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CN-122011035-A - Asymmetric catalytic synthesis of pentavalent oxygen sulphur phosphane monomer and preparation method of intermediate thereof

CN122011035ACN 122011035 ACN122011035 ACN 122011035ACN-122011035-A

Abstract

The invention provides an asymmetric preparation method of a pentavalent oxygen sulphur phosphine monomer, wherein the structure of the pentavalent oxygen sulphur phosphine monomer is shown as a formula 3: wherein R2 is any one of hydrogen, alkyl and halogen. The invention is prepared from key starting materials Starting from, with nucleosides under catalysis of cyclohexanediamine catalysts The 5' -OH of the formula (I) is subjected to coupling reaction to synthesize a three-dimensional pure pentavalent oxygen-sulfur-phosphine monomer, so that a synthesis method of the three-dimensional pure oxygen-sulfur-phosphine monomer is expanded, and the obtained three-dimensional pure oxygen-sulfur-phosphine monomer can smoothly realize solid phase synthesis of chiral PS and PS/PO mixed skeleton oligonucleotides and synthesis of PS cyclic dinucleotides, thereby greatly promoting research and development of orphan drugs and anticancer drugs.

Inventors

  • SHANG MING
  • FANG SHUAISHUAI

Assignees

  • 上海交通大学

Dates

Publication Date
20260512
Application Date
20241112

Claims (10)

  1. 1. An intermediate compound, characterized in that the intermediate compound has the structure shown in the following formula 1: wherein X is O or S, R1 is one or more substituents on the benzene ring, and each substituent is any one of hydrogen, alkyl, halogen, cyano, trifluoromethyl and nitro.
  2. 2. A process for producing an intermediate compound according to claim 1, comprising the steps of reacting a compound represented by the formula 1a-1 with phosphorus pentasulfide in the presence of a base, and then cyclizing the obtained compound represented by the formula 1a-2 with ethylene oxide under the action of trifluoroacetic acid to obtain an intermediate compound represented by the formula 1; The structure of the compound of formula 1a-1 is as follows: Wherein X is O or S, R1 is one or more substituents on the benzene ring, and the substituents are any one of hydrogen, methyl, fluorine, cyano, trifluoromethyl, bromine and nitro. The structure of the compound of formula 1a-2 is as follows: Wherein X is O or S, and R1 is any one of hydrogen, alkyl, halogen, cyano, trifluoromethyl and nitro.
  3. 3. The method for producing an intermediate compound according to claim 2, wherein the molar ratio of the compound represented by formula 1a-1 to phosphorus pentasulfide is 2:1, and the molar ratio of the compound represented by formula 1a-1 to a base is 2:2.1; The base is triethylamine; The molar ratio of the compound shown in the formula 1a-2 to the ethylene oxide is 1:1.5; The molar ratio of the compound shown in the formula 1a-2 to trifluoroacetic acid is 1:1.5.
  4. 4. An intermediate compound, characterized in that the intermediate compound has the structure shown in the following formula 2: wherein R2 is any one of hydrogen, alkyl and halogen.
  5. 5. A process for preparing an intermediate compound according to claim 4, comprising the steps of protecting a compound represented by formula 2a-1 with TBSCl, attaching a DMTr group to the compound, and removing the TBS protecting group from the compound represented by formula 2a-2 to obtain an intermediate compound represented by formula 2; The structure of the compound shown in the formula 2a-1 is as follows: wherein R2 is any one of hydrogen, alkyl and halogen; the structure of the compound shown in the formula 2a-2 is as follows: wherein R2 is any one of hydrogen, alkyl and halogen.
  6. 6. The process for the preparation of an intermediate compound according to claim 5, characterized in that the specific steps of the process are: A1, adding imidazole and TBSCl into a compound shown in a formula 2a-1, reacting to obtain a TBS protection intermediate compound, adding DMTrCl into the TBS protection intermediate compound, and reacting to obtain a compound shown in a formula 2 a-2; a2, adding a compound shown in a formula 2a-2 into tetrabutylammonium fluoride, and reacting to obtain an intermediate compound shown in a formula 2; the molar ratio of the formula 2a-1 to TBSCl is 1:1.2, and the molar ratio of the formula 2a-1 to imidazole is 1:1.5. The molar ratio of the formula 2a-2 to tetrabutylammonium fluoride is 1:1.5.
  7. 7. The pentavalent oxygen sulphur phosphine monomer is characterized in that the pentavalent oxygen sulphur phosphine monomer has a structure shown in the following formula 3: wherein R2 is any one of hydrogen, alkyl and halogen.
  8. 8. A process for the preparation of pentavalent oxygen sulphur phosphane monomer according to claim 7, characterised in that it comprises the steps of: And (3) under the catalysis of a cyclohexanediamine catalyst, carrying out asymmetric catalytic coupling reaction on the intermediate compound shown in the formula 1 in the claim 1 and the intermediate compound shown in the formula 2 in the claim 4 to obtain the pentavalent oxygen-sulfur phosphane monomer.
  9. 9. The method for preparing pentavalent oxygen sulfur phosphane monomer of claim 8, characterized in that the cyclohexanediamine catalyst has a compound structure as shown in any one of the following formulas C1-C3: The molar ratio of the intermediate compound shown in the formula 1 to the intermediate compound shown in the formula 2 is 2-3:1, and the addition amount of the catalyst is 10-20mol% of the total molar amount of reactants; The reaction is carried out in the presence of a solvent, wherein the solvent is at least one of toluene, fluorobenzene, anisole and tetrahydrofuran; The temperature of the reaction is-10 ℃ to 40 ℃.
  10. 10. Use of a pentavalent oxygen thiophosphine monomer according to claim 7 in the preparation of PS cyclic dinucleotides or in the preparation of chiral PS and PS/PO mixed backbone oligonucleotides.

Description

Asymmetric catalytic synthesis of pentavalent oxygen sulphur phosphane monomer and preparation method of intermediate thereof Technical Field The invention relates to the technical field of chemical synthesis, in particular to an asymmetric catalytic synthesis method of a pentavalent oxygen sulphur phosphine monomer and a preparation method of an intermediate thereof. Background PS (phosphorothioate) DNA has a stronger oxidation resistance than the common PO (phosphate) DNA, and can protect microorganisms from the attack of oxides. Phosphorothioate modifications do not significantly affect the structure of the nucleic acid, and PS oligonucleotides can still form duplex structures with complementary DNA or RNA single strands. In addition, PS oligonucleotides can be better taken up by cells by dynamic covalent exchange with cell thiols and disulfides, with higher affinity to proteins within the cell. Thus, PS modifications are widely used in nucleic acid pharmaceuticals including antisense oligonucleotides (ASOs) and Cyclic Dinucleotides (CDNs). The thio modification makes the original achiral P atom of the phosphodiester have chirality, and two three-dimensional configurations of R p and S p are generated. The natural PS modification found in bacterial DNA is R p configuration, and in vitro research shows that (S p) -PSDNA has stronger oxidation resistance and higher nuclease resistance than (R p) -PSDNA, so that development of a stereoselective PS oligonucleotide synthesis method is attracting great attention. Compared with a trivalent phosphorus monomer, the pentavalent oxygen sulfur phosphane monomer has better stability, does not need to strictly control anhydrous and anaerobic conditions in the monomer preparation process, does not need to oxidize and sulfide in the oligonucleotide and cyclic dinucleotide synthesis process, has simpler synthesis cycle, and is a research direction worthy of deep exploration for preparing the three-dimensional pure PS oligonucleotide and cyclic dinucleotide by developing the pentavalent oxygen sulfur phosphane monomer with higher coupling activity. The stec subject group discloses a method for preparing a stereo-pure pentavalent oxygen-sulfur phosphane monomer, diastereoisomeric pure substrates are obtained through complicated silica gel column chromatography or expensive preparative HPLC, and then the subject group greatly reduces the classification difficulty of the stereo-pure monomer by introducing a spiro structure into the oxygen-sulfur phosphane monomer, and two diastereoisomers with different configurations can be obtained through one-time column separation. The synthesis of pentavalent oxygen sulphur phosphine monomer is to synthesize pentavalent oxygen sulphur phosphine chloride intermediate from aldehyde through multi-step reaction, then to produce coupling reaction with nucleoside in alkaline condition, finally to oxidize and sulfurize to obtain racemized pentavalent oxygen sulphur phosphine monomer. The specific synthetic route of the method is as follows: The method for synthesizing the oxathiolane monomer can obtain two diastereomers at the same time, but the trivalent phosphorus method has long steps, expensive and difficult to obtain raw materials for reaction, and can use dangerous chemical sulfur, thereby being not friendly to the environment and more limiting the application of the trivalent phosphorus method in actual production due to unavoidable configuration separation. Disclosure of Invention In order to solve the problems, the invention aims to provide an asymmetric catalytic synthesis method of a pentavalent oxygen sulphur phosphine monomer and a preparation method of an intermediate thereof, in particular to an asymmetric synthesis method of a pentavalent oxygen sulphur phosphine monomer, which has the advantages of cheap and easily available raw materials, short reaction route, high total yield and environmental friendliness. The invention aims at realizing the following technical scheme: in a first aspect, the present invention provides an intermediate compound having the structure shown in formula 1 below: wherein X is O or S, and R1 is any one of hydrogen, alkyl, halogen, cyano, trifluoromethyl and nitro. Preferably, when X is O, R1 is any one of hydrogen, alkyl, halogen, cyano, trifluoromethyl, and nitro; When X is S, R1 is any one of hydrogen, alkyl, cyano, trifluoromethyl, bromine and nitro. As a further preferable scheme, when R1 is alkyl, the alkyl is selected from C1-C10 straight-chain or branched-chain alkyl. In a second aspect, the invention provides a preparation method of the intermediate compound, which comprises the following steps of reacting a compound shown in a formula 1a-1 with phosphorus pentasulfide in the presence of alkali, and then cyclizing the obtained compound shown in a formula 1a-2 with ethylene oxide under the action of trifluoroacetic acid to obtain the intermediate compound shown in a formula 1; The structure o