CN117603287A - One-pot synthesis process of 3',3' -dimeric phosphoramidite - Google Patents
One-pot synthesis process of 3',3' -dimeric phosphoramidite Download PDFInfo
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- CN117603287A CN117603287A CN202311472379.1A CN202311472379A CN117603287A CN 117603287 A CN117603287 A CN 117603287A CN 202311472379 A CN202311472379 A CN 202311472379A CN 117603287 A CN117603287 A CN 117603287A
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- 238000000034 method Methods 0.000 title claims abstract description 46
- 150000008300 phosphoramidites Chemical class 0.000 title claims abstract description 34
- 230000008569 process Effects 0.000 title claims abstract description 31
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 21
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 17
- 239000011574 phosphorus Substances 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000012038 nucleophile Substances 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- -1 isobutyryl Chemical group 0.000 claims description 16
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical group ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 229940043279 diisopropylamine Drugs 0.000 claims description 8
- 239000012434 nucleophilic reagent Substances 0.000 claims description 8
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Chemical group 0.000 claims description 5
- 229910052739 hydrogen Chemical group 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 4
- FCTXEFOUDMXDPD-UHFFFAOYSA-N 3-sulfanylpropanenitrile Chemical compound SCCC#N FCTXEFOUDMXDPD-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 229930024421 Adenine Chemical group 0.000 claims description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical group NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Chemical group OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 229960000643 adenine Drugs 0.000 claims description 2
- 150000001540 azides Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229940104302 cytosine Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229940113082 thymine Drugs 0.000 claims description 2
- 229940035893 uracil Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000007867 post-reaction treatment Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000004811 liquid chromatography Methods 0.000 description 7
- 150000007523 nucleic acids Chemical class 0.000 description 7
- 238000000605 extraction Methods 0.000 description 6
- 108020004707 nucleic acids Proteins 0.000 description 6
- 102000039446 nucleic acids Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- UBTJZUKVKGZHAD-UPRLRBBYSA-N 1-[(2r,4s,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxyoxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)C[C@H](N2C(NC(=O)C(C)=C2)=O)O1 UBTJZUKVKGZHAD-UPRLRBBYSA-N 0.000 description 3
- 229940125644 antibody drug Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108050001049 Extracellular proteins Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MFDHAVFJDSRPKC-YXINZVNLSA-N 1-[(2r,3r,4r,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-methoxyoxolan-2-yl]pyrimidine-2,4-dione Chemical compound C([C@@H]1[C@@H](O)[C@H]([C@@H](O1)N1C(NC(=O)C=C1)=O)OC)OC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 MFDHAVFJDSRPKC-YXINZVNLSA-N 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- FINUHOJILDNELQ-PMFUCWTESA-N n-[1-[(2r,3r,4r,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-methoxyoxolan-2-yl]-2-oxopyrimidin-4-yl]acetamide Chemical compound C([C@@H]1[C@@H](O)[C@H]([C@@H](O1)N1C(N=C(NC(C)=O)C=C1)=O)OC)OC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 FINUHOJILDNELQ-PMFUCWTESA-N 0.000 description 1
- DDOOVEXTSRBCMU-VYUOYPLNSA-N n-[9-[(2r,3r,4r,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-3-fluoro-4-hydroxyoxolan-2-yl]purin-6-yl]benzamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)[C@@H](F)[C@H](N2C3=NC=NC(NC(=O)C=4C=CC=CC=4)=C3N=C2)O1 DDOOVEXTSRBCMU-VYUOYPLNSA-N 0.000 description 1
- ISQLJOGRNUQHJX-WIFIACMTSA-N n-[9-[(2r,3r,4r,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-methoxyoxolan-2-yl]-6-oxo-3h-purin-2-yl]-2-methylpropanamide Chemical compound C([C@@H]1[C@@H](O)[C@H]([C@@H](O1)N1C2=C(C(N=C(NC(=O)C(C)C)N2)=O)N=C1)OC)OC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 ISQLJOGRNUQHJX-WIFIACMTSA-N 0.000 description 1
- SARHDAQOZNKZCC-CJEGOSRCSA-N n-[9-[(2r,3r,4r,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-methoxyoxolan-2-yl]purin-6-yl]benzamide Chemical compound C([C@@H]1[C@@H](O)[C@H]([C@@H](O1)N1C2=NC=NC(NC(=O)C=3C=CC=CC=3)=C2N=C1)OC)OC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 SARHDAQOZNKZCC-CJEGOSRCSA-N 0.000 description 1
- LPICNYATEWGYHI-WIHCDAFUSA-N n-[9-[(2r,4s,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxyoxolan-2-yl]purin-6-yl]benzamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)C[C@H](N2C3=NC=NC(NC(=O)C=4C=CC=CC=4)=C3N=C2)O1 LPICNYATEWGYHI-WIHCDAFUSA-N 0.000 description 1
- UPPVRFOGRCBSJP-UHFFFAOYSA-N n-dichlorophosphanyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)P(Cl)Cl UPPVRFOGRCBSJP-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012772 sequence design Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The application relates to the technical field of biological medicine and production processes, in particular to a process for synthesizing 3',3' -dimeric phosphoramidite by a one-pot method; a one-pot synthesis process of 3',3' -dimeric phosphoramidite comprises the following synthesis steps: reacting a compound shown in a formula 1 with a phosphorus source and alkali to obtain an intermediate; reacting the intermediate with a nucleophile, and extracting to obtain 3',3' -dimeric phosphoramidite shown in formula 2; the method for synthesizing 3',3' dimeric phosphoramidite greatly improves the yield, simplifies the steps and post-reaction treatment processes of the reaction, greatly reduces the cost, shortens the reaction time and the production period, and can realize large-scale amplified production.
Description
Technical Field
The application relates to the technical fields of biological medicines and production processes, in particular to a process for synthesizing 3',3' -dimeric phosphoramidite by a one-pot method.
Background
Aiming at the functions and action mechanisms of different kinds of nucleic acids, the research on nucleic acid medicines with disease treatment functions becomes the popular field of the current new medicine development. The nucleic acid medicine has the outstanding advantages of high treatment efficiency, low medicine toxicity, high specificity, wide application field and the like, is hopeful to become a third-large type medicine after micromolecular chemical medicines and antibody medicines, and has wide future development and application prospects.
Traditional small molecule drugs and antibody drugs mostly work by combining with target proteins, but the development of the traditional small molecule drugs and antibody drugs is limited by drug property (drug) of the target proteins, only 3,000 of the 20,000 proteins coded by human genome are patentable according to Nature report, and only 700 corresponding drugs are developed at present; furthermore, antibody drugs generally only work against cell membranes and extracellular proteins; the nucleic acid medicine is regulated by the gene related to protein expression, and can play a role in regulating intracellular and extracellular and cell membrane proteins, and the action base of most nucleic acid medicines is a base complementary pairing principle, so that the sequence design of the nucleic acid medicine is easy only by knowing the base sequence of a target gene.
In the sequence synthesis process, after the conventional nucleic acid sequence is removed, the 5 'terminal end is correspondingly modified and changed, and the 5' dinucleotide phosphate is a main research direction.
In the related art, the following problems exist in synthesizing 3',3' -dimeric phosphoramidite:
(1) The p-nitrobenzenesulfone is required to be used as an activating agent, so that the reaction step is increased, and meanwhile, the intermediate is required to be purified, so that the amplification difficulty of the reaction is increased;
(2) The final product can be obtained by purifying with a chromatographic column, and cannot be produced in an amplified manner;
(3) The isolation yield is only 7%, and the yield is too low.
Therefore, the development of a scheme for synthesizing 3',3' dimeric phosphoramidite with simple synthesis process, high yield, low purification difficulty and capability of rapidly and effectively synthesizing a large amount of raw materials is urgent.
Disclosure of Invention
Aiming at the defects existing in the prior art, the application provides a process for synthesizing 3',3' -dimeric phosphoramidite by a one-pot method.
The application provides a process for synthesizing 3',3' dimeric phosphoramidite by a one-pot method, which adopts the following technical scheme:
a one-pot synthesis process of 3',3' -dimeric phosphoramidite comprises the following synthesis steps:
wherein,
b is a natural, unnatural or modified base; preferably, B is cytosine, uracil, thymine, adenine, guanine or hypoxanthine;
y is acetyl, benzoyl, isobutyryl, dimethylformamide or hydrogen;
x is hydrogen, hydroxy, fluoro, methoxy, methoxyethyl, azide, propargyloxy, tert-butyldimethylsilyl-protected hydroxy or triisopropylsiloxymethyl-protected hydroxy;
r is N, N-dimethylamino, N-diethylamino, N-diisopropylamino, tetrahydropyrrolyl, methoxy, ethoxy, methylthio, ethylthio, 2-cyanoethoxy or 2-cyanoethylthio.
A one-pot synthesis process of 3',3' -dimeric phosphoramidite comprises the following synthesis steps: dissolving a compound shown in a formula 1 in a reaction solvent, and adding a phosphorus source and alkali for reaction to obtain an intermediate; dissolving nucleophilic reagent in reaction solvent, adding into intermediate to make reaction, extracting to obtain 3',3' -dimeric phosphoramidite shown in formula 2.
Preferably, the intermediate is prepared as follows: after the compound shown in the formula 1 reacts with alkali, a phosphorus source is added for reaction in an inert atmosphere to obtain an intermediate.
Preferably, the step of adding a phosphorus source to effect the reaction is as follows: and (3) dropwise adding a phosphorus source at the temperature of-20 ℃ to 0 ℃, reacting for 10 to 30 minutes at the temperature of-20 ℃ to 0 ℃ after the dropwise adding, and heating to the temperature of 20 ℃ to 25 ℃ to react for 2 to 4 hours.
Preferably, the phosphorus source is phosphorus trichloride.
Preferably, the base is at least one of triethylamine, diisopropylethylamine and pyridine.
Preferably, the reaction is carried out by adding a nucleophile as follows: and (3) dropwise adding a nucleophilic reagent at the temperature of-20 to 0 ℃, adjusting the temperature to 0 to 25 ℃ after the dropwise adding is finished, and reacting for 2 to 4 hours.
Preferably, the nucleophile is at least one of N, N-dimethylamine, N-diethylamine, N-diisopropylamine, tetrahydropyrrole, methanol, ethanol, methyl mercaptan, ethyl mercaptan, 3-hydroxypropionitrile or 3-mercaptopropionitrile.
Preferably, the solvent used for extraction is n-heptane.
Preferably, the reaction solvent is at least one of acetonitrile, ethyl acetate, dichloromethane, acetone, N-heptane, N-hexane, N-dimethylformamide, toluene and tetrahydrofuran.
Preferably, the mol ratio of the compound shown in the formula 1, the phosphorus source and the alkali is 1 (1-1.2): 3-5; the molar ratio of the compound shown in the formula 1 to the nucleophile is 1 (1-3).
The application discloses a process for synthesizing 3',3' dimeric phosphoramidite by a one-pot method, which is suitable for synthesizing various dimeric phosphoramidites and has good adaptability to substrates.
In a specific embodiment, a process for synthesizing 3',3' dimeric phosphoramidite in one pot comprises the following steps:
dissolving nucleoside (a compound shown in a formula 1) in a solvent with 10 times of volume, adding alkali, reducing the temperature (internal temperature) of a reaction solution to minus 20 ℃ under the protection of inert atmosphere, slowly dropwise adding a phosphorus source, controlling the temperature not higher than 0 ℃ during the dropwise adding, reacting for 10-30 minutes at minus 20 ℃ after the dropwise adding is completed, and heating to 20-25 ℃ for reacting for 2-4 hours; after the reaction is completed, cooling to-20 ℃; and dissolving a nucleophilic reagent in a solvent, slowly dripping the nucleophilic reagent into a reaction system, controlling the temperature to be not higher than 0 ℃, adjusting the temperature to 0-25 ℃ after dripping, and reacting for 2-4 hours. After completion of the reaction, the white solid was removed by filtration as judged by liquid chromatography, and 10 volumes of n-heptane was added to extract twice. Concentrating to remove the solvent. The solid was recrystallized from 2-fold volume of n-heptane and filtered to obtain the 3',3' -dimeric phosphoramidite (compound represented by formula 2).
Preferably, the reaction solvent is at least one of acetonitrile, ethyl acetate, dichloromethane, acetone, N-heptane, N-hexane, N-dimethylformamide, toluene and tetrahydrofuran.
Preferably, the phosphorus source is phosphorus trichloride.
Preferably, the base is one or two of triethylamine and diisopropylethylamine.
Preferably, the nucleophile is at least one of N, N-dimethylamine, N-diethylamine, N-diisopropylamine, tetrahydropyrrole, methanol, ethanol, methyl mercaptan, ethyl mercaptan, 3-hydroxypropionitrile or 3-mercaptopropionitrile.
Preferably, the mol ratio of the compound shown in the formula 1, the phosphorus source and the alkali is 1 (1-1.2): 3-5; the molar ratio of the compound shown in the formula 1 to the nucleophile is 1 (1-3).
In the method, phosphorus trichloride is selected as a phosphorus source, triethylamine is selected as alkali, a dimerization intermediate is synthesized at the temperature of minus 20 ℃ to 0 ℃, a nucleophilic reagent is added after the reaction is carried out for subsequent reaction, and a high-purity product is obtained by extraction after the reaction; avoiding the purification by using chromatographic technique and being capable of carrying out the amplification production with the kilogram level or more.
In summary, the present application has the following beneficial effects:
the process for synthesizing 3',3' dimeric phosphoramidite by the one-pot method has the advantages of greatly improving the yield, simplifying the steps and post-reaction treatment processes of the reaction, greatly reducing the cost, shortening the reaction time and the production period and realizing large-scale amplified production.
Drawings
FIG. 1 is a mass spectrum of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O- (2-methoxy) ethyladenosine 3',3' -dimeric phosphoramidite prepared in example 1;
FIG. 2 is a hydrogen spectrum of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O- (2-methoxy) ethyladenosine 3',3' -dimeric phosphoramidite prepared in example 1;
FIG. 3 is a chromatogram of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O- (2-methoxy) ethyladenosine at the 3',3' -position of dimeric phosphoramidite prepared in example 1.
Description of the embodiments
The following examples further illustrate the contents of the present application, but should not be construed as limiting the present application. Modifications and substitutions to methods, procedures, or conditions of the present application without departing from the spirit and substance of the present application are intended to be within the scope of the present application.
The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated; the reagents used in the examples were all commercially available unless otherwise specified.
Example 1
N-benzoyl-5' -O- [ bis (4-methoxyphenyl) phenylmethyl]73.1 g of 2' -O- (2-methoxy) ethyl adenosine is dissolved in 731 ml of acetonitrile solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours; after the reaction is completed, the temperature is reduced to-20 ℃, 28 ml of N, N-diisopropylamine is dissolved in 56 ml of acetonitrile, N-diisopropylamine solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃ during the period, and the temperature is raised to 0 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration as judged by liquid chromatography, and 731 ml of n-heptane was added for extraction twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 146 ml of n-heptane and filtered to give 50.1 g of the product in 63% yield and 98.0% purity. Theoretical molecular weight 1590.65[ (M-H) - ]Mass spectrum peak 1590.53 [ (M-H) - ]。
Example 2:
68.7 g of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O-methyl-adenosine is dissolved in 680 ml of acetonitrile solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 28 ml of N, N-diisopropylamine is dissolved in 56 ml of acetonitrile, N-diisopropylamine solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃ during the period, and the temperature is raised to 0 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration as judged by liquid chromatography, and 680 ml of n-heptane was added to extract twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 136 ml of n-heptane and filtered to give 45.8 g of the product in 61% yield and 98.2% purity.
Example 3:
66.9 g of N-isobutyryl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O-methyl-guanosine is dissolved in 669 ml of acetonitrile solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 28 ml of N, N-diisopropylamine is dissolved in 56 ml of acetonitrile, N-diisopropylamine solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃, and the temperature is raised to 25 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration as judged by liquid chromatography, and 669 ml of n-heptane was added to extract twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 134 ml of n-heptane and filtered to give 41.8 g of the product in 57% yield and 98.8% purity.
Example 4:
56 g of 5'-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O-methyl-uridine are dissolved in 560 ml of dichloromethane solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ at room temperature for 4 hours; after the reaction is completed, the temperature is reduced to minus 20 ℃, 28 ml of N, N-diisopropylamine is dissolved in 56 ml of dichloromethane, the N, N-diisopropylamine solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃, and the reaction is carried out after the dripping is completed and the temperature is increased to 25 ℃. After completion of the reaction, the white solid was removed by filtration as judged by liquid chromatography, and 560 ml of n-heptane was added for extraction twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 112 ml of n-heptane and filtered to give 38.7 g of the product in 62% yield and 98.0% purity.
Example 5:
60.1 g of N-acetyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O-methyl-cytidine is dissolved in 600 ml of dichloromethane solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃ during the period, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 28 ml of N, N-diisopropylamine is dissolved in 56 ml of dichloromethane, N-diisopropylamine solution is slowly added into the reaction system in a dropwise manner, the temperature is controlled to be not higher than 0 ℃, and the temperature is increased to 25 ℃ after the dropwise addition is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration, and 600 ml of n-heptane was added twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 120 ml of n-heptane and filtered to give 45.9 g of the product in 69% yield and 98.2% purity.
Example 6:
73.1 g of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -O- (2-methoxy) ethyl-adenosine is dissolved in 730 ml of acetonitrile solution, 74 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 42 milliliters of N, N-diisopropylamine is dissolved in 28 milliliters of acetonitrile, N-diisopropylamine solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃, and the temperature is raised to 25 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, the white solid was removed by filtration as judged by liquid chromatography, and 730 ml of n-heptane was added for extraction twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 146 ml of n-heptane and filtered to give 50 g of the product in 62% yield and 98.7% purity.
Example 7:
65.7 g of N-benzoyl-5' -O- [ bis (4-methoxyphenyl) phenylmethyl ] -deoxyadenosine is dissolved in 657 ml of dichloromethane solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 14.2 g of 3-hydroxy propionitrile is dissolved in 28 ml of acetonitrile, 3-hydroxy propionitrile solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃, and the temperature is increased to 25 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration, and 657 ml of isopropyl ether was added to extract twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 146 ml of isopropyl ether and filtered to give 37.4 g of the product in 53% yield and 98.5% purity.
Example 8:
67.5 g of N-benzoyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -2' -fluoro-deoxyadenosine is dissolved in 675 ml of dichloromethane solution, 55.6 ml of triethylamine is added, the temperature (internal temperature) of the reaction solution is reduced to minus 20 ℃ under the protection of nitrogen, 9.2 ml of phosphorus trichloride is slowly added dropwise, the temperature is controlled to be not higher than 0 ℃, after the dropwise addition is finished, the reaction is carried out for 30 minutes at minus 20 ℃, and then the temperature is raised to 25 ℃ for 4 hours at room temperature; after the reaction is completed, the temperature is reduced to-20 ℃, 14.2 g of 3-hydroxy propionitrile is dissolved in 28 ml of acetonitrile, 3-hydroxy propionitrile solution is slowly dripped into the reaction system, the temperature is controlled to be not higher than 0 ℃, and the temperature is increased to 25 ℃ after the dripping is completed, and the reaction is carried out for 4 hours. After completion of the reaction, a white solid was removed by filtration as judged by liquid chromatography, and 675 ml of isopropyl ether was added for extraction twice. Concentrating to remove the solvent. The remaining solid was recrystallized from 146 ml of isopropyl ether and filtered to obtain 48.6 g of product; yield 67%, purity 99.3%.
Comparative example
Diisopropylamino phosphorus dichloride 201.0 g is dissolved in 1000 ml tetrahydrofuran, under the protection of nitrogen, tetrahydrofuran solution of p-nitrophenol and triethylamine (347.6 g of p-nitrophenol and 417 ml of triethylamine are dissolved in 5000 ml of tetrahydrofuran) is slowly dripped into the mixture, after the reaction is carried out for 2 hours at room temperature and 25 ℃, the solvent is removed by rotary evaporation under reduced pressure, the remainder is dissolved by dichloromethane/petroleum ether, and column chromatography is carried out, so that 346 g of intermediate 1 is obtained, and the yield is 85%.
163.3 g of 5-methyl-5' -O- [ bis (4-methoxyphenyl) phenylmethyl ] -deoxyuridine and 50.2 g of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene) were dissolved in 300 ml of anhydrous acetonitrile, an acetonitrile solution of intermediate 1 (134.4 g of intermediate 1 was dissolved in 300 ml of anhydrous acetonitrile) was slowly added dropwise thereto under the protection of nitrogen, after the completion of the dropwise addition, the reaction was carried out at room temperature of 25℃for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure, and the residue was dissolved with methylene chloride and separated by column chromatography to give 170.6 g of intermediate 2 in a yield of 70%.
121.8 g of intermediate 2 and 25.1 g of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene) were dissolved in 150 ml of anhydrous acetonitrile, and a solution of 5-methyl-5 '-O- [ bis (4-methoxyphenyl) phenylmethyl ] -deoxyuridine in acetonitrile (90 g of 5-methyl-5' -O- [ bis (4-methoxyphenyl) phenylmethyl ] -deoxyuridine was dissolved in 150 ml of anhydrous acetonitrile) was slowly dropped thereto under the protection of nitrogen, after the completion of the dropping reaction, the solvent was removed by rotary evaporation under reduced pressure at room temperature of 25℃and the residue was dissolved in methylene chloride, and separated by column chromatography to give 116.9 g of the product in a yield of 64%. The total yield of the three steps is 38.1 percent.
Compared with the comparative example, the process for synthesizing 3',3' -dimeric phosphoramidite by the one-pot method greatly improves the yield and simplifies the steps and post-reaction treatment process of the reaction.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.
Claims (10)
1. A process for synthesizing 3',3' dimeric phosphoramidite by a one-pot method is characterized by comprising the following synthesis steps:
；
wherein,
b is a natural, unnatural or modified base; preferably, B is cytosine, uracil, thymine, adenine, guanine or hypoxanthine;
y is acetyl, benzoyl, isobutyryl, dimethylformamide or hydrogen;
x is hydrogen, hydroxy, fluoro, methoxy, methoxyethyl, azide, propargyloxy, tert-butyldimethylsilyl-protected hydroxy or triisopropylsiloxymethyl-protected hydroxy;
r is N, N-dimethylamino, N-diethylamino, N-diisopropylamino, tetrahydropyrrolyl, methoxy, ethoxy, methylthio, ethylthio, 2-cyanoethoxy or 2-cyanoethylthio.
2. The process for synthesizing 3',3' dimeric phosphoramidite according to claim 1, wherein the synthesis steps are as follows: dissolving a compound shown in a formula 1 in a reaction solvent, and adding a phosphorus source and alkali for reaction to obtain an intermediate;
dissolving nucleophilic reagent in reaction solvent, adding into intermediate to make reaction, extracting to obtain 3',3' -dimeric phosphoramidite shown in formula 2.
3. The process for synthesizing 3',3' dimeric phosphoramidite by one-pot method according to claim 2, wherein the preparation steps of the intermediate are as follows: after the compound shown in the formula 1 reacts with alkali, a phosphorus source is added for reaction in an inert atmosphere to obtain an intermediate.
4. A process for synthesizing 3',3' dimeric phosphoramidite according to claim 3, wherein the step of adding a phosphorus source for reaction comprises the steps of: and (3) dropwise adding a phosphorus source at the temperature of-20 ℃ to 0 ℃, reacting for 10 to 30 minutes at the temperature of-20 ℃ to 0 ℃ after the dropwise adding, and heating to the temperature of 20 ℃ to 25 ℃ to react for 2 to 4 hours.
5. A process for one-pot synthesis of 3',3' dimeric phosphoramidite according to claim 2, 3 or 4, wherein: the phosphorus source is phosphorus trichloride.
6. A process for the one-pot synthesis of 3',3' dimeric phosphoramidite according to claim 2 or 3, wherein: the base is at least one of triethylamine, diisopropylethylamine and pyridine.
7. The process for synthesizing 3',3' dimeric phosphoramidite according to claim 2, wherein the step of adding a nucleophile for reaction comprises the steps of: and (3) dropwise adding a nucleophilic reagent at the temperature of-20 to 0 ℃, adjusting the temperature to 0 to 25 ℃ after the dropwise adding is finished, and reacting for 2 to 4 hours.
8. The process for synthesizing 3',3' dimeric phosphoramidite according to claim 2 or 7, wherein the process comprises the following steps: the nucleophilic reagent is at least one of N, N-dimethyl amine, N-diethyl amine, N-diisopropyl amine, tetrahydropyrrole, methanol, ethanol, methyl mercaptan, ethanethiol, 3-hydroxy propionitrile or 3-mercapto propionitrile.
9. The process for synthesizing 3',3' dimeric phosphoramidite by a one-pot method according to claim 2, wherein the process comprises the following steps: the mol ratio of the compound shown in the formula 1, the phosphorus source and the alkali is 1 (1-1.2): 3-5; the molar ratio of the compound shown in the formula 1 to the nucleophile is 1 (1-3).
10. The process for synthesizing 3',3' dimeric phosphoramidite by a one-pot method according to claim 2, wherein the process comprises the following steps: the reaction solvent is at least one of acetonitrile, ethyl acetate, dichloromethane, acetone, N-heptane, N-hexane, N-dimethylformamide, toluene and tetrahydrofuran.
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