9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application

A trimethylacetyl, methoxyl technology, applied in chemical instruments and methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problem of large solvent consumption, unfavorable use of adefovir dipivoxil, and unfavorable environment. protection, etc.

Inactive Publication Date: 2003-06-04
CHF SHANGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this comparative literature, adenine is used as a starting material, and a mixed solution containing AD is synthesized by using reaction reagents such as ethylene carbonate, bromotrimethylsilane, chloromethyl pivalate, acetonitrile and toluene, Then use a mixed solution selected from acetone, di-n-butyl ether, a mixed solution of ethyl acetate and di-n-propyl ether, a mixed solution of tert-butanol and di-n-butyl ether, dichloromethane and di-n-butyl ether The mixture of diethyl ether and di-n-propyl ether, the mixture of tetrahydrofuran and di-n-butyl ether, the mixture of ethyl acetate and di-n-butyl ether, the mixture of tetrahydropyran and di-n-butyl ether Mixed solution, mixed solution of ethyl acetate and diethyl ether, tert-butyl methyl ether, diethyl ether, di-n-butyl ether, tert-butanol, toluene, isopropyl acetate or ethyl acetate for crystallization to obtain AD crystals , the crystallization yield is less than 50%
Total yield less than 10%
[0007] The above-mentioned part of reagents and crystallization solvents either depend on foreign imports, or their cost is expensive, thereby greatly increasing the production cost of adefovir dipivoxil crystals, which is unfavorable for the use of adefovir dipivoxil, low yield, and large solvent consumption. Some solvents are highly toxic, which is not conducive to environmental protection

Method used

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  • 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application
  • 9-[2-[[[di (trimethylacetoxyl) methyl phosphoroso] methoxy]-ethyl] adenine crystal and its prepn and crystal application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Synthesis of Diethylsulfonate Oxymethyl Phosphate (I)

[0111] to N 2 Add 1.0Kg (7.24 moles) of diethyl phosphite (purchased from Zhejiang Lanxi Jiahua Chemical Co., Ltd.) and 0.28 kg of paraformaldehyde (purchased from Shanghai Solvent Factory, ACS: 3525-89-4) in the protected reactor. (8.77 moles), stirred and reacted for 2 hours, added 1.25 kg (6.57 moles) of sulfuryl chloride below 0° C., 1 kg (9.88 moles) of triethylamine, stirred and reacted at room temperature for 8 to 10 hours, and TLC detected that the reaction was complete. Filtrate, wash with solvent 2 × 250ml, wash the combined filtrates with water, decolorize and dry with activated carbon, and distill under reduced pressure until the solvent content is less than 1% (GC), to obtain an oil, which is syrupy after cooling to obtain (I). Yield: 75-80%, content: ≥85% (HPLC).

Embodiment 2

[0113] Synthesis of 9-(2-hydroxyethyl)adenine (II):

[0114] Drying Reactor N 2 Protection, drop into diethyl carbonate (purchased from Shanghai Reagent General Factory) 0.75kg (6.35 moles), ethylene glycol (purchased from Shanghai Reagent General Factory) 0.4Kg (6.45 moles and DMF 1kg) to form a mixed solution, insulated and stirred until The reaction is completed, after dropping into sodium hydroxide 0.005kg (0.125 moles, finely ground), adenine (purchased from Zhejiang Chengyi Pharmaceutical Co., Ltd.) 1kg (USP24) (7.40 moles), insulated and stirred HPLC monitoring adenine content≤0.3%, Reaction finishes, add 4.0kg isopropyl acetate and stir for 2 hours, filter out solid, wash with isopropyl acetate, vacuum-dry, obtain powdery solid (II), yield 90%~95%, content ≥ 90% (HPLC ).

Embodiment 3

[0116] Synthesis of 9-[2-(diethylphosphomethoxy)ethyl]adenine(III)

[0117] Drying Reactor N 2 For protection, add (II) 1.0kg (5.58 moles), DMF 4.8kg, CH3ONa1.0kg, (I) 2.25kg (6.98 moles) successively, stir for 8-10 hours, HPLC monitors that the reaction is complete, neutralize with glacial acetic acid and then add Stir with 16kg of dichloromethane, filter out the solid, wash with 2×1.5kg of dichloromethane, combine the filtrate, wash with 2×0.8kg of water, extract the aqueous phase with 2×1.5kg of dichloromethane, combine the organic phases, and recover the dichloromethane Add 3 kg of cyclohexane, stir to obtain a solid, and dry in vacuo for 2 days to obtain a light brown solid (III), with a yield of 50-65%, content ≥ 90% (HPLC), mp 136-138°C.

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Abstract

The present invention relates to one kind of 9-[2-[[[di(trimethyl acetoxyl)methyl] phosphoroso] methoxy]-ethyl] adenine crystal. The crystal has space group P-1, crystal cell parameters a=6.020(2) angstrom, b=11.155(4) angstrom, c=20.833(8) angstrom, alpha=93.798(6) deg, beta=97.458(6) deg, and gamma=102.897(6) deg, and crystal cell volume 1345.5(9) cubic angstrom. The present invention also relates to the process of crystallization in absolute alcohol to obtain 9-[2-[[[di(trimethyl acetoxyl)methyl] phosphoroso] methoxy]-ethyl] adenine crystal. The present invention also relates to the application of the crystal in preparing antiviral medicine.

Description

technical field [0001] The present invention relates to a novel crystal of 9-[2-[[[bis(trimethylacetoxy)methyl]phosphoryl]methoxy]-ethyl]adenine (adefovir dipivoxil). The invention also relates to a method for preparing the crystal, and the invention further relates to the application of the crystal. Background technique [0002] The chemical structural formula of Adefovir Dipivoxil (AD) is 9-[2-[[[bis(trimethylacetoxy)methyl]oxonyl]methoxy]-ethyl]adenine, It has strong in vitro antiviral activity against HIV, HBV, human CMV, HSV-1 and HSV-2, and can inhibit the replication of human herpesvirus 6 (HHV-6) in HSB-2 cells, thus inhibiting HHV -6-induced cytopathic effect and HHV-6-specific antigen expression. After in vivo administration, the compound can also significantly delay MSV-induced tumor formation and death of mice and significantly inhibit FLV-induced splenomegaly. [0003] Clinical studies have found that adefovir dipivoxil can effectively treat HIV-infected pati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675A61P31/12C07F9/6561
Inventor 李科汪元璋李庭华李启升
Owner CHF SHANGHAI PHARMA
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