Crystalline form of Adefovir ester and preparation method

A technology of adefovir dipivoxil and new crystallization, applied in the field of AD synthesis, purification and preparation

Inactive Publication Date: 2004-05-26
XICHUAN INST OF ANTIBIOTIC IND NAT MEDICINE SUPERVISION BUREAU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] So far, the report about AD crystalline form except that the patent specification CN 1251592A that Gilead (Gilled Science Co., Ltd.) company applied for in China on July 23, 1998 describes the synthesis method and the

Method used

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  • Crystalline form of Adefovir ester and preparation method
  • Crystalline form of Adefovir ester and preparation method
  • Crystalline form of Adefovir ester and preparation method

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experiment example

[0029] Characterization of AD Crystalline Morphology

[0030]The inventors used several methods (usually using XRD and DSC differential thermograms, and Fourier transform infrared absorption spectroscopy can also be used to supplement evidence) to characterize the characteristics of the crystal form of AD. Operators generally use XRD to characterize the composition of crystals or to identify them (see "United States Pharmacopoeia" Vol. 23, 1995, Method 941, pp. 1843-1845, published by U.S. Pharmacopeial Convention, Inc., Rockville, MD; Stout et al., X -Ray Structure Determination; A Practical Guide, published by MacMillan Company in New York City, New York, 1968; see also "Pharmacopoeia of the People's Republic of China" 2000 Edition, Part Two, Appendix IX F Method, Appendix 70, Appendix VIII Q Method, Appendix 65 Appendix IV C method, appendix 27 pages, Chemical Industry Press). Diffraction patterns obtained from crystalline compounds are often characteristic of a given crys...

Embodiment 1

[0044] The synthesis of embodiment 1 AD

[0045] Add 2kg (7.3mol) of PMEA, 1.8kg (18mol) of triethylamine and 20kg of DMF into a 50L reactor, raise the temperature to about 45°C, stir for 30 minutes, add 2.1kg (18mol) of chloromethyl pivalate, and continue to stir the reaction 7 hours, lowered to room temperature and continued to stir for 12 hours, added 100kg of ethyl acetate, stirred, filtered, the filtrate was washed with about 80kg×2 saturated sodium bicarbonate solution, about 80Kg×2 saturated salt water, filtered to remove solid impurities, and concentrated to obtain Dissolve the obtained oil in 10L of ethanol, add 20Kg of water to precipitate under stirring, filter, top wash with an aqueous solution containing 25% ethanol, and drain to obtain a wet product AD 3.28Kg.

Embodiment 2

[0047] 200g of the AD wet product obtained in Example 1 was azeotropically crystallized with 2L of ethyl acetate and 50ml of water at an appropriate temperature (40°C-50°C) and under vacuum conditions, and vacuum-dried at 40°C for 4 hours to obtain AD108. 7g. Based on the external standard substance, the purity of the adefovir dipivoxil in the new crystalline form determined by HPLC is 99.5%.

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Abstract

A new crystal form of nucleotide analog 9-[2-bis(tert-amylacyloxymethoxy) phosphomethoxy ethyl] adenine (or adefovir dipivoxil-AD), its preparing process and its application are disclosed. Its process for synthesizing, purifying and preparing AD is also disclosed.

Description

technical field [0001] The present invention relates to nucleotide analogue 9-[2-bis(pivaloyloxymethoxy)phosphonomethoxyethyl]adenine (namely "adefovir dipivoxil (adefovir dipivoxil)" or " AD") The preparation and application of new crystal forms. At the same time, the invention also relates to the synthesis, purification and preparation methods of AD. technical background [0002] AD is the bis-pivaloyloxymethyl ester of the parent compound 9-[2-bis(pivaloyloxymethoxy)phosphonomethoxyethyl]adenine (PMEA), which is resistant to humans and animals. Viral activity. AD and PMEA are described in the following patent documents: US4724233, US4808716, EP481214, US5514798; also described in the following non-patent documents: Nucleoside and Nucleotides (1995) 14 (3-5): 563-565; Collect.Czech.Chem. Commun (1989) 54: 2190-2201, (1987) 52: 2801-2809; (1988) 53: 2753-2777; Antiviral. Res. (1992) 19: 267-273; J. Med. Chem. (1994) 37: 1861-1864. [0003] So far, the report about ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 蒋宁杨正军杨红丁涛
Owner XICHUAN INST OF ANTIBIOTIC IND NAT MEDICINE SUPERVISION BUREAU
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