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Sulfur-containing ring-free nucleosides phosphonate analogue and preparation method thereof

A technology of nucleoside phosphonic acid and analogues, which is applied in the field of medicine and chemical industry, can solve problems not in the research field of nucleoside phosphonic acid analogues, and achieve the effects of easy-to-obtain raw materials, high yield, and easy operation

Inactive Publication Date: 2008-03-19
SHANGHAI JIAO TONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Found through literature search to prior art, G.King Farrington etc. published ("Design and Synthesis of New Transition-State Analogue Inhibitors of AspartateTranscarbamylase") in "Journal of Medicinal Chemistry" (Journal of Medicinal Chemistry, 1985 No. 28) ( Design and synthesis of novel aspartate transcarbamoylase inhibitor transition state analogues), in this paper, phosphonic acid methylene sulfide methylene succinic acid was designed and synthesized, which is effective for aspartate transcarbamoylase Acylase shows a certain inhibitory activity, but this compound does not combine the important component base of nucleosides with phosphonic acid methylene sulfide, so it does not belong to the research field of nucleoside phosphonic acid analogs

Method used

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  • Sulfur-containing ring-free nucleosides phosphonate analogue and preparation method thereof
  • Sulfur-containing ring-free nucleosides phosphonate analogue and preparation method thereof
  • Sulfur-containing ring-free nucleosides phosphonate analogue and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1 (S)-9-N-(2-phosphonomethylene mercaptopropyl)-adenine synthesis

[0030] 1. Synthesis of (R)-propylene carbonate

[0031] Add (R)-1,2-propanediol (1eq), diethyl carbonate (1.5eq), sodium methoxide (0.02eq) into the flask, heat up and distill under normal pressure, when the ethanol evaporated is about 1eq, distill under reduced pressure , the 95-96°C / 3mmHg fraction was collected to give (R)-propylene carbonate (76.2%) as a colorless liquid. 1 H NMR (CDCl 3 ): δ4.811 (m, 1H, OCH 2 CHCH 3 ), δ4.518(t, 1H, OCH 2 CHCH 3 ), δ3.983(t, 1H, OCH 2 CHCH 3 ), δ1.431 (d, 3H, OCH 2 CHCH 3 ).

[0032] 2. Synthesis of diisopropyl p-toluenesulfonyloxymethylphosphonate

[0033] Diisopropyl phosphite (1eq), paraformaldehyde (1.2eq), and TEA (0.5ml) were refluxed for 3h, then cooled to 0°C, p-toluenesulfonyl chloride (0.9eq) and TEA (6ml) were added slowly, After adding, it was raised to room temperature. After reacting for 4h, diethyl ether (20ml) was added, filt...

Embodiment 2

[0040] Example two (R)-9-N-(2-phosphonomethylene mercaptopropyl)-adenine synthesis

[0041] (R)-9-N-(2-phosphonomethylenemercaptopropyl)-adenine can be obtained (56%) by using (R)-1,2-propanediol as raw material and referring to the conditions of Example 1.

Embodiment 3

[0042] Example 3 Synthesis of (R)-1-N-[(2-phosphonomethylene mercapto-3-hydroxyl-propyl)]-cytosine

[0043] 1. Synthesis of (R)-benzylglycidol

[0044] Under the protection of N2, add (R)-glycidol (1eq) dropwise to the NaH (1eq) / DMF suspension in an ice bath, stir for 30min, then add BnCl (1.2eq) dropwise, naturally rise to room temperature, and stir for 2.5h Stop the reaction, remove the DMF solvent, and use ethyl acetate / water solution. The organic layer was washed with saturated NaHCO 3 solution, saturated NaCl solution and washed with anhydrous NaCl 2 SO 4 After drying, a pale yellow liquid (55%) was obtained.

[0045] 2. Synthesis of (R)-1-N-[(2-hydroxyl-3-benzyloxy)propyl]cytosine

[0046] N 2 Under protection, add cytosine (1eq), anhydrous DMF, NaH (0.6eq) into the flask, stir for 1.5h, add (R)-benzylglycidol (0.9eq), react at 110°C for 3h, remove DMF, Extract with dichloromethane / tert-butanol / water, and extract the aqueous layer with dichloromethane / tert-butanol...

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Abstract

The present invention discloses a sulfur-containing acyclic nucleoside phosphonate analog and a preparation method, which belongs to the technical fields of medicines and chemistry. The structural formula of the compound of the present invention is shown on the right, wherein, B is one of adenine, guanine, cytimidine, uracil and thymine and the substituted base, X is one of hydrogen, hydroxyl, fluorin, methoxyl and azido, and the carbon atom shown as * is a chiral carbon, which has two types of chiral enantiomers, the R-configuration and the S-configuration. The compound of the present invention can apply the market-purchased three carbon chiral material and can be prepared by a fundamental chain containing a three carbon alkyl side chain, which is obtained by a reaction between the material and a base, protection by an active group, the introduction of sulfur atoms, the linkage of a phosphonic acid-containing side chain and the removal of the protective group. The synthesis method of the present invention has the advantages of easy acquirement of materials, mild reaction conditions and convenient operation.

Description

technical field [0001] The invention relates to a compound in the technical field of medicine and chemical industry and a preparation method thereof, in particular to a sulfur-containing acyclic nucleoside phosphonic acid analog and a preparation method thereof. Background technique [0002] Since the discovery in 1978 that DHPA (under the trade name of Duvira gel, which is marketed in the Czech Republic as a superficial drug for herpes virus infection) has obvious inhibitory activity against various DNA viruses and RNA viruses, the antiviral research on acyclic nucleoside analogs has been considerable. Actively, a series of high-efficiency and low-toxicity drugs have been launched successively, such as Acyclovir (Acyclovir), Valciclovir (Valciclovir) and in October 2006 approved by the US State Food and Drug Administration (FDA). Telbivudine for Hepatitis Treatment. Acyclic nucleoside phosphonic acid analogs have a phosphonic acid group in their structure, avoiding the ste...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07F9/6512
CPCY02P20/55
Inventor 傅磊彭英丹张健存陈尧刘文陆
Owner SHANGHAI JIAO TONG UNIV
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