A method for synthesizing chiral pyrimidine acyclic nucleosides with sulfur side chains by conjugated addition-protonation reaction

A technology of conjugated addition and acyclic nucleosides, applied in the field of chiral pyrimidine acyclic nucleosides, can solve the problems of expensive raw materials and complicated processes, and achieve the effects of easy availability of raw materials, simple operation and high yield

Active Publication Date: 2020-06-16
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, seeking a simple, green, and efficient asymmetric conjugated addition-protonation reaction to synthesize chiral pyrimidine acyclic nucleoside analogs with sulfur side chains is based on solving the problem of expensive raw materials and difficult processes in the synthesis of such compounds. It is very important to provide reference value for the synthesis and application of nucleoside drugs, and to meet the demand for raw materials in the research of new antiviral and antitumor drugs.

Method used

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  • A method for synthesizing chiral pyrimidine acyclic nucleosides with sulfur side chains by conjugated addition-protonation reaction
  • A method for synthesizing chiral pyrimidine acyclic nucleosides with sulfur side chains by conjugated addition-protonation reaction
  • A method for synthesizing chiral pyrimidine acyclic nucleosides with sulfur side chains by conjugated addition-protonation reaction

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Substrate synthesis and reaction condition screening

[0030]

[0031] Add 3-protected pyrimidine substrate 1 (10mmol, 1.0equiv), PPh3 (0.2mmol, 0.02equiv) in a round bottom flask, then add sodium acetate (2mmol, 0.2equiv) and 30ml of anhydrous toluene, and then use Add glacial acetic acid (5mmol, 0.5equiv) with a pipette and stir evenly, then add propiolate (12mmol, 1.2equiv), then place the reaction in an oil bath at 105°C and replace nitrogen, and stir overnight. After the reaction, the reaction was removed from the oil bath and cooled to room temperature, then 80 mL of ethyl acetate was added to the reaction solution, extracted three times with water, dried and filtered through a drying cup, and the remaining solvent was spin-dried with a rotary evaporator at 60°C, and silica gel was added. After stirring, pass through the column with petroleum ether and ethyl acetate to obtain the substrate 3 substituted with acrylate at the 1-position of pyrimidine.

[0032] S...

Embodiment 2

[0039]

[0040] Add 25mg 4A molecular sieves to the reaction tube, then dissolve the quinine thiourea catalyst (0.9mg, 0.0015mmol) in 0.4mL ether and add it to the reaction tube, then pipette (3.6μL, 0.05mmol) of thioacetic acid Add to the reaction tube and then place the reaction tube in a -20°C ice bath and stir for 15 minutes. The double bond substrate (0.05 mmol) was then added as a solid to the reaction solvent and stirring was continued for 15 minutes. After the reaction was completed, 5 mL of dichloromethane was added to the reaction tube, extracted three times with water, then filtered and dried through a drying cup, then silica gel was added to spin dry the remaining solvent, and the reaction product was obtained by passing through the column with ethyl acetate and petroleum ether. The absolute chiral configuration of the product was determined to be S by X-ray single crystal diffraction. Yield 99%, ee: 99%. [α] D 26 =+21.5 (c=1.0, CHCl3). 1 H NMR (600MHz, CDC...

Embodiment 3

[0042]

[0043] Add 25mg 4A molecular sieves to the reaction tube, then dissolve the quinine thiourea catalyst (0.9mg, 0.0015mmol) in 0.4mL cyclopentyl methyl ether and add it to the reaction tube, then pipette the (3.6μL, 0.05mmol) Thioacetic acid was added into the reaction tube, and then the reaction tube was placed in a -20°C ice bath and stirred for 15 minutes. The double bond substrate (0.05 mmol) was then added as a solid to the reaction solvent and stirring was continued for 15 minutes. After the reaction was completed, 5 mL of dichloromethane was added to the reaction tube, extracted three times with water, then filtered and dried through a drying cup, then silica gel was added to spin dry the remaining solvent, and the reaction product was obtained by passing through the column with ethyl acetate and petroleum ether. Yield 99%, ee: 80%. [α] D 26 =+13.9 (c=0.5, CHCl 3 ). 1 H NMR (600MHz, CDCl3): 7.99 (d, J = 7.2Hz, 2H), 7.68 (t, J = 7.2Hz, 1H), 7.52 (t, J = 7.8H...

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Abstract

The invention discloses a method for synthesizing chiral pyrimidine non-cyclo nucleoside with sulfur side chains through conjugate addition-protonation reaction. The method comprises the following step: enabling thioacetic acid and a double-bond substrate 3 to react in an ether solvent or methylbenzene by using a quinine-thiourea catalyst, thereby obtaining chiral pyrimidine non-cyclo nucleoside 4with sulfur side chains. By adopting the method, a chiral product with sulfur can be prepared with high yield and corresponding high selectivity through specific chiral catalysts and reaction conditions. The method has the advantages of being easy in raw material obtaining, gentle in reaction condition, green and environmental-friendly in catalyst, and the like, and a concise and practical synthesis method is provided for synthesizing chiral pyrimidine non-cyclo nucleoside analogs.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis chemistry, and specifically relates to a method for synthesizing chiral pyrimidine acyclic nucleosides with sulfur side chains through a conjugate addition-protonation reaction. Background technique [0002] Acyclic nucleoside drugs occupy a very important position in antiviral and antitumor drugs. In recent decades of drug development, the field of acyclic nucleosides has contributed a variety of effective drugs. Nowadays, a large amount of resources are continuously invested in the research and development of new acyclic nucleoside drugs. Among the drugs currently on the market and in the clinical stage, acyclic nucleoside drugs also occupy a high proportion. However, the acyclic nucleoside drugs currently on the market still generally have problems such as many adverse reactions, low bioavailability, easy drug resistance, and rapid metabolism. Therefore, it is imperative to study new...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B53/00C07D239/54C07D239/553C07D405/06
CPCC07B53/00C07B2200/07C07D239/54C07D239/553C07D405/06
Inventor 谢明胜郭海明王东超王海霞李建平脱灏然渠桂荣
Owner HENAN NORMAL UNIV
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