Preparation method of valaciclovir hydrochloride hydrate

Abstract

The invention provides a preparation method of valaciclovir hydrochloride hydrate, and belongs to the technical field of organic compound synthesis. According to the preparation method, L-valine and acetoacetate are subjected to a reaction in the presence of an alkaline compound under the heating condition, and the valaciclovir side chain (E)-(4-ethoxy-4-oxobutyl-2-ene-2-yl)-L-valine is obtained; then, the valaciclovir side chain and acyclovir are subjected to a reaction, and Ec-valine-acyclovir is obtained; and reacting the Ec-valine-acyclovir with hydrochloric acid to obtain the valaciclovir hydrochloride hydrate. When the valaciclovir hydrochloride hydrate is prepared from the valaciclovir side chain, the yield is remarkably improved, the output of three wastes is greatly reduced, the production cost is greatly reduced, and the quality of the obtained valaciclovir hydrochloride hydrate meets the standards of EP, USP and CP, so that the valaciclovir hydrochloride side chain is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing valacyclovir hydrochloride hydrate. Background Art

[0002] The chemical name of valacyclovir hydrochloride is L-valine-2-[(6-oxo-2-amino-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl ester hydrochloride. It is a prodrug of acyclovir and is suitable for all acyclovir indications. The main routes for synthesizing valacyclovir hydrochloride in existing technologies are as follows:

[0003] Route 1: Acyclovir reacts with Cbz-L-valine in the presence of DCC, DMAP, and DMF to produce Cbz-valine-acyclovir. Palladium-carbon (Pd / C) is used as a catalyst to remove the protecting group from Cbz-valine-acyclovir under a hydrogen atmosphere. The product is then salted with hydrochloric acid and crystallized to produce valacyclovir hydrochloride. This route is currently the most commonly used method for domestic production of valacyclovir hydrochloride. While the process is relatively stable, it requires a large amount of Pd / C and is relatively expensive.

[0004] Route 2: Acyclovir reacts with Boc-L-valine in the presence of EDC hydrochloride, DMAP, and DMF to produce Boc-valine-acyclovir. The protecting groups are then removed and the salt is formed under acid to produce valacyclovir. This route has the advantage of not using a precious metal catalyst for hydrogenolysis and relatively mild reaction conditions. However, EDC hydrochloride is relatively expensive, and acid hydrolysis easily destroys the ester bond. The post-processing process is complex and the product quality is unstable.

[0005] Route 3: N-9-Fmoc-L-valine is coupled with acyclovir in the presence of DCC or EDC hydrochloride in DMF to form an ester. The N-9-Fmoc-L-valine protecting group is then removed with piperidine, followed by salt crystallization. This route has the advantage of not requiring a noble metal catalyst for deprotection. However, the raw material N-9-Fmoc-L-valine is difficult to obtain and relatively expensive, making it a cost-effective alternative.

[0006] Route 4: 1-chloro-2-(chloromethoxy)ethane (b) is prepared by chloromethylation of 2-chloroethanol. Compound b reacts with sodium acetate to produce 1-chloro-2-(acetoxymethoxy)ethane (c). Compound c is condensed with 2,9-diacetylguanine to produce 2-acetyl-9-(2-chloroethoxymethyl)guanine (d). Compound d is deacetylated in methanol to produce 9-(2-chloroethoxymethyl)guanine (e). Compound e reacts with sodium L-valine (f), followed by hydrolysis and salt formation to produce valacyclovir hydrochloride. The total yield is approximately 18.4%. This method has a very low yield, resulting in high product costs and a large amount of waste, making it unsuitable for industrial production. Summary of the Invention

[0007] Based on the above technical problems, the present invention provides a method for preparing valacyclovir hydrochloride hydrate. A valacyclovir side chain is obtained by reacting L-valine with acetoacetate. When valacyclovir hydrochloride hydrate is prepared using this side chain, the yield is significantly improved, the generation of three wastes is significantly reduced, and the production cost is significantly lowered. Furthermore, the quality of the obtained valacyclovir hydrochloride hydrate meets the standards of EP, USP, and CP, making it suitable for industrial production.

[0008] Specifically, in order to achieve the above-mentioned purpose, the present invention adopts the following technical solutions:

[0009] A method for preparing valacyclovir hydrochloride hydrate comprises the following steps:

[0010] S1, L-valine and acetoacetate are reacted under heating conditions in the presence of a basic compound. After the reaction, the temperature is lowered to 30°C to 40°C, filtered, and the filtrate is concentrated under reduced pressure to obtain a valacyclovir side chain;

[0011] S2. In the presence of DMAP and DCC, the valacyclovir side chain reacts with acyclovir in a second organic solvent at 0° C. to 10° C.; after the reaction, the reaction is filtered, the filtrate is concentrated under reduced pressure, a third organic solvent is added, and the temperature is raised to reflux and maintained for 30 to 60 minutes; the temperature is then lowered to 10° C. to 20° C. and filtered, and the filter cake is washed with the third organic solvent and then dried to obtain Ec-valine-acyclovir;

[0012] S3, the Ec-valine-acyclovir is reacted with hydrochloric acid in a fourth organic solvent. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, water is added to dissolve it, and then activated carbon is added for decolorization; the mixture is filtered, the filter cake is washed with water, the filtrate and the washing liquid are combined, and a fifth organic solvent is added dropwise; after the addition is completed, the temperature is lowered to -5°C to 10°C, the filter cake is washed with the fifth organic solvent, and then dried to obtain the valacyclovir hydrochloride hydrate.

[0013] In a preferred embodiment, the molar ratio of the L-valine, the acetoacetate, and the basic compound is 1:(0.5-1.0):(0.45-2.0).

[0014] In a preferred embodiment, the acetoacetate is at least one of methyl acetoacetate, ethyl acetoacetate, and propyl acetoacetate.

[0015] In a preferred embodiment, the basic compound is a combination of one or more organic bases, inorganic bases, and basic salts.

[0016] In a preferred embodiment, L-valine and acetoacetate react in the presence of a basic compound in a first organic solvent; the first organic solvent is a combination of one or more of alcohols, ketones, esters, ethers, halogenated hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, and amide solvents.

[0017] In a further preferred embodiment, the molar ratio of the L-valine, the acetoacetate, the basic compound, and the first organic solvent is 1:(0.5-1.0):(0.45-2.0):(1-16).

[0018] In a preferred embodiment, L-valine and acetoacetate are reacted in the presence of a basic compound at 40° C. to 80° C. for 3 to 10 hours.

[0019] In a preferred embodiment, in step S1, the filter cake obtained by filtration is rinsed with a first organic solvent, the filtrate and the washing liquid are combined, and the first organic solvent is evaporated off by concentration under reduced pressure to obtain the valacyclovir side chain.

[0020] In a preferred embodiment, the molar ratio of the valacyclovir side chain, the DMAP, the DCC and the acyclovir is (1.5-4.5):(0.01-0.06):(1.5-2.5):1.

[0021] In a preferred embodiment, in step S3, the Ec-valine-acyclovir is reacted with hydrochloric acid in a fourth organic solvent at 35° C. to 50° C. for 0.5 to 2 h.

[0022] In a preferred embodiment, in step S3, the temperature for adding the fifth organic solvent dropwise is 40°C to 50°C.

[0023] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0024] (1) In the present invention, L-valine and acetoacetate are heated to react in the presence of an alkaline compound, the reaction solution is cooled to 30°C to 40°C, filtered, and the filtrate is concentrated under reduced pressure to obtain a valacyclovir side chain. This side chain directly participates in subsequent reactions, contributing to the subsequent improvement of the yield and purity of Ec-valine-acyclovir. At the same time, when using this side chain to prepare valacyclovir or a pharmaceutically acceptable salt of valacyclovir, there is no need to use precious metals as catalysts or to use flammable and explosive hydrogen for the reaction.

[0025] (2) The yield of valacyclovir hydrochloride hydrate prepared by the method provided in the present invention is significantly improved, the amount of three wastes generated is greatly reduced, and the quality of the obtained valacyclovir hydrochloride hydrate meets the standards of EP, USP and CP.

[0026] (3) The raw materials in the application are common raw materials on the market, which are convenient to purchase and relatively cheap. Meanwhile, the product purity and yield are high, and the reaction conditions are relatively mild, so that the cost of the prepared valaciclovir hydrochloride hydrate is greatly reduced, and the industrial production is more suitable. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 HPLC chart for the control detection when synthesizing compound II in Example 1 of the application;

[0028] Figure 2 HPLC chart for the control detection when synthesizing compound II in Example 1 of the application;

[0029] Figure 3 HPLC chart for the control detection when synthesizing valaciclovir hydrochloride hydrate in Example 1 of the application;

[0030] Figure 4 HPLC chart for the control detection when synthesizing valaciclovir hydrochloride hydrate in Example 1 of the application;

[0031] Figure 5 HPLC chart for the control detection when synthesizing compound II in Example 2 of the application;

[0032] Figure 6 HPLC chart for the control detection when synthesizing compound II in Example 2 of the application;

[0033] Figure 7 HPLC chart for the control detection when synthesizing valaciclovir hydrochloride hydrate in Example 2 of the application;

[0034] Figure 8 HPLC chart for the control detection when synthesizing valaciclovir hydrochloride hydrate in Example 2 of the application. DETAILED DESCRIPTION

[0035] The following description of the technical solutions in the application is made in conjunction with the embodiments, so that those skilled in the art can fully understand the application. Obviously, the described embodiments are only some preferred embodiments of the application, but not all embodiments. Any equivalent changes or replacements made by those skilled in the art without creative labor to the following embodiments shall fall within the protection scope of the application.

[0036] The meanings of the abbreviations or abbreviations in the application are as follows:

[0037] Cbz: Carbobenzyloxy, benzyloxy carbonyl;

[0038] Boc:t-Butyloxy carbonyl, tert-butyloxycarbonyl;

[0039] Ec:ethyl (Z)-but-2-enoate, (Z)-but-2-enoic acid ethyl ester;

[0040] DCC: N,N'-dicyclohexylcarbodiimide;

[0041] DMAP: 4-dimethylaminopyridine;

[0042] DMF: N,N-dimethylformamide;

[0043] DMA: N,N-dimethylacetamide;

[0044] EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0045] DMSO: dimethyl sulfoxide;

[0046] TLC: thin layer chromatography;

[0047] EP: European Pharmacopoeia;

[0048] USP: United States Pharmacopoeia;

[0049] CP: Chinese Pharmacopoeia.

[0050] The specific embodiment of the present application provides a method for preparing valacyclovir hydrochloride hydrate, comprising the following steps:

[0051] S1. Synthesis of (E)-(4-ethoxy-4-oxobut-2-en-2-yl)-L-valine (Compound IV)

[0052] L-valine, a basic compound, and acetoacetate were added to a reaction vessel, and stirring was started. The temperature was raised to 40°C-80°C and the reaction was carried out for 3-10 hours. TLC (the chromatography solvent was a mixture of dichloromethane, methanol, and petroleum ether in a volume ratio of 10:1:1) was used to detect that the reaction of acetoacetate was basically complete. The temperature was lowered to 30°C-40°C and filtered. The filter cake was rinsed with the first organic solvent. The filtrate and the washing liquid were combined and concentrated under reduced pressure to evaporate the first organic solvent to obtain compound IV (valacyclovir side chain).

[0053] S2. Synthesis of Ec-valine-acyclovir (II)

[0054] A second organic solvent, compound IV synthesized in step S1, DMAP, DCC, and acyclovir are added to the reaction vessel, and the mixture is reacted at 0°C-10°C for 16-24 hours. Samples are taken for HPLC detection to confirm whether the reaction is complete. After the reaction is completed, the reaction solution is filtered, the filter cake is rinsed with the second organic solvent, the filtrate and washings are concentrated under reduced pressure at 50°C-70°C, concentrated and evaporated to dryness, and a third organic solvent is added. The mixture is heated to reflux and maintained for 30-60 minutes, then cooled to 10°C-20°C and filtered. The filter cake is rinsed with the third organic solvent, and the filter cake is dried under reduced pressure at 50°C-70°C to obtain compound II.

[0055] S3. Synthesis of valacyclovir hydrochloride hydrate

[0056] Compound II, a fourth organic solvent, and hydrochloric acid are added to a reaction vessel and reacted at 35°C-50°C for 0.5-2 hours. Samples are collected and analyzed by HPLC to confirm the completion of the reaction. After the reaction, the reaction solution is concentrated to dryness under reduced pressure at 40-60°C. Water (the amount of water is generally 2-3 times the weight of the concentrated residue) is added and dissolved at 45-55°C. Activated carbon is added for decolorization at 45-55°C for 30-60 minutes. The mixture is filtered and the filter cake is rinsed with water. The filtrate and washings are combined, and the fifth organic solvent is added dropwise at 40-50°C. After complete addition, the mixture is cooled to -5-10°C and filtered. The filter cake is rinsed with the fifth organic solvent and dried by vacuum drying at 50-70°C for 6-10 hours to obtain valacyclovir hydrochloride hydrate.

[0057] When synthesizing compound IV in step S1, L-valine, the basic compound, and acetoacetate can react in the absence of a solvent or in the presence of a first organic solvent.

[0058] In a preferred embodiment, the molar ratio of L-valine, acetoacetate, and the basic compound is 1:(0.5-1.0):(0.45-2.0). For example, the molar ratio of L-valine, acetoacetate, and the basic compound is 1:0.5:0.45, 1:0.7:0.8, 1:0.72:1.67, 1:0.86:0.51, 1:0.91:1.06, 1:1:1.2, 1:0.95:1.02, 1:0.96:1.06, and 1:1:2.

[0059] In a preferred embodiment, in step S1, L-valine, the basic compound, and acetoacetate react in the presence of a first solvent.

[0060] In a further preferred embodiment, the molar ratio of L-valine, acetoacetate, basic compound, and first organic solvent is 1:(0.5-1.0):(0.45-2.0):(1-16). For example, the molar ratio of L-valine, acetoacetate, basic compound, and first organic solvent is 1:0.5:0.45:5, 1:0.5:2:1, 1:0.7:0.8:2, 1:0.72:1.67:7.2, 1:0.85:1.0:5, 1:0.86:0.51:11.5, 1:0.95:1.02:8.8, 1:0.96:1.06:14, and 1:1:2:16.

[0061] In a preferred embodiment, the molar ratio of compound IV, DMAP, DCC and acyclovir in step S2 is (1.5-4.5):(0.01-0.06):(1.5-2.5):1. For example, the molar ratio of compound IV, DMAP, DCC and acyclovir is 1.5:0.01:1.5:1, 1.6:0.04:1.9:1, 1.7:0.04:1.9:1, 1.8:0.04:1.9:1, 2.0:0.04:1.9:1, 2.0:0.02:2.0:1, 2.5:0.03:1.8:1, 2 .0:0.06:2.0:1, 2.5:0.06:2.0:1, 2.6:0.06:2.0:1, 3.5:0.05:2.0:1, 2.8:0.04:2.0:1, 3.0:0.04:2.0:1, 3.5:0.04:2.0:1, 4.0:0.04:2.0:1, 4.5:0.06:2.5:1.

[0062] In a preferred embodiment, the molar ratio of Compound II to HCl in hydrochloric acid in step S3 is 1:(1.05-1.6). For example, the molar ratio of Compound II to HCl in hydrochloric acid is 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.4, 1:1.5, or 1:1.6.

[0063] As an example, the first organic solvent is at least one of methanol, ethanol, tetrahydrofuran, acetonitrile, DMA, and DMSO, preferably DMSO.

[0064] As an example, the alkaline compound is any one of potassium hydroxide, sodium carbonate, sodium bicarbonate, liquid ammonia (ammonia gas), methylamine, ethylamine, diethylamine, triethylamine, propylamine, and ethylenediamine, preferably triethylamine.

[0065] As an example, the acetoacetate is at least one of methyl acetoacetate, ethyl acetoacetate, and propyl acetoacetate, preferably ethyl acetoacetate.

[0066] As an example, the reaction temperature in step S1 is 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C.

[0067] As an example, the reaction time in step S1 is 3h, 3.5h, 4h, 5h, 5.5h, 6h, 7h, 8h, 9h, 10h.

[0068] As an example, the temperature for the reduced pressure concentration in step S1 is 40°C~55°C. For example, the temperature for the reduced pressure concentration is 40°C, 42°C, 45°C, 50°C, 55°C.

[0069] As an example, the second organic solvent in step S2 is DMF.

[0070] As an example, the third organic solvent in step S2 is an alcohol solvent, such as methanol, ethanol, isopropanol.

[0071] As an example, the fourth organic solvent in step S3 is an alcohol solvent, such as methanol, ethanol.

[0072] As an example, the fifth organic solvent in step S3 is ethanol, isopropanol, acetone.

[0073] In a preferred embodiment, the time for dropping the fifth organic solvent in step S3 is 0.5~3 hours, such as 0.5h, 1h, 1.5h, 2h, 2.5h, 3h.

[0074] Example 1

[0075] A preparation method of valaciclovir hydrochloride hydrate, comprising the following steps:

[0076] S1, synthesis of (E)-(4-ethoxy-4-oxobut-2-en-2-yl)-L-valine (compound IV)

[0077] In a 500mL clean three-necked reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 28.0g (0.239mol) of L-valine, 24.6g (0.243mol) of triethylamine, 29.4g (0.226mol) of ethyl acetoacetate, 150mL of DMSO were added, the stirring was started, the temperature was raised to 78°C~80°C, and the reaction was carried out for 5h. TLC (the chromatographic solvent was a mixture of dichloromethane, methanol and petroleum ether in a volume ratio of 10:1:1) detection showed that the ethyl acetoacetate was substantially reacted, the temperature was lowered to 35°C, and the filter cake was washed with 20mL of DMSO. The filter cake and the washing liquid were combined, and the DMSO was removed by reduced pressure concentration. Compound IV was obtained. The main reaction equation of this step is as follows:

[0078]

[0079] S2. Synthesis of Ec-valine-acyclovir (II)

[0080] In a 500 mL clean three-necked reaction flask equipped with a thermometer and mechanical stirring, compound IV synthesized in step S1 and 200 mL of DMF were added, followed by 0.6 g (0.005 mol) of DMAP, 52.0 g (0.252 mol) of DCC, and 30 g (0.133 mol) of acyclovir (compound III). The mixture was reacted at 0°C for 24 h, and samples were taken for HPLC detection. The test results are shown in FIG. Figure 1 (The reaction is considered complete if the residual acyclovir content is <0.5%). The reaction solution is filtered, and the filter cake is rinsed with 50 mL of DMF. The filtrate and washings are concentrated under reduced pressure at 60°C, evaporated to dryness, and 400 mL of ethanol is added. The temperature is raised to reflux and maintained for 40 minutes, then cooled to 10°C and filtered. The filter cake is rinsed with 50 mL of ethanol and dried under reduced pressure at 58°C-60°C to obtain 56.6 g of compound II, with a yield of 97.3%. Samples are taken for HPLC analysis, and the test results are shown in the table. Figure 2 , the purity of compound II is 97.94%.

[0081] The conditions for two HPLC tests in this step are as follows:

[0082] Mobile phase: 0.02 mol / L potassium hydrogen phosphate: acetonitrile = 65:35 (volume ratio), pH 9.6,

[0083] Diluent: 0.02 mol / L potassium hydrogen phosphate: acetonitrile = 50:50 (volume ratio),

[0084] Chromatographic conditions: isocratic elution, 30 min (can be extended appropriately),

[0085] Flow rate: 1 mL / min,

[0086] UV: 250nm,

[0087] Column temperature: 20°C,

[0088] Injection volume: 10 μL,

[0089] Chromatographic column: YMC Triant C18 column 4.6*250mm*5μm,

[0090] Test sample concentration: 1 mg / mL (solid) or 1 drop / 5 mL (liquid).

[0091] The main reaction equation of this step is as follows:

[0092]

[0093] S3. Synthesis of valacyclovir hydrochloride hydrate

[0094] In a 500 mL clean three-necked reaction flask equipped with a thermometer and mechanical stirring, 56.6 g of compound II, 300 mL of methanol, and 20.0 g of 36% hydrochloric acid (0.2 mol) were added and reacted at 48°C-50°C for 1 h. Samples were taken for HPLC detection (the detection conditions were the same as those for detecting the purity of compound II in step S2). The detection results are shown in FIG. Figure 3 (The reaction is considered complete when the residual amount of Compound II (i.e., the ester on the spectrum) is less than 0.2%). The reaction solution is concentrated to dryness under reduced pressure at 50°C~52°C, 96 mL of purified water is added, and the mixture is dissolved at 45°C. 2.0 g of activated carbon is added for decolorization at 45°C for 60 min, filtered, and the filter cake is rinsed with 5 mL of water. The filtrate and washing liquid are combined and transferred to a 1000 mL clean three-necked reaction flask equipped with a thermometer and mechanical stirring. 600 mL of acetone is added dropwise at 45°C (1.5 hours to complete the addition). After the acetone is added, the temperature is lowered to -5°C and filtered. The filter cake is rinsed with 50 mL of acetone and dried. The filter cake is vacuum dried at 60°C for 8 hours to obtain 43.8 g (dry weight) of valacyclovir hydrochloride hydrate (Compound І). The molar yield based on acyclovir is 86.8%. Sampling is performed by HPLC detection according to the method in EP11.0. The test results are shown in the table. Figure 4 , the purity of valacyclovir hydrochloride hydrate is 99.6%. According to the above process, the workshop is scaled up for production, and the finished product is tested according to the standards in USP-NF2024. The contents of valacyclovir impurities E, F, and G meet the requirements, valacyclovir impurities C and D are not detected, the content of D-valacyclovir is 0.1%, the content of other unknown impurities is 0.03%, the total impurities is 0.6%, and the content of valacyclovir hydrochloride hydrate is 99.2%. The main reaction equation of this step is as follows:

[0095]

[0096] Example 2

[0097] A method for preparing valacyclovir hydrochloride hydrate comprises the following steps:

[0098] S1. Synthesis of (E)-(4-ethoxy-4-oxobut-2-en-2-yl)-L-valine (Compound IV)

[0099] In a 500 mL clean three-necked reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 62.4 g (0.53 mol) of L-valine, 56.6 g (0.56 mol) of triethylamine, 65.9 g (0.51 mol) of ethyl acetoacetate, 300 mL of methanol were added, the stirring was started, the temperature was raised to reflux, and the reaction was allowed to proceed for 7 h. TLC (the same as in Example 1) showed that the reaction of ethyl acetoacetate was substantially complete. The temperature was lowered to 30 °C, and the reaction mixture was filtered. The filter cake was washed with 20 mL of methanol. The filtrate and the washing were combined, and the methanol was distilled off under reduced pressure at (50 ± 5) °C. Compound IV was obtained.

[0100] S2, synthesis of Ec-valine-aciclovir (II)

[0101] In a 500 mL clean three-necked reaction flask equipped with a thermometer and a mechanical stirrer, 112.2 g of compound II, 600 mL of methanol, and 41.0 g of 36% hydrochloric acid (0.4 mol) were added. The reaction was allowed to proceed at 35 °C to 38 °C for 2 h. The sample was analyzed by HPLC (the same as in step S2). The results are shown in Table 1. Figure 5 (Aciclovir residual amount < 0.5%, i.e. the reaction was considered complete). The reaction mixture was filtered. The filter cake was washed with 100 mL of DMF. The filtrate and the washing were combined, and concentrated under reduced pressure at 50 °C. The residue was transferred into a 1000 mL reaction flask, 800 mL of ethanol was added, the temperature was raised to reflux, and the reaction was allowed to proceed for 30 min. The temperature was then lowered to 15 °C, and the reaction mixture was filtered. The filter cake was washed with 50 mL of ethanol. The filter cake was dried under reduced pressure at 50 °C to 53 °C. 112.2 g of compound II was obtained in a yield of 96.5%. The sample was analyzed by HPLC (the same as in Example 1). The results are shown in Table 1. Figure 6 The purity of compound II was 97.42%.

[0102] S3, synthesis of valaciclovir hydrochloride hydrate

[0103] In a 1000 mL clean three-necked reaction flask equipped with a thermometer and a mechanical stirrer, 112.2 g of compound II, 600 mL of methanol, and 41.0 g of 36% hydrochloric acid (0.4 mol) were added. The reaction was allowed to proceed at 35 °C to 38 °C for 2 h. The sample was analyzed by HPLC (the same as in step S2). The results are shown in Table 1. Figure 7(The reaction is considered complete when the residual amount of compound II (i.e., the ester on the spectrum) is less than 0.2%). The reaction solution is concentrated to dryness under reduced pressure at 40-43°C, 200 mL of purified water is added, and the mixture is dissolved at 50°C. 5.0 g of activated carbon is added for decolorization at 50°C for 40 minutes, filtered, and the filter cake is rinsed with 20 mL of water. The filtrate and washing liquid are combined and transferred to a 2000 mL clean three-necked reaction flask equipped with a thermometer and mechanical stirring. 1500 mL of acetone is added dropwise at 40°C (it takes about 3 hours to drip completely). After the acetone is dripped, the temperature is lowered to 0°C and filtered. The filter cake is rinsed with 50 mL of acetone and dried. The filter cake is vacuum-dried at 50°C for 10 hours to obtain 86.8 g (dry weight) of valacyclovir hydrochloride hydrate (compound І). The molar yield based on acyclovir is 86.0%. Sampling is performed by HPLC detection according to the method in EP11.0. The test results are shown in the table. Figure 8 The purity of valacyclovir hydrochloride hydrate was 99.5%. The above process was used for scaled-up production in a workshop, and the finished product was tested according to the standards in USP-NF2024. The contents of valacyclovir impurities E, F, and G met the requirements. Impurities C and D were not detected. The content of D-valacyclovir was 0.1%, the content of other unknown impurities was 0.02%, and the total impurities were 0.5%. The content of valacyclovir hydrochloride hydrate was 99.2%.

[0104] Example 3

[0105] A method for preparing valacyclovir hydrochloride hydrate comprises the following steps:

[0106] S1. Synthesis of (E)-(4-ethoxy-4-oxobut-2-en-2-yl)-L-valine (Compound IV)

[0107] In a 500 mL clean three-necked reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 42.0 g (0.3585 mol) of L-valine, 33.6 g (0.5988 mol) of potassium hydroxide, 30.0 g (0.2584 mol) of methyl acetoacetate, and 150 mL of ethanol were added, and stirring was started. The temperature was raised to reflux for reaction for 8 h. TLC (chromatographic conditions were the same as in Example 1) detected that the reaction of methyl acetoacetate was basically completed. The temperature was lowered to 40 ° C and filtered. The filter cake was rinsed with 20 mL of ethanol. The filtrate and washings were combined and concentrated under reduced pressure at 46 ° C to evaporate the ethanol to obtain compound IV.

[0108] S2. Synthesis of Ec-valine-acyclovir (II)

[0109] To a clean 500 mL three-necked reaction flask equipped with a thermometer and mechanical stirring, compound IV synthesized in step S1 and 200 mL of DMF were added. 0.4 g (0.0033 mol) of DMAP, 52.5 g (0.2544 mol) of DCC, and 30.0 g (0.1332 mol) of acyclovir (compound III) were then added. The reaction was allowed to proceed at 10°C for 16 h. Samples were collected for HPLC analysis (HPLC analysis conditions were the same as in Example 1). After confirming the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with 100 mL of DMF. The filtrate and washings were concentrated under reduced pressure at 70°C, evaporated to dryness, and transferred to a 1000 mL reaction flask. 400 mL of methanol was added, and the temperature was raised to reflux for 60 min. The temperature was then lowered to 20°C, filtered, and the filter cake was rinsed with 50 mL of methanol. The filter cake was then dried under reduced pressure at 68-70°C to obtain 57.1 g of compound II, with a yield of 98.2%. A sample was taken for HPLC detection (HPLC detection conditions were the same as in Example 1), and the purity of Compound II was 96.8%.

[0110] S3. Synthesis of valacyclovir hydrochloride hydrate

[0111] To a clean, 1000-mL, three-necked reaction flask equipped with a thermometer and mechanical stirring, add 57.1 g (0.1308 mol) of Compound II, 250 mL of methanol, and 16.1 g of 36% hydrochloric acid (0.159 mol). The mixture was reacted at 48-50°C for 0.5 h. Samples were collected for HPLC analysis (HPLC conditions were the same as in Example 1). After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure at 58-60°C. 98 mL of water was added and dissolved at 55°C. 1.8 g of activated carbon was added for decolorization at 55°C for 30 min. The mixture was filtered, and the filter cake was rinsed with 6 mL of water. The combined filtrate and washings were transferred to a clean, 2000 mL, three-necked reaction flask equipped with a thermometer and mechanical stirring. 650 mL of acetone was added dropwise at 50°C (over 2 hours). After the acetone was added, the temperature was lowered to 10°C and filtered. The filter cake was rinsed with 60 mL of acetone and dried under vacuum at 70°C for 6 hours to yield 42.6 g (dry weight) of valacyclovir hydrochloride hydrate (Compound I). The molar yield, based on acyclovir, was 84.4%. Samples were collected and analyzed by HPLC according to the method described in EP11.0. The purity of the valacyclovir hydrochloride hydrate was 99.2%.

[0112] Example 4

[0113] A method for preparing valacyclovir hydrochloride hydrate comprises the following steps:

[0114] S1. Synthesis of (E)-(4-ethoxy-4-oxobut-2-en-2-yl)-L-valine (Compound IV)

[0115] In a 500 mL clean three-necked reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 43.7 g (0.3730 mol) of L-valine, 20.0 g (0.1887 mol) of sodium carbonate, 46.1 g (0.3198 mol) of propyl acetoacetate, and 400 mL of DMA were added. Stirring was started, the temperature was raised to 60°C~63°C and the reaction was carried out for 5 h. TLC (chromatographic conditions were the same as in Example 1) detected that the reaction of propyl acetoacetate was basically completed. The temperature was lowered to 35°C and filtered. The filter cake was rinsed with 25 mL of DMA, the filtrate and washings were combined, and the DMA was evaporated under reduced pressure to obtain compound IV.

[0116] S2. Synthesis of Ec-valine-acyclovir (II)

[0117] To a clean 500 mL three-necked reaction flask equipped with a thermometer and mechanical stirring, compound IV synthesized in step S1 and 350 mL of DMF were added. Then, 1.2 g (0.0098 mol) of DMAP, 69.2 g (0.3354 mol) of DCC, and 37.5 g (0.1665 mol) of acyclovir (compound III) were added and reacted at 3°C ​​for 22 h. A sample was taken for HPLC analysis (HPLC analysis conditions were the same as in Example 1). After confirming the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with 80 mL of DMF. The filtrate and washings were concentrated under reduced pressure at 55°C, evaporated to dryness, and transferred to a 1000 mL reaction flask. 600 mL of isopropanol was added, and the temperature was raised to reflux and maintained for 50 min. The temperature was then lowered to 15°C, filtered, and the filter cake was rinsed with 50 mL of isopropanol. The filter cake was then dried under reduced pressure at 55-57°C to obtain 70.4 g of compound II, with a yield of 96.9%. A sample was taken for HPLC detection (HPLC detection conditions were the same as in Example 1), and the purity of Compound II was 97.1%.

[0118] S3. Synthesis of valacyclovir hydrochloride hydrate

[0119] To a clean, 1000-mL, three-necked reaction flask equipped with a thermometer and mechanical stirring, add 70.4 g of Compound II, 450 mL of ethanol, and 23.2 g of 36% hydrochloric acid (0.2291 mol). The mixture was reacted at 40–42°C for 1.5 h. Samples were collected for HPLC analysis (HPLC conditions were the same as in Example 1). After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure at 45–48°C. 120 mL of water was added and dissolved at 50°C. 2.5 g of activated carbon was added for decolorization at 50°C for 45 min. The mixture was filtered, and the filter cake was rinsed with 10 mL of water. The combined filtrate and washings were transferred to a clean, 2000 mL, three-necked reaction flask equipped with a thermometer and mechanical stirring. 800 mL of ethanol was added dropwise at 48°C. After the ethanol was completely added, the temperature was lowered to 5°C and filtered. The filter cake was rinsed with 60 mL of ethanol and dried under vacuum at 65°C for 9 hours to yield 52.3 g (dry weight) of valacyclovir hydrochloride hydrate (Compound I), with a yield of 82.9%. Samples were collected and analyzed by HPLC according to the method described in EP11.0. The purity of the valacyclovir hydrochloride hydrate was 99.0%.

[0120] The embodiments described above are merely preferred embodiments of the present application and are not intended to limit the scope of protection of the present application. For any person skilled in the art, the present application may have various modifications and variations. Any simple equivalent changes and modifications made based on the scope of protection of the present application and the contents of the specification should be included in the scope of protection of the present application.

Claims

1. A method for preparing valacyclovir hydrochloride hydrate, characterized in that: The following steps are involved: S1, L-valine and acetoacetate are reacted under heating conditions in the presence of a basic compound. After the reaction, the temperature is lowered to 30°C to 40°C, filtered, and the filtrate is concentrated under reduced pressure to obtain a valacyclovir side chain; S2. In the presence of DMAP and DCC, the valacyclovir side chain reacts with acyclovir in a second organic solvent at 0° C. to 10° C.; after the reaction is completed, the reaction is filtered, and the filtrate is concentrated under reduced pressure and then added with a third organic solvent, and the temperature is raised to reflux and maintained for 30 to 60 minutes; then the temperature is lowered to 10° C. to 20° C. and filtered, and the filter cake is washed with the third organic solvent and then dried to obtain Ec-valine-acyclovir; S3, the Ec-valine-acyclovir is reacted with hydrochloric acid in a fourth organic solvent. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure, water is added to dissolve it, and then activated carbon is added for decolorization; the mixture is filtered, the filter cake is washed with water, the filtrate and the washing liquid are combined, and a fifth organic solvent is added dropwise; after the addition is completed, the temperature is lowered to -5°C to 10°C, the filter cake is washed with the fifth organic solvent, and then dried to obtain the valacyclovir hydrochloride hydrate.

2. The preparation method according to claim 1, characterized in that The molar ratio of the L-valine, the acetoacetate, and the basic compound is 1:(0.5-1.0):(0.45-2.0).

3. The preparation method according to claim 1, characterized in that The acetoacetate is at least one of methyl acetoacetate, ethyl acetoacetate, and propyl acetoacetate; or / and the basic compound is a combination of one or more of an organic base, an inorganic base, and an alkaline salt.

4. The preparation method according to claim 1, characterized in that L-valine and acetoacetate react in the presence of a basic compound in a first organic solvent; the first organic solvent is a combination of one or more of alcohols, ketones, esters, ethers, halogenated hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, and amide solvents.

5. The preparation method according to claim 1, characterized in that L-valine and acetoacetate are reacted in the presence of an alkaline compound at 40°C~80°C for 3~10 hours.

6. The preparation method according to claim 1, characterized in that In step S1, the filter cake obtained by filtration is washed with a first organic solvent, the filtrate and the washing liquid are combined, and the first organic solvent is evaporated off by concentration under reduced pressure to obtain the valacyclovir side chain.

7. The preparation method according to claim 1, characterized in that The molar ratio of the valacyclovir side chain, the DMAP, the DCC and the acyclovir is (1.5-4.5):(0.01-0.06):(1.5-2.5):

1.

8. The preparation method according to claim 1, characterized in that In step S3, the Ec-valine-acyclovir is reacted with hydrochloric acid in a fourth organic solvent at 35° C. to 50° C. for 0.5 to 2 h.

9. The preparation method according to claim 1, characterized in that The temperature for adding water for dissolution in step S3 is 45° C. to 55° C.; or / and the temperature for activated carbon decolorization is 45° C. to 55° C., and the decolorization time is 30 to 60 minutes.

10. The preparation method according to claim 1, characterized in that The temperature for adding the fifth organic solvent dropwise in step S3 is 40° C. to 50° C.

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