CN110498822A - The synthetic method of on-DNA aryl azide chemical combination object in the building of DNA encoding compound library - Google Patents
The synthetic method of on-DNA aryl azide chemical combination object in the building of DNA encoding compound library Download PDFInfo
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- CN110498822A CN110498822A CN201910830681.7A CN201910830681A CN110498822A CN 110498822 A CN110498822 A CN 110498822A CN 201910830681 A CN201910830681 A CN 201910830681A CN 110498822 A CN110498822 A CN 110498822A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
Abstract
The invention discloses a kind of preparation methods of on-DNA aryl azide chemical combination object: on-DNA aromatic amine compound and nitrite, sulfonic compound and azide hybrid reaction are obtained on-DNA aryl azide chemical combination object, the present invention does not need that metallic catalyst participates in, reaction condition is mild, raw material is easy to get, is at low cost, is easy to operate, high income, is suitable for the synthesis of the DNA encoding compound library of porous plate progress.
Description
Technical field
The invention belongs to DNA encoding compound library technical fields, and in particular to a kind of on-DNA aromatic amine compound and nitrous
The method that hydrochlorate, sulfonic acid reagent and Azide reagenl one kettle way obtain On-DNA aryl azide chemical combination object.
Background technique
U.S. Scripps graduate Sydney Brenner and Richard Lerner professor proposed in 1992
DNA encoding compound library (DNA Encoded Library, vehicle economy L) concept (bibliography:
Proc.Natl.Acad.Sci., 1992,89,5381), this method is by by the unique sequence of a small organic molecule reagent and one section
The DNA of column is attached in molecular level, quick by two to more circulations using " combination-fractionation " strategy of combinatorial chemistry
Ground constructs the compound library of enormous amount, each compound is by different small organic molecule reagent residue groups in the compound library
At, and identified by the DNA of corresponding unique base sequence, a small amount of DNA encoding compound library and target are subjected to affine screening,
The library molecule not adsorbed with target is first washed off, and the library molecule that leaving has absorption with target elutes again, is at this moment obtained
Library molecular concentration is very low, and conventional means are difficult to analyze and identify, passes through the exclusive polymerase chain reaction (Polymerase of DNA
Chain Reaction, abbreviation PCR) there can be the part DNA in the library molecule of absorption to carry out duplication expansion with target what is obtained
Increase until obtained amount of DNA can be identified by DNA sequencer, when the data after sequencing pass through building DNA encoding compound library again
Relation table between the small organic agents and DNA base sequence of creation decodes, and then finds opposite with potential activity molecule
The corresponding small organic agents of the particular compound answered, then these small organic agents are combined by traditional methodology of organic synthesis
The target molecule screened together, the bioactivity for detecting and confirming it to target.
There are mainly three types of the construction methods of DNA encoding compound library, the first is sharp based on Ensemble company, the U.S.
DNA guide molecule library (DNA-Templated Chemical Library Synthesis, the letter obtained with DNA profiling technology
Claim DTCL), it is for second to be obtained using DNA marker technology based on X-Chem company and domestic Chengdu guide with GSK company, the U.S.
DNA record library of molecules (DNA-Recorded Chemical Library, abbreviation DRCL) arrived, the third is with Switzerland
Drug based on Philogen company based on segment designs (Fragment-based drug discovery, abbreviation FBDD) skill
Coding self assembly molecule library (Encoded Self-Assembling Chemical Libraries, the abbreviation that art obtains
ESAC), at present industrially by largely with the method for building DNA encoding compound library be mainly second, this method operation
Simply, cost is lower, can obtain the DNA encoding compound of the compound containing magnanimity using combinational chemistry more quickly
Library.
Other than DNA Start Fragment (being detailed in our company's patent of invention: CN108070009A), a large amount of DNA mark is needed
Label and the small organic molecule reagent that can be reacted according to certain sequence.The coding of DNA label can pass through certain calculating
Machine program obtains specific DNA alkali to obtain and (be detailed in our company's patent of invention: CN107958139A), then by DNA synthesizer
The primer of basic sequence.The acquisition of small organic molecule reagent can be used certain computer program and carry out reagent inventory to acquisition
It is screened to obtain and (be detailed in our company's patent of invention: CN108959855A).
The most important work at present of the library DEL field first is that the exploitation chemically reacted on DNA, abbreviation on-DNA chemistry is anti-
It answers.Because DNA must just be able to maintain stabilization in certain water phase, under pH, temperature, concentration of metal ions and inorganic salt concentration,
Therefore, small to DNA damage, have the on-DNA of the preferable rate of recovery and substrate wide adaptability chemical reaction, be only large-scale application
Required for the synthesis of DNA encoding compound library.The on-DNA of open report chemically reacts nearly 60 kinds of type at present, every kind
Reaction condition is few then a kind of, how then ten several, it may be said that in the case where other situations are the same, the kind of on-DNA chemical reaction
Class is more, and condition is abundanter, and the selectivity in the design of DNA encoding compound library is just more, final DNA encoding compound library
Synthesis success rate it is just higher, the diversity of obtained DNA encoding compound library is just abundanter.
Table 1 can be used for the On-DNA chemical reaction type and actual conditions of DRCL building
In on-DNA chemical reaction, the selection of buffer is particularly significant, we determined that several common buffers
Preparation and quality detecting method (being detailed in our company's patent of invention: CN109456368A), and provide several under the buffer conditions
The specific On-DNA chemical reaction (being detailed in our company's patent of invention: CN109680342A) of kind.
Aryl azide chemical combination object has special structure and physicochemical property, can be used for drug, pesticide and functional material etc.
Synthesis (bibliography: Angew.Chem.Int.Ed., 2005,44,5188).Aryl azide chemical combination object is also important organic conjunction
At intermediate, it can be reduced to obtain arylamine (bibliography: Tetrahedron Lett., 2002,43,1919), can pass through
CuAAC reaction reacts to obtain with alkynes -1,2, the 3- 3-triazole compounds of substitution of Isosorbide-5-Nitrae-two, moreover it is possible to the officials such as imines, itrile group, alkene
It can roll into a ball and 1,3- Dipolar Cycloaddition occurs, synthesis penta azacyclo compound (bibliography: Synlett., 2002,3,
513)。
At present in DNA encoding compound library field, on-DNA aryl azide chemical combination object mainly pass through on-DNA compound with
It is reacted with azido and with the binary small organic agents that the functional group complementary function of on-DNA compound is rolled into a ball to prepare, such as DNA
Amino-compound and the binary reagent containing azido and carboxyl are by condensation reaction preparation on-DNA azido compound, due to this
Class binary reagent is rare and nitrine class reagent has certain risk, limits the acquisition of on-DNA azido compound, in turn
It limits and converts to obtain the bis- substitution -1,2,3- triazole chemical combination of 1,4- of on-DNA aromatic amine compound and on-DNA by functional group
The type and quantity of object.We developed a kind of presence in copper catalyst, ligand (DMEDA) and alkali (anti-sepsis acid sodium) before
Under, the method for efficiently preparing on-DNA aryl azide chemical combination object with reaction of sodium azide by on-DNA aryl halides (is detailed in
Our company's patent of invention: CN201910383114.1), but since this method needs to use metallic catalyst, and reaction temperature
It is higher, limit its further application in the synthesis of DNA encoding compound library.
It is as above in order to solve the problems, such as, it is intended that develop it is a kind of do not need metallic catalyst participation, can obtain under room temperature
To the method for on-DNA aryl azide base, to adapt to the demand that the DNA encoding compound library of high-volume porous plate produces.
Summary of the invention
The first technical problem to be solved by the present invention is to provide a kind of in the building of DNA encoding compound library
The method that on-DNA aromatic amine compound is converted to on-DNA aryl azide chemical combination object, this method do not need metallic catalyst participate in,
Both available on-DNA aryl azide chemical combination object under room temperature.
In order to solve the above technical problems, the present invention provides a kind of on-DNA virtue in the building of DNA encoding compound library
The method that amine compounds are converted to on-DNA aryl azide chemical combination object, wherein the structural formula of on-DNA novel arylamine compound are as follows:
DNA-Ar-NH2, the structural formula of preparation-obtained on-DNA aryl azide chemical combination object is as shown: DNA-Ar-N3。
Wherein, the DNA in structural formula is the list by polymerizeing through manually modified and/or unmodified nucleotide monomer
The nucleotide chain of chain or double-strand；
Wherein, the Ar in structural formula is monocycle or bicyclic aromatic rings, the NH of the on-DNA novel arylamine compound2Connection
In on the ring of Ar, the N of the on-DNA nitrine aryl compound3It is connected on the ring of Ar；
Wherein, the DNA in structural formula and Ar is keyed by a chemical bond or multiple chemistry.When one chemical bond, it is
Refer to that the DNA and Ar in structural formula is connected directly；When multiple chemical bonds, refers to and be spaced multiple chemistry between DNA and Ar in structural formula
Key is connected, for example, passing through methylene (- CH between DNA and Ar2) be connected, that is, pass through two chemistry key connections；Or DNA
The amino of DNA is connect by a carbonyl (- CO-) with Ar, and passes through two chemistry key connections；Or DNA and Ar passes through one
Methylene carbonyl (- CH2CO- the amino of DNA) is connected, and passes through three continuous chemistry key connections.
Specifically, Ar can be selected from following group:
R1For hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfydryl, aryl ketone, alkylphenones, C1-C12Alkyl, C1-C6
Alkylene, C1-C6Alkynes base, C3-C8Naphthenic base, C1-C6Alkyl oxy, C1-C6In alkyl amino any one to it is a variety of with
Machine combination, Ar is upper can one or more R1Group；R2For the functional group for connecting the part DNA, specifically one can be with DNA
On functional group complementary interaction functional group, can be amino, carboxyl, aldehyde radical, any one in fragrant halogen, R2Can directly with
Ar is connected, and can also be spaced multiple chemical bonds and be connected；Y is any one in O, S, NH or alkyl-substituted amino.
The second technical problem to be solved by the present invention, be to provide it is a kind of it is being participated in without metallic catalyst, under room temperature
Both the on-DNA aryl azide chemical combination object of DNA encoding compound library production can having reacted, suitable for high-volume porous plate
Synthetic method.It is condensed the on-DNA virtue nitro compound generated in situ with DNA profiling and containing fragrant nitrocarboxylic acid binary compound,
Further reduction generates on-DNA aromatic amine compound as raw material, with acetonitrile, dimethylformamide, dimethyl acetamide, N-
It is methyl pyrrolidone, dimethyl sulfoxide, methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, tetrahydrofuran, water, inorganic salt buffer, organic
Acid buffer, any one in organic base buffer or several are solvent, with sodium nitrite, potassium nitrite, the tertiary fourth of nitrous acid
The mixture of one or more of ester, isobutyl nitrite or isoamyl nitrite as diazo reagent, with benzene sulfonic acid,
One or more of mixtures of p-methyl benzenesulfonic acid, dodecyl benzene sulfonic acid or methanesulfonic acid are as sulphonic acids reagent, with nitrine
Change lithium, sodium azide, potassium azide, fluoroform sulfonyl azide, azidotrimethylsilane, diphenyl phosphate azide, Azide three
Phenylmethane, two (p-nitrophenyl) azide phosphonates, tributyl tin azide, Azide tetrabutylammonium, nitrine tetramethyl
Guanidine, ethyl nitrine acetate, tosyl nitrine, 4- P-acetamido benzene sulfonyl nitrine or 2- nitrine -1,3- methylimidazole
One or more of mixtures of quinoline hexafluorophosphate react 1 under conditions of temperature is -5~40 DEG C as Azide reagenl
~24 hours, specific reaction equation was as follows:
The present invention provides new method for the synthesis of on-DNA aryl azide chemical combination object, and the present invention does not need metallic catalyst
It participates in, reaction condition is mild, selective height, yield is high, post-processing is simple, the DNA encoding compound of suitable high-volume porous plate
The production in library.
Detailed description of the invention
Fig. 1 is the method for preparing raw material of the method for the present invention, DNA-NH2It is used with containing fragrant nitrocarboxylic acid binary compound
EDCI is condensing agent, s-NHS be condensation activator, generate on-DNA virtue nitro compound, further with B2(OH)4Occur also
The chemical equation of the original reaction corresponding on-DNA aromatic amine compound of in-situ preparation.
Fig. 2 is present invention on-DNA aromatic amine compound and sodium nitrite, p-methyl benzenesulfonic acid and azidotrimethylsilane
Mixing, reaction in-situ obtain the chemical equation of corresponding on-DNA aryl azide compound.
Fig. 3 is the conversion ratio statistics (conversion for the raw material on-DNA aromatic amine compound that two steps of the method for the present invention are prepared
Rate is subject to the TIC peak area on LCMS-LTQ).
Fig. 4 is the conversion of the representative structure formula for the raw material on-DNA aromatic amine compound that two steps of the method for the present invention are prepared
Rate (conversion ratio be subject to the TIC peak area on LCMS-LTQ).
Fig. 5 is present invention on-DNA aromatic amine compound and sodium nitrite, p-methyl benzenesulfonic acid and azidotrimethylsilane
Mixing, reaction in-situ obtain corresponding on-DNA aryl azide compound conversion ratio statistics (conversion ratio is on LCMS-LTQ
TIC peak area subject to).
Fig. 6 is that present invention DNA aromatic amine compound and sodium nitrite, p-methyl benzenesulfonic acid and azidotrimethylsilane are mixed
It closes, reaction in-situ obtains the conversion ratio of the representative structure formula of corresponding on-DNA aryl azide compound, and (conversion ratio is with LCMS-
Subject to TIC peak area on LTQ).
Specific embodiment
Clear, complete description is carried out to technical solution of the present invention below in conjunction with attached drawing, it is clear that described implementation
Example is a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment 1, the synthesis of on-DNA aromatic amine compound
DNA-NH2(such as the starting head segment of patent CN108070009A referred to) is dissolved in 250mM, the boron of pH=9.4
Acid buffer is configured to 1mM strength solution, is dispensed into 96 orifice plates, uses with 360 containing fragrant nitrocarboxylic acid binary compound
EDCI as condensing agent, s-NHS condensation activator react to obtain corresponding on-DNA virtue nitro compound (bibliography:
Nat.Chem., 2015,7,3,241), this only does ethanol precipitation processing after the reaction was completed, is directly used in after concentrate drying in next step
Reduction reaction.
Above-mentioned on-DNA virtue nitro compound is dissolved in 250mM, and it is molten to be configured to 1mM concentration for the borate buffer of pH=9.4
Liquid is dispensed into 96 orifice plates, uses B2(OH)4Reducing agent react to obtain in-situ preparation novel arylamine compound (bibliography:
CN109680342A), this only does ethanol precipitation processing after the reaction was completed, and on-DNA aryl azide is directly used as after concentrate drying
The raw material (see Fig. 2) of object synthesis is closed, wherein conversion ratio is more than 50% there are 198, is folded to preferably verify on-DNA aryl
Nitrogen compound synthetic method, it is more than 50% generated in-situ on-DNA arylamine chemical combination that we, which only select this 198 conversion ratios,
Object for reacting in next step.
Embodiment 2, the synthesis of on-DNA aryl azide chemical combination object
To above-mentioned generated in-situ 198 DNA-Ar-NH2Each hole (10 μ L, 10nmol, 1mM aqueous solution) successively plus
Enter sodium nitrite solution (10 μ L, 1000nmol, 100mM ultrapure waters, 100 molar equivalents) and p-methyl benzenesulfonic acid solution (10 μ L,
125nmol, 12.5mM ultrapure water, 12.5 molar equivalents), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, is placed in
It shakes 5 minutes, is centrifuged at 20 DEG C, azidotrimethylsilane is added, and (10 μ L, 2000nmol, 200mM DMA solution, 200 moles are worked as
Amount), it is reacted 16 hours at 20 DEG C in 96 orifice plate earthquake instruments.
Ethanol precipitation is added:
The 5M sodium chloride solution of overall reaction liquid product 10% is added to the reacting hole of 96 orifice plates, sealer adds after oscillation mixes
Enter 3 times of total volume -20 DEG C store cold dehydrated alcohol, in -80 DEG C refrigerator freezing 2 hours, take out later 4 DEG C with
The centrifugal force of 4000G 30 minutes absorbs supernatant, in -40 DEG C of vacuum freeze-dryings after precipitating deionized water dissolving, is produced
Object detects OD by microplate reader and confirms the rate of recovery, while detecting the conversion ratio that LC-MS confirms each small molecule (see Fig. 5).In original
It is 48% that the on-DNA aromatic amine compound of position conversion ratio > 50%, which obtains the conversion ratio of on-DNA aryl azide chemical combination object,.The first step
The conversion ratio that the higher substrate of conversion ratio obtains second step product is also higher.
In conclusion the various embodiments described above and attached drawing are only presently preferred embodiments of the present invention, not to limit this
The protection scope of invention, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done all are answered
It is included within the scope of the present invention.
Claims (13)
1. nonmetal catalyzed in a kind of DNA encoding compound library building folded by on-DNA aromatic amine compound preparation on-DNA aryl
The synthetic method of nitrogen compound, which is characterized in that the structural formula of the on-DNA aromatic amine compound are as follows: DNA-Ar-NH2, described
The structural formula of on-DNA aryl azide chemical combination object are as follows: DNA-Ar-N3；Molar concentration is the on-DNA arylamine chemical combination of 0.1~2.0mM
Object aqueous solution is in the nitrite of 50~500 molar equivalents, the sulfonic compound solution and 50~300 of 5~100 molar equivalents
Under the azide solution effect of molar equivalent, 1~24 hour one kettle way is reacted at normal temperature, on-DNA aryl azide is made
Object is closed,
Wherein, the DNA in structural formula be by through polymerize single-stranded of manually modified and/or unmodified nucleotide monomer or
The nucleotide chain of double-strand；
Wherein, the Ar in structural formula is monocycle or bicyclic aromatic rings, and DNA and Ar in structural formula pass through one or more chemistry
Key connection.
2. the method as described in claim 1, which is characterized in that the Ar can be selected from following group:
R1For hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfydryl, aryl ketone, alkylphenones, C1-C12Alkyl, C1-C6Alkene
Base, C1-C6Alkynes base, C3-C8Naphthenic base, C1-C6Alkyl oxy, C1-C6Any one in alkyl amino is to a variety of random groups
It closes；Ar is upper can one or more R1Group；R2For connect the part DNA functional group, specifically one can on DNA
The functional group of functional group complementary interaction can be amino, carboxyl, aldehyde radical, any one in fragrant halogen；R2Can directly with Ar phase
Even, multiple chemical bonds can also be spaced to be connected；Y is any one in O, S, NH or alkyl-substituted amino.
3. the method as described in claim 1, which is characterized in that the on-DNA aromatic amine compound is dissolved in mole after aqueous solution
Concentration is 0.1~2.0mM；Preferably, it is 0.1mM that the on-DNA aromatic amine compound, which is dissolved in the molar concentration after aqueous solution,
0.2mM, 0.3mM, 0.4mM, 0.5mM, 0.6mM, 0.7mM, 0.8mM, 0.9mM, 1.0mM, 1.1mM, 1.2mM, 1.3mM,
1.4mM, 1.5mM, 1.6mM, 1.7mM, 1.8mM, 1.9mM or 2.0mM；It is highly preferred that the on-DNA aromatic amine compound is dissolved in
The molar concentration of aqueous solution is 1.0mM.
4. the method as described in claim 1, which is characterized in that the solution is containing acetonitrile, dimethylformamide, dimethyl second
Amide, N-Methyl pyrrolidone, dimethyl sulfoxide, methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, tetrahydrofuran, inorganic salt buffer,
Any one or a few aqueous mixed solvent in organic acid buffer liquid, organic base buffer, and the content of water is not less than
20%；Preferably, the on-DNA aromatic amine compound is dissolved in water.
5. the method as described in claim 1, which is characterized in that the nitrite be sodium nitrite, potassium nitrite, nitrous
The mixture of one or more of tert-butyl acrylate, isobutyl nitrite or isoamyl nitrite；Preferably, the nitrous acid
Salt is sodium nitrite.
6. the method as described in claim 1, which is characterized in that the molar equivalent of the nitrite is 50~500 equivalents；It is excellent
Choosing, the molar equivalent of the nitrite is 50 equivalents, 100 equivalents, 150 equivalents, 200 equivalents, 250 equivalents, 300 equivalents,
350 equivalents, 400 equivalents, 450 equivalents or 500 equivalents；It is highly preferred that the molar equivalent of the nitrite is 100 equivalents.
7. the method as described in claim 1, which is characterized in that the sulphonic acids reagent is benzene sulfonic acid, p-methyl benzenesulfonic acid, ten
The mixture of one or more of dialkyl benzene sulfonic acids or methanesulfonic acid；Preferably, the sulphonic acids reagent is to methylbenzene sulphur
Acid.
8. the method as described in claim 1, which is characterized in that the equivalent of the sulphonic acids reagent is 5~100 equivalents；It is preferred that
, the equivalent of the sulphonic acids reagent is 5 equivalents, and 10 equivalents, 20 equivalents, 30 equivalents, 40 equivalents, 50 equivalents, 60 equivalents, 70 work as
Amount, 80 equivalents, 90 equivalents or 100 equivalents；It is highly preferred that the equivalent of the sulphonic acids reagent is 20 equivalents.
9. the method as described in claim 1, which is characterized in that the Azide reagenl is Lithium Azide, sodium azide, nitrine
Change potassium, fluoroform sulfonyl azide, azidotrimethylsilane, diphenyl phosphate azide, Azide triphenyl methane, two (to nitro
Phenyl) azide phosphonate, tributyl tin azide, Azide tetrabutylammonium, nitrine tetramethylguanidine, ethyl nitrine acetate,
Tosyl nitrine, 4- P-acetamido benzene sulfonyl nitrine or 2- nitrine -1,3- methylimidazole quinoline hexafluorophosphate；It is preferred that
Ground, Azide reagenl are azidotrimethylsilanes.
10. the method as described in claim 1, which is characterized in that the molar equivalent of the Azide reagenl is 50~300 to work as
Amount；Preferably, the molar equivalent of the Azide reagenl is 50 equivalents, 75 equivalents, 100 equivalents, 125 equivalents, 150 equivalents, 175
Equivalent, 200 equivalents, 225 equivalents, 250 equivalents, 275 equivalents or 300 equivalents；It is highly preferred that mole of the Azide reagenl
Equivalent is 200 equivalents.
11. the method as described in claim 1, which is characterized in that the room temperature of the reaction refers to -5~40 DEG C；Preferably, institute
The reaction temperature for stating reaction is 20 DEG C.
12. the method as described in claim 1, which is characterized in that the reaction time of the reaction is 1~24 hour；Preferably
, reaction time of the reaction is 1 hour, 2 hours, 3 hours, and 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours,
10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours,
21 hours, 22 hours, 23 hours or 24 hours；It is highly preferred that the reaction time of the reaction is 16 hours.
13. the method as described in claim 1, which is characterized in that porous plate of the method for batch operates；Preferably,
Synthesis of the method for the DNA encoding compound library of porous plate.
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| CN114478670A (en) * | 2020-10-27 | 2022-05-13 | 成都先导药物开发股份有限公司 | Method for synthesizing On-DNA beta substituted ketone compound |
| CN114478670B (en) * | 2020-10-27 | 2024-01-30 | 成都先导药物开发股份有限公司 | Method for synthesizing On-DNA beta substituted ketone compound |
| CN113698441A (en) * | 2021-09-17 | 2021-11-26 | 康龙化成(宁波)科技发展有限公司 | Method for converting terminal alkyne into carboxylic acid and application of method in construction of gene coding library |
| CN113698441B (en) * | 2021-09-17 | 2023-11-14 | 康龙化成(宁波)科技发展有限公司 | Method for converting terminal alkyne into carboxylic acid and application of method in construction of gene coding library |
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