Preparation method of aryloxy phosphorylated amino-acid ester compound

A technology for aryloxy phosphorylation of amino acid esters and compounds, which is applied in the field of medicine, can solve the problems of high production equipment requirements, high production costs, and high reactivity, and achieve large-scale production, increase total yield, and reduce costs Effect

Pending Publication Date: 2022-06-21
ACADEMY OF MILITARY MEDICAL SCI
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  • Abstract
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Problems solved by technology

[0013] At present, the method for synthesizing aryloxyphosphorylated amino acid esters still needs to be improved. The problems in the above-mentioned method are due to the high reactivity of the raw material (substituted) phenoxyphosphoryl dichloride. In order to control the reaction of the raw material with the equivalent reactant, the reaction It needs to be carried out at low temperature, the operation is complicated, the requirements for production equipment are high, and the production cost is high

Method used

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  • Preparation method of aryloxy phosphorylated amino-acid ester compound
  • Preparation method of aryloxy phosphorylated amino-acid ester compound
  • Preparation method of aryloxy phosphorylated amino-acid ester compound

Examples

Experimental program
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Effect test

Embodiment

[0120] These examples are not provided to limit the scope of the invention, but merely to illustrate various elements of the invention in greater detail.

[0121] The structures of the compounds were determined by NMR spectroscopy ( 1 H NMR) and / or mass spectrometry (MS) for confirmation.

[0122] Chemical shifts (δ) are given in parts per million (ppm). 1 The determination of H NMR was carried out on a Bruker 400 or Bruker 600 or Varian 300 nuclear magnetic instrument, and the test solvent was deuterated methanol (CD). 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ), the internal standard is tetramethylsilane (TMS).

[0123] LC-MS was measured on Agilent LC-MS-1110 LC / MS, Agilent LC-MS-6110 LC / MS, Agilent LC-MS-6120 LC / MS (manufacturer: Agilent) or Shimadzu LC - On MS 2020.

[0124] Preparative high performance liquid chromatography was performed using an MS-triggered automated purification system (Waters), a Gilson GX-281 (Gilson...

Embodiment 2

[0132] Example 2: Preparation of [(2s)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphoryl]-L-alanine isopropyl ester

[0133]

[0134] The method is the same as in Example 1, except that L-alanine (2-ethylbutyl) ester in the raw material is replaced with L-alanine isopropyl ester 1.312g (10.0mmol) to obtain the target product [(2s)-( 2,3,4,5,6-Pentafluoro-phenoxy)-phenoxy-phosphoryl]-L-alanine isopropyl ester.

[0135] its nuclear magnetic 1 H NMR (600MHz, CDCl 3 ):δ1.25(t,J=7.8Hz,6H),1.46(d,J=7.2Hz,3H),3.94-4.00(m,1H),4.01(t,J=10.2Hz,2H),4.11 -4.17(m,1H), 5.02-5.06(m,1H), 7.20-7.37(m,5H); NMR 13 C NMR (125MHz, CDCl 3 ): δ172.48, 172.42, 150.17, 150.12, 129.83, 125.63, 120.06, 120.03, 69.60, 50.61, 21.62, 21.59, 20.96, 20.93; NMR 31 P NMR (240MHz, CDCl 3 ): δ-1.59; high resolution mass spectrometry HRMS (ESI) calcd.for C 18 H 18 F 5 NO 5 P + [M+H] + :454.0837,found:454.0819.

Embodiment 3

[0136] Example 3: Preparation of [(2s)-(4-nitro-phenoxy)-phenoxy-phosphoryl]-L-alanine (2-ethylbutyl) ester

[0137]

[0138] The method is the same as in Example 1, except that 2,3,4,5,6-pentafluorophenol in the raw material is replaced by 1.391g (10.0mmol) of 4-nitrophenol to obtain the target product [(2s)-(4-nitrophenol) -Phenoxy)-phenoxy-phosphoryl]-L-alanine (2-ethylbutyl) ester.

[0139] its nuclear magnetic 1 H NMR (600MHz, CDCl 3 ):δ0.87(t,J=7.2Hz,6H),1.29-1.35(m,4H),1.41(d,J=7.2Hz,3H),1.47-1.53(m,1H),3.97(dd, J=11.4, 9.6Hz, 1H), 4.04(qd, J=10.8, 6.0Hz, 2H), 4.13-4.19(m, 1H), 7.19-7.24(m, 3H), 7.35(t, J=7.8Hz ,2H),7.40(d,J=9.0Hz,2H); NMR 13 C NMR (125MHz, CDCl 3 ): δ173.17,173.11,155.60,155.56,150.23,150.19,144.67,129.88,125.64, 125.53,120.82,120.78,120.13,120.10,67.84,50.54,50.52,45.79,40.23, 23.18,23.15,21.16,21.13,10.96, 10.93, 8.63; NMR 31 P NMR (240MHz, CDCl 3 ): δ-3.16; high resolution mass spectrometry HRMS (ESI) calcd.for C 21 H 28 N 2 O 7 P + ...

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Abstract

The invention discloses a preparation method of an aryloxy phosphorylated amino-acid ester compound. The aryloxy phosphorylated amino-acid ester compound can be used for synthesis of ProTide drugs. The synthesis method specifically comprises the following steps: reacting (substituted) phenyl dichlorophosphate 1H-1, 2, 4-triazole to generate an intermediate product, directly reacting with amino-acid ester at normal temperature, then reacting with (substituted) phenol to obtain an aryloxy phosphorylated amino-acid ester compound, and continuing recrystallization to prepare the single-configuration target aryloxy phosphorylated amino-acid ester compound. The aryloxy phosphorylated amino-acid ester compound can be further used for synthesis of ProTide drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing aryloxy phosphorylated amino acid esters, which can be used for the preparation of Protide medicines. Background technique [0002] Antiviral drugs are a powerful weapon for mankind to defeat viruses. In the field of antiviral drugs, since the first synthetic nucleoside drug iodouridine was approved for marketing in 1963, nucleoside analogs have become one of the key areas of drug development. After decades of development, nucleoside drugs have become an important class of drugs in the field of antitumor and antiviral therapy. At present, dozens of nucleoside drugs are clinically used for the treatment of tumors and viral infections. The mechanism of action of nucleoside drugs is that after they are converted into triphosphate forms in vivo, they exert corresponding biological activities by inhibiting DNA or RNA polymerase, or by incorporating nucleic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24C07F9/6561C07H1/00C07H19/10
CPCC07F9/2458C07F9/242C07F9/6561C07H19/10C07H1/00
Inventor 王保刚贝祝春宋亚彬张东娜徐力昆曹玢旺
Owner ACADEMY OF MILITARY MEDICAL SCI
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