Method for synthesizing alpha-difluoro methylene phosphonic lactone

A technology of difluoromethylenephosphonolactone and difluoromethylene, which is applied in the field of synthesis of α-difluoromethylenephosphonolactone, can solve the problem of lack of synthesis methods, The biological activity of esters has not been found in the open literature and other issues, and the method is simple, the yield is high, and the conditions are mild.

Inactive Publication Date: 2011-06-01
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] On the other hand, due to the lack of synthetic methods for such compounds, reports on the biolog

Method used

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  • Method for synthesizing alpha-difluoro methylene phosphonic lactone
  • Method for synthesizing alpha-difluoro methylene phosphonic lactone
  • Method for synthesizing alpha-difluoro methylene phosphonic lactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] in N 2 Under gas protection, add 0.5 mmol 4,4-dimethyl-1,1-difluoromethylene-2,3-alkenylphosphonic acid monoethyl ester, 0.75 mmol NIS and 6 mL CH 3 CN, normal temperature reaction, TLC tracking, dilute with ethyl acetate after the reaction, followed by 5% Na 2 S 2 o3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was purified by flash column chromatography.

[0037] The structure of the obtained phosphonolactone is as follows, and the yield is 88%.

[0038]

[0039] m.p.: 90-91 °C.

[0040] IR (KBr): 1623, 1268, 1046, 1005 cm -1 .

[0041] 1 H NMR (300 MHz, CDCl 3 ): δ 6.56-6.45 (m, 1 H), 4.36-4.26 (m, 2 H), 1.75 (s, 3 H), 1.69 (s, 3 H), 1.36 (t, J = 6.9 Hz, 3 H).

[0042] 13 C NMR (100 MHz, CDCl 3 ): δ 132.6-131.9 (m), 116.3-116.1(m), 108.6 (td, J C-F = 254.0 Hz, J C-P = 200.0 Hz), 89.4 (d, J C-P = 8.0 Hz), 65.6 (d, J C-P = 6.0 ...

Embodiment 2

[0049] in N 2 Under air protection, add 0.5 mmol 4-(1,4-butylene)-1,1-difluoromethylene-2,3-alkenylphosphonic acid monoethyl ester, 0.75 mmol NIS and 6 mL CH 3 CN, normal temperature reaction, TLC tracking, dilute with ethyl acetate after the reaction, followed by 5% Na 2 S 2 o 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was purified by flash column chromatography.

[0050] Its structure of the obtained phosphonolactone is as follows,

[0051]

[0052] m.p.: 101-102 °C.

[0053] IR (KBr): 1619, 1287, 1044, 1000 cm -1 .

[0054] 1 H NMR (300 MHz, CDCl 3 ): δ 6.69-6.57 (m, 1 H), 4.41-4.31 (m, 2 H), 2.40-2.33 (m, 3 H), 2.19-2.11 (m, 1 H), 2.00-1.72 (m, 4 H), 1.42 (t, J = 6.9 Hz, 3 H).

[0055] 13 C NMR (125 MHz, CDCl 3 ): δ 133.9-133.4 (m), 116.4-116.2 (m), 109.5 (td, J C-F = 255.2 Hz, J C-P = 200.5 Hz), 98.9 (d, J C-P = 8.8 Hz), 65.7 ...

Embodiment 3

[0062] in N 2 Under gas protection, add 0.5 mmol 4,4-diethyl-1,1-difluoromethylene-2,3-alkenylphosphonic acid monoethyl ester, 1 mmol I 2 and 6 mL CH 3 CN, normal temperature reaction, TLC tracking, dilute with ethyl acetate after the reaction, followed by 5% Na 2 S 2 o 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was purified by flash column chromatography.

[0063] Its structure of the obtained phosphonolactone is as follows,

[0064]

[0065] m.p.: 39-40 °C.

[0066] IR (KBr): 1619, 1285, 1053, 1001 cm -1 .

[0067] 1 H NMR (300 MHz, CDCl 3 ): δ 6.76-6.64 (m, 1 H), 4.39-4.31(m, 2 H), 2.11-1.94 (m, 4 H), 1.41 (t, J = 6.9 Hz, 3 H), 1.02 (t, J =7.2 Hz, 3 H), 0.96 (t, J =7.2 Hz, 3 H).

[0068] 13 C NMR (CDCl 3 , 125 MHz): δ 134.6-134.1 (m), 115.2-115.0 (m), 110.0 (td, J C-F = 253.7 Hz, J C-P = 199.1 Hz), 94.5 (d, J C-P = 9.8 Hz), 6...

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Abstract

The invention discloses a method for synthesizing alpha-difluoro methylene phosphonic lactone. In the method, 2,3-allene phosphoni monoester substituted by alpha-difluoro methylene is used as raw material; an iodine cyclizing reagent is added into 2,3-allene phosphoni monoester; an intramolecular iodine cyclizing reaction is performed at normal temperature to obtain alpha-difluoro methylene phosphonic lactone with a six-membered ring structure. After being subjected to recrystallization or column chromatography purification, the prepared phosphonic lactone is expected to become an important enzyme inhibitor. The method is simple and convenient and has high efficiency, mild conditions and high yield. The yield of an aimed compound phosphonic lactone can reach 76 percent to 93 percent.

Description

technical field [0001] The invention relates to a synthesis method of natural cyclic phosphate analogs of biologically active substances, in particular to a synthesis method of α-difluoromethylene phosphonolactone. Background technique [0002] Phosphate ester is a very important organic substance in organisms, which plays a key role in the signal transduction process in organism cells and is closely related to human life activities. There are two types of phosphates in the human body, one is open-chain phosphates; the other is cyclic phosphates. These phosphate esters can be combined with various enzymes in the body to exert various physiological effects. For example: adenosine triphosphate (ATP) in open-chain phosphate is an important energy carrier in the body, uridine triphosphate participates in the synthesis of glycogen, and cytidine triphosphate participates in the synthesis of phospholipids. Another example: cyclic adenosine monophosphate (cAMP) and cyclic guanosin...

Claims

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Application Information

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IPC IPC(8): C07F9/6574
Inventor 林云刘金涛
Owner NANJING NORMAL UNIVERSITY
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