CN101891767B - Preparation method of adefovir dipivoxil - Google Patents

Abstract

The present invention relates to a preparation method of adefovir dipivoxil. Under nitrogen protection, a solvent, a protective agent and adefovir are sequentially added, stirred, and cooled; triethylamine and chloromethyl pivalate are added dropwise, and the temperature is slowly raised after the dripping to complete the reaction; the temperature is lowered to room temperature, isopropyl acetate is added and filtered to obtain a mother liquor; the mother liquor is washed with water twice, dried with anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to an oily substance; the oily substance is subjected to silica gel column chromatography, the eluent containing the product is collected, and the product is concentrated under reduced pressure to a small amount; activated carbon is added, decolorized and filtered, the filtrate is concentrated under reduced pressure to dryness, the material is discharged, and the product is dried to a crude product; the crude product is subjected to silica gel column chromatography, the eluent containing the product is collected, and the product is concentrated under reduced pressure to a small amount; activated carbon is added, decolorized and filtered, the filtrate is concentrated under reduced pressure to dryness, the material is discharged, and the product is dried to a finished product. The present invention can reduce the side reactions generated during the reaction of adefovir dipivoxil, thereby improving the reaction conversion rate and reducing the production cost.

Description

A kind of preparation method of adefovir dipivoxil

technical field

The invention relates to a preparation method of adefovir dipivoxil.

Background technique

9-[2-[[bis[(pivalate oxy)methoxy]phosphoryl]methoxy]ethyl]adenine (adefovir dipivoxil or adefovir dipivoxil) is produced by the United States A low-toxicity and high-efficiency nucleoside antibacterial drug researched and developed by Gilead Company has a significant inhibitory effect on hepatitis B virus; its structural formula is as follows:

The drug was approved for marketing in the United States in 2002 and in China in 2005. Chinese patent documents ZL02151028.8, ZL200410015562.X, and foreign patent documents EP1256584 and EP481214 all report their synthesis methods, that is, through different methods, adefovir is obtained, and then reacted with chloromethyl pivalate to obtain adefovir ester.

However, the preparation of adefovir dipivoxil disclosed in the above documents has the problems of low reaction conversion rate (low yield) and high production cost.

Contents of the invention

In order to solve the above problems, the present invention provides a method for preparing adefovir dipivoxil that can reduce the side reactions generated during the reaction of adefovir dipivoxil, thereby increasing the reaction conversion rate and reducing production costs.

In order to achieve the above object, the technical solution adopted in the present invention is:

A preparation method of adefovir dipivoxil, comprising the steps of:

1) Under the protection of nitrogen, add 30-35ml of solvent, 0.5-1.0g of protective agent and 5-10g of adefovir in sequence, after stirring evenly, cool down to 0-10°C;

2) Add 12-16ml of triethylamine dropwise and stir evenly;

3) Add 28-32ml of chloromethyl pivalate dropwise, and slowly raise the temperature to 60°C until the reaction is complete;

4) Cool down to room temperature, add 105-115ml of isopropyl acetate and filter to obtain the mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor; (the components of the filter cake are adefovir and the reaction intermediate adefovir mono ester)

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to a small amount remaining;

7) Add activated carbon, decolorize and filter, and concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) After the crude product was dissolved in dichloromethane, it was subjected to silica gel column chromatography, wherein the weight ratio between the eluent methanol and dichloromethane was 1:19, and the eluate containing the product was collected and concentrated under reduced pressure to a small amount remaining;

9) Add activated carbon, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge the material, and dry it to obtain a finished product;

Above-mentioned, take adefovir as raw material, in the presence of protective agent and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

As a further preference of the above method, the preparation method of said adefovir dipivoxil comprises the following steps:

1) Under the protection of nitrogen, add 32ml of solvent, 0.8g of protective agent and 8g of adefovir in sequence, after stirring evenly, cool down to 5°C;

2) Add 15ml of triethylamine dropwise and stir evenly;

3) Add 30ml of chloromethyl pivalate dropwise, and slowly raise the temperature to 60°C until the reaction is complete;

4) Cool down to room temperature, add 110ml of isopropyl acetate and filter to obtain the mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor; (the filter cake components are adefovir and the reaction intermediate adefovir monoester)

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to a small amount remaining;

7) Add activated carbon, decolorize and filter, and concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) After the crude product was dissolved in dichloromethane, it was subjected to silica gel column chromatography, wherein the weight ratio between the eluent methanol and dichloromethane was 1:19, and the eluate containing the product was collected and concentrated under reduced pressure to a small amount remaining;

9) Add activated carbon, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge the material, and dry it to obtain a finished product;

Above-mentioned, take adefovir as raw material, in the presence of protective agent and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

The protective agent is sodium sulfite, sodium bisulfite, vitamin C, 2,6-di-tert-butyl-4-methylphenol, 4,4'-thiobis-(3-methyl 6-tert-butylphenol ) in one.

The solvent is one of N-methylpyrrolidone and N-formyl dimethylamide.

The theoretical basis of the present invention is that adefovir dipivoxil is prepared by reacting adefovir dipivoxil with chloromethyl pivalate. The reaction structure is as follows:

Both adefovir and adefovir dipivoxil contain amino functional groups, which are easily oxidized at high temperatures and produce by-products, so the reaction crude product generally appears red or yellow or light red or light yellow, thereby reducing the reaction Yield. The present invention considers the protection of the amino group, generally with a protecting group for protection and deprotection (such as benzyloxycarbonyl protection, hydrogenation deprotection), or adding a small amount of effective antioxidant for protection. After theoretical and experimental selection, we found that the cost of protecting and deprotecting the protective group is too high and the economic benefit is poor. Therefore, we choose to add a small amount of effective antioxidant for protection through experiments, and the effect is obvious, the reaction yield is increased from 45% to about 52%, and the production cost is reduced by about 20%.

Detailed ways

The present invention will be further described below through specific examples, but the present invention is not limited by the following examples.

Comparative Experiment:

Add 8g of adefovir (PMEA) and 32ml of N-methylpyrrolidone (NMP) into the reaction bottle and stir, add dropwise 15ml of triethylamine and 30ml of chloromethyl pivalate, then slowly heat to 60°C, and react 4 Hours, the reaction was complete (analyzed by TLC). Cool to room temperature and add 110ml of isopropyl acetate to filter, the filter cake is washed with isopropyl acetate, the obtained organic phase (mother liquor) is washed twice with water, dried with anhydrous MgSO4, filtered, and the filtrate is concentrated under reduced pressure to an oily substance for silica gel column chromatography , methanol: dichloromethane (1:19) elution, the eluate was concentrated to about 30ml, added activated carbon and stirred for 30 minutes, filtered, the filtrate was concentrated to dryness, discharged, and dried to obtain a crude product.

Dissolve 20 g of the crude product in 40 ml of dichloromethane, put it on a silica gel column (400 g), elute with methanol: dichloromethane (1:19), collect the eluate containing the product, concentrate it under reduced pressure to about 100 ml, add 1 g of activated carbon , stirred for 0.5 hour, filtered, the filtrate was concentrated to dryness under reduced pressure, discharged, and dried to obtain the finished product with a yield of 45%.

Embodiment 1 of the present invention:

1) Under the protection of nitrogen, add 32ml of N-methylpyrrolidone, 0.8g of 2,6-di-tert-butyl-4-methylphenol and 8g of adefovir in sequence, stir evenly, and cool down to 5°C;

2) Add 15ml of triethylamine dropwise and stir evenly;

3) 30 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 110ml of isopropyl acetate and filter to obtain a mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 52%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent 2,6-di-tert-butyl-4-methylphenol and triethylamine, react with chloromethyl pivalate to prepare adefovir dipivoxil The reaction equation is as follows:

Embodiment 2 of the present invention:

1) Under the protection of nitrogen, add 30ml of N-methylpyrrolidone, 0.5g of sodium bisulfite and 5g of adefovir in sequence, stir evenly, and cool down to 0°C;

2) Add 12ml of triethylamine dropwise and stir evenly;

3) 28 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 105ml of isopropyl acetate and filter to obtain mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 48%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent sodium bisulfite and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

Embodiment 3 of the present invention:

1) Under the protection of nitrogen, add 33ml of N-methylpyrrolidone, 0.7g of sodium sulfite and 6g of adefovir in sequence, stir evenly, and cool down to 3°C;

2) Add 14ml of triethylamine dropwise and stir evenly;

3) 29 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 108ml of isopropyl acetate and filter to obtain mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 50%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent sodium sulfite and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

Embodiment 4 of the present invention:

1) Under the protection of nitrogen, add 34ml of N-methylpyrrolidone, 0.9g of vitamin C and 9g of adefovir in sequence, stir evenly, and cool down to 8°C;

2) Add 15ml of triethylamine dropwise and stir evenly;

3) 31 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 112ml of isopropyl acetate and filter to obtain mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 51%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent vitamin C and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

Embodiment 5 of the present invention:

1) Under the protection of nitrogen, add 35ml of N-methylpyrrolidone, 1.0g of vitamin C and 10g of adefovir in sequence, stir evenly, and cool down to 10°C;

2) Add 16ml of triethylamine dropwise and stir evenly;

3) 32 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 115ml of isopropyl acetate and filter to obtain mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 50%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent vitamin C and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

Embodiment 6 of the present invention:

1) Under the protection of nitrogen, add 32ml of N-formyldimethylamide, 0.8g of 2,6-di-tert-butyl-4-methylphenol and 8g of adefovir in sequence, stir evenly, and cool down to 5°C;

2) Add 15ml of triethylamine dropwise and stir evenly;

3) 30 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 110ml of isopropyl acetate and filter to obtain a mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 50%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent 2,6-di-tert-butyl-4-methylphenol and triethylamine, react with chloromethyl pivalate to prepare adefovir dipivoxil The reaction equation is as follows:

Embodiment 7 of the present invention:

1) Under the protection of nitrogen, add 32ml of N-formyldimethylamide, 0.8g of sodium bisulfite and 8g of adefovir in sequence, stir evenly, and cool down to 5°C;

2) Add 15ml of triethylamine dropwise and stir evenly;

3) 30 ml of chloromethyl pivalate was added dropwise, and the temperature was slowly raised to 60° C. until the reaction was complete (analyzed by TLC);

4) Cool down to room temperature, add 110ml of isopropyl acetate and filter to obtain a mother liquor; the filter cake is washed with isopropyl acetate to obtain a small amount of mother liquor;

5) washing the mother liquor twice with water, drying and filtering with anhydrous magnesium sulfate, and concentrating the filtrate under reduced pressure to an oil;

6) Silica gel column chromatography on the oil, wherein the weight ratio between eluent methanol and dichloromethane is 1:19, collect the eluate containing the product, and concentrate under reduced pressure to 30ml;

7) Add activated carbon and stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a crude product;

8) 20g of the crude product was dissolved in 40ml of dichloromethane, and subjected to silica gel column chromatography (400g), wherein the weight ratio between the eluent methanol and dichloromethane was 1: 19, and the eluent containing the product was collected and subtracted. Concentrate to 100ml under pressure;

9) Add 1 g of activated carbon, stir for 30 minutes, decolorize and filter, concentrate the filtrate to dryness under reduced pressure, discharge, and dry to obtain a finished product with a yield of 51%.

Above-mentioned, take adefovir as raw material, in the presence of protective agent sodium bisulfite and triethylamine, react with chloromethyl pivalate to prepare the reaction equation of adefovir dipivoxil as follows:

Claims (3)

1. the preparation method of an adefovir ester is characterized in that comprising the steps:

1) under nitrogen protection, add solvent 30-35ml, protective material 0.5-1.0g and Adefovir 5-10g successively, after stirring, be cooled to 0-10 ℃; Wherein, protective material be S-WAT, sodium sulfite anhy 96, vitamins C, 2,6 di tert butyl 4 methyl phenol, 4,4 '-a kind of in thiobis-(the 3-methyl 6-t-butyl phenol);

2) be added dropwise to triethylamine 12-16ml, stir;

3) be added dropwise to chloromethyl pivalate 28-32ml, drip off and slowly be warming up to 60 ℃, to reacting completely;

4) be cooled to room temperature, add isopropyl acetate 105-115ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;

5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;

6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;

7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;

8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;

9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;

Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:

2. the preparation method of a kind of adefovir ester as claimed in claim 1 is characterized in that comprising the steps:

1) under nitrogen protection, add solvent 32ml, protective material 0.8g and Adefovir 8g successively, after stirring, be cooled to 5 ℃; Wherein, protective material be S-WAT, sodium sulfite anhy 96, vitamins C, 2,6 di tert butyl 4 methyl phenol, 4,4 '-a kind of in thiobis-(the 3-methyl 6-t-butyl phenol);

2) be added dropwise to triethylamine 15ml, stir;

3) be added dropwise to chloromethyl pivalate 30ml, drip off and slowly be warming up to 60 ℃, to reacting completely;

4) be cooled to room temperature, add isopropyl acetate 110ml and filter, obtain mother liquor; Filter cake obtains a small amount of mother liquor again with the isopropyl acetate washing;

5) mother liquor is used washing twice, use anhydrous magnesium sulfate drying, filtration again, filtrate decompression is concentrated into oily matter;

6) silica gel column chromatography on the oily matter, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;

7) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is bullion;

8) after bullion dissolves with methylene dichloride, last silica gel column chromatography, wherein the weight ratio between eluent methyl alcohol and the methylene dichloride is 1: 19, collects the elutriant that contains product, is evaporated to residue on a small quantity;

9) add activated carbon, decolorization filtering, filtrate decompression is concentrated into dried, and discharging is dried and is finished product;

Above-mentioned, be raw material with the Adefovir, in the presence of protective material and triethylamine, the reaction equation that makes adefovir ester with the chloromethyl pivalate reaction is following:

3. according to claim 1 or claim 2 a kind of preparation method of adefovir ester is characterized in that: said solvent is a kind of in N-Methyl pyrrolidone, the N-formyl n n dimetylaniline.