CN1850831A

CN1850831A - Method for preparing 9-(diethoxy phosphoryl methoxy ethyl)-adenine

Info

Publication number: CN1850831A
Application number: CN 200610026902
Authority: CN
Inventors: 沈永嘉; 王成云; 任晓莉; 叶传永; 叶波
Original assignee: SANMEN TENGLONG CHEMICAL CO Ltd; East China University of Science and Technology
Current assignee: SANMEN TENGLONG CHEMICAL CO Ltd; East China University of Science and Technology
Priority date: 2006-05-26
Filing date: 2006-05-26
Publication date: 2006-10-25
Anticipated expiration: 2026-05-26
Also published as: CN100395248C

Abstract

This invention relates to 9-(bi ethoxy phosphoryl methoxyl group ethyl)-gland piaolin preparation method. (1) Materials are paraformaldehyde, 2-chlorohydrin, diethyl phosphate and dry chlorine hydride gas, they are reacted for 6-8 hours at 90-125 degree centigrade under condition of anhydrous aluminium chloride existing, and then bi ethoxy phosphoryl methoxyl group ethyl is got after decompression and distillation. (2) The bi ethoxy phosphoryl methoxyl group ethyl made in (1) is condensed reacted with gland piaolin to get the object. Comparing to existing technique, this invention simplifies preparation methods, and reduces operation cost. Furthermore, it is friendly to environment.

Description

Preparation method of 9- (diethoxyphosphoryl methoxyethyl) -adenine

Technical Field

The invention relates to a preparation method of 9- (diethoxyphosphoryl methoxyethyl) -adenine.

Background

Viral hepatitis b is a disease that seriously threatens human health. In order to treat hepatitis B patients, various drugs have been developed, wherein 9- (2-phosphorylmethoxyethyl) -adenine (the structure is shown in formula 1, hereinafter referred to as compound 1) is an effective drug, which can rapidly and effectively reduce the serum HBV DNA level of hepatitis B patients, can also reduce transaminase, and does not generate drug resistance after long-term administration.

A key intermediate for synthesizing the compound 1 is 9- (diethoxyphosphorylmethoxyethyl) -adenine (the structure of which is shown in a formula 2 and is hereinafter referred to as a compound 2).

The methods for synthesizing compound 2 reported in the literature so far are mainly three methods:

firstly: a method reported in 1989 by Holy A et al (Collection Czech Chem Commun, 1989, 5: 2190) uses adenine and diethoxyphosphorylmethoxyethyl chloride (the structure is shown in formula 3, hereinafter referred to as compound 3) to prepare compound 2 by condensation reaction:

the main defects of the method are two, one is that: the raw materials are difficult to obtain, namely the compound 3 is prepared by the reaction of chloroethyl chloromethyl ether (the structure of which is shown as formula 4 and is hereinafter referred to as compound 4) and triethyl phosphite,

the compound 4 is prepared by reacting anhydrous hydrogen chloride, paraformaldehyde and chloroethanol;

the second is that: the step for obtaining the target compound (compound 2) is long and the cost per step is high, that is, in the preparation of compound 4, the by-product is water, and the presence of water is disadvantageous for the preparation of compound 3, so that the compound 4 needs to be dehydrated by a special method and then purified; in addition, because the compound 4 is harmful to human bodies, special protection facilities are required to be provided for operators in the processes of refining and using the compound 4.

The following: U.S. Pat. No.6,451,340 discloses a method for preparing a compound 2 by esterifying 9- (2-hydroxyethyl) -adenine (the structure is shown as formula 6, hereinafter referred to as compound 6) prepared from adenine and diethyl carbonate, and then p-toluenesulfonyloxymethylphosphonic acid diethyl ester (the structure is shown as formula 5, hereinafter referred to as compound 5):

also, the method has the disadvantages of difficult raw material availability and high operation cost. For example, compound 5 is prepared from p-toluenesulfonyl chloride, paraformaldehyde and diethyl phosphite:

in the above reaction, in order to determine the end point of the reaction, it is necessary to detect the amounts of p-toluenesulfonyl chloride and diethyl phosphite remaining in the reaction product by using a nuclear magnetic resonance spectrometer.

Thirdly: chinese patent (application No. 200410015562.X) discloses a method for preparing 9- (bis-trifluoroethyl phosphoryl methoxyethyl) -adenine (structure is shown in formula 8, hereinafter referred to as compound 8) by condensing adenine and 2- [ bis (trifluoroethyl) -phosphoryl methoxy]ethyl chloride (structure is shown in formula 7, hereinafter referred to as compound 7):

although compound 8 is different from compound 2, compound 1 can be obtained by removing the trifluoroethyl group from compound 8, so compound 8 is also a key intermediate for preparing compound 1. The compound 7 is needed for preparing the compound 8, and the preparation of the compound 7 needs two-step chemical reaction, namely, preparing tris (trifluoro) ethyl phosphite (the structure of which is shown in the formula 9, and is referred to as the compound 9 hereinafter) from phosphorus trichloride and trifluoroethanol:

and reacting the compound 9 with the compound 4 to obtain a compound 7:

it follows that the synthesis of compound 8 requires the use of trifluoroethanol, which is very expensive. Also, in view of the preparation of the starting materials, there were four reactions in total for the synthesis of compound 8.

Disclosure of Invention

The invention aims to provide a method for preparing 9- (diethoxyphosphorylmethoxyethyl) -adenine (compound 2) which is simple in preparation (only two steps including preparation of raw materials) andlow in operation cost, so as to overcome the defects of long preparation steps and high operation cost in the prior art.

The method for preparing 9- (diethoxyphosphoryl methoxyethyl) -adenine comprises the following steps:

(1) under the condition of the existence of anhydrous aluminum trichloride, taking paraformaldehyde, 2-chloroethanol, diethyl phosphite and dry hydrogen chloride gas as raw materials, reacting for 6-8 hours at 90-125 ℃, and obtaining diethoxyphosphoryl methoxyethyl chloride (compound 3) through reduced pressure distillation;

(2) and (2) carrying out condensation reaction on the diethoxy phosphoryl methoxyethyl chloride prepared in the step (1) and adenine to prepare a target compound (compound 2).

In the invention, the preferred molar ratio of anhydrous aluminum trichloride to paraformaldehyde is 1: 3-4; the optimal molar ratio of the paraformaldehyde to the 2-chloroethanol to the diethyl phosphite is 1 to (0.5-1.1) to (0.5-1.5), and the optimal molar ratio is 1 to (0.8-1.0) to (0.7-1.0); the preferable molar ratio of the diethoxyphosphorylmethoxyethyl chloride to the adenine is 1: 0.5 to 1.1, and the most preferable molar ratio is 1: 0.8 to 1.0.

The raw materials (such as paraformaldehyde, 2-chloroethanol, diethyl phosphite and adenine) and the reagents related to the invention are commercially available chemical pure reagents or industrial products, wherein the paraformaldehyde is a commercially available chemical pure reagent (Shanghai laboratory reagent Co., Ltd.).

According to the technical scheme, the method comprises the following steps: in the step (1), water generated in the reaction immediately reacts with anhydrous aluminum trichloride to generate aluminum hydroxide and hydrogen chloride due to the existence of the anhydrous aluminum trichloride:

the generated hydrogen chloride reacts with the 2-chloroethanol and the paraformaldehyde, thereby ensuring that no water exists in a reaction system. Since there is no water in the reaction system, the main product of the reaction of hydrogen chloride, 2-chloroethanol and paraformaldehyde is chloroethyl chloromethyl ether (compound 4):

the product can react with diethyl phosphite without dehydration to generate diethoxyphosphoryl methoxyethyl chloride (compound 3):

likewise, the hydrogen chloride, a by-product of the reaction, can react with 2-chloroethanol and paraformaldehyde. Therefore, the invention simplifies the steps for preparing 9- (diethoxyphosphorylmethoxyethyl) -adenine (only two steps are needed including the preparation of raw materials) and reduces the operation cost. In addition, the present invention is also environmentally friendly since the hydrogen chloride gas can be reused.

Detailed Description

(1) under the condition of existence of anhydrous aluminum trichloride, taking paraformaldehyde, 2-chloroethanol, diethyl phosphite and dry hydrogen chloride gas as raw materials, reacting for 6-8 hours at 90-125 ℃, carrying out reduced pressure distillation, and collecting 140-150 ℃/10mmHg fractions to obtain diethoxyphosphorylmethoxyethyl chloride (compound 3);

wherein: the recommended dosage of the anhydrous aluminum trichloride is that the molar ratio of the anhydrous aluminum trichloride to the paraformaldehyde is 1: 3-4; the optimal molar ratio of the paraformaldehyde to the 2-chloroethanol to the diethyl phosphite is 1 to (0.5-1.1) to (0.5-1.5), and the optimal molar ratio is 1 to (0.8-1.0) to (0.7-1.0); the preferable molar ratio of the diethoxyphosphorylmethoxyethyl chloride to the adenine is 1: 0.5 to 1.1, and the most preferable molar ratio is 1: 0.8 to 1.0.

(2) Carrying out condensation reaction on the diethoxy phosphoryl methoxyethyl chloride prepared in the step (1) and adenine at the temperature of 60-80 ℃ in the presence of inert gas, and filtering, washing, evaporating a solvent, recrystallizing and the like on a reaction product to obtain a target product (a compound 2);

wherein the molar ratio of the diethoxyphosphoryl methoxyethyl chloride to the adenine is 1: 0.5-1.1; the inert gas refers to a gas which is chemically stable and does not participate in the reaction, such as (but not limited to) helium, neon or nitrogen.

The invention is further illustrated by the following examples, which are intended to better understand the content of the invention and not to limit the scope of protection of the invention:

example 1

Paraformaldehyde (chemical purity, Shanghai laboratory reagents Co., Ltd.) (94g, 3.24mol), 2-chloroethanol (255g, 3.16mol), anhydrous aluminum trichloride (139g, 1.04mol) and diethyl phosphite (industrial product, Yixing, Tanbai chemical Co., Ltd.) (385g, 2.5mol) at 25 ℃, introducing dry hydrogen chloride gas (generated from concentrated sulfuric acid and concentrated hydrochloric acid, and dried with concentrated sulfuric acid and anhydrous sodium sulfate) into the system under stirring, stopping introducing hydrogen chloride when the solid in the mixture is completely dissolved, heating to 90 ℃ within 1 hour, reacting for 4 hours, heating to 125 ℃ again, reacting for 2 hours, then, the reaction device is changed into a reduced pressure distillation device, and the distillate of 140-150 ℃/10mmHg is collected to obtain yellowish liquid (250g, 1.04mol), the purity is 96% (gas chromatography content), and the yield is 41.6% (based on diethyl phosphite).

Adding adenine (25g, 0.185mol) and anhydrous potassium carbonate (50g, 0.36mol) to 2000mL of DMF (900mL) under stirring, heating to 60 ℃ under nitrogen protection, dropwise adding compound 3(42g, 0.175mol) within 30 minutes, continuing heating to 80 ℃ for reaction for 24 hours, controlling the reaction endpoint by thin plate chromatography (silica gel plate, developing agent petroleum ether: ethyl acetate 2: 1(v/v)), cooling to 30 ℃, adding kieselguhr (2g), stirring for 15 minutes, filtering, washing a filter cake with DMF (100mL), combining filtrate and washing solution, evaporating all the solvent under reduced pressure, adding dichloromethane (400mL) to the residue, heating to reflux, keeping the temperature for 30 minutes, filtering while hot, removing insoluble substances, evaporating the solvent in the filtrate, dissolving the residue with ethyl acetate (600mL), adding activated carbon (1g), heating to reflux, keeping the temperature for 30 minutes, filtering while hot, removing insoluble substances, evaporating solvent 1/2 in the filtrate, cooling to 0 ℃, standing for 24 hours, filtering precipitated crystals, drying at 70 ℃ to obtain white crystals (28g, 0.085mol), namely the compound 2, mp130-132 ℃, the yield is 48.6 percent,

example 2

Polyformaldehyde (47kg, 1.62kmol), 2-chloroethanol (127.5kg, 1.58kmol), anhydrous aluminum trichloride (69.5kg, 520mol) and diethyl phosphite (192.5kg, 1.25kmol) are added into a 1000L glass lining reaction kettle, dry hydrogen chloride gas (generated byconcentrated sulfuric acid and concentrated hydrochloric acid and dried by concentrated sulfuric acid and anhydrous sodium sulfate) is introduced into the system under stirring at 25 ℃, after all solids in the mixture are dissolved, the introduction of hydrogen chloride is stopped, the temperature is raised to 90 ℃ within 1 hour, the temperature is raised to 125 ℃ for reaction for 2 hours, then the reaction device is switched to a reduced pressure distillation state, fractions with the temperature of 140-.

Adding DMF (450L) into a 1000L glass lining reaction kettle, adding adenine (12.5kg, 92.5mol) and anhydrous potassium carbonate (25kg, 180mol) under stirring, heating to 60 deg.C under the protection of nitrogen, dropwise adding compound 3(21kg, 87.5mol) within 30 min, heating to 80 deg.C, reacting for 24 hr, controlling the reaction end point by thin plate chromatography (silica gel plate, developing agent petroleum ether: ethyl acetate: 2: 1(v/v)), cooling to 30 deg.C, adding diatomaceous earth (1kg), stirring for 15 min, filtering, washing filter cake with DMF (50L), combining filtrate and washing liquid, distilling off solvent under reduced pressure, adding dichloromethane (200L) into residue, heating to reflux, maintaining temperature for 30 min, filtering while hot, discarding insoluble substances, distilling off solvent in filtrate, dissolving residue with ethyl acetate (300L), adding activated carbon (500g), heating to reflux, keeping the temperature for 30 minutes, filtering while the solution is hot, discarding insoluble substances, evaporating solvent 1/2 in the filtrate, cooling to 0 ℃, standing for 24 hours, filtering precipitated crystals, and drying at 70 ℃ to obtain white crystals (14kg, 42.5mol), namely the compound 2, mp130-132 ℃, and the yield is 48.6%.

Claims

1. A method for preparing9- (diethoxyphosphorylmethoxyethyl) -adenine is characterized by comprising the following steps:

(1) under the condition of the existence of anhydrous aluminum trichloride, taking paraformaldehyde, 2-chloroethanol, diethyl phosphite and dry hydrogen chloride gas as raw materials, reacting for 6-8 hours at 90-125 ℃, and obtaining diethoxy phosphoryl methoxyethyl chloride through reduced pressure distillation;

(2) and (2) carrying out condensation reaction on the diethoxy phosphoryl methoxy ethyl chloride prepared in the step (1) and adenine to prepare a target product.

2. The method according to claim 1, wherein the condensation reaction in the step (2) is carried out at a temperature of 60 ℃ to 80 ℃.

3. The method according to claim 1 or 2, wherein the molar ratio of paraformaldehyde to 2-chloroethanol to diethyl phosphite is 1: 0.5 to 1.1: 0.5 to 1.5.

4. The method according to claim 3, wherein the molar ratio of anhydrous aluminum trichloride to paraformaldehyde is 1: 3 to 4.

5. The method of claim 4, wherein the molar ratio of diethoxyphosphorylmethoxyethyl chloride to adenine is 1: 0.5 to 1.1.

6. The method of claim 5 wherein the condensation of the diethoxyphosphorylmethoxyethyl chloride with the adenine is carried out in the presence of an inert gas.

7. The method of claim 6, wherein the inert gas is nitrogen.