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Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof

A technology of phosphorodiamidate morpholine and solid-phase synthesis, which is applied in the fields of chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., and can solve problems such as high synthesis cost and expensive resin

Inactive Publication Date: 2012-10-03
天津特安化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that this method has been used for twenty years. For solid-phase synthesis, the resin LCAA-CPG is used as the solid-phase carrier. This resin is extremely expensive, and there is no domestic production, only imported, and the price is 15,000 yuan / 10 grams (Sigma-Aldrich price), so the synthesis cost is huge

Method used

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  • Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof
  • Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof
  • Phosphorodiamidate morpholino oligomer synthetized by solid phase and method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: the synthesis of compound PMO (A-T):

[0066] Taking bases A and T as an example, the synthesis route of PMO (A-T) is:

[0067]

[0068] The feed ratio (molar ratio) of T-5 and tert-butyldimethylchlorosilane is 1 / 1.3, dissolved in dichloromethane. Add imidazole under stirring at room temperature, and the molar ratio of the added amount of imidazole to the morpholino derivative is 3 / 1. After reacting for 5 hours, the reactant was washed with water, dried with anhydrous sodium sulfate, and the crude product T-6 was obtained as a colorless oil after removing the solvent.

[0069] Second step reaction:

[0070]

[0071] T-6 was dissolved in trifluoroacetic acid containing acetic acid, the volume ratio of acetic acid and trifluoroacetic acid was 1 / 50, stirred for 4 hours, and then the solvent was removed to obtain T-7.

[0072] The third step reaction:

[0073]

[0074] T-7 was dissolved in water and dioxane (volume ratio: 1 / 1), and sodium carbonat...

Embodiment 2

[0090] Embodiment 2: the synthesis of compound PMO (C-A-T):

[0091] synthetic route:

[0092]

[0093] First step response:

[0094]

[0095] Compounds C-8 and R-4 (molar feeding ratio: 9 / 1) were dissolved in triethylamine dichloromethane solution (concentration: 50 mg / ml) and placed in a solid-phase synthesis tube. R-5 was obtained after overnight reaction and washed with copious amounts of dichloromethane.

[0096] Second step reaction:

[0097]

[0098] Add tetrabutylammonium fluoride tetrahydrofuran solution (solution concentration: 100 mg / ml) into the solid-phase synthesis tube equipped with R-5. Then the solid-phase synthesis tube was placed on a shaker to react for 4 hours, and the solid-phase resin was washed with tetrahydrofuran and dichloromethane to obtain R-6.

[0099] Tenth step reaction:

[0100]

[0101] Under the condition of ammonia water, R-4 was cut off from the solid phase support of Wang resin to obtain PMO (C-A-T). The amino group on t...

Embodiment 3

[0102] Embodiment 3: the synthesis of compound PMO (G-C-A-T):

[0103]

[0104] First step response:

[0105]

[0106] Compounds G-8 and R-6 (molar feed ratio: 2 / 1) were dissolved in triethylamine dichloromethane solution (concentration: 50 mg / ml) and placed in a solid-phase synthesis tube. R-7 was obtained after overnight reaction and washed with copious amounts of dichloromethane.

[0107] Second step reaction:

[0108]

[0109] Add tetrabutylammonium fluoride tetrahydrofuran solution (solution concentration: 100 mg / ml) into the solid-phase synthesis tube equipped with R-7. Then the solid-phase synthesis tube was placed on a shaker to react for 4 hours, and the solid-phase resin was washed with tetrahydrofuran and dichloromethane to obtain R-8.

[0110] The third step reaction:

[0111]

[0112] Under the condition of ammonia water, R-8 was cut off from the solid phase support of Wang resin to obtain PMO (G-C-A-T). The amino group on the terminal morpholine ...

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Abstract

The invention relates to a method for synthetizing phosphorodiamidate morpholino oligomer by solid phase. A cheap resin is utilized; Wang resin is as a solid phase carrier; the phosphorodiamidate morpholino oligomer (PMO) structure of which terminal hydroxyl is protected by tert-butyl dimethyl silicon is shown in the description, wherein a structure of basic group B is any one of adenine (A), guanine (G), cytosine (C) and thymine (T). Compared with the existing solid phase synthetic technology, the method provided by the invention can greatly reduce synthetic cost, and can be suitable for mass production of phosphorodiamidate morpholino oligomer.

Description

technical field [0001] The invention relates to the technical field of organic biomedicine, and independently researches and develops a novel solid-phase synthesis of phosphorodiamidate morpholino oligonucleotide (PMO) and a method thereof. Background technique [0002] US Patent No. 5,185,444 mainly introduces a method for artificially synthesizing phosphorodiamidate morpholino oligonucleotides. Its greatest contribution is the first complete method of artificially synthesizing phosphorodiamidate morpholino oligonucleotides. The disadvantage is that this method has been used for twenty years. For solid-phase synthesis, the resin LCAA-CPG is used as the solid-phase carrier. This resin is extremely expensive, and there is no domestic production, only imported, and the price is 15,000 yuan / 10 grams (Sigma-Aldrich company price), so the synthesis cost is huge. At this stage, due to breakthroughs in medical applications of phosphorodiamidate morpholino oligonucleotides, it has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C08G79/02
Inventor 刘杨腾飞陈禹全祝士忠李茜
Owner 天津特安化学科技有限公司
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