMUYSGQZXAET-ZBFHGGJFSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of a novel chiral non-cycle purine nucleoside analogue. The method has the beneficial effects that reaction steps are few, a chiral source is easily available, reaction conditions are relatively mild, and meanwhile, a side chain containing two chiral centers can be constructed; reference values are provided for synthesis and application of non-cycle nucleoside drugs, and a raw material is provided for the research of novel antiviral and anti-tumor drugs; meanwhile, an effective effect is provided for the construction of other non-cycle nucleosides and analogues of the other non-cycle nucleosides; furthermore, the method has wide industrial application prospect. The method comprises the steps of firstly carrying out Sharpless epoxidation reaction to obtain epoxy propenol compounds with relatively high Ee value and yield, and opening cycles of the chiral epoxy compounds by virtue of a purine base, so as to obtain the novel non-cycle nucleoside analogue containing two chiral centers, wherein an aryl substituent is located at a site 1' of the novel non-cycle nucleoside analogue.
Description
Technical field
The present invention relates to and chemical and medical art, be specifically related to a kind of synthetic method of novel chiral acyclic purine nucleoside analogs.
Background technology
Nucleoside compound is made up of base and glycosyl, and in structure, the similarity of they and natural nucleus glycoside various degrees, so there is the effect of mixing the spurious with the genuine in vivo, thus can disturb or directly act on the biosynthesizing of protein and nucleic acid.Many nucleoside analogs are the inhibitor of enzyme in virus replication, the activity of viral DNA polymerase and reversed transcriptive enzyme can be suppressed and mix viral DNA chain with Nucleotide competitiveness, thus stop or suppress prolongation and the synthesis of viral DNA chain, make copying and being suppressed and playing antivirus action of virus, therefore the structure of natural nucleus glycoside is modified or transformed and just may obtain new antiviral.Going on the market or be in the antiviral of clinical trial at present, the overwhelming majority is nucleoside compound, and therefore nucleoside compound also becomes the compound of the generally acknowledged antiviral potential of most.
Acyclonucleosides refers to the nucleoside compound introducing other hydroxyl side chains on ribose position, and acyclic nucleic acid refers to that the hydroxyl on nucleosides side chain is by the acyclonucleosides compounds of methylphosphonate.Since Wellcoem company of Britain develops non-cyclic guanosine acyclovir (Acyclovir, ACV), and since finding that it has herpesvirus resisting activity, acyclonucleosides (nucleic acid) attracts much attention day by day as antiviral.Up to the present, acyclonucleosides (nucleic acid) class medicine for the various virus disease of clinical treatment has: acyclovir (Acyclovir, ACV), ganciclovir (Ganciclovir, GAV), Penciclovir (Penciclovir, PCV), Famciclovir (Famciclovir, FCV), Adefovir (Adefovir, PMEA) etc.Common acyclonucleosides and nucleic acid drug as follows,
Chirality acyclonucleosides (nucleic acid) refers to acyclonucleosides (nucleic acid) compounds of side chain with chiral radicals.Compared with above-mentioned acyclonucleosides (nucleic acid) class medicine, its pharmacologically active and resistance are all greatly increased.Have for clinical chirality acyclonucleosides (nucleic acid) class medicine: cidofovir (Cidofovir, HPMPC), tynofovir (Tenofovir, R-PMPA) etc.Cidofovir is the acyclonucleosides phosphoric acid ester medicine with broad-spectrum antiviral character; It has the character of anti-herpes simplex virus HSV-1, HSV-2, the banded virus of varicella and cytomegalovirus (CMV), but the cytotoxicity of cidofovir is less; In addition, the ability of cidofovir to T suppression cell hugeization virus replication is very strong.Tynofovir has the anti AIDS virus (HIV) of wide spectrum and the effect of hepatitis B virus (HBV) and immunoregulatory activity; In addition, tynofovir also has good pharmacokinetic characteristics, significant antivirus action and hypotoxicity.Tynofovir two pyrrole furan ester (Viread) is novel nucleotide reverse transcriptase inhibitor, by the function of interference hepatitis B virus DNA polysaccharase, suppressing hepatitis B virus duplication, reduce the virus load in serum and hepatic tissue, is treatment chronic viral hepatitis B active drug.The new drug Valcyte new indication that under the Roche group of U.S. FDA approval, Genentech company produces, the adult patient of the high risk population namely infected for cytomegalovirus (CMV)-accepted renal transplantation, granted significant of Valcyte new indication, can utilize it greatly to reduce the infection of CMV virus in the renal transplant recipients critical period after surgery.S-DHPA Epidemic Hemorrhagic Fever virus (EHF) has copied good restraining effect in vivo.In addition, although a lot of chirality acyclonucleosides and ucleotides compound be not if R-PMPDAD, S-HPMPA, S-FPMPA etc. are for clinical, according to the literature, good antiviral activity is all had.Common chirality acyclonucleosides and nucleic acid drug as follows:
In sum, chirality acyclonucleosides and nucleotide drug are just playing irreplaceable effect in disease therapy, and developing chirality acyclonucleosides and ucleotides new drug is one of focus of current nucleosides and nucleotide drug research.Chirality acyclonucleosides and nucleotide drug often wherein a kind of configuration to certain virus, there is good pharmacologically active, and the existence of another kind of configuration, its pharmacologically active may be affected and even produce toxic side effect, therefore the chirality acyclonucleosides of synthesis of optically active and ucleotides compound, not only can improve raw-material utilization ratio, and the activity of medicine can be improved and reduce toxic side effect, so, the research and development of chirality acyclonucleosides and Nucleotide medicine have broad application prospects, and will produce profound significance to human health.And China is a populous nation, at present in this kind of medicament research and development far away from western developed country, therefore develop the novel chiral acyclonucleosides and ucleotides new drug with independent intellectual property right, and put into production as early as possible, dominate the market share in advance, particularly important to China.
Owing to having, toxic side effect is little waits excellent biological activity to chirality acyclonucleosides, has therefore attracted the extensive concern of more and more chemist to the research of this compounds.The synthetic method reported mainly contains:
(1) alkylated reaction: the method is the method for conventional synthesis of chiral acyclonucleosides analogue.The method generally with halogenated alkane or sulphonate as nucleophilic reagent, with purine or pyrimidine bases generation nucleophilic substitution reaction.Halogenated alkane generally comprises chloro, bromo and alkane iodide; Sulphonate comprises methanesulfonates, p-methyl benzenesulfonic acid ester and trifluoromethane sulfonic acid ester etc.Such as, Abushanab etc. are raw material with chiral epoxy propane, through 6 step reactions, total recovery with 36.4% has synthesized chirality chloroparaffin side chain, then synthesized chirality acyclonucleosides analogue with the pyrimidine bases generation halogenating reaction of silicon etherification protection, eventually passed deprotection and obtain chirality acyclonucleosides; For another example, 2008, it is raw material that professor Lv Wei of East China Normal University waits with L MALIC ACID, through 3 step reactions, yield with 40.8% has synthesized chirality alkylsulphonic acid ester side chain, then with purine bases generation nucleophilic substitution reaction, further deriving obtains chirality acyclonucleosides analogue (total recovery 6.5%).
(2) ring-opening reaction of propylene oxide: purine or pyrimidine bases can with the derivative generation ring-opening reaction of chiral epoxy propane, be used for synthesis of chiral acyclonucleosides analogue.The advantage of the method is that reaction conditions is simple, and yield is higher.Weak point is: chiral epoxy propane derivative structure is single at present, and the chirality acyclonucleosides structure obtained has limitation.
(3) Aza-Michael addition reaction: base pair α, the aza-Michael addition of beta-unsaturated carbonyl compound also can synthesis of chiral acyclonucleosides analogue.Such as: 2005, it is raw material that the people such as professor He Lan of Beijing Normal University report with furtural, the α with chiral auxiliary(reagent) has been synthesized through 3 steps, β-unsaturated lactone, Michael addition reaction is there is again with adenine base, yield with the 68% and enantioselectivity of 98% is excessive obtains adduct, and then with lithium aluminium hydride reduction, obtain chirality acyclonucleosides.
(4) addition reaction of base pair chiral aldehydes: 2004, Battistini etc. are raw material with the aldehyde containing chiral radicals, react with purine or pyrimidine bases, be catalyzer with TBSOTf, with medium yield and 7: 3 the excessive acyclonucleosides analogue obtained containing two chiral radicals of cis-selectivity.
Up to the present, chemist both domestic and external has done a large amount of work in this respect, for very large contribution has been made in the synthesis of chirality acyclonucleosides and nucleotide drug, screening, exploitation, but the weak points such as reactions steps is many, yield is low, expensive raw material price, chiral source are not easy to obtain, target product structure is single that current reported method often exists, seriously limit the development and application of acyclonucleosides class medicine, be badly in need of the method and access of the new synthesis of chiral acyclonucleosides compound of exploitation.
Meanwhile, along with the appearance of new virus and the increase of original virus drug resistance, in the urgent need to development of new, the antiviral with superior bio activity.Chirality acyclonucleosides has good biological activity, the biological activity of acyclonucleosides can be made to be improved by changing side chain, therefore the approach that a kind of convenient, fast, efficient synthesis has the novel chiral acyclonucleosides of potential pharmacologically active is developed, based on problems such as in this type of compou nd synthesis process of solution, reactions steps are many, yield is low, expensive raw material price, chiral source are not easy to obtain, target product structure is single, not only there is important theory significance, and be with a wide range of applications.
Summary of the invention
In order to solve the deficiencies in the prior art, the invention provides a kind of synthetic method of novel chiral acyclic purine nucleoside analogs.The present invention obtains side chain 1 ' position with the chiral open loop of epoxy compound of purine bases has aryl substituent and the acyclonucleosides analogue containing two chiral centres.
Technical scheme of the present invention is: a kind of synthetic method of novel chiral acyclic purine nucleoside analogs, and reaction equation is as follows:
Wherein: R
1represent the one in following groups: NH
2,
R
2represent the one in following groups: NH
2, H;
R
3represent the one in following groups:
cH
3.
Further improvement of the present invention comprises:
Described synthetic method specifically comprises the following steps, first in reaction vessel, the t-BuOK of purine compound 0.1mmol and 0.05mmol is dissolved in the DMF of 0.5mL, stirred at ambient temperature 2 hours, then 0.11moL chiral epoxy compound is added, stirring reaction 12 hours at 80 DEG C, is separated and obtains novel chiral acyclonucleosides analogue.
Described novel chiral acyclic purine nucleoside analogs 1 ' position has aryl substituent and chiral side chain contains two chiral centres.
Described novel chiral acyclic purine nucleoside analogs specifically can be in following 13 compounds any one:
Described epoxy compounds
reaction equation as follows:
Described epoxy compounds
concrete preparation process comprise, get 0.6g
molecular sieve joins in the flask of 100mL drying, add magneton, nitrogen replacement three times, dry adds methylene dichloride 23mL, then methylene dichloride 1.12mmol allyl alcohol compound being dissolved in 10mL joins in reaction system again, reaction flask is placed in-20 DEG C of stirrings and adds L-TARTARIC ACID diisopropyl ester 0.39g with syringe again in ten minutes, reaction solution stirs 20 minutes, makes its temperature drop to-15 to-20 DEG C.Add the Ti (i-PrO) of 0.332mL
4, then stir 40 minutes; Maintain the temperature at-20 to-25 DEG C, slowly add TBHP (5M toluene solution) 4.48mL, drip one hour; React 6 hours, add the saturated common salt aqueous solution of the sodium hydroxide of 30% of 0.1mL, 0 DEG C is stirred 20min, add 1.3g anhydrous sodium sulphate again and stir ten minutes, cross diatomite, with anhydrous sodium sulfate drying, cross short column, use petroleum ether/ethyl ether at-20 DEG C of recrystallizations again, finally obtain the epoxy compounds of high corresponding selection and high yield.
This method provide that a kind of reactions steps is few, chiral source is easy to get, reaction conditions is gentleer, the method for the synthesis acyclonucleosides compounds containing two chiral centre side chains can be built simultaneously, based on complex steps, expensive raw material price in this type of compou nd synthesis process of solution, the problem such as chiral source not easily obtains, severe reaction conditions, product yield are low, target product structure is single, for the synthesis of acyclonucleosides class medicine and application provide reference value, for the research of novel antiviral and antitumor drug is supplied raw materials.Simultaneously for the structure of the chiral centre of other acyclonucleosides and analogue thereof provides effective ways, and there is prospects for commercial application widely.The present invention first obtains epoxy allyl alcohol compound by Sharpless epoxidation reaction with higher Ee value and yield, then obtains 1 ' position with the chiral open loop of epoxy compound of purine bases and have aryl substituent and containing the novel acyclonucleosides analogue of two chiral centres.The method has the advantages such as reactions steps is few, chiral source is easy to get, reaction conditions is gentleer, can build 1 ' position simultaneously and have aryl substituent and the novel acyclonucleosides compounds containing two chiral centre side chains, the synthesis for chirality acyclonucleosides analogue provides the synthetic method of a brief and practical.
Embodiment
Below the present invention is elaborated.
Embodiment 1
First in reaction vessel, the t-BuOK of VITAMIN B4 0.1mmol and 0.05mmol is dissolved in the DMF of 0.5mL, stirred at ambient temperature 2 hours, then 0.11moL epoxy styryl carbinol is added, stirring reaction 12 hours at 80 DEG C, separation obtains chirality acyclonucleosides analogue, white solid, yield 90%, ee>99%.
1h NMR (DMSO-d
6, 400MHz) and δ 8.46 (s, 1H), 8.12 (s, 1H), 7.48 (d, J=6.8,1H), 7.33-7.25 (M, 5H), 5.76 (d, J=5.6Hz, 1H), 5.57 (d, J=5.2Hz, 1H), 4.89 (q, J=5.4Hz, 1H), 4.46-4.40 (m, 1H), 3.33-3.28 (m, 1H), 3.24-3.18 (m, 1H)
13cNMR (DMSO-d
6, 100MHz) and δ 156.4,152.8,149.6,140.5,137.8,129.2,128.6,128.1,118.8,72.4,63.1,59.4, HRMS:calcd for C
14h
16n
5o
2[M+H
+] 286.1299, found 286.1293.HPLC DAICELCHIRALCEL OJ-H, hexane/iPOH=90/10, λ=254nm; Retention time: 43.196min (minor), 49.238min (major), 99%ee.flow rate 1.0mL/min.
Embodiment 2
Alkali t-BuOK in embodiment 1 is changed to NaH, and other conditions are constant, obtain chirality acyclonucleosides analogue yield 88%, ee value 99%.
Embodiment 3
Change the temperature of reaction in embodiment 1 into 110 DEG C, other conditions are constant, obtain chirality acyclonucleosides analogue yield 93%, ee value 99%.
Embodiment 4
Get 0.6g
molecular sieve joins in the flask of 100ml drying, add magneton, nitrogen replacement three times, dry adds methylene dichloride 23ml, then methylene dichloride 1.5g (1.12mmol) styryl carbinol being dissolved in 10mL joins in reaction system again, reaction flask is placed in-20 DEG C of stirrings and adds L-TARTARIC ACID diisopropyl ester 0.39g with syringe again in ten minutes, reaction solution stirs 20 minutes, makes its temperature drop to-15 to-20 DEG C.Add the Ti (i-PrO) 4 of 0.332ml, then stir 40 minutes; Maintain the temperature at-20 to-25 DEG C, slowly add TBHP (5M toluene solution) 4.48ml, drip one hour; React 6 hours, add the saturated common salt aqueous solution of the sodium hydroxide of 30% of 0.1ml, 0 DEG C is stirred 20min, then adds 1.3g anhydrous sodium sulphate and stir ten minutes, crosses diatomite, with anhydrous sodium sulfate drying, cross short column, then use petroleum ether/ethyl ether at-20 DEG C of recrystallizations, finally obtain water white transparency needle-like crystal, yield 70%, ee value 98%.
1H NMR(CDCl
3,400MHz)δ7.36-7.28(m,5H),4.09-4.04(m,1H),3.94(d,J＝2.0Hz,1H),3.86-3.77(m,1H),3.24-3.22(m,2H),1.75-1.72(m,1H)。
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (6)
1. a synthetic method for novel chiral acyclic purine nucleoside analogs, is characterized in that, reaction equation is as follows:
Wherein: R
1represent the one in following groups: NH
2,
R
2represent the one in following groups: NH
2, H;
R
3represent the one in following groups:
2. the synthetic method of a kind of novel chiral acyclic purine nucleoside analogs according to claim 1, it is characterized in that, comprise the following steps, first in reaction vessel, the t-BuOK of purine compound 0.1mmol and 0.05mmol is dissolved in the DMF of 0.5mL, stirred at ambient temperature 2 hours, then add 0.11moL chiral epoxy compound, stirring reaction 12 hours at 80 DEG C, be separated and obtain novel chiral acyclonucleosides analogue.
3. the synthetic method of a kind of novel chiral acyclic purine nucleoside analogs according to claim 1, is characterized in that, described novel chiral acyclic purine nucleoside analogs 1 ' position has aryl substituent and chiral side chain contains two chiral centres.
4. the synthetic method of a kind of novel chiral acyclic purine nucleoside analogs according to claim 1 or 3, is characterized in that, described novel chiral acyclic purine nucleoside analogs specifically can be in following 13 compounds any one:
5. the synthetic method of a kind of novel chiral acyclic purine nucleoside analogs according to claim 1, is characterized in that, described epoxy compounds
reaction equation as follows:
6. the synthetic method of a kind of novel chiral acyclic purine nucleoside analogs according to claim 5, is characterized in that, described epoxy compounds
concrete preparation process comprise, get 0.6g
molecular sieve joins in the flask of 100mL drying, add magneton, nitrogen replacement three times, dry adds methylene dichloride 23mL, then methylene dichloride 1.12mmol allyl alcohol compound being dissolved in 10mL joins in reaction system again, reaction flask is placed in-20 DEG C of stirrings and adds L-TARTARIC ACID diisopropyl ester 0.39g with syringe again in ten minutes, reaction solution stirs 20 minutes, makes its temperature drop to-15 to-20 DEG C.Add the Ti (i-PrO) of 0.332mL
4, then stir 40 minutes; Maintain the temperature at-20 to-25 DEG C, slowly add TBHP (5M toluene solution) 4.48mL, drip one hour; React 6 hours, add the saturated common salt aqueous solution of the sodium hydroxide of 30% of 0.1mL, 0 DEG C is stirred 20min, add 1.3g anhydrous sodium sulphate again and stir ten minutes, cross diatomite, with anhydrous sodium sulfate drying, cross short column, use petroleum ether/ethyl ether at-20 DEG C of recrystallizations again, finally obtain the epoxy compounds of high corresponding selection and high yield.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107827890A (en) * | 2017-11-17 | 2018-03-23 | 河南师范大学 | Pass through the method for the Dynamic Kinetic Resolution synthesis of chiral purine acyclonucleosides of purine, aldehyde and acid anhydrides |
| CN110838372A (en) * | 2019-11-18 | 2020-02-25 | 武汉大学 | Personalized cancer medication database system and establishment method |
| CN112778224A (en) * | 2021-01-29 | 2021-05-11 | 河南师范大学 | Method for synthesizing ganciclovir analogue |
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| CN107827890B (en) * | 2017-11-17 | 2020-03-27 | 河南师范大学 | Method for synthesizing chiral purine acyclic nucleosides through dynamic kinetic resolution of purines, aldehydes and anhydrides |
| CN110838372A (en) * | 2019-11-18 | 2020-02-25 | 武汉大学 | Personalized cancer medication database system and establishment method |
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| CN112778224A (en) * | 2021-01-29 | 2021-05-11 | 河南师范大学 | Method for synthesizing ganciclovir analogue |
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