Process for the preparation of an intermediate of emtricitabine

Abstract

The application discloses a preparation method of an intermediate of entecavir, and the intermediate is prepared from dimethyl oxalate through four steps of amidation, ring closure, reduction and chlorination to obtain 3-(chloromethyl)-1-methyl-1 H -1,2,4-triazole hydrochloride with high purity. The application has the advantages of mild reaction condition, simple operation, high yield, low cost and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, an intermediate of ensitver. BACKGROUND

[0002] 3CL protease inhibitor is one of the focuses of new crown drug research and development, and is also the most studied one by scientists on the structure of SARS virus and novel coronavirus (SARS-Cov-2) protease. Ensitver belongs to 3CL protease inhibitor, which is a new coronavirus specific drug developed and marketed by Japan's Shionogi Pharmaceutical. 3-(chloromethyl)-1-methyl-1 H -1,2,4-triazole hydrochloride is one of the key raw materials for synthesizing ensitver, but due to the significant regioselectivity problem of the methyl in the compound, the synthesis is very challenging, therefore, developing a synthesis method with process amplification potential has a very broad market prospect.

[0003] 3-(chloromethyl)-1-methyl-1 H -1,2,4-triazole hydrochloride preparation method is reported as follows:

[0004] Chinese patent CN107879992A reports a synthesis method of 3-(chloromethyl)-1-methyl-1 H -1,2,4-triazole hydrochloride, and the synthesis route is as follows:

[0005]

[0006] This method uses methyl hydroxyacetate as the starting material, and synthesizes the target compound through condensation, hydroxyl protection, formylation, ring closure, chlorination and other steps. The raw material is easy to obtain, but due to the selectivity problem of methyl hydrazine ring closure, the ratio of product and isomer is about 1:3, which is not easy to separate, and the product has excellent water solubility, making purification extremely difficult, with low yield and poor industrialization prospect.

[0007] Literature RSC Adv. , 2022, 12 , 34808 reports a similar methyl hydrazine ring closure method, and the synthesis route is as follows:

[0008]

[0009] Compared with the previous method, this method has fewer steps, but still faces the problems of poor selectivity of ring closure reaction, difficult purification and low yield, which is not suitable for industrial amplification.

[0010] Chinese patent CN115466227A reported that ethyl glycolate was used for amidation with methylhydrazine, ring closure with formamidine acetate, and finally chlorination to obtain 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride.

[0011] The process selects ethyl glycolate as the starting material, and the water solubility of the raw material and the intermediate is good, so that the process has high operation difficulty in the separation and purification process, cannot effectively remove impurities, has low production efficiency, and takes a long time for single batch production, which seriously affects the production capacity; in addition, the material cost of this route is relatively high, which greatly affects the market competitiveness of the product. Therefore, it is of great practical significance and economic value to develop a new synthetic process. SUMMARY

[0012] The purpose of the present application is to provide a preparation method of an intermediate of nesperdine, which has mild reaction conditions, simple operation, high yield, low cost and is suitable for industrial production.

[0013] The technical scheme adopted by the present application to solve the technical problems is:

[0014] A preparation method of an intermediate of nesperdine, comprising the following steps:

[0015] (1) oxalic acid dimethyl ester is used as a starting raw material, and amine ester exchange reaction is carried out with methylhydrazine to obtain 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester;

[0016] (2) 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester, triethyl orthoformate and ammonium formate are subjected to ring closure reaction to obtain 1-methyl-1 H -1,2,4-triazole-3-methyl formate;

[0017] (3) 1-methyl-1 H -1,2,4-triazole-3-methyl formate is reduced by a reducing agent to obtain (1-methyl-1 H -1,2,4-triazole-3-yl)methanol;

[0018] (4) (1-methyl-1 H -1,2,4-triazole-3-yl)methanol is chlorinated by a chlorinating agent to obtain 3-(chloromethyl)-1-methyl-1 H -1,2,4-triazole hydrochloride.

[0019] In step (1), the solvent is selected from one or more of methanol, ethanol, dichloromethane, acetonitrile, and toluene.

[0020] In step (1), the molar ratio of dimethyl oxalate: methylhydrazine = 1:1.0-3.0, the reaction temperature of the amine ester exchange reaction is controlled at 0-30℃, and the reaction time is 2-3 hours. Preferably, the reaction temperature of the amine ester exchange reaction is controlled at 0-5℃.

[0021] In step (2), the solvent used is selected from one or more of toluene, N,N-dimethylformamide, dioxane, acetonitrile.

[0022] In step (2), the molar ratio of 2-(2-methylhydrazino)-2-oxoethyl acetate: triethyl orthoformate: ammonium formate = 1:1.0-2.5:1.0-5.0, and the reaction temperature of the ring closure reaction is controlled at 80-120℃.

[0023] In step (3), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride, borane tetrahydrofuran.

[0024] In step (3), the solvent used for the reduction reaction is one or more of anhydrous ethanol, anhydrous methanol, anhydrous tetrahydrofuran, and the reaction temperature of the reduction reaction should be controlled at 0-30℃. Preferably, the reaction temperature is 0-5℃.

[0025] In step (4), the chlorinating agent is selected from one or more of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride.

[0026] In step (4), the molar ratio of (1-methyl-1H-1,2,4-triazol-3-yl)methanol: chlorinating agent = 1:1.5-3.0, and the reaction temperature of the chlorination is controlled at 25-30℃. H

[0027] The method for preparing 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride according to the present application has the advantages that the raw materials are simple and easy to obtain, the price is lower than that of the method reported in the literature, the operation is simple, the production capacity is greatly improved, the material consumption is significantly reduced, the ring closure reaction is improved, and the problem of poor selectivity of methylhydrazine ring closure reaction is solved.

[0028] The present application uses dimethyl oxalate as a raw material, and through four steps of amidation, ring closure, reduction, and chlorination, the target product with a purity of greater than 99.6% is obtained, and the total yield reaches 54.7%. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is the nuclear magnetic resonance spectrum of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V).

[0030] Figure 2 is the nuclear magnetic resonance spectrum of 2-(2-methylhydrazino)-2-oxoethyl acetate (II). ​

[0031] Figure 3 is 1-methyl-1 H The nuclear magnetic spectrum of methyl 1,2,4-triazole-3-carboxylate (III) is shown in the following. DETAILED DESCRIPTION

[0032] The technical solutions of the present application are further described in detail below through specific examples.

[0033] In the present application, the raw materials and equipment used, unless specified, can be purchased from the market or commonly used in the art. The methods in the following examples, unless specified, are conventional methods in the art.

[0034] The synthetic route of the present application is as follows:

[0035] Step 1: obtaining methyl 2-(2-methylhydrazino)-2-oxoacetate (II) from dimethyl oxalate (I) through amine ester exchange reaction

[0036]

[0037] Step 2: preparing 1-methyl-1 H methyl 1,2,4-triazole-3-carboxylate (III) from methyl 2-(2-methylhydrazino)-2-oxoacetate (II) and triethyl orthoformate

[0038]

[0039] Step 3: obtaining (1-methyl-1H-1,2,4-triazol-3-yl)methanol (IV) from 1-methyl-1 H methyl 1,2,4-triazole-3-carboxylate (III) through reduction

[0040]

[0041] Step 4: obtaining 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V) from (1-methyl-1H-1,2,4-triazol-3-yl)methanol (IV) through chlorination.

[0042] .

[0043] Example 1: synthesis of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V)

[0044] First step: In a 500 mL three-necked flask with mechanical stirring and thermometer, add dimethyl oxalate 50 g (0.423 mol, 1.0 eq), add dichloromethane 300 mL to stir and dissolve, control the temperature at 20-25℃. Slowly drop 40% methylhydrazine aqueous solution 73.2 g (0.635 mol, 1.5 eq), keep the reaction for 2-3 h after dropping, stand and separate, the lower organic phase is dehydrated under reduced pressure, add n-heptane 150 mL to make a slurry, filter to get white solid 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester (II) (NMR spectrum is shown in Figure 2 ) 48.9 g, HPLC purity 97.1%, yield 89.2%.

[0045] Second step: In a 1000 mL three-necked flask with mechanical stirring and thermometer, add toluene 320 mL, add 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester (II) 32.0 g (0.242 mol, 1.0 eq), add triethyl orthoformate 43.07 g (0.290 mol, 1.2 eq), add ammonium formate 45.8 g (0.727 mol, 3.0 eq), reflux for 12 h until the reaction is complete. Cool to room temperature, add water 250 mL to stir and dissolve, stand and separate, spin dry the upper organic phase to get oil, add ethanol 64 mL to heat and dissolve, cool to 0-5℃ to crystallize, filter to get white solid 1-methyl-1 H -methyl-1,2,4-triazole-3-carboxylic acid methyl ester (III) (NMR spectrum is shown in Figure 2 ) 24.8 g, HPLC purity 99.1%, yield 72.6%.

[0046] Third step: In a 500 mL three-necked flask with mechanical stirring and thermometer, add 1-methyl-1 H -methyl-1,2,4-triazole-3-carboxylic acid methyl ester (III) 30.5 g (0.216 mol, 1.0 eq) and 150 mL anhydrous ethanol, add sodium borohydride 12.3 g (0.324 mol, 1.5 eq) in portions, control the temperature at 20-25℃, add for 1 h until the reaction is complete, quench the reaction by adding 2M dilute hydrochloric acid, adjust pH to 6-7, dehydrate to dryness under reduced pressure, add 120 mL saturated sodium bicarbonate solution, 480 mL dichloromethane, stir and separate, spin dry the organic phase to get oil compound (1-methyl-1H-1,2,4-triazol-3-yl)methanol (IV) 21.6 g, HPLC purity 97.9%, yield 88.3%.

[0047] Fourth step: In a 500 mL three-necked flask with mechanical stirring and thermometer, add (1-methyl-1H-1,2,4-triazol-3-yl)methanol (Ⅳ) 21.3 g (0.191 mol, 1.0 eq), add DCM 100 mL, drop chlorosulfoxide 28.9 g (0.286 mol, 1.5 eq), 25-30 °C reaction for 24 h, control reaction complete, reduce pressure to dryness, add ethyl acetate 150 mL, 2 h, filter, vacuum dry white solid 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (Ⅴ) (NMR spectrum see Figure 1 ) 26.4 g, HPLC purity 99.5%, yield 82.3%.

[0048] Example 2: Synthesis of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (Ⅴ)

[0049] First step: In a 500 mL three-necked flask with mechanical stirring and thermometer, add dimethyl oxalate 50 g (0.423 mol, 1.0 eq), add dichloromethane 300 mL, stir to dissolve, cool to 0-5 °C. Slowly drop 40% methylhydrazine aqueous solution 73.2 g (0.635 mol, 1.5 eq), drop to keep reaction for 2-3 h, stand to separate, lower organic phase reduce pressure to dryness, add n-heptane 150 mL, filter to get white solid (Ⅱ) 51 g, purity 98.8%, yield 91.3%.

[0050] Second step: In a 1000 mL three-necked flask with mechanical stirring and thermometer, add acetonitrile 320 mL, add 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester (Ⅱ) 32.0 g (0.242 mol, 1.0 eq), add triethyl orthoformate 43.07 g (0.290 mol, 1.2 eq), add ammonium formate 45.8 g (0.727 mol, 3.0 eq), reflux reaction for 12 h, control reaction complete. Reduce pressure to dryness, add water 250 mL, add dichloromethane 250 mL, stir to dissolve, stand to separate, lower organic phase spin dry to get oil, add ethanol 64 mL, heat to dissolve, cool to 0-5 °C, filter to get white solid (Ⅲ) 21.1 g, HPLC purity 99.2%, yield 61.8%.

[0051] Third step: In a 500 mL three-necked flask with mechanical stirring and thermometer, replace with nitrogen, add lithium aluminum hydride 8.2 g (0.216 mol, 1.0 eq), add 100 mL anhydrous tetrahydrofuran, 1-methyl-1 H-1,2,4-triazole-3-carboxylic acid methyl ester (III) 30.5 g (0.216 mol, 1.0 eq) was dissolved in 100 mL of tetrahydrofuran and slowly added to the reaction bottle, controlling the temperature at 0-10°C, and the reaction was allowed to proceed for 1 h after the addition was completed. After the reaction was determined to be complete, 8.2 g of water was added dropwise, followed by the addition of 8.2 g of a 15% sodium hydroxide solution and 24.6 g of water. The temperature was controlled at 0-20°C, and the organic phase was filtered through diatomite. The oil obtained after the organic phase was dried by rotary evaporation was (IV) 23.5 g, with a purity of 98.7% and a yield of 96.2%.

[0052] Fourth step: In a 500 mL three-necked flask with mechanical stirring and a thermometer, (1-methyl-1H-1,2,4-triazol-3-yl)methanol (IV) 21.3 g (0.191 mol, 1.0 eq) was added, toluene 100 mL was added, and phosphorus oxychloride 43.7 g (0.286 mol, 1.5 eq) was added dropwise. The reaction was allowed to proceed at 75-80°C for 4-5 h, and the reaction was determined to be complete. The solvent was removed under reduced pressure until dryness, dichloromethane 150 mL was added, and saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH to 7-8. The organic phase was separated, dried with 20 g of anhydrous sodium sulfate, and then salted with 4M hydrochloric acid in ethyl acetate (85.8 mL, 1.2 eq). The white solid obtained after filtration and vacuum drying was 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V) 25.6 g, with a purity of 99.8% and a yield of 81.1%.

[0053] Example 3: Synthesis of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V)

[0054] First step: In a 500 mL three-necked flask with mechanical stirring and a thermometer, dimethyl oxalate 50 g (0.423 mol, 1.0 eq) was added, dichloromethane 300 mL was added to dissolve the clear solution, and the solution was cooled to 0-5°C. 40% methylhydrazine aqueous solution 97.6 g (0.846, 2.0 eq) was slowly added dropwise, and the reaction was allowed to proceed for 2-3 h after the addition was completed. After standing and separation, the lower organic phase was removed under reduced pressure, and n-heptane 150 mL was added to the slurry. The white solid obtained after filtration was (II) 51.7 g, with a purity of 98.9% and a yield of 92.5%.

[0055] Second step: in a 1000 mL three-necked flask with mechanical stirring and thermometer, add toluene 320 mL, add 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester (II) 32.0 g (0.242 mol, 1.0 eq), add triethyl orthoformate 86.14 g (0.580 mol, 2.4 eq), add ammonium formate 45.8 g (0.727 mol, 3.0 eq), reflux for 12 h, control reaction completion. Reduce pressure to dryness, add water 250 mL, add dichloromethane 250 mL, stir to dissolve, stand to separate, spin dry the lower organic phase to obtain an oil, add ethanol 64 mL, heat to dissolve, cool to 0-5 ℃ to crystallize, filter to obtain white solid (III) 19.8 g, HPLC purity 99.2%, yield 57.9%.

[0056] Third step: in a 500 mL three-necked flask with mechanical stirring and thermometer, add 1-methyl-1 H -1,2,4-triazole-3-methyl formate (III) 30.5 g (0.216 mol, 1.0 eq) and 150 mL anhydrous ethanol, add sodium borohydride 16.4 g (0.432, 2.0 eq) in batches, control temperature 20-25 ℃, add completely for 1 h, control reaction completion, add 2M dilute hydrochloric acid dropwise to quench the reaction, adjust pH=6-7, reduce pressure to dryness, add 120 mL saturated sodium bicarbonate solution, 480 mL dichloromethane, stir to separate, spin dry the organic phase to obtain oil compound (IV) 23.2 g, HPLC purity 98.2%, yield 94.9%.

[0057] Fourth step: in a 500 mL three-necked flask with mechanical stirring and thermometer, add (1-methyl-1H-1,2,4-triazol-3-yl)methanol (IV) 21.3 g (0.191 mol, 1.0 eq), add dichloromethane 100 mL, add thionyl chloride 45.4 g (0.382 mol, 2.0 eq) dropwise, 25-30 ℃ for 24 h, control reaction completion, reduce pressure to dryness, add dichloromethane 150 mL to remove, add ethyl acetate 150 mL, beat for 2 h, filter, vacuum dry to obtain white solid 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (V) 26.8 g, purity 99.6%, yield 84.7%.

[0058] The above-described embodiments are only a preferred scheme of the present application, and do not limit the present application in any form, and other variants and modifications are possible without exceeding the technical scheme recited in the claims.

Claims

1. A process for the preparation of an intermediate of Elbasvir, characterized in that, The method comprises the following steps: (1) oxalic acid dimethyl ester is used as a starting material to react with methylhydrazine to obtain 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester through an amine-ester exchange reaction; (2) 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester and triethyl orthoformate and ammonium formate via a ring closure reaction to give 1-methyl-1 H - 1,2,4-triazole-3-carboxylic acid methyl ester; (3) 1 -methyl- 1 H -1,2,4-triazole-3-carboxylic acid methyl ester is reduced with a reducing agent to give (1 -methyl- 1 H -1,2,4-triazol-3-yl)methanol; (4) (1 -methyl- 1 H -1,2,4-triazol-3-yl)methanol is chlorinated with a chlorinating reagent to give 3-(chloromethyl)- 1 -methyl- 1 H -1,2,4-triazole hydrochloride.

2. The method of claim 1, wherein: In step (1), the solvent is selected from one or more of methanol, ethanol, dichloromethane, acetonitrile and toluene.

3. The method of claim 1, wherein: In step (1), the molar ratio of oxalic acid dimethyl ester to methylhydrazine is 1:1.0-3.0, the reaction temperature of the amine-ester exchange reaction is controlled at 0-30 ℃, and the reaction time is 2-3 hours.

4. The method of claim 1, wherein: In step (2), the solvent is selected from one or more of toluene, N,N-dimethylformamide, dioxane and acetonitrile.

5. The method of claim 1, wherein: In step (2), the molar ratio of 2-(2-methylhydrazino)-2-oxoacetic acid methyl ester to triethyl orthoformate to ammonium formate is 1:1.0-2.5:1.0-5.0, and the reaction temperature of the ring closure reaction is controlled at 80-120 ℃.

6. The method of claim 1, wherein: In step (3), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride and borane tetrahydrofuran.

7. The method of claim 1, wherein: In step (3), the solvent for the reduction reaction is one or more of anhydrous ethanol, anhydrous methanol and anhydrous tetrahydrofuran, and the reaction temperature of the reduction reaction should be controlled at 0-30 ℃.

8. The method of claim 1, wherein: In step (4), the chlorinating agent is selected from one or more of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride.

9. The method of claim 1, wherein: In step (4), (1-methyl-1 H -1,2,4-triazol-3-yl)methanol: molar ratio of chlorinating reagent = 1: 1.5-3.0, the reaction temperature of chlorination is controlled at 25-30°C.

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