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Synthesis method of phosphorothioate compounds and application thereof to synthesis of various medicines

A technology of phosphorothioate and phosphorothioate, which is applied in the field of synthesis of phosphorothioate compounds, can solve the problems of poor functional group compatibility, large substrate limitations, and difficulty in putting into use, and achieve mild and simple reaction conditions, Effect of less waste discharge and lower cost

Inactive Publication Date: 2017-06-30
PEKING UNIV
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Problems solved by technology

The disadvantage of this strategy is that the system is too oxidative, the functional group compatibility is poor, and the substrate is limited; third, the transition metal activation strategy, oxidative addition, reduction elimination to construct phosphorothioate [Y.Zhu, T.Chen, S.Li, S.Shimada, L.-B.Han, J.Am.Chem.Soc.2016,138,5825]
This type of strategy has good functional group compatibility and wide substrate applicability. However, in drug production, the use of transition metals is strictly limited, and this type of method is difficult to put into use
Therefore, for alkyl phosphorothioate compounds, mild, green, concise and efficient synthetic methodology research is extremely challenging and has application value, which is also the significance of our work

Method used

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  • Synthesis method of phosphorothioate compounds and application thereof to synthesis of various medicines
  • Synthesis method of phosphorothioate compounds and application thereof to synthesis of various medicines
  • Synthesis method of phosphorothioate compounds and application thereof to synthesis of various medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1 O, the synthesis of O-diethyl-S-n-octane phosphorothioate

[0071]

[0072] a): Take a 25mL reaction tube, add catalyst cesium carbonate 8.2mg, diethyl phosphite 34.5mg, n-octane mercaptan 43.9mg, acetonitrile 1mL, stir at 40°C for 12 hours, the gas atmosphere is air at a standard atmospheric pressure . After the reaction was completed, 12.7 mg of O, O-diethyl-S-n-octane phosphorothioate was obtained through column chromatography, with a yield of 18%.

[0073] b): Take a 25mL reaction tube, add catalyst cesium carbonate 16.4mg, diethyl phosphite 34.5mg, n-octane mercaptan 43.9mg, acetonitrile 1mL, stir at 40°C for 12 hours, the gas atmosphere is air at a standard atmospheric pressure . After the reaction was completed, 24.0 mg of O, O-diethyl-S-n-octane phosphorothioate was obtained through column chromatography, with a yield of 34%.

[0074] c): Take a 25mL reaction tube, add catalyst cesium carbonate 16.4mg, diethyl phosphite 34.5mg, n-octane mercap...

Embodiment 2

[0103] Example 2 Synthesis of O, O-dibutyl-S-n-octane phosphorothioate

[0104]

[0105] Take a 25mL reaction tube, add catalyst cesium carbonate 41.0mg, dibutyl phosphite 48.6mg, n-octane mercaptan 43.9mg, acetonitrile 1mL, stir at 80°C for 3 hours, the gas atmosphere is oxygen at a standard atmospheric pressure. After the reaction was completed, 77.6 mg of O, O-dibutyl-S-n-octane phosphorothioate was obtained through column chromatography, with a yield of 92%.

[0106] 1 H NMR (400MHz, CDCl 3 ):δ4.16-4.02(m,4H),2.86-2.79(m,2H),1.72-1.65(m,6H),1.47-1.28(m,14H),0.95(t,J=7.2Hz,6H ),0.88(t,J=6.4Hz,3H). 13 C NMR (100MHz, CDCl 3 ):δ67.0(d,J C-P =6.0Hz), 32.0(d, J C-P =7.4Hz), 31.6, 30.7(d, J C-P =4.7Hz), 30.6, 29.0, 28.9, 28.4, 22.5, 18.6, 14.0, 13.5. 31 P NMR (162MHz, CDCl 3 ): δ28.5. HRMS m / z (ESI) calcd for C 16 h 36 o 3 PS[M+H] + 339.2123,found: 339.2118.

Embodiment 3

[0107] Example 3 O, the synthesis of O-diisopropyl-S-n-octane phosphorothioate

[0108]

[0109] Take a 25mL reaction tube, add catalyst cesium carbonate 41.0mg, diisopropyl phosphite 41.6mg, n-octane mercaptan 43.9mg, acetonitrile 1mL, stir at 80°C for 3 hours, the gas atmosphere is a standard atmospheric pressure of oxygen. After the reaction was completed, 63.1 mg of O, O-diisopropyl-S-n-octane phosphorothioate was obtained through column chromatography, with a yield of 82%.

[0110] 1 H NMR (400MHz, CDCl 3 ):δ4.78-4.70(m,2H),2.87-2.79(m,2H),1.72-1.65(m,2H),1.38-1.27(m,22H),0.88(t,J=6.4Hz,3H ). 13 C NMR (100MHz, CDCl 3 ):δ72.3(d,J C-P =6.1Hz),31.7,31.0(d,J C-P =4.7Hz), 30.6(d, J C-P =6.3Hz), 29.1, 28.9, 28.6, 23.8 (d, J C-P =3.3Hz), 23.5(d, J C-P =5.6Hz), 22.6, 14.0. 31 P NMR (162MHz, CDCl 3 ): δ25.8. HRMS m / z (ESI) calcd for C 14 h 32 o 3 PS[M+H] + 311.1810,found: 311.1807.

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Abstract

The invention discloses a synthesis method of phosphorothioate compounds with general formula (III), and aims to provide a novel synthesis method of phosphorothioate compounds with simple conditions and easy industrial production. The method is to mix the organophosphorus oxygen compound having the general formula (I) with the mercaptan or thiophenol compound having the general formula (II), and react under the action of a catalyst to prepare the compound of the general formula (III). Phosphorothioate compounds. By adopting the method of the invention, phosphorothioate compounds can be synthesized cheaply and efficiently, and will have wide application prospects in actual production.

Description

technical field [0001] The invention relates to a method for synthesizing phosphorothioate compounds, belonging to the field of organic synthesis chemistry. Background technique [0002] Phosphorothioate compounds, especially alkyl phosphorothioate compounds, have significant biological activity and are widely present in the skeleton structures of drugs (treatment of glaucoma, cancer chemotherapy, etc.) and pesticides (insecticides). , which has important scientific significance and application value for the efficient synthesis of phosphorothioate compounds. [0003] However, the existing synthetic methodologies are limited to the preparation of aryl phosphorothioate compounds, while the synthesis of alkyl phosphorothioate compounds is difficult and rarely reported. Existing strategies are mainly divided into three categories, one, Atherton-Todd type reaction, first halogenation and then coupling reaction [a) F.R.Atherton, A.R.Todd, J.Chem.Soc.1947,674; b) E.M.Georgiev, J ...

Claims

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Application Information

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IPC IPC(8): C07F9/17C07F9/165C07F9/177C07F9/655C07F9/6561C07F9/40C07H19/10C07H1/00
CPCC07F9/17C07F9/1651C07F9/177C07F9/4021C07F9/4075C07F9/65515C07F9/6561C07H1/00C07H19/10
Inventor 焦宁张逸群宋颂
Owner PEKING UNIV
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