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Platelet activating factor derivative and synthesis method thereof

A technology of activating factor and synthetic method, applied in the preparation of 2-thio fatty chain carboxylic acid platelet activating factor and its derivatives, in the field of platelet activating factor derivatives, can solve the problem of unstable yield and low 2-S-PAF , limit the market application of 2-S-PAF and other issues, and achieve the effect of low cost

Inactive Publication Date: 2017-07-21
NORTHWEST A & F UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the basis of PAF-5, it believes that the most important thing is the migration of the trityl group, protecting the 2-position, and then reacting with phosphorylcholine. Finally, under the action of the catalyst, the 2-position is substituted to obtain the final product, but , when the phosphorus oxychloride ring is docked and opened, the yield is unstable, and toxic gas hydrogen sulfide is used in the synthetic route, and the intermediate product is easily oxidized and deteriorated
Masakazu Murata et al. used (S)-1-O-acetyl-2-O-benzylglycerol as a raw material for lipase-catalyzed esterification as a chiral source, and selected tetrahydropyranyl groups to protect primary hydroxyl groups to prevent The formation of epoxide and the migration of S→O acyl group, the configuration inversion of the 2-position and p-nitrobenzenesulfonyl chloride, and then the deprotection of PPTS weak acid and weak base salts to generate unstable key intermediates, and finally react with phosphorylcholine to obtain The final product, but the synthetic route needs to be protected and deprotected, and the overall yield is low
[0007] Although the existing research has done some prospective exploratory work on 2-S-PAF, the existing synthetic route is only suitable for small-scale preparation, the amount of 2-S-PAF obtained is small, and the synthetic route is long in cycle, which cannot Large-scale synthesis makes it difficult to commercialize 2-S-PAF, which limits the market application of 2-S-PAF
Currently, the market price of 2-S-PAF is 35,000 yuan / 100mg, which is due to its complicated synthetic route and difficulty in mass production

Method used

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  • Platelet activating factor derivative and synthesis method thereof
  • Platelet activating factor derivative and synthesis method thereof
  • Platelet activating factor derivative and synthesis method thereof

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Embodiment 1

[0037] Embodiment 1, the synthesis of 2-S-PAF

[0038] This embodiment provides the synthetic route figure of 2-S-PAF, see for details image 3 . The final product 2-S-PAF is denoted by TM.

[0039] In the synthetic route given in this example, the specific operation of step 1 is to add 300 mL of dimethylformamide (DMF) solution dissolved with NaH (7.26 g, 0.182 mol) in a round bottom flask, and then add compound 1 (20.0 g, 0.151mol), stirred for 30min; then hexadecylsulfonate (58.21g, 0.182mol) was added to the reaction solution, and reacted at room temperature for 12 hours; the reaction solution was processed, extracted to obtain an organic phase, and silica gel column purification (elution The solvent is n-hexane / ethyl acetate, v / v=95 / 5) to obtain 39.0 g of compound 2 with a yield of 85%.

[0040] 1 H NMR (CDCl 3 )δ0.88(t,J=6.4Hz,6H),1.30(m,28H),1.56(m,5H),3.63(m,5H).

[0041] The specific operation of step 2 is that compound 2 (52.37g, 0.147mol) is dissolved in 370mL...

Embodiment 2

[0060] Embodiment 2, the synthesis of a kind of 2-S-PAF derivative

[0061] The synthetic route given in this embodiment can be found in image 3 , see embodiment 1 for the specific operation of steps 1-8.

[0062] The specific operation of step 9 is to dissolve compound 9 (30mg, 0.05mmol) in 2mL of MeCN, add KI (8.3mg, 0.05mmol), DMAP (6mg, 0.05mmol) and hexadecanoyl chloride (137mg, 0.5mmol ), reacted for 16-24h to obtain the product. with CHCl 3 / MeOH as the eluent, separated and purified by column chromatography to obtain 2-S-PAF derivatives with a yield of 61%.

[0063] 1 H NMR (CDCl 3 )δ0.88(t, J=6.4Hz, 3H), 0.89(t, J=6.4Hz, 3H), 0.91(t, J=6.4Hz, 3H), 1.20-1.42(m, 64H), 1.42- 1.60(m,2H),1.60-1.80(m,2H),1.96-2.18(m,4H),2.33(t,J=7.6Hz,2H),2.54(t,J=7.6Hz,2H),2.72 -2.92(m,6H),3.30-3.47(m,2H),3.40(s,9H),3.48-3.68(m,2H),3.75-4.03(m,5H),4.26-4.42(m,2H) ,5.24-5.50(m,8H).

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Abstract

The invention belongs to the technical field of chemical synthesis and discloses platelet activating factor derivatives with the structure of formula (I), wherein the substituent R represents an acyl group. Its synthetic route uses the acetonide of the chiral source S configuration as the initial reactant. After 9 steps of reaction, the present invention adopts this method for the first time to synthesize 2-thioplatelet activating factor and its derivatives, with high yield and easy advantages of separation. The invention realizes the low-cost and large-scale synthesis of 2-S-PAF and its derivatives, and is of great significance to the activity research, biological experiment, clinical application and disease treatment of 2-S-PAF and its derivatives.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to a kind of platelet activating factor derivatives, in particular to a preparation method of 2-thio fatty chain carboxylic acid platelet activating factor and its derivatives. Background technique [0002] The structure of platelet activating factor (Platelet Activity Factor, PAF) is ether bond phospholipid-1-O-alkyl-2-acetyl-sn-glycerol-3-phosphatidylcholine, such as figure 1 shown. The molecular weight of PAF is 1100. Its structure has a high degree of stereospecificity and is closely related to its biological effects. It can be synthesized by various cells in the body. At present, most scholars generally believe that neutrophils, basophils, eosinophils, platelets, vascular endothelial cells, renal medullary cells, and epithelial cells are active in agonists (thrombin, bradykinin, histamine, tumors, etc.) PAF can be produced under the action of necrosis factor, leukotri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/10
CPCC07F9/10
Inventor 杜振亭马瑞月
Owner NORTHWEST A & F UNIV
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