CN108203446B - Phenoxy acryloyl group-containing phosphoramidite, preparation method and application thereof - Google Patents
Phenoxy acryloyl group-containing phosphoramidite, preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2408—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyalkyl compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
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- 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
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/52—Amides or imides
- C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F220/60—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen
- C08F220/606—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing nitrogen in addition to the carbonamido nitrogen and containing other heteroatoms
Abstract
The invention provides phenoxy acryloyl group-containing phosphoramidite, a preparation method and application thereof. Specifically, the invention provides a reagent which can be used for solid phase synthesis, and the compound has a structure shown in formula I, wherein R is1、R2、R3、R4、R5And m is as defined in the specification. By this compound, an acryl group can be introduced into a nucleic acid and further polymerization reaction can be carried out. The invention also discloses a preparation method and application of the compound shown in the formula I.
Description
Technical Field
The invention relates to phenoxy acryloyl group-containing phosphoramidite, a preparation method and application thereof, in particular to phenoxy acryloyl group-containing phosphoramidite for nucleic acid structure modification, a preparation method and application thereof.
Background
The biomacromolecule nucleic acid has the functions of specificity recognition and self-assembly, and the solid-phase synthesis technology enables the short-chain oligomeric nucleic acid to be synthesized automatically and efficiently by a DNA synthesizer. At present, the oligomeric nucleic acid is widely applied to the fields of biology, medicine, nanotechnology and the like. Small interfering nucleic acids (siRNA) can silence pathogenic genes (Elbashir S, Tuschl T, et al, Duplexes of 21-nucleotid RNAs medium RNA interference in cultured mammalian cells. Nature, 2001, 411, 494 988; Hamilton A, Baulcombe D, A species of Small antisense RNAs in posttranscriptional gene cloning in plants, Science, 1999, 286, 950.) and act to treat diseases. Therefore, the siRNA has important application value in clinic as a biological macromolecule medicament, and a plurality of siRNA medicaments enter a clinical test stage at present. Aptamers are oligomeric single-stranded nucleic acids with specific sequences obtained by In vitro screening technology, can be combined with targets with high specificity and selectivity (Ellington AD, Szostak JW, In vitro selection of RNA molecules which bind specific ligands, Nature, 1990, 346, 818), have the effect similar to antibodies, are called chemical antibodies, and have wide application In biological detection and drug delivery. Nucleic acids have poor stability in blood circulation and poor cell membrane penetration, and thus have many limitations in biological detection, drug delivery, and their own application as biomacromolecule drugs. Nucleic acids can be modified by introducing functional groups at specific positions of the oligonucleic acids by chemical synthesis. PCT patent application WO2011/153493 discloses that the stability and cell-entering ability of siRNA are significantly improved by the ainylami company by adding hydrophobic groups to both ends of the siRNA.
The acryloyl is introduced into nucleic acid, and the nucleic acid can be conveniently connected into a high molecular polymer through polymerization reaction, and can be applied to the fields of hydrogel preparation, drug delivery and the like. In order to solve the problem of difficulty in preparation and purification of chemically crosslinked DNA hydrogel in the prior art, the Chinese invention patent CN 103819501A discloses a methyl propenyl phosphoramidite monomer and a synthesis method thereof, and the invention leads corresponding DNA to obtain a DNA single chain with methyl propenyl with higher purity in the process of high performance liquid chromatography by introducing a triphenylmethyl group with larger hydrophobicity into the phosphoramidite monomer. The invention obtains single protected triphenyl methyl ether by reacting 2-substituted-1, 3-propanediol with 4, 4' -dimethoxy triphenyl chloromethane and protecting a hydroxyl. Since both the 1-and 3-hydroxyl groups are symmetric primary hydroxyl groups, disubstituted by-products are easily generated, resulting in low synthesis efficiency. In addition, the acryl group separated from DNA by the aliphatic chain of the flexible structure is weak in hydrophobicity and insufficient in rigidity, and may be disadvantageous to polymerization reaction. The existing synthesis yield of the acryloyl phosphoramidite is low, and the corresponding chain between the propenyl and the DNA is an aliphatic chain, so that the types are single.
There is therefore a need in the art to develop acryloyl phosphoramidites having a structural diversity.
Disclosure of Invention
The invention aims to provide phenoxy acryloyl group-containing phosphoramidite.
Another object of the present invention is to provide a process for the preparation of the compound.
It is a further object of the invention to provide the use of such compounds.
In a first aspect of the present invention, there is provided a phenoxyacryloyl group-containing phosphoramidite having the structure of formula I:
in the formula, R1Selected from: H. f, Cl, Br, I, C1-C6 alkyl, C6-C20 aryl, C3-C8 cycloalkyl, C1-C10 heterocycloalkyl, C5-C20 heteroaryl;
each R2、R3、R4、R5Independently selected from: H. f, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, C6-C20 aryl;
m is CH2The number of groups, m is 1, 2, 3, 4 or 5.
In another preferred embodiment, R is1Is methyl (-CH)3) A substituent group, and having one or more characteristics selected from the group consisting of:
(a) each R2、R3、R4、R5Independently selected from: H. f, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, C6-C20 aryl;
(b) m is CH2The number of groups, m is 1, 2, 3, 4 or 5.
In another preferred embodiment, each R2、R3、R4、R5Independently selected from: H. C1-C3 alkoxy, C1-C3 alkyl.
In another preferred embodiment, the R2 is a hydrogen (-H) substituent and the CH2The number m of groups is 2.
In another preferred embodiment, each R3、R4、R5Independently selected from: H. -OCH3。
In another preferred embodiment, each R3Is H, R4、R5is-OCH3。
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I, comprising the steps of:
(a) providing a dihydroxy compound having the structure of formula II;
wherein the content of the first and second substances,R1、R2m is as defined in the first aspect;
(b) subjecting the compound of formula II to a two-step general solid phase synthesis reagent preparation reaction to yield the compound of the first aspect.
In another preferred embodiment, there is provided a process for the preparation of a compound of formula II, comprising the steps of:
(a) providing a compound having the structure of formula III;
wherein R is1、R2M is as defined in the first aspect;
(b) reacting a compound of formula III with glycidol (HOCH)2CH(O)CH2) Reaction to give the compound of formula II as described in the second aspect.
In another preferred embodiment, the synthesis method of the compound of formula II comprises the following steps:
(a) providing a compound having the structure of formula IV;
wherein X is F, Cl, Br, I, OH, R1、R2M is as defined in the first aspect;
(b) mixing the compound of formula IV with glycerol (HOCH)2CHOHCH2OH) to give a compound of formula II as described in the second aspect.
In another preferred embodiment, the synthesis method of the compound of formula II comprises the following steps:
(a) providing a compound having the structure of formula IV-a;
wherein X ═ F, Cl, Br, I, R1M is defined as the first partyThe method comprises the following steps of (1);
(b) reacting a compound of formula IV-a with glycerol (HOCH)2CHOHCH2OH) to give a compound of formula II as described in the second aspect.
In another preferred embodiment, there is provided a process for the preparation of a compound of formula III:
a compound having the structure of formula V, obtained commercially or synthetically, with R1And (3) reacting the substituted acryloyl chloride to obtain the compound with the structure of the formula III.
In another preferred embodiment, there is provided a process for the preparation of a compound of formula III:
a compound having the structure of formula V, obtained commercially or synthetically, with R1And (3) reacting the substituted acrylic acid to obtain the compound with the structure of the formula III.
In another preferred embodiment, there is provided a process for the preparation of a compound of formula IV:
a compound having the structure of formula VI, either commercially available or synthetically derived, with R1And (3) reacting the substituted acryloyl chloride to obtain the compound with the structure of the formula IV.
In another preferred embodiment, there is provided a process for the preparation of a compound of formula IV:
a compound having the structure of formula VI, either commercially available or synthetically derived, with R1And (3) reacting the substituted acrylic acid to obtain the compound with the structure of the formula IV.
In a third aspect of the invention, there is provided the use of a compound of formula I for the synthesis of a phenoxy-acryloyl-containing nucleic acid.
In another preferred embodiment, the compound of formula I can be used for efficiently joining phenoxy-acryloyl at the 3 '-end or 5' -end of nucleic acid, and the nucleic acid containing phenoxy-acryloyl can be used for polymerization reaction monomers to smoothly carry out polymerization reaction to obtain the water-soluble polymer.
In another preferred embodiment, the compound of formula I is used to efficiently access 1-5 phenoxy-acryloyl groups at the 3 '-end and the 5' -end of a nucleic acid, and the nucleic acid containing multiple phenoxy-acryloyl groups has significantly improved biological stability.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. For reasons of space, they will not be described in detail.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
Synthesis of intermediate 1:
the method A comprises the following steps: methacryloyl chloride (11.4g, 110mmol) was added dropwise to a round bottom flask containing a solution of 4- (2-aminoethyl) phenol (13.7g, 100mmol) in pyridine (100mL) at 0 deg.C, and the reaction was allowed to warm to room temperature for 2 hours. The reaction was terminated by adding a saturated sodium bicarbonate solution, pyridine was removed by distillation under the reduced pressure, and the obtained residue was subjected to column chromatography to give compound 1(16.8 g, 82%) as a pale yellow solid.
The method B comprises the following steps: a solution of methacrylic acid (0.86 g, 10mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (EDC. HCL, 1.91 g, 10mmol), N-hydroxysuccinimide (NHS, 1.15 g, 10mmol), 4- (2-aminoethyl) phenol, (1.37g, 10mmol) in dichloromethane (30mL) was reacted at room temperature for 12 hours. The reaction mixture was washed with aqueous sodium bicarbonate and saturated brine, and the organic phase was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue, which was subjected to column chromatography to give compound 1(1.78 g, 87%).
1H NMR(400MHz，DMSO)δ9.20(s，1H)，7.98(t，J＝5.3Hz，1H)，6.98(d，J＝8.3Hz，2H)，6.68(d，J＝8.3Hz，2H)，5.61(s，1H)，5.30(s，1H)，3.25(dd，J＝14.4，6.3Hz，2H)，2.63(t，J＝7.2Hz，2H)，1.84(s，3H)；13C NMR(101MHz，DMSO)δ166.13，155.03，136.41，131.39，130.50，121.30，116.07，43.22，35.93，16.43.MS(ESI+)：m/e＝206(M+1)。
Example 2
Synthesis of intermediate 2:
the method A comprises the following steps: methacryloyl chloride (1.2g, 11mmol) was added dropwise to a round bottom flask containing a solution of 2- (4-iodophenyl) ethylamine (2.47g, 10mmol) in pyridine (10mL) at 0 deg.C, and the reaction was allowed to warm to room temperature for 5 hours. The reaction was terminated by adding a saturated sodium bicarbonate solution, pyridine was removed by distillation under the reduced pressure, and the obtained residue was subjected to column chromatography to give compound 2(2.8 g, 89%) as a pale yellow solid.
1H NMR(400MHz，DMSO)δ9.20(s，1H)，8.02(t，J＝5.3Hz，1H)，7.61(d，J＝8.3Hz，2H)，7.02(d，J＝8.3Hz，2H)，5.63(s，1H)，5.31(s，1H)，3.24(dd，J＝14.4，6.3Hz，2H)，2.66(t，J＝7.2Hz，2H)，1.83(s，3H)；13C NMR(101MHz，DMSO)δ167.09，155.13，137.41，130.95，130.13，121.12，115.32，43.21，36.32，16.03.MS(ESI+)：m/e＝316(M+1)。
Example 3
Synthesis of intermediate 3:
glycidol (6.5 g, 88mmol), N- (4-hydroxyphenylethyl) methacrylamide (16.4 g, 80mmol) and triethylamine (8mL) in ethanol (80mL) were reacted for 10 h at reflux. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was subjected to column chromatography to give compound 2(17.6 g, 79%) as a white solid.
1H NMR(400MHz，DMSO)δ7.99(s，1H)，7.10(d，J＝8.4Hz，2H)，6.85(d，J＝8.4Hz，2H)，5.61(s，1H)，5.30(s，1H)，4.95(d，J＝4.7Hz，1H)，4.68(t，J＝5.6Hz，1H)，3.95(dd，J＝9.3，3.7Hz，1H)，3.83-3.75(m，2H)，3.43(t，J＝5.4Hz，2H)，3.27(dd，J＝13.9，6.7Hz，2H)，2.68(t，J＝7.4Hz，2H)，1.83(s，3H)；13C NMR(101MHz，DMSO)δ167.32，157.11，140.00，131.27，129.52，118.80，114.24，69.91，69.4562.68，40.76，34.16，18.63.MS(ESI+)：m/e＝280(M+1)。
Example 4
Synthesis of intermediate 3:
to a solution of glycerol (1.01 g, 11mmol) and compound 2(3.15 g, 10mmol) in dimethylformamide (30mL) was added potassium carbonate (2.75 g, 20mmol), and the reaction was carried out at 110 ℃ for 10 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was subjected to column chromatography to give compound 3(1.70 g, 61%) as a white solid.
Example 5
Synthesis of intermediate 4:
to a solution of compound 3(13.9 g, 50mmol) in pyridine (50mL) was added 4, 4' -dimethyltriphenylchloromethane (18.6 g, 55mmol) in portions, reacted at room temperature for 5 hours, and then methanol was added to terminate the reaction. Pyridine was removed by distillation under the reduced pressure, and the obtained residue was subjected to column chromatography to give compound 4(24.7 g, 85%) as a white solid.
1H NMR(400MHz，DMSO)δ7.97(t，J＝5.5Hz，1H)，7.40(d，J＝7.6Hz，2H)，7.29(d，J＝7.4Hz，1H)，7.25(dd，J＝8.7，1.3Hz，4H)，7.21(t，J＝7.2Hz，1H)，7.11(d，J＝8.4Hz，2H)，6.86(dd，J＝8.8，1.8Hz，4H)，6.82(d，J＝8.5Hz，2H)，5.61(s，1H)，5.29(s，1H)，5.14(d，J＝4.9Hz，1H)，4.01-3.88(m，3H)，3.73(s，6H)，3.28(dd，J＝14.0，6.5Hz，2H)，3.06(d，J＝4.4Hz，2H)，2.68(t，J＝7.4Hz，2H)，1.83(s，3H)；13C NMR(101MHz，DMSO)δ167.82，158.48，157.45，145.51，140.53，136.24，131.90，130.20，130.02，128.23，127.05，119.23，114.81，113.58，85.73，69.89，68.62，64.93，55.48，41.24，34.67，19.12.MS(ESI+)：m/e＝582(M+1)。
Example 6
Synthesis of the desired product phenoxyacryloyl phosphoramidite 5
A round-bottom flask containing a solution of compound 4(5.81 g, 10mmol) in dichloromethane (30mL) was placed under nitrogen and cooled to 0 ℃. N, N-diisopropylethylamine and 2-cyanoethyl-N, N-diisopropylphosphoramidite were added dropwise. After two hours of reaction, the reaction solution is washed by sodium bicarbonate aqueous solution and saturated salt water, the organic phase is dried by sodium sulfate and then the solvent is removed by evaporation under reduced pressure, and the obtained residue is subjected to column chromatography to obtain a product 5.1H NMR(400MHz，acetone-d6)：δ7.44-7.53(m，4H)，7.26-7.34(m，7H)，7.05-7.10(m，2H)，6.84-6.87(m，J＝7.5Hz，4H)，5.61(s，1H)，5.29(s，1H)，4.10-4.39(m，2H)，3.76(s，6H)，3.56-3.88(m，2H)，3.29-3.40(m，2H)，2.86(m，2H)，2.72-2.74(m，1H)，2.60-2.63(m，1H)，1.83(s，3H)，1.05-1.28(m，12H)；31P NMRδ：149.51，149.23.MS(ESI+)：m/e＝782(M+1)。
Example 7
Synthesis of phenoxy-acryloyl-containing nucleic acids:
compound 5 was formulated as a 0.1 mol/L solution in anhydrous acetonitrile and loaded into a DNA synthesizer. CPG is used as a solid phase carrier, and the functionalized nucleic acid with any sequence is synthesized through computer programming design. This example synthesizes two typical functionalized nucleic acids for illustrating application studies: nucleic acid I: 5' -xttttagcctttac, nucleic acid two: 5 '-XXTTTTAGTCCTTTAXX-3'; wherein X represents a unit synthesized using compound 5. And (3) carrying out standard deprotection and high performance liquid chromatography purification on the nucleic acid obtained by solid phase synthesis to obtain a nucleic acid I connected with 1 acryloyl group and a nucleic acid II connected with 4 acryloyl groups.
Example 8
Preparing a high molecular nucleic acid polymer by nucleic acid one: dissolving the first nucleic acid in ultrapure water to prepare a solution having a concentration of 1mM, and adding acrylamide to the solution to prepare a mixed solution containing 3-6% acrylamide. Adding a polymerization initiator, and reacting at room temperature for 10-30 minutes to obtain the high molecular nucleic acid polymer which can be used for preparing hydrogel.
Example 9
The prepared nucleic acid II and the corresponding nucleic acid III (sequence: 5'-TTTTTTAGTCCTTTATT-3') all consisting of natural bases were added to the following biological solutions, respectively: serum solution, cell lysate, and placed in a 37 ℃ cell incubator. The sampling detection is carried out according to the gradient of 1, 2, 4, 8 and 16 hours, the PAGE gel result shows that the second nucleic acid can stably exist for more than 8 hours in the environment, and the third natural nucleic acid is rapidly degraded in biological environments such as serum solution, cell lysate and the like. This example demonstrates that the phosphoramidite provided by the present invention can significantly improve the stability of nucleic acids by grafting hydrophobic groups to both ends of the nucleic acids.
Claims (7)
1. A phenoxyacryloyl phosphoramidite comprising a compound having the structure of formula I:
in the formula, R1Selected from: H. f, Cl, Br, I, C1-C6 alkyl, C6-C20 aryl, C3-C8 cycloalkyl, C1-C10 heterocycloalkyl, C5-C20 heteroaryl;
each R2、R3、R4、R5Independently selected from: H. f, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, C6-C20 aryl;
m is CH2The number of groups, m is 1, 2, 3, 4 or 5.
2. A compound of claim 1, wherein R is1Is methyl (-CH)3) A substituent group, and having one or more characteristics selected from the group consisting of:
(a) each R2、R3、R4、R5Independently selected from: H. f, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, C6-C20 aryl;
(b) m is CH2The number of groups, m is 1, 2, 3, 4 or 5.
3. The compound of claim 2, wherein each R is2、R3、R4、R5Independently selected from: H. C1-C3 alkoxy, C1-C3 alkyl.
4. A compound of claim 3 wherein R is2Is a hydrogen (-H) substituent, and the CH2The number m of groups is 2.
5. The compound of claim 4, wherein each R is3、R4、R5Independently selected from: H. -OCH3。
6. The use of a compound of formula I according to claim 1, wherein the incorporation of nucleic acids into the polymer is facilitated by introducing an acryloyl group at any position in the nucleic acid, which acryloyl group undergoes polymerization.
7. The use of a compound of formula I according to claim 1, wherein the biostability of nucleic acids is improved by introducing a phenoxyacryloyl containing substituent in the end of the nucleic acid by the compound of formula I.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219819A (en) * | 2011-04-19 | 2011-10-19 | 李辉 | Nucleotide monomer capable of improving Tm value of oligonucleotide chain as well as preparation method and application thereof |
| CN102439025A (en) * | 2008-09-06 | 2012-05-02 | 坎姆根公司 | Rna synthesis - phosphoramidites for synthetic rna in the reverse direction, and application in convenient introduction of ligands, chromophores and modifications of synthetic rna at the 3' - end |
| CN103819501A (en) * | 2014-03-19 | 2014-05-28 | 厦门大学 | Methyl propenyl phosphoramidite monomer and synthetic method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102439025A (en) * | 2008-09-06 | 2012-05-02 | 坎姆根公司 | Rna synthesis - phosphoramidites for synthetic rna in the reverse direction, and application in convenient introduction of ligands, chromophores and modifications of synthetic rna at the 3' - end |
| CN102219819A (en) * | 2011-04-19 | 2011-10-19 | 李辉 | Nucleotide monomer capable of improving Tm value of oligonucleotide chain as well as preparation method and application thereof |
| CN103819501A (en) * | 2014-03-19 | 2014-05-28 | 厦门大学 | Methyl propenyl phosphoramidite monomer and synthetic method thereof |
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