Preparation method of famciclovir

Abstract

The invention discloses a preparation method of famciclovir. The preparation method comprises the following steps: reacting diethyl malonate serving as a starting material with ethylene oxide to obtain an intermediate 1, reacting the intermediate 1 with paratoluensulfonyl chloride to generate an active ester side chain intermediate 2, and performing high-selectivity substitution reaction on the active ester side chain intermediate 2 and the ninth site of 2-amino-6-chloropurine to obtain a key intermediate 3; the intermediate 3 is subjected to ester bond reduction and ester formation through an existing mature famciclovir process, and finally pd / C dechlorination is performed to obtain the famciclovir. Compared with methods reported in existing literatures, the method has the advantages that raw materials are simple and easy to obtain, reaction conditions are simple, 9-site selectivity is larger than 99%, the total reaction yield is high, and industrial large-scale production is facilitated.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically a method for preparing famciclovir. Background Technology

[0002] Famciclovir, developed by SmithKline Beecham in the 1990s, is a novel nucleoside analogue-based broad-spectrum antiviral drug widely used for severe herpes zoster and primary genital herpes. Its chemical name is 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol-diethyl ester, and its chemical structure is shown below. Its molecular formula is C1. 14 H 19 N4O5, CAS number 104227-87-4, molecular weight 321.337; .

[0003] Domestic and international literature and patent reports indicate that there are various methods for preparing famciclovir, with the most typical methods falling into two main categories: Prior art 1: The synthetic routes reported in patents such as EP182024, EP0302644, US5138057, and CN108314658 are as follows: .

[0004] The method reported in prior art 1 mainly involves first constructing a purine main ring, then linking it with a side ring, continuing the reaction to obtain the key intermediate of famciclovir, and finally reacting to obtain famciclovir.

[0005] When this type of method performs substitution reactions, both the 7-N and 9-N positions on the purine parent ring can react. Approximately one-third of the reaction is the undesirable 7-N product. The products at the 7 and 9 positions have similar properties, making them difficult to separate, resulting in cumbersome operations and high industrial production costs. The structural formula of the 7-position product is as follows:

[0006] Existing technology 2: The synthetic routes reported in WO2004110343, US5917041, CN101555249, CN102924455, etc. are as follows: .

[0007] The method reported in prior art 2 mainly uses pyrimidine rings with different substitutions as starting materials, introduces a side chain on the nitrogen at the 9-position in advance, and then carries out a ring-closing reaction to obtain a purine ring structure, and continues subsequent reactions to obtain famciclovir.

[0008] This type of method introduces a side chain at a specific 9-position to avoid the generation of positional isomers. However, the synthetic route of this patent is long and the overall yield is low. The purine halide derivative obtained in the sixth step has poor stability and will undergo self-condensation reaction. Therefore, the production cost of this route is high and it is not conducive to large-scale industrial production.

[0009] In summary, while the method reported in Existing Technology 1 has a shorter reaction route, it suffers from poor selectivity during the substitution reaction, resulting in the formation of a certain amount of positional isomers. Removing these impurities is cumbersome and inefficient, leading to high production costs. Although the method reported in Existing Technology 2 overcomes the drawback of Existing Technology 1, which suffers from poor selectivity and difficulty in removing isomer impurities, it has a longer reaction route, an overall yield of less than 10%, and high production costs, making it unsuitable for large-scale industrial production. Summary of the Invention

[0010] The purpose of this invention is to address the shortcomings of famciclovir preparation technology by providing a simple, high-yield, high-purity, and relatively economical method for large-scale industrial production.

[0011] US Patent 5138057 reports high selectivity at the 9-position N of the purine ring because a chlorine atom is introduced at the 8-position. However, this method has a serious problem: it requires high hydrogenation pressure to reduce and remove chlorine.

[0012] The method of this invention allows us to obtain the key intermediate famciclovir with high selectivity and high yield. The positional isomer impurity at the 3 and 7 positions is less than 1%, and the selectivity for N at the 9 position is greater than 99%, thereby greatly reducing the pressure of the post-processing purification process and improving the reaction yield.

[0013] To achieve the technical objective of this invention, the following technical solution is provided: This invention uses commercially available diethyl malonate as a starting material to prepare famciclovir, and the route is as follows: .

[0014] 1) The reaction in step 1 is as follows: .

[0015] In step 1, the base 1 used is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); In step 1, the molar ratio of diethyl malonate to alkali is 1:1 to 2 (preferably 1:1 to 1.5). Solvent 1 mentioned in step 1 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, dioxane, and chloroform; In step 1, the molar ratio of diethyl malonate to propylene oxide is 1:1 to 2 (preferably 1:1 to 1.5). In step 1, diethyl malonate is dissolved in solvent 1, alkali 1 is added, and the mixture is stirred at 0-5℃ until dissolved. Ethylene oxide is added, and the mixture is reacted at 0-5℃ for 3-5 hours. After the reaction is completed, intermediate 1 is obtained.

[0016] 2) The reaction formula for step 2 is as follows: .

[0017] In step 2, the base 2 used is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); In step 2, the molar ratio of intermediate 1 to alkali 2 is 1:1 to 1.5 (preferably 1:1 to 1.3). Solvent 2 in step 2 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, dioxane, and acetone. In step 2, the molar ratio of intermediate 1 to p-toluenesulfonyl chloride is 1:1 to 1.3 (preferably 1:1 to 1.2). In step 2, intermediate 1 is dissolved in solvent 2, alkali 2 is added, and the mixture is stirred at 20-25℃ until dissolved. Then, p-toluenesulfonyl chloride is added, and the mixture is reacted at 20-25℃ for 2-3 hours. After the reaction is completed, intermediate 2 is obtained.

[0018] 3) The reaction formula for step 3 is as follows: .

[0019] Among them, the base 3 used in step 3 is one or more of potassium tert-butoxide and sodium hydride; In step 3, the molar ratio of intermediate 2 to alkali 3 is 1:1 to 1.3 (preferably 1:1 to 1.1). Solvent 3 in step 3 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, and dioxane; In step 3, the molar ratio of intermediate 2 to 2-amino-6-chloropurine is 1:1 to 1.4 (preferably 1:1 to 1.2). In step 3, intermediate 2 is dissolved in solvent 3, alkali 3 is added, and the mixture is stirred at 30-35℃ until dissolved. Then, 2-amino-6-chloropurine is added, and the mixture is reacted at 30-35℃ for 5-7 hours. After the reaction is completed, intermediate 3 is obtained.

[0020] 4) The reaction formula for step 4 is as follows: .

[0021] Solvent 4 mentioned in step 4 is one or more of methanol and diethylene glycol dimethyl ether; In step 4, intermediate 3 is dissolved in solvent 4, sodium borohydride is added, aluminum trichloride catalyst is added, and the mixture is stirred at 45-50℃ for 2-3 hours. After the reaction is completed, intermediate 4 is obtained.

[0022] 5) The reaction formula for step 5 is as follows: .

[0023] Solvent 5 in step 5 is one or more of dichloromethane, trichloromethane, and dioxane; Wherein, the base mentioned in step 5 is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); In step 5, intermediate 4 is dissolved in solvent 5, alkali 5 is added, acetic anhydride is added dropwise, and the mixture is stirred at 30-35℃ for 2-3 hours. After the reaction is completed, intermediate 5 is obtained.

[0024] 6) The reaction formula for step 6 is as follows:

[0025] In step 6, intermediate 5 is dissolved in ethyl acetate, triethylamine and pd / C are added, hydrogen gas is introduced and the mixture is stirred at 40-45℃ for 10-12 hours. After the reaction is completed, famciclovir is obtained.

[0026] The starting materials of this invention are simple and readily available, the reaction operation is convenient, and it is conducive to large-scale production.

[0027] The preparation process of this invention is characterized by mild conditions, minimal process impurities, and low production costs.

[0028] The beneficial effects of this invention are as follows: This invention provides a novel method for preparing famciclovir. Compared with existing processes, we can obtain the key famciclovir intermediate 3 with high selectivity and high yield. We tested other active ester intermediates 2, and through extensive experimentation, we found that intermediate 2 of the p-toluenesulfonic acid active ester has less than 1% of the positional isomer impurity at the 7-position and a selectivity of more than 99% for the N at the 9-position, thereby greatly reducing the pressure of the post-processing purification and improving the reaction yield. Specific Implementation

[0029] To further understand the present invention, the preparation method of famciclovir provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and not to limit the scope of the present invention or the scope of the claims.

[0030] Example 1: 1) Preparation of intermediate 1 100 g (0.625 mol) of diethyl malonate was dissolved in 200 ml of THF, and 94.6 g (0.93 mol) of triethylamine was added. The mixture was cooled to 0-5 °C, and 300 ml of ethylene oxide (3 M / L) in THF solution was added. The reaction was continued at 0-5 °C for 4 h. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain 125 g of intermediate 1, with a yield of 98%.

[0031] 2) Preparation of intermediate 2 100 g (0.49 mol) of intermediate 1 was dissolved in 300 ml of tetrahydrofuran, 64.2 g (0.635 mol) of triethylamine and 112 g (0.59 mol) of p-toluenesulfonyl chloride were added, and the mixture was stirred at 20-25 °C for 3 h. After the reaction was completed, 300 ml of water and 300 ml of dichloromethane were added, and the mixture was stirred to separate the layers. The organic layer was concentrated under reduced pressure to obtain 172 g of intermediate 2, with a yield of 98%.

[0032] 3) Preparation of intermediate 3 100 g (0.279 mol) of intermediate 2 was dissolved in 300 ml of tetrahydrofuran. 34.4 g (0.306 mol) of potassium tert-butoxide was added at 20-25 °C. The temperature was raised to 30-35 °C, and 51.9 g (0.306 mol) of 2-amino-6-chloropurine was added. The reaction was continued at this temperature for 5 h. After the reaction was completed, 500 ml of ice water was added, followed by 300 ml of ethyl acetate. The mixture was stirred and separated into layers. The organic layer was concentrated under reduced pressure to obtain 94 g of intermediate 3, with a yield of 95% and 0.8% of the 7-position isomer.

[0033] 4) Preparation of intermediate 4 90 g (0.253 mol) of intermediate 3 was dissolved in 300 ml of diethylene glycol dimethyl ether, 12.5 g of sodium borohydride was slowly added, and 8 g of aluminum trichloride was slowly added. The mixture was stirred at 45-50 °C for 2 h. After the reaction was completed, the reaction solution was poured into 300 ml of ice water containing 30 ml of concentrated hydrochloric acid. The solid was filtered to obtain the solid, washed with ice water, and dried under reduced pressure to obtain 62 g of intermediate 4, with a yield of 90%.

[0034] 5) Preparation of intermediate 5 60 g (0.22 mol) of intermediate 4 was dissolved in 200 ml of chloroform, 44.6 g (0.44 mol) of triethylamine was added, 0.6 g of DMAP was added, and 56 g of acetic anhydride was slowly added. The mixture was placed at 30-35 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature, sodium carbonate solution was added, and the pH was adjusted to 6-7. The mixture was separated into two layers to obtain an organic layer. The organic layer was washed twice with water, dried, and then evaporated to dryness to obtain 74 g of intermediate 5, with a yield of 94.8%.

[0035] 6) Preparation of Famciclovir 70 g (0.196 mol) of intermediate 5 was dissolved in 600 ml of ethyl acetate, 7 ml of triethylamine and 7 g of 10% palladium on carbon were added, and the mixture was hydrogenated at 0.1 MPa at 40-45 °C for 10 h. After the reaction was completed, the palladium on carbon was removed by filtration, and 300 ml of water was added to the filtrate. The layers were separated to obtain the ethyl acetate layer, which was dried and evaporated to dryness to obtain 60 g of famciclovir, with a yield of 95%.

[0036] Example 2: Following the method described above, intermediate 3 was prepared according to step 3 (different intermediate 2).

[0037] .

[0038] By preparing intermediate 3 using different active esters of intermediate 2, this invention found that p-toluenesulfonate has the highest selectivity at the 9-position, reaching a high selectivity of 99.2%.

Claims

1. A method for preparing famciclovir, comprising the following steps: 。 2. The preparation method according to claim 1, wherein the reaction formula in step 1 is as follows: ； in, The base 1 used in step 1 is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); In step 1, the molar ratio of diethyl malonate to alkali is 1:1 to 1.

5. Solvent 1 mentioned in step 1 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, dioxane, and chloroform; In step 1, the molar ratio of diethyl malonate to propylene oxide is 1:1 to 1.

5.

3. The preparation method according to claim 1, wherein the reaction formula in step 2 is as follows: ； in, The base 2 used in step 2 is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); In step 2, the molar ratio of intermediate 1 to alkali 2 is 1:1 to 1.

3. Solvent 2 in step 2 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, dioxane, and acetone. In step 2, the molar ratio of intermediate 1 to p-toluenesulfonyl chloride is 1:1 to 1.

2.

4. The preparation method according to claim 1, wherein the reaction formula in step 3 is as follows: ； in, The base 3 used in step 3 is one or more of potassium tert-butoxide and sodium hydride; In step 3, the molar ratio of intermediate 2 to alkali 3 is 1:1 to 1.

1. Solvent 3 in step 3 is one or more of tetrahydrofuran, acetonitrile, methyltetrahydrofuran, and dioxane; In step 3, the molar ratio of intermediate 2 to 2-amino-6-chloropurine is 1:1 to 1.

2.

5. The preparation method according to claim 1, wherein the reaction formula in step 4 is as follows: ； in, Solvent 4 mentioned in step 4 is one or more of methanol and diethylene glycol dimethyl ether.

6. The preparation method according to claim 1, wherein the reaction formula in step 5 is as follows: ； in, Solvent 5 mentioned in step 5 is one or more of dichloromethane, trichloromethane, and dioxane; The base mentioned in step 5 is one or more of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

7. The preparation method according to claim 1, wherein the reaction formula in step 6 is as follows: ； in, Step 6 involves hydrogenating intermediate 5 via a Pd / C reaction to obtain famciclovir.

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