CN105294762A - Preparation method of adefovir dipivoxil impurities - Google Patents

Abstract

The invention relates to a brand-new synthetic method of three adefovir dipivoxil impurities. The synthetic method is of great significance for synthesis of high-quality adefovir dipivoxil. The invention mainly studies synthesis of adefovir dipivoxil methyl ester impurity [[2-(6-amino-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl)(methyl)ester (III), adefovir dipivoxil ethyl ester impurity [[2-(6-amino-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl)(ethyl)ester (IV), adefovir dipivoxil amide impurity [[2-(6-pivaloylamido-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid bi(pivaloyloxymethyl)ester (V). The specific synthetic route of the impurities is as shown in the specification.

Description

The preparation method of adefovir dipivoxil impurity

technical field

The invention relates to a preparation method of adefovir dipivoxil impurities.

Background technique

Adefovir Dipivoxil (Adefovir Dipivoxil), the chemical name is [[2-(6-amino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid bis(pivaloyloxymethyl)ester , is an acyclic analogue of 5'-monophosphate deoxy vidarabine, a precursor of adefovir, which is activated into adefovir diphosphate under the action of cellular kinases, through the interaction with the natural substrate deoxyadenosine Glycoside triphosphate competition and integration into viral DNA cause DNA chain elongation and termination to inhibit HBV DNA polymerase to play an antiviral role. The compound was developed by GileadSciences in the United States and was approved by the FDA in 2002. The specification is 10 mg/tablet, and the trade name is Hepsera. It is clinically used to treat chronic hepatitis B in adults. In 2003, the European Union approved the drug for marketing, and the drug has been listed in many countries at present. In 2003, Tianjin Pharmaceutical Research Institute Pharmaceutical Co., Ltd. submitted the new drug application for adefovir dipivoxil raw materials and tablets for the first time in China, and obtained the national first-class new drug certificate and production approval in 2005. At present, more than 30 domestic production enterprises have obtained the production license of the raw materials and preparations of the drug.

The synthetic main reaction route of adefovir dipivoxil (I) is as follows:

(1) Using 2-chloroethanol as a raw material, react with paraformaldehyde, triisopropyl phosphite and adenine to obtain [[2-(6-amino-9H-purin-9-yl)ethoxy]methyl ] Diisopropyl phosphonate, adefovir dipivoxil was obtained by trimethylbromosilane deisopropylation, and finally adefovir dipivoxil was obtained through esterification.

(2) Use ethylene oxide as a raw material, condense with adenine, and carry out alkylation reaction with diethyl p-toluenesulfonyloxymethylphosphonate under the action of sodium reagent to obtain [[2-(6-amino- 9H-purin-9-yl)ethoxy]methyl]phosphonic acid diethyl ester, finally hydrolyzed with trimethylbromosilane or trimethylchlorosilane to obtain Adefovir, and then esterified to obtain Adefovir Vidoxil.

(3) Use ethylene carbonate as raw material, condense with adenine under the action of alkali to generate 9-(2-hydroxyethyl) adenine, and react with p-toluenesulfonyloxymethylphosphonic acid diethyl under the action of sodium reagent The ester is subjected to an alkylation reaction to obtain [[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphonic acid diethyl ester, and then trimethylbromosilane or trimethylchlorosilane Adefovir dipivoxil is obtained through hydrolysis and deethylation, and finally adefovir dipivoxil is obtained through esterification.

The key to the synthesis of adefovir dipivoxil lies in the control of its impurities, so the research on the synthesis of adefovir dipivoxil impurities is of great significance. The literature points out that the impurities needed for adefovir dipivoxil research include: adefovir dipivoxil methyl ester impurity, chemical name: [[2-(6-amino-9H-purin-9-yl)-ethoxy]methyl ] Phosphonic acid (pivaloyloxymethyl) (methyl) ester; adefovir dipivoxil ethyl ester impurity, chemical name: [[2-(6-amino-9H-purin-9-yl)-ethyl Oxy]methyl]phosphonic acid (pivaloyloxymethyl) (ethyl) ester; adefovir dipivoxil amide impurity, chemical name: [[2-(6-pivaloylamino-9H-purine- 9-yl)-ethoxy]methyl]phosphonic acid bis(pivaloyloxymethyl)ester, etc. There are very few reports on the synthesis of adefovir dipivoxil impurities at home and abroad, especially for adefovir dipivoxil methyl ester impurities (III), adefovir dipivoxil ethyl ester impurities (IV) and adefovir dipivoxil impurities. The synthesis of the amide impurity (V) has not been reported in the literature so far.

Contents of the invention

The present invention relates to the synthesis of three impurities of adefovir dipivoxil: adefovir dipivoxil methyl ester impurity (III), adefovir dipivoxil ethyl ester impurity (IV) and adefovir dipivoxil amide impurity (V) Method, the synthetic route of the present invention is as follows:

The impurity (III) and the impurity (IV) use adefovir monopivalate methyl ester (II) as a raw material, and the impurity (V) uses adefovir dipivoxil (I) as a raw material.

The preparation methods of impurities (III), (IV) and (V) have not been reported in the literature so far.

The synthetic steps of the present invention are as follows:

(1) Preparation of [[2-(6-amino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl) (methyl) ester (III)

① The preparation of adefovir dipivoxil methyl ester (III) takes adefovir monopivalate methyl ester (II) as a raw material, and slowly drops oxalyl chloride in the presence of a catalyst for chlorination, and then carries out esterification with methanol Reaction temperature: first ice-salt bath and then room temperature.

② In the preparation method of adefovir dipivoxil methyl ester (III), the solvent used is selected from acetone, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, tetrahydropyrrole, pyridine, and N-methylpyrrolidone.

In the preparation method of adefovir dipivoxil methyl ester (III), the molar ratio of adefovir monopivalate methyl ester (II) to oxalyl chloride is 1: 1.0～1.5, adefovir monopivalate The molar ratio of methyl ester (II) to methanol is 1:1.5-2.0, and the mass volume ratio of adefovir monopivalate methyl ester (II) to solvent is 1:15-25.

③The preparation method of adefovir dipivoxil methyl ester (III) requires acid chlorination in the presence of a catalyst, the catalyst mainly being N,N-dimethylformamide, N,N-dimethylaniline and pyridine.

4. in the preparation method of adefovir dipivoxil methyl ester (III), extract with the bigger solvent of polarity, solvent used is selected from methanol, ethanol, Virahol, n-butanol, ethyl acetate, dichloromethane, chloroform , tetrahydrofuran, toluene, acetone. The present invention preferably dichloromethane series solvent.

⑤ In the preparation method of adefovir dipivoxil methyl ester (III), its purification adopts silica gel column chromatography, and the eluent adopts methanol/dichloromethane system, preferably methanol:dichloromethane=1:25～35.

(2) Preparation of [[2-(6-amino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl) (ethyl) ester (IV)

1. The preparation of adefovir dipivoxil ethyl ester impurity (IV) takes adefovir monopivalate methyl ester (II) as a raw material, slowly drips oxalyl chloride under the presence of a catalyst for chlorination, and then carries out with ethanol Esterification, reaction temperature: first ice-salt bath, then room temperature.

② In the preparation method of adefovir dipivoxil ethyl ester impurity (IV), the solvent used is selected from acetone, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, tetrahydropyrrole, pyridine, and N-methylpyrrolidone.

In the preparation method of adefovir dipivoxil ethyl ester impurity (IV), the molar ratio of adefovir monopivalate methyl ester (II) to oxalyl chloride is 1: 1.0～1.5, adefovir monopivalate The molar ratio of methyl ester (II) to ethanol is 1:1.5-2.5, and the mass-volume ratio of methyl adefovir monopivalate (II) to solvent is 1:15-25.

③The preparation method of adefovir dipivoxil ethyl ester impurity (IV) requires acid chlorination in the presence of a catalyst, the catalyst mainly being N,N-dimethylformamide, N,N-dimethylaniline and pyridine.

4. in the preparation method of adefovir dipivoxil ethyl ester impurity (IV), extract with the bigger solvent of polarity, solvent used is selected from methanol, ethanol, Virahol, n-butanol, ethyl acetate, dichloromethane, Chloroform, tetrahydrofuran, toluene, acetone,. The present invention preferably dichloromethane series solvent.

5. in the preparation method of adefovir dipivoxil ethyl ester impurity (IV), its refinement adopts the silica gel column chromatography method, and eluent adopts methanol/methylene chloride system, preferably methanol: methylene chloride=1: 25～35 .

(3) Preparation of [[2-(6-pivaloylamino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid bis(pivaloyloxymethyl)ester (V)

① The adefovir dipivoxil amide impurity (V) is made from adefovir dipivoxil (I) by dropping pivaloyl chloride in the presence of an acid-binding agent for amidation. The amidation reaction temperature: first after ice-salt bath room temperature.

2. in the preparation method of adefovir dipivoxil amide impurity (VI), solvent used is selected from methanol, ethanol, Virahol, n-butanol, acetone, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, tetrahydropyrrole, N-methylpyrrolidone, N,N-dimethylformamide.

In the preparation method of adefovir dipivoxil amide impurity (V), the mol ratio of adefovir dipivoxil (I) to pivaloyl chloride is: 1: 1.0～1.5; the mass of adefovir dipivoxil (I) and solvent The volume ratio is 1:15-25.

3. drop pivaloyl chloride under the presence of an acid-binding agent to obtain the adefovir dipivoxil amide impurity (V), wherein the acid-binding agent is selected from triethylamine and pyridine, adefovir dipivoxil (I) and binding The molar ratio of acid agent is 1:1.2～1.8.

4. in the preparation method of adefovir dipivoxil amide impurity (V), directly remove solvent after reacting to the end point and get adefovir dipivoxil amide impurity (VI) crude product, its purification adopts silica gel column chromatography method, eluent adopts methanol /ethyl acetate system, preferably methanol:ethyl acetate=1:40～50.

detailed description

The following examples further illustrate the invention, but the invention is not limited thereto.

Example:

Example 1 Preparation of [[2-(6-amino-9H-purin-9-yl)-ethoxy] methyl] phosphonic acid (pivaloyloxymethyl) (methyl) ester

Put adefovir monopivalate methyl ester (3.0g, 7.75mmol) in a 100mL three-neck flask, add 50mL of dichloromethane, and then add 7 to 8 drops of N,N-dimethylformamide as a catalyst, A solution of oxalyl chloride (1.47 g, 11.57 mmol) dissolved in 10 ml of dichloromethane was slowly added dropwise in an ice-salt bath. After the dropwise addition, the reaction was continued at room temperature for 2 hours, and the end point was judged by spotting the plate; TLC conditions: dichloromethane-methanol (8:1). After the reaction was complete, the solvent was rotary evaporated to dryness immediately, and then dissolved with 10 ml of dichloromethane for use in the next step.

Measure methanol (0.50g, 15.63mmol) into a 100mL three-neck flask, add 50ml of dichloromethane, and slowly add the above solution dropwise in an ice-salt bath; after the dropwise addition, place it at room temperature to react for 3 hours, and point the plate to judge the end point ; TLC conditions: dichloromethane-methanol (8:1). After the reaction was completed, the solvent was rotary evaporated to dryness, cooled to room temperature, 40ml of dichloromethane was added to dissolve, the layers were left to stand, and the solid was removed by suction filtration to obtain a filtrate. The filtrate was concentrated, and the concentrate was separated by column chromatography to obtain 1.21g of a white solid. Yield 38.93%.

Its structural identification data are as follows:

1H-NMR (300Mz, DMSO-d ₆ ) δ: 8.13(s, 1H, H-2), 8.07(s, 1H, H-8), 7.20(s, 1H, N H ₂ ), 5.52(d, J= _12.81Hz , 2H , OCH2O), 4.31~4.34(t, J =5.01, 2H , _{NCH2CH2 )} , 3.87~ _3.99 (m, _7H , OCH2P , _CH2CH2 O, OCH ₃ ), 1.13-1.18 (m, 9H, 3× CH ₃ ).

ESI-MS (m/z): 424 [M+Na] ⁺ .

Example 2 Preparation of [[2-(6-amino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl) (ethyl) ester

Put adefovir monopivalate methyl ester (3.0g, 7.75mmol) in a 100mL three-neck flask, add 50mL of dichloromethane, and then add 7 to 8 drops of N,N-dimethylformamide as a catalyst, A solution of oxalyl chloride (1.47 g, 11.57 mmol) dissolved in 10 ml of water and dichloromethane was slowly added dropwise in an ice-salt bath. After the dropwise addition, the reaction was continued at room temperature for 2 hours, and the end point was judged by spotting the plate; TLC conditions: dichloromethane-methanol (8:1). After the reaction was complete, the solvent was rotary evaporated to dryness immediately, and then dissolved with 10 ml of dichloromethane for use in the next step.

Measure ethanol (0.72g, 15.65mmol) into a 100mL three-neck flask, add 50ml of dichloromethane, and slowly add the above solution dropwise in an ice-salt bath; after the dropwise addition, place it at room temperature for 3 hours, and point the plate to judge the end point ; TLC conditions: dichloromethane-methanol (8:1). After the reaction, the solvent was rotary evaporated to dryness, cooled to room temperature, added 40ml of dichloromethane to dissolve, left to separate layers, and the solid was removed by suction filtration to obtain a filtrate, the filtrate was concentrated, and the concentrate was separated by column chromatography to obtain 1.18g of a white solid. Yield 36.69%.

Its structural identification data are as follows:

1H-NMR (300Mz, DMSO-d ₆ ) δ: 8.13(s, 1H, H-2), 8.07(s, 1H, H-8), 7.20(s, 2H, N H ₂ ), 5.52(d, J =12.45, OCH ₂ O), 4.30-4.34 (t, J=5.07, N CH ₂ CH ₂ ), 3.87-3.94 (m, 4H , OCH ₂ P, CH ₂ CH ₂ O), 3.60 ( d, J = 10.95, 2H , _OCH2CH3 ), 1.23 (s, 3H , _{CH2CH3 )} , 1.14 (s, 9H, ₃ x _CH3 ) . ·

ESI-MS (m/z): 415 [M+H] ⁺ .

Example 3 Preparation of [[2-(6-pivaloylamino-9H-purin-9-yl)-ethoxy]methyl]phosphonic acid bis(pivaloyloxymethyl)ester

Adefovir dipivoxil (I) (2.0g, 3.99mmol) was placed in a 100mL three-necked flask, triethylamine (0.60g, 5.94mmol) was added at room temperature, and then 40ml of dichloromethane was added, under ice-salt bath conditions Pivaloyl chloride (0.62g, 5.19mmol) was slowly added dropwise; after the dropwise addition, the reaction was continued at room temperature for 8 hours, and the plate was spotted to determine the end point; TLC conditions: methanol-ethyl acetate (1:18). After the reaction, the solvent was rotary evaporated to dryness, and the concentrate was separated by column chromatography to obtain 1.78 g of a white oil. Yield 76.13%.

Its structural identification data are as follows:

1H-NMR (300Mz, DMSO-d ₆ ) δ: 10.08(s, 1H, N H ), 8.66(s, 1H, H-2), 8.37(s, 1H, H-8), 5.53(d, J = _12.75Hz , 4H , ₂ ×OCH2O), 4.43~4.46(t, J =4.47, 2H , _NCH2CH2 ), 3.92~3.98(m, 4H , _OCH2P , _{CH2CH 2} O), 1.27 (s, 9H, 3× CH ₃ ), 1.13 (s, 18H, 6× CH ₃ ).

ESI-MS (m/z): 587 [M+H] ⁺ .

Claims (10)

1. the preparation method of adefovir ester impurity, is characterized in that comprising following three synthetic routes:

(1) Adefovir list trimethylacetic acid methyl esters (II) obtains [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester (III) (being called for short adefovir ester methyl ester impurity) through chloro, esterification;

(2) Adefovir list trimethylacetic acid methyl esters (II) obtains [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester (IV) (being called for short adefovir ester ethyl ester impurity) through chloro, esterification;

(3) adefovir ester (I) and pivaloyl chloride carry out amidation and obtain [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester (V) (being called for short adefovir ester amide impurities).

。

2. the preparation method of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester (III) according to claim 1, it is characterized in that the preparation of adefovir ester methyl ester impurity (III) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with methyl alcohol: room temperature after first cryosel bath; Solvent for use be selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.

3. carry out chlorination under catalyzer existence condition according to claim 2, it is characterized in that used catalyst is selected from DMF, DMA and pyridine, preferred DMF; Chlorinating agent used is sulfur oxychloride and oxalyl chloride, preferred oxalyl chloride.

4. in the preparation method of adefovir ester methyl ester impurity (III) according to claim 2, it is characterized in that Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.0 with the mol ratio of methyl alcohol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.

5. the preparation method of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester (IV) according to claim 1, it is characterized in that the preparation of adefovir ester ethyl ester impurity (IV) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with ethanol: room temperature after first cryosel bath; Solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.

6. carry out chlorination under catalyzer existence condition according to claim 5, it is characterized in that used catalyst is selected from DMF, DMA and pyridine, preferred DMF; Chlorinating agent used is sulfur oxychloride and oxalyl chloride, preferred oxalyl chloride.

7. the preparation method of adefovir ester ethyl ester impurity (IV) according to claim 5, it is characterized in that Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.5 with the mol ratio of methyl alcohol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.

8. the preparation of [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester (V) according to claim 1, it is characterized in that adefovir ester amide impurities (V) with adefovir ester (I) for raw material, drip pivaloyl chloride under acid binding agent existence condition to carry out amidation and obtain, amidate action temperature: room temperature after the bath of first cryosel; Solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, N-Methyl pyrrolidone, DMF.

9. generate adefovir ester amide impurities (V) under acid binding agent existence condition according to claim 8, it is characterized in that acid binding agent used is triethylamine, adefovir ester (I) is 1: 1.2 ~ 1.8 with the mol ratio of triethylamine.

10. the preparation method of adefovir ester amide impurities (V) according to claim 8, it is characterized in that the refining employing silica gel column chromatography method of adefovir ester amide impurities (VI), eluent adopts methanol/ethyl acetate system, particular methanol: ethyl acetate=1: 40 ~ 50.