CN108822174A - 2 '-EOE- guanosine of novel nucleoside modifier and preparation method thereof - Google Patents
2 '-EOE- guanosine of novel nucleoside modifier and preparation method thereof Download PDFInfo
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- CN108822174A CN108822174A CN201810995034.7A CN201810995034A CN108822174A CN 108822174 A CN108822174 A CN 108822174A CN 201810995034 A CN201810995034 A CN 201810995034A CN 108822174 A CN108822174 A CN 108822174A
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- XWYCURZQQOHJDQ-NQBHXWOUSA-N CCOCCO[C@H](CC[n]1c(N=C(N)NC2=O)c2nc1)[C@H]([C@@H](CO)OC)O Chemical compound CCOCCO[C@H](CC[n]1c(N=C(N)NC2=O)c2nc1)[C@H]([C@@H](CO)OC)O XWYCURZQQOHJDQ-NQBHXWOUSA-N 0.000 description 1
- 0 Nc(n*1N)nc2c1nc[n]2[C@]1OC(CO)=CC1OCCO Chemical compound Nc(n*1N)nc2c1nc[n]2[C@]1OC(CO)=CC1OCCO 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The present invention relates to a kind of preparation methods of 2 '-EOE- guanosine of novel nucleoside modifier.Method of the invention is with 2,6- diamino-purine nucleosides is starting material, it is first reacted with metal hydride, generates alcohol sodium form reactive intermediate, then reacted with 2- halogenated ethyl ethylether, generate the 2 of Targeting groups modification, 6- diamino-purine nucleosides intermediate converts carbonyl for the amino of compound B specific site using biological enzyme then by biochemical reaction, to in high yield, generate 2 '-EOE- guanosine of target product with high selectivity.Method of the invention easy, economically a large amount of can synthesize 2 '-EOE- guanosines.
Description
Technical field
The invention belongs to nucleoside compounds to synthesize field, more particularly it relates to a kind of novel nucleoside modifier 2 '-
The preparation method of EOE- guanosine.
Background technique
In recent years, with the development of genome wound medicine, antisense oligonucleotides drug rapidly developed, the reason is that its compared with
There is following advantage for conventional medicament：1) specificity is stronger.The antisense oligonucleotides of one 15 aggressiveness contains 30-45 hydrogen
Key, and low molecular conventional medicament (200-600u) and target spot generally only form 1-4 key；2) information content is larger.Hereditary information
From DNA-RNA- protein, it is very accurately that the synthesis of certain albumen is blocked with complementary oligonucleotide；3) antisense drug is with nucleic acid
It is easier to rationally design novel drugs compared with protein is as target spot for target spot.Due to acting on the upstream of hereditary information transmitting,
Required dose is lower, and side effect may be less.
With the propulsion of technical research, get up to the positive prosperity of the research of antisense drug.Existing Shuo Jia R&D institution of the country is just
Carrying out the research of antisense drug, and having several antisense oligonucleotides acid products and be in the preclinical test stage, it is believed that is domestic anti-
Adopted drug is expected to list within 5~8 years futures and benefits domestic many patients.
But the industrial synthesis technique of antisense drug was carried out still in the primary stage at present, and the work of laboratory scale
Skill preparation, is unable to satisfy industrial requirement.
Therefore, there is an urgent need in the art to provide effectively and without special equipment, it is suitble to large-scale industrial production antisense medicine
The technology of object or its of synthesis material early period.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of 2 '-EOE- guanosine of novel nucleoside modifier.
In the first aspect of the present invention, a kind of preparation method of compound shown in formula A is provided,
The method includes：
(1) it with compound C (2,6- diamino-purine nucleosides) for starting material, is first reacted with metal hydride, generates alcohol
Sodium form reactive intermediate；Then it is reacted with 2- halogenated ethyl ethylether, obtains 2,6- diamino-purine nucleosides intermediate B；
(2) deamination enzymatic 2,6- diamino-purine nucleosides intermediate C, converts carbonyl for the amino of its specific site,
To obtain compound A (2 '-EOE- guanosine).
In a preferred embodiment, in (1), the metal hydride is NaH, KH, CaH2；Preferably NaH.
In another preferred example, in (1), the halogenated ethylene glycol monoethyl ether of 2- is selected from：2- Chloroethyl ethylether, 2- bromine
For ethyl diethyldithiocarbamate ether, 2- iodoethyl ethylether；Preferably, the halogenated ethylene glycol monoethyl ether of the 2- is 2- bromoethyl ethyl
Ether.
In another preferred example, in (1), after alcohol sodium form reactive intermediate is reacted with 2- halogenated ethyl ethylether, further include：
Crystallization purifying is carried out to containing 2,6- diamino-purine nucleosides intermediate B crude product；Preferably, using methanol or ethyl alcohol as knot
Brilliant solvent；It is highly preferred that using ethyl alcohol as the solvent of crystallization；It is further preferred that the dosage of ethyl alcohol and compound C weighing body
Product is than being 1: 10-30 (preferably 1: 15-25；It is most preferably 1: 20).
In another preferred example, in (1), with n,N-Dimethylformamide (DMF), DMSO or glycol dimethyl ether (DME)
As the solvent of compound C, preferably using n,N-Dimethylformamide as the solvent of compound C；After dissolution, it is cooled to 0 ± 2
DEG C, it is reacted under inert gas (preferably argon gas or nitrogen) atmosphere with metal hydride；Preferably, according to bulking value
Than the dosage of solvent is 3~10 times (preferably 5~10 times) of compound C.
In another preferred example, in (1), the molar ratio of the gold compound C and metal hydride be 1: 1.0-3.0 (compared with
It goodly is 1: 1.2-2.5；It is most preferably 1: 1.5)；And/or
2- halogenated ethyl ethylether dosage is 0.8~1.8 molar equivalent of compound C, it is therefore preferable to which 1~1.5 mole is worked as
Amount.
In another preferred example, in (2), the deaminase is adenosine deaminase；Preferably, deaminase is pressed with compound B
It is 1: 1000-3000 (preferably 1: 2000-3000 according to weight ratio；It is most preferably 1: 2500)；Preferably, enzymic catalytic reaction
Temperature be 18~45 DEG C (preferably 25~45 DEG C, be more preferably 40 DEG C)；Or in (2), in neutral conditions, preferably pH
It is reacted under the conditions of=7-8.
In another preferred example, in (2), after production A compound represented, further include：It will include shown in formula Aization
The product for closing object carries out recrystallization purifying, obtains the compound shown in formula A of high-purity；Preferably, with water (preferably go from
Sub- purified water) it is recrystallization solvent；It is highly preferred that compound B and water according to w/v be 1: 20-40 (preferably 1:
25-35；It is most preferably 1: 30).
In another aspect of this invention, a kind of compound is provided, structural formula is as shown in formula A：
In another preferred example, the compound is prepared by any the method in front.
In another aspect of this invention, the purposes of the compound is provided, synthesising antisense scant nucleotide is used for.
Other aspects of the invention are apparent to those skilled in the art due to this disclosure
's.
Specific embodiment
Inventor by extensive research and test, find for the first time be with 2,6- diamino-purine nucleosides (compound C)
Starting material is first reacted with sodium hydride, is generated alcohol sodium form reactive intermediate, is then followed by and reacts with 2- bromoethyl ethylether,
2 '-EOE-2 of Targeting groups modification are generated, 6- diamino-purine nucleosides intermediate (compound B) then passes through biochemical reaction,
Carbonyl is converted by the amino of compound B specific site using adenosine deaminase, in high yield, generate target with high selectivity
2 '-EOE- guanosine (compound A) of product.Method set forth in the present invention can easy, economically a large amount of synthesis 2 '-
EOE- guanosine obtains the target compound of very high-purity.Method of the invention is not necessarily to special equipment, is suitable for advising greatly
Mould industrialized production.
In pharmaceuticals production, in order to inhibit the secondary product generated by the impurity contained as much as possible, it is necessary to use
The very few nucleosides of high-purity.Therefore, the invention proposes a kind of 5 '-DMTr-2 '-EOE- thymidines for preparing high-purity
The method of nucleosides.
In the present invention, the structure such as following formula A of the 2 '-EOE- guanosines：
Firstly, the present invention provides a kind of method of purine nucleoside compound for preparing specific objective base group modification, the change
Closing object has the structural formula as shown in following formula B (2,6- diamino-purine nucleosides intermediate B).
The preparation method of the formula B compound includes：It is that starting is former with compound C (2,6- diamino-purine nucleosides)
Material is first reacted with metal hydride, generates alcohol sodium form reactive intermediate；Then it is reacted with 2- halogenated ethyl ethylether.It is synthesized
Route is as follows：
After obtaining intermediate as above, further, the present invention provides a kind of suitable industrialized productions to prepare 2 '-EOE-
The method of guanosine (formula A compound), including：In neutral conditions, it is preferably urged under the conditions of pH=7-8 with deaminase
Change 2,6- diamino-purine nucleosides intermediate B, carbonyl is converted by the amino of its specific site, to obtain compound A (2 '-
EOE- guanosine).Its synthetic route is as follows：
In the synthesis of each step of the present invention, Solvent 1 can choose DMF, DMSO or DME.It should be understood that
Solvent 1 can be using those of familiar to those skilled in the art, as long as can be realized dissolution reactant substrate C, while not
The reagent to react with the metal hydride (preferably NaH) can be used in the present invention.As of the invention
Preferred embodiment, 1 reagent of Solvent are DMF.
As preferred embodiment of the invention, the metal hydride is NaH, mole of the compound C and sodium hydride
Than being 1: 1.0-3.0；Preferably 1: 1.2-2.5；It is most preferably 1: 1.5.
As preferred embodiment of the invention, the dosage of solvent DMF is 5~10 w/vs of compound C；The halogenated second of 2-
Benzyl ethyl ether is preferred：2- bromoethyl ethylether, and its dosage is 0.8~1.8 molar equivalent of compound C；Preferably 1:
0.8-1.2；It is most preferably 1: 1.
As preferred embodiment of the invention, it is more preferably deionized water that Solvent 2, which is water,；The crystallization purifying work
Recrystallisation solvent in sequence is selected from：Deionized purified water；Wherein the dosage of deionized purified water and compound B w/v are 1:
20-40；Preferably 1: 25-35；It is most preferably 1: 30.
As preferred embodiment of the invention, the deaminase is adenosine deaminase, preferably, itself and compound B weight ratio
It is 1: 1000-3000；Preferably 1: 2000-3000；It is most preferably 1: 2500；Preferably, it participates in reaction temperature when reacting
Degree is：18~45 DEG C；Preferably：25~45 DEG C；It is most preferably 40 DEG C.
It further include step after carrying out enzyme reaction：The crude reaction of compound containing formula A is recrystallized, into
And obtain the formula A compound of high-purity.It should be understood that although providing preferred recrystallisation solvent system, this field in the present invention
Known some alternative dicyandiamide solutions are also the purifying that can be used for formula A compound.
In a specific embodiment of the present invention, a kind of preparation method of formula A compound, including step are provided：
Compound C is dissolved in DMF by the first step, is cooled to -2~2 DEG C；Then sodium hydride is added, is stirred to react, is made
Sodium alkoxide reactive intermediate；
2- bromoethyl ethylether is added into above-mentioned system, is reacted for second step, and compound B crude product is made；
Obtained crude compound B alcohol crystal is obtained the formula B intermediate of high-purity by third step；
Compound B is dissolved in deionized water by the 4th step, and adenosine deaminase is added, is reacted, and 2 '-EOE- birds are made
Purine nucleosides crude product (i.e. formula A compound)；
6th step obtains the target compound A of high-purity by formula A crude product by recrystallization purifying technique.
Accordingly, the present invention provides effectively and without special equipment, it is suitble to large-scale industrial production, high-purity can be obtained
The preparation method of 2 '-EOE- guanosines, can meet the needs of market.
The present invention also provides 2 '-EOE- guanosines of new compound, can be used as synthesizing new antisense oligonucleotides
The basic material of acid, can be applied to the synthesis field of antisense oligonucleotides.
Also, in addition to it can be used as drug development tool, 2 '-EOE- guanosines can also be used in scientific research, especially
Functional genomics research.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification
All features can be used in combination with any composition form, each feature disclosed in specification, any can provide it is identical,
The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy
The general example of sign.
Main advantages of the present invention are：
1, after inventor's screening is compared with many condition, discovery can compound C be specifically starting material, exist with metal hydride
Under specific reaction condition, 2 '-EOE-2 can be synthesized with advantage, bis--aminopurine nucleoside of 6-, that is, compound B is greatly low to reduce
The generation of isomers significantly improves conversion ratio and reduces the purifying difficulty of midbody compound B, is convenient for scale metaplasia
It produces.
2, without special or abnormally dangerous property reagent in preparation process of the present invention, to equipment, peopleware etc. is without high-grade
It is required that.
3, process of the present invention is simple, convenient, the target compound that can be made by simple three-step reaction.
4, simple purification method provided by the invention is not necessarily to special installation, low in cost.
5, purification process significant effect provided by the invention, the content of target compound can achieve 99% or more.
6, method of the invention easy, economically a large amount of can synthesize 2 '-EOE- guanosines, can be applied to industry
Change large-scale production.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, the percentage of the amount for defining each reagent in embodiment
(%) is mass volume ratio (w/v).
HPLC (high performance liquid chromatography) condition in the following embodiments of the present invention：
Column：YMC-AQ C18 5μm 4.6*250mm
Flow velocity：0.8mL/min
Wavelength：260nm
Mobile phase：A liquid：TEAA buffer (acetic acid aqueous solution of 0.1 mol/L is adjusted to PH=7.0 with triethylamine).B
Liquid：Hplc grade methanol.A liquid in analytic process, B liquid on-line degassing, helium flow velocity 50ml/min.
Gradient：
Embodiment 1, the preparation (compound B) of 2 '-ethoxyethyls (EOE) -2,6-diaminopurine nucleosides
Weigh 2,6-diaminopurine nucleosides (No. CAS：2096-10-8) 135.58kg is dissolved in 1350L DMF, reaction
Liquid is cooled to 0 ± 2 DEG C, and argon gas protection is lower to be added NaH 29.10kg, 0 DEG C~5 DEG C of adition process temperature, finishes 0 DEG C of stirring 1h.
After above-mentioned reaction system spontaneous recovery to room temperature, 73.64 kg of 2- bromoethyl ethylether is added dropwise into system, drop finishes
Reaction is stirred at room temperature.Reaction is not further added by product.Water quenching reaction is slowly added to system at 0 ± 2 DEG C.Slowly into system
2M HCl solution is added, adjusts pH to neutrality.65 DEG C are concentrated in vacuo to and do not drip, and residual solid crystallizes obtain in ethanol
72.91kg faint yellow solid is 2 '-EOE-2,6- diamino purine nucleoside.Purity 98.3%, yield 42.8%.
1H NMR(500MHz,DMSO-d6)δ(ppm):7.95 (s, 1H), 6.80 (brs, 2H), 5.83 (d, J=6.5Hz,
1H), 5.75 (brs, 2H), 5.46 (brs, 1H), 5.01 (d, J=4.5Hz, 1H), 4.49-4.47 (m, 1H), 4.30-4.25
(m,1H),3.96-3.91(m,1H),3.68-3.60(m,2H),3.59-3.51(m, 2H),3.44-3.40(m,2H),3.37-
3.29 (m, 2H), 1.01 (t, J=7.0Hz, 3H)
The preparation (compound A) of embodiment 2,2 '-EOE- guanosines
2 '-EOE-2, the 6- diamino purine nucleoside 52.91kg of the acquisition of previous embodiment 1 are weighed, 1060L water, pH is added
For deaminase is added after neutrality, 37~42 DEG C are stirred to react test paper detection architecture.Reaction solution is in oil pump water-bath 55 after reaction
± 2 DEG C are concentrated into small size, have a large amount of white crystals to be precipitated, then by 0 DEG C of holding 1h of system ice bath, filter, and filter cake is washed with ice water
It washs, filter cake water recrystallizes once, and product 47.64kg is obtained after centrifugal drying, is 2 '-EOE- guanosines.Purity
99.6%, yield：90.0%.
1H NMR(600MHz,DMSO-d6)δ(ppm):10.63(s,1H),7.95(s,1H),6.46 (brs,2H),5.78
(d, J=6.6Hz, 1H), 5.06 (t, J=5.4Hz, 1H), 5.04 (d, J=4.8Hz, 1H), 4.38-4.36 (m, 1H),
4.26-4.23(m,1H),3.91-3.89(m,1H),3.68-3.64(m,1H), 3.61-3.50(m,3H),3.44-3.42(m,
2H), 3.36-3.33 (m, 2H), 1.02 (t, J=7.2Hz, 3H)
The technique of embodiment 3,2 '-EOE- guanosines synthesis downstream product
Utilize the technical process of " 2 '-EOE- guanosine " synthesis downstream product as follows.
According to process above process, useful downstream product is obtained, is applied to antisense oligonucleotides drug field.
The foregoing is merely illustrative of the preferred embodiments of the present invention, the substantial technological content model being not intended to limit the invention
It encloses, substantial technological content of the invention is broadly defined in the scope of the claims of application, any technology that other people complete
Entity or method also or a kind of equivalent change, will if identical with defined in the scope of the claims of application
It is considered as being covered by among the scope of the claims.
Claims (11)
1. a kind of preparation method of compound shown in formula A,
It is characterized in that, the method includes：
(1) it using compound C as starting material, is first reacted with metal hydride, generates alcohol sodium form reactive intermediate；Then with 2- halogen
It is reacted for ethyl diethyldithiocarbamate ether, obtains 2,6- diamino-purine nucleosides intermediate B；
(2) deamination enzymatic 2,6- diamino-purine nucleosides intermediate C, converts carbonyl for the amino of its specific site, thus
Obtain compound A.
2. the method as described in claim 1, which is characterized in that (1) in, the metal hydride is NaH, KH, CaH2；Compared with
It goodly is NaH.
3. the method as described in claim 1, which is characterized in that (1) in, the halogenated ethylene glycol monoethyl ether of 2- is selected from：2- chlorine
For ethyl diethyldithiocarbamate ether, 2- bromoethyl ethylether, 2- iodoethyl ethylether；Preferably, the halogenated ethylene glycol monoethyl ether of the 2-
For 2- bromoethyl ethylether.
4. the method as described in claim 1, which is characterized in that (1) in, alcohol sodium form reactive intermediate and 2- halogenated ethyl ethyl
After ether reaction, further include：Crystallization purifying is carried out to containing 2,6- diamino-purine nucleosides intermediate B crude product；Preferably, with
The solvent of methanol or ethyl alcohol as crystallization；It is highly preferred that using ethyl alcohol as the solvent of crystallization；It is further preferred that the use of ethyl alcohol
Amount is 1: 10-30 with compound C w/v.
5. the method as described in claim 1, which is characterized in that (1) in, with n,N-Dimethylformamide, DMSO or ethylene glycol
Solvent of the dimethyl ether as compound C, preferably using n,N-Dimethylformamide as the solvent of compound C；After dissolution, cooling
To 0 ± 2 DEG C, reacted under atmosphere of inert gases with metal hydride；Preferably, according to w/v, the dosage of solvent is
3~10 times of compound C.
6. the method as described in claim 1, which is characterized in that (1) in, mole of gold the compound C and metal hydride
Than being 1: 1.0-3.0；And/or
2- halogenated ethyl ethylether dosage is 0.8~1.8 molar equivalent of compound C, it is therefore preferable to 1~1.5 molar equivalent.
7. the method as described in claim 1, which is characterized in that (2) in, the deaminase is adenosine deaminase；Preferably, it takes off
Adnosine deaminase is 1: 1000-3000 according to weight ratio with compound B；Preferably, the temperature of enzymic catalytic reaction is 18~45 DEG C；Or
(2) it in, in neutral conditions, is preferably reacted under the conditions of pH=7-8.
8. the method as described in claim 1, which is characterized in that (2) in, after production A compound represented, further include：It will
Product comprising compound shown in formula A carries out recrystallization purifying, obtains the compound shown in formula A of high-purity；Preferably, with
Water is recrystallization solvent；It is highly preferred that compound B and water are 1: 20-40 according to w/v.
9. a kind of compound, structural formula is as shown in formula A：
10. compound as claimed in claim 9, which is characterized in that it is obtained by any the method preparation of claim 1~9
?.
11. the purposes of compound described in claim 9~10 is used for synthesising antisense scant nucleotide.
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| CN109796513A (en) * | 2019-03-01 | 2019-05-24 | 上海兆维科技发展有限公司 | A kind of compound and its preparation method and application |
| CN114317704A (en) * | 2021-06-11 | 2022-04-12 | 北京大学 | Method and kit for detecting N6-methyladenine in nucleic acid molecule |
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| CN114317704A (en) * | 2021-06-11 | 2022-04-12 | 北京大学 | Method and kit for detecting N6-methyladenine in nucleic acid molecule |
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