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Method of Synthesizing adefovir dipivoxil

A raw material, dioxane technology, applied in chemical instruments and methods, compounds of elements of group 5/15 of the periodic table, organic chemistry, etc., can solve the problem of low total yield, reduce by-products, and reduce reaction conditions Mild, easy-to-prepare effects

Inactive Publication Date: 2007-10-24
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overall yield of the target product is low

Method used

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  • Method of Synthesizing adefovir dipivoxil
  • Method of Synthesizing adefovir dipivoxil

Examples

Experimental program
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Embodiment 1

[0027] Embodiment 1: the preparation of ethyl 2-chloromethoxyacetate (4)

[0028] Add 1,3-dioxopentacycline (2) (78 g, 0.99 mol) and acetyl chloride (3) (111 g, 1.49 mol) after anhydrous treatment into a 500 ml one-necked flask, and stir evenly. Heating in an oil bath kept the reaction under reflux for 2h. After the reflux, change the distillation device to distill under reduced pressure (533Pa), and collect fractions at 65-70°C. A total of 107 g of ethyl 2-chloromethoxyacetate (2) was obtained. The yield is 82%, and the boiling point is 68°C / 4mmHg (533Pa). MS (EI): m / z = 117.1.

Embodiment 2

[0029] Embodiment 2: preparation of triisopropyl phosphite (7)

[0030] In a 150ml three-necked flask, add isopropanol (18g, 0.3mol), pyridine (25.5g, 0.3mol) and petroleum ether (100ml). Stir mechanically, cool in an ice-water bath, add dropwise a mixed solution of phosphorus trichloride (5) (13.75 g, 0.1 mol) and petroleum ether (40 ml) into the flask, and stir vigorously. With the dropwise addition of phosphorus trichloride petroleum ether solution, the reaction solution turned into white foam. After 30 minutes, the dropwise addition was completed, and changed to a 50°C water bath to heat the reaction for 1 hour, filtered, the filter cake was washed with petroleum ether, the filtrate was combined, and the 72-75°C / 30mmHg (4000Pa) fraction was collected by vacuum distillation to obtain 13.5g of a colorless liquid. Yield 65%. MS (EI+1.64e4): m / z=208.0. IR (KBr pellet, cm -1 ): 3800cm -1 (w, v CH ), 2960cm -1 (s, v CH3 ), 1185cm -1 (w, v C-O ), 980cm -1 (s, v P-O )....

Embodiment 3

[0031] Embodiment 3: the preparation of diisopropyl acetyl ethoxymethyl phosphonate (8)

[0032] Add ethyl 2-chloromethoxyacetate (4) (10.7 g, 70 mmol) into a 50 ml three-necked flask. With magnetic stirring, the oil bath was heated to 90°C, and triisopropyl phosphite (7) (18.6 g, 90 mmol) was slowly added dropwise, and the dropwise addition was completed in about 1 hour. Raise the temperature to 125°C and keep the reaction temperature for 4h. TLC followed the reaction. After heating, replace the vacuum distillation device, vacuum distillation, collect 168-172 ℃ / 1mmHg (133Pa) fraction, obtain colorless liquid 16g, yield 71%. MS (EI+6.47e4): m / z=282.1. 1 H-NMR (ppm, CDCl 3 ): δ4.73(m, OCH 2 ), δ4.21(s, OCH 2 P), δ3.80(m, CH 2 CH 2 O), δ3.64(t, CHCH 3 ), δ2.01(s, COCH 3 ), δ1.32(m, CH 3 ).

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Abstract

The invention discloses a making method of adefovir dipivoxil, which comprises the following steps: adopting 1,3-pentacyclic dioxide as raw materia; opening ring; rearranging altrose; hydrolyzing; chlorinating; proceeding N-alkylating reaction; obtaining the product with mild reacting condition, little by-product and superior object product.

Description

technical field [0001] The invention relates to a preparation method of adefovir Background technique [0002] Adefovir, chemical name: 9-(2-phosphorylmethoxyethyl) adenine [its chemical structural formula is shown in (1) below] is an important nucleoside anti-hepatitis B virus drug, anti-hepatitis B The new drug Adefovir Dipivoxil is its prodrug. Adefovir can inhibit the activity of DNA polymerase and reverse transcriptase of the virus; and compete with nucleotides for incorporation into the DNA chain of the virus, terminate the elongation and synthesis of the DNA chain, inhibit the replication of the virus and play an antiviral role [0003] [0004] R = H, C 3 h 7 , C 6 h 11 o 2 etc. [0005] Bibliography reports that the synthetic method of adefovir is mainly to be starting raw material with isopropanol and 1-chloro-2-chloromethoxyethane, at first isopropanol reacts with phosphorus trichloride to obtain triisopropyl phosphite, Arbuzov reaction with 1-chloro-2...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 虞心红吕和平刘金平王伟张昊张卫东焦国华汤建马红梅唐云孔德周付收徐玉芳蒋华良钱旭东吴总社宋喜芳
Owner TOPFOND PHARMA CO LTD
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