CN110204505B - Preparation process of (S) -3-benzyloxycarbonyl-4-isopropyl-2, 5-oxazolidinedione - Google Patents

Abstract

The invention provides a preparation process of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione, (S)-3-benzyloxycarbonyl-4-isopropyl-2 , 5-oxazolidinedione can be used as valganciclovir hydrochloride intermediate, and it comprises the following operations: get L-valine starting material to react with benzyl chloroformate, generate N-benzyloxycarbonyl-L-valanciclovir N-benzyloxycarbonyl-L-valine reacts with N,N-carbonyldiimidazole (CDI) to generate (S)-3-benzyloxycarbonyl-4-isopropyl-2,5- Oxazolidinediones. The preparation process is simple, easy to purify, stable in process, controllable in quality, greatly improved in product yield, does not cause environmental pollution, and is suitable for large-scale industrial production.

Description

Preparation process of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

technical field

The invention relates to a preparation process of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione, which belongs to the field of chemical synthesis and production.

Background technique

Valganciclovir hydrochloride (valganciclovir hydrochloride) (formula 4) is a kind of oral anti-cytomegalovirus infection medicine researched and developed by Roche Company of Switzerland, the paper " the development of valganciclovir hydrochloride that Zhao Shikui et al. Synthesis", introduced a hydroxyl group of the ganciclovir derivative N, O-di(trityl) ganciclovir (formula 5) and (S)-3-benzyloxycarbonyl- 4-isopropyl-2,5-oxazolidinedione (Formula 3) is condensed, and the trityl protecting group is removed by trifluoroacetic acid in 2,2,2-trifluoroethanol, and then acidified, Hydrogen reduction to obtain valganciclovir hydrochloride.

Currently, the preparation of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione (Formula 3) is carried out in two steps according to the reaction scheme 2, the first step: L-valline Acid (formula 7) and phosgene or triphosgene to obtain (S)-4-isopropyloxazole-2,5-dione (formula 6), the second step: (S)-4-isopropyloxazole -2,5-diketone (Formula 6) reacts with benzyl chloroformate (Formula 8) in an alkaline environment to obtain (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazole Alkanediones (Formula 3). Among them, the raw material phosgene in the first step is a highly toxic gas, and triphosgene will also produce phosgene during the reaction process, which is easy to cause environmental pollution; the condensation reaction in the second step must use the hydrogen chloride generated in the alkali absorption reaction to promote the reaction. , but (S)-4-isopropyloxazole-2,5-dione (Formula 6) and (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione (Formula 3) is unstable in an alkaline environment and will allow (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione (formula 3) to open the ring, in order to reduce The decomposition of raw materials and products requires a reaction below -25°C and only N-methylmorpholine can be used as an acid-binding agent. The reported yield of this method can only reach 50%. Cause this step reaction waste much, be difficult to purify, the shortcoming of high cost.

Reaction route:

US 5359086 uses N,N-carbonyldiimidazole (formula 9) as a cyclizing agent, with N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine as raw material, at the reaction temperature Prepare N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxy anhydride at -5～0°C.

CN106831630A uses N,N-carbonyldiimidazole (formula 9) as a cyclizing agent, with L-alanine (formula 10), L-tyrosine, L-glutamic acid-γ-benzyl ester or L-ε-three Fluoroacetyl-lysine is raw material, generates L-alanine-N-anhydride (formula 11), 5-bean ester-N-carboxyl anhydride, N-(4-( 2,5-dioxo-4-oxazolidinyl)butyl)-2,2,2-trifluoroacetamide or (4S)-4-[(4-hydroxyphenyl)methyl]-2, 5-Oxazolidinedione.

But at present, the above reaction has not been used in the preparation of valganciclovir hydrochloride intermediate (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione (Formula 3).

The present invention finds in preliminary experiments that if the following hypothetical reaction process is used directly, the target product cannot be obtained.

After carrying out many tests to experimental conditions etc., it is found that the problem must be solved by heating in a neutral and slightly alkaline environment, but (S)-4-isopropyloxazole-2,5-dione (formula 6 ) is easy to open the ring in an alkaline environment, and the combination of solvent and weak base has a great influence on the yield.

Contents of the invention

In order to overcome the shortcoming that exists in the prior art, the object of the present invention is to provide the preparation technology of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione, will have to The reaction of benzyl chloroformate, which can only be carried out in a neutral environment, is carried out first, and then the base-labile (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione is allowed to Prepared under weakly alkaline environment. The scheme has the characteristics of high safety, less environmental pollution, simple reaction operation, high product yield, low production cost, and is suitable for large-scale industrial production.

The invention provides the preparation technology of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione, which comprises the following operations:

S1. get L-valine and benzyl chloroformate to react under alkaline conditions to generate N-benzyloxycarbonyl-L-valine, and the synthetic method comprises dissolving L-valine in sodium hydroxide solution, During the reaction, add benzyloxycarbonyl chloride or 1,4-dioxane solution containing benzyl chloroformate dropwise, and react at normal temperature;

S2. Extraction and separation, discarding the organic phase, retaining the water, adjusting the pH of the water to acidity, and then extracting with a reaction solvent, taking the organic phase and transferring it to a kettle under a nitrogen protection environment to mix with an alkaline accelerator and cooling, then Add dropwise the reaction solvent containing N,N-carbonyldiimidazole, react for 6-14 hours in a neutral to slightly alkaline environment and reaction temperature, and generate (S)-3-benzyloxycarbonyl-4-isopropyl-2 , The reaction solvent of 5-oxazolidinedione.

The neutral to weakly alkaline environment described in the present invention is relative to the pH of the solution measured by a calibrated pH meter = 7. When the measured pH of the reaction solution is greater than 7, the neutral to weakly alkaline environment described in the present invention is satisfied.

In a specific embodiment of the present invention, the pH of the solution used in step S2 is 7.3-9.0.

In a specific embodiment of the present invention, the reaction solvent in step S2 is selected from one or both of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, formamide, 1,4-dioxane, and acetonitrile and combinations of the above.

In a specific embodiment of the present invention, preferably, the reaction solvent in step S2 is selected from the combination of dichloromethane and tetrahydrofuran, N,N-dimethylformamide or dichloromethane and acetonitrile, N,N-dimethylformamide combination of amides.

In a specific embodiment of the present invention, further, when the reaction solvent in step S2 is a combination of dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, the reaction temperature is 0-25°C.

In a specific embodiment of the present invention, further, when the reaction solvent in step S2 is a combination of dichloromethane, acetonitrile and N,N-dimethylformamide, the reaction temperature is 0-40°C.

In a specific embodiment of the present invention, preferably, the alkaline promoter in step S3 is at least one selected from 4-dimethylaminopyridine, pyridine, and piperidine.

In a specific embodiment of the present invention, further, the alkaline promoter in step S3 is 4-dimethylaminopyridine.

In a specific embodiment of the present invention, preferably, the molar ratio of the alkaline accelerator to N-benzyloxycarbonyl-L-valine in step S3 is (0.05-0.2):1.

In a specific embodiment of the present invention, preferably, the molar ratio of N-benzyloxycarbonyl-L-valine to N,N-carbonyldiimidazole in step S3 is 1: (1-2).

Preferably, after the reaction in step S2 is completed, a purification step is also included:

Add hydrogen chloride tetrahydrofuran solution or hydrogen chloride ethyl acetate solution dropwise to the reaction solvent containing (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione or pass through dry hydrogen chloride gas to neutralize And the alkaline substances in the reaction solution, so that the entire system is kept in an acidic environment during the post-treatment process to protect the product;

Add a good solvent to (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione and filter to remove the salt generated in the reaction, and then add a poor solvent to the filtrate to filter to remove impurities. Precipitation under liquid freezing;

The poor solvent is selected from at least one of methyl tert-butyl ether, toluene, n-hexane, sherwood oil;

Described good solvent is selected from at least one in methylene chloride, ethyl acetate;

The impurity refers to the impure components included in the target compound, including but not limited to imidazole, a by-product produced by the reaction, and incompletely reacted reaction materials.

Preferably, step S2 also includes a purification step of N-benzyloxycarbonyl-L-valine before using the reaction solvent for extraction: extracting the aqueous liquid with the reaction solvent, drying the extraction layer, and then distilling the reaction solvent under reduced pressure to obtain N- Benzyloxycarbonyl-L-valine;

Or adjust the acidity of the water solution to crystallize and dry to obtain N-benzyloxycarbonyl-L-valine.

Preferably, step S2 further includes a step of removing impurities from the organic phase after extraction with a reaction solvent: washing with saturated brine, drying with anhydrous sodium sulfate, and filtering to obtain an anhydrous, salt-free organic phase.

Based on the above-mentioned same principle, the present invention also provides a method for synthesizing N-benzyloxycarbonyl-α-amino acid-NCA with α-amino acid as raw material, characterized in that it comprises the following steps

Take the α-amino acid shown in formula 10, react with benzyl chloroformate under alkaline conditions to generate the compound of formula 12, then separate the compound of formula 12, turn it into the reaction solvent under acidic conditions, and combine with the basic promoter, React with N,N-carbonyldiimidazole in a neutral slightly alkaline environment and reaction temperature to generate the compound of formula 13, the α-amino acid includes: glycine, alanine, valine, leucine, Isoleucine, Phenylalanine, Tryptophan, Serine, Tyrosine, Cysteine, Methionine, Asparagine, Glutamine, Threonine, Aspartic Acid, Glutamic Acid, Lysine acid, arginine, histidine.

The present invention has the following technical effects:

When using any of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, formamide, 1,4-dioxane, and acetonitrile as the reaction solvent, dichloromethane and tetrahydrofuran, N,N-di The combination of methylformamide or dichloromethane with acetonitrile and N,N-dimethylformamide gave the highest yield of the target compound.

When using pyridine or piperidine as the basic accelerator, the yield of the target compound is lower than that of 4-dimethylaminopyridine as the basic accelerator.

The yield of the target compound is higher when the molar ratio of basic accelerator to N-benzyloxycarbonyl-L-valine is (0.05-0.2):1. With the increase of the amount of alkaline accelerator, the yield of the target product did not increase, and when the molar ratio exceeded 0.2, the yield of the target product decreased instead.

In this preparation process, the benzyl chloroformate reaction, which must be carried out in an alkaline environment, is carried out first, and then the (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazole which is unstable to alkali Alkanediones are prepared in a neutral to slightly alkaline environment. The overall process has high safety, less environmental pollution, and the reaction is simple and easy to operate, avoiding (S)-3-benzyloxycarbonyl-4-isopropyl-2,5 - Oxazolidinedione ring-opening under alkaline environment, high product yield, low production cost, suitable for large-scale industrial production.

Description of drawings

Fig. 1 is the nuclear magnetic spectrum of the white solid that embodiment 1 of the present invention obtains;

Fig. 2 is the NMR spectrum of the white powdery solid obtained in Example 2 of the present invention.

Detailed ways

The above-mentioned content of the present invention will be further described in detail below through the form of specific embodiments. However, it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

The synthesis of embodiment 1 N-benzyloxycarbonyl-L-valine

Get 1.17Kg (10mol) of L-valine, 5L of sodium hydroxide solution of 2mol/L, 1.06Kg (10mol) sodium carbonate and add in the 20L reactor, start stirring, after the L-valine dissolves completely, dissolve the solution When the temperature dropped below 0°C, 5L of 1,4-dioxane solution containing 2.05Kg (12mol) of benzyl chloroformate was added dropwise, and the temperature of the solution was kept below 20°C during the dropping process. After the reaction, the reaction solution was extracted with 2.5L of dichloromethane, the organic phase was discarded, the water phase was cooled to below 10°C, concentrated hydrochloric acid was added dropwise until the pH = 2, and then stirred at 10°C for 30min, a large amount of white solid was precipitated, and filtered with suction , the filter residue was washed with water, and the white solid was dried in a vacuum oven to obtain 2.35Kg of white N-benzyloxycarbonyl-L-valine, with a yield of 93.7%, a purity of 99.6% (HPLC), and an optical rotation of -4.1 °(C=2, glacial acetic acid, T=20°C); NMR test results are shown in Figure 1, 1H NMR (400MHz, DMSO) δ12.59(s, 1H), 7.50(d, J=8.5Hz, 1H ),7.41–7.27(m,5H),5.04(s,2H),3.88(dd, J=8.5,6.0Hz,1H),2.05(dq,J=13.4,6.7Hz,1H),0.89(t, J=6.8Hz, 6H).

Advantages of the method in this example: adding 1,4-dioxane can make the reaction more complete and reduce the consumption of benzyl chloroformate; the product that is separated out after using dichloromethane to extract impurities can be dried and directly used in the next step The reaction was purified without further recrystallization. The precipitated product after acid adjustment can be directly extracted and dried with dichloromethane and used in the next reaction without purification.

The synthesis of embodiment 2 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Get 1.17Kg (10mol) of L-valine, 5L of sodium hydroxide solution of 2mol/L, 1.06Kg (10mol) sodium carbonate and add in the 20L reactor, start stirring, after the L-valine dissolves completely, dissolve the solution When the temperature dropped below 0°C, 5L of 1,4-dioxane solution containing 2.05Kg (12mol) of benzyl chloroformate was added dropwise, and the temperature of the solution was kept below 20°C during the dropping process. After the reaction is complete, the reaction solution is extracted with 2.5 L of dichloromethane, the organic phase is discarded, the water phase is cooled to below 10°C, concentrated hydrochloric acid is added dropwise until pH=2, the mixture is extracted 3 times with 3 L of dichloromethane, and the organic phases are combined. The organic phase was washed with 3L saturated brine, dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was transferred to a 20L kettle protected with nitrogen, and 122g (1mol) of 4-dimethylaminopyridine, N,N-dimethylformamide After stirring at 2L room temperature for 30min, lower the temperature of the solution to 0-5°C and slowly add N, N-carbonyldiimidazole 1.78Kg (11mol) in 4L tetrahydrofuran solution dropwise. After the completion of the reaction, keep the solution at 40°C for 5 hours. After the reaction is complete, add 1 L of 10 mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 4 L of dichloromethane to the residue, heat to reflux for 30 min, filter while it is hot, and add 15 L of dichloromethane to the filtrate. After toluene, stir at room temperature for 30min and then filter, the filtrate was cooled to -10°C and stirred for 2h, a large amount of white solid precipitated, filtered with suction, the filter residue was washed with cold toluene, and dried in vacuo to obtain a white powdery solid (S)-3-benzyloxycarbonyl- 4-isopropyl-2,5-oxazolidinedione 2.39Kg, yield 86.4%, purity 99.3% (HPLC), optical rotation +60.4° (C=1, THF, T=25°C); The NMR test results are shown in Figure 2, 1H NMR (400MHz, DMSO) δ7.51–7.32 (m, 5H), 5.40–5.28 (m, 2H), 4.72 (d, J=3.6Hz, 1H), 2.47– 2.37(m, 1H), 1.07(d, J=7.1Hz, 3H), 0.85(d, J=6.9Hz, 3H).

The synthesis of embodiment 3 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Get 1.17Kg (10mol) of L-valine, 5L of sodium hydroxide solution of 2mol/L, 1.06Kg (10mol) sodium carbonate and add in the 20L reactor, start stirring, after the L-valine dissolves completely, dissolve the solution When the temperature dropped below 0°C, 5L of 1,4-dioxane solution containing 2.05Kg (12mol) of benzyl chloroformate was added dropwise, and the temperature of the solution was kept below 20°C during the dropping process. After the reaction is complete, the reaction solution is extracted with 2.5 L of dichloromethane, the organic phase is discarded, the water phase is cooled to below 10°C, concentrated hydrochloric acid is added dropwise until pH=2, the mixture is extracted 3 times with 3 L of dichloromethane, and the organic phases are combined. The organic phase was washed with 3L saturated brine, dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was transferred to a 20L kettle protected with nitrogen, and 122g (1mol) of 4-dimethylaminopyridine, N,N-dimethylformamide After stirring at 2L room temperature for 30min, lower the temperature of the solution to 0-5°C and slowly add N, N-carbonyldiimidazole 1.78Kg (11mol) in 4L of acetonitrile dropwise. After the completion of the reaction, keep the solution at 40°C for 5 hours. After the reaction is completed, add 1 L of 10 mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 4 L of dichloromethane to the residue, heat to reflux for 30 min, filter while it is hot, and add 20 L of dichloromethane to the filtrate. After methyl tert-butyl ether, stir at room temperature for 30 minutes and then filter, cool the filtrate to -10°C and stir for 2 hours, a large amount of white solid precipitates, filter with suction, wash the filter residue with cold methyl tert-butyl ether, and dry in vacuo to obtain a white powdery solid (S)-3-Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 2.36Kg, the yield is 85.1%, the purity is 99.2% (HPLC), the optical rotation value is +59.8 ° (C= 1, THF, T=25°C);

The synthesis of embodiment 4 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of tetrahydrofuran, and 31g (0.25mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen After stirring at room temperature for 30 minutes, the temperature of the solution was lowered to 0-5 and slowly added dropwise N, N-carbonyldiimidazole 891g (5.5mol) dissolved in 2L tetrahydrofuran solution, and the temperature of the solution was kept below 20°C during the dropping process. After dropping, keep the solution at 20-25°C for 6 hours. After the reaction is completed, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 2L of dichloromethane to the residue, heat and reflux for 30min, and filter while hot. After adding 5L of n-hexane to the mixture, stir at room temperature for 30min and then filter, the filtrate is cooled to -10°C and stirred for 2h, a large amount of white solid is precipitated, filtered with suction, the filter residue is washed with cold methyl tert-butyl ether, and dried in vacuum to obtain a white powdery solid ( S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 1.22Kg, yield 88.3%, purity 99.5% (HPLC), optical rotation +60.1° (C=1 , THF, T=25°C);

The synthesis of embodiment 5 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of tetrahydrofuran, and 122g (1mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen , after stirring at room temperature for 30 minutes, lower the solution temperature to 0-5 and slowly add N, N-carbonyldiimidazole 891g (5.5mol) dissolved in 2L tetrahydrofuran solution, the temperature of the solution during the dropping process is kept below 20°C, drop After the completion of the reaction, keep the solution at 20-25°C for 6 hours. After the reaction is complete, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 2L ethyl acetate to the residue, heat and reflux for 30min, and filter while hot. After adding 5L of petroleum ether, stir at room temperature for 30min and then filter. The filtrate is cooled to -10°C and stirred for 2h. A large amount of white solid is precipitated, which is filtered with suction. The filter residue is washed with cold methyl tert-butyl ether and dried under vacuum to obtain a white powdery solid (S )-3-Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 1.19Kg, yield 85.9%, purity 99.2% (HPLC), optical rotation +60.3° (C=1, Tetrahydrofuran, T=25°C)

The synthesis of embodiment 6 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of tetrahydrofuran, and 153g (1.25mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen After stirring at room temperature for 30 minutes, the temperature of the solution was lowered to 0-5 and slowly added dropwise N, N-carbonyldiimidazole 891g (5.5mol) dissolved in 2L tetrahydrofuran solution, and the temperature of the solution was kept below 20°C during the dropping process. After dropping, keep the solution at 20-25°C for 6 hours. After the reaction is completed, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 2L of dichloromethane to the residue, heat and reflux for 30min, and filter while hot. After adding 7.5L of toluene, stirred at room temperature for 30min and then filtered, the filtrate was cooled to -10°C and stirred for 2h, a large amount of white solid was precipitated, filtered with suction, the filter residue was washed with cold toluene, and dried in vacuum to obtain a white powdery solid (S)-3- Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 809g, yield 58.4%, purity 98.3% (HPLC), optical rotation +62.0° (C=1, THF, T=25 °C)

The synthesis of embodiment 7 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of tetrahydrofuran, and 79g (1mol) of pyridine into a 20L kettle protected by nitrogen, and stir at room temperature for 30min Finally, lower the temperature of the solution to 0-5 ℃ and slowly add a solution of N, N-carbonyldiimidazole 1.62Kg (10mol) dissolved in 2L tetrahydrofuran. The temperature of the solution during the dropping process is kept below 20°C. After dropping, keep the solution React at 30-40°C for 12 hours. After the reaction is complete, add 500ml of 10mol/L ethyl hydrogen chloride solution dropwise and recover the solution. Add 2L of dichloromethane to the residue, heat to reflux for 30min, and filter while it is hot. Add 10L of methyl alcohol to the filtrate. After methyl tert-butyl ether, stirred at room temperature for 30min and then filtered, the filtrate was cooled to -10°C and stirred for 2h, a large amount of white solid was precipitated, filtered with suction, the filter residue was washed with cold methyl tert-butyl ether, and dried in vacuo to obtain a white powdery solid ( S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 0.93Kg, the yield is 71.7%, the purity is 99.2% (HPLC), the optical rotation value is +61.1° (C=1 , THF, T=25°C).

The synthesis of embodiment 8 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of tetrahydrofuran, and 85g (1mol) of piperidine into a 20L kettle protected by nitrogen, and stir at room temperature After 30 minutes, lower the temperature of the solution to 0-5 ℃ and slowly add a solution of N,N-carbonyldiimidazole 1.22Kg (7.5mol) dissolved in 2L tetrahydrofuran dropwise. The solution was kept at 40°C for 10 hours. After the reaction was completed, 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution was added dropwise, and the solution was recovered. 2L of dichloromethane was added to the residue, heated to reflux for 30min, filtered while hot, and 10L of methyl tertiary Butyl ether, stirred at room temperature for 30 minutes and then filtered, the filtrate was cooled to -10°C and stirred for 2 hours, a large amount of white solid precipitated, filtered with suction, the filter residue was washed with cold methyl tert-butyl ether, and dried in vacuum to obtain a white powdery solid (S)- 3-Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 1.02Kg, yield 73.5%, purity 98.8% (HPLC), optical rotation +59.8° (C=1, THF, T = 25°C).

The synthesis of embodiment 9 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 1L of N,N-dimethylformamide, 4L of acetonitrile, and 92g (0.75mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen After stirring at room temperature for 30 minutes, lower the temperature of the solution to 0-5 ℃ and slowly add N, N-carbonyldiimidazole 891g (5.5mol) in 2L of acetonitrile dropwise, and keep the temperature of the solution below 20°C during the dropping process. After dropping, keep the solution at 40°C for 8 hours. After the reaction is complete, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise, recover the solution, add 2L of dichloromethane to the residue, heat and reflux for 30min, filter while hot, and add 10L of methyl tert-butyl ether, stirred at room temperature for 30 minutes and then filtered, the filtrate was cooled to -10°C and stirred for 2 hours, a large amount of white solid was precipitated, filtered with suction, the filter residue was washed with cold methyl tert-butyl ether, dried under vacuum to obtain a white powdery solid (S)-3-Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 1.2Kg, the yield is 86%, the purity is 99% (HPLC), the optical rotation value is +60.5 ° (C= 1, tetrahydrofuran, T=25°C).

The synthesis of embodiment 10 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 8L of tetrahydrofuran, and 92g (0.75mol) of 4-dimethylaminopyridine into a 20L kettle with nitrogen protection, and stir at room temperature for 30min. Slowly add a solution of N, N-carbonyldiimidazole 1.22Kg (7.5mol) dissolved in 2L tetrahydrofuran dropwise at 0 to 5 ℃, keep the temperature of the solution below 20°C during the dropwise addition, and keep the solution at 40°C for reaction after dropping After 14 hours, the reaction was completed, and the solution was recovered after passing through dry hydrogen chloride gas for 5 minutes, and 2 L of dichloromethane was added to the residue, heated to reflux for 30 minutes, filtered while hot, and 10 L of methyl tert-butyl ether was added to the filtrate, stirred at room temperature for 30 minutes, and then filtered , the filtrate was cooled to -10°C and stirred for 2h, a large amount of white solid was precipitated, filtered with suction, the filter residue was washed with cold methyl tert-butyl ether, and dried in vacuo to obtain a white powdery solid (S)-3-benzyloxycarbonyl-4-iso Propyl-2,5-oxazolidinedione 0.75Kg, yield 53.8%, purity 98.5% (HPLC), optical rotation +62.1° (C=1, tetrahydrofuran, T=25°C).

The synthesis of embodiment 11 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 8L of 1,4-dioxane, and 92g (0.75mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen, and After stirring for 30 minutes, lower the temperature of the solution to 0-5 ℃ and slowly add a solution of N, N-carbonyldiimidazole 1.22Kg (7.5mol) dissolved in 2L of tetrahydrofuran dropwise. Keep the solution at 40°C for 14 hours. After the reaction is complete, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise and recover the solution. Add 2L of dichloromethane to the residue, heat to reflux for 30min, and filter while it is hot. Add 10L of methyl alcohol to the filtrate. tert-butyl ether, stirred at room temperature for 30 minutes and then filtered, cooled the filtrate to -10°C and stirred for 2 hours, a large amount of white solid precipitated, filtered with suction, washed the filter residue with cold methyl tert-butyl ether, dried under vacuum to obtain a white powdery solid (S) -3-Benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione 632g, yield 45.6%, purity 98.0% (HPLC), optical rotation +62.9° (C=1, THF, T = 25°C).

The synthesis of embodiment 12 (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione

Add 1.25Kg (5mol) of N-benzyloxycarbonyl-L-valine, 8L of formamide, and 92g (0.75mol) of 4-dimethylaminopyridine into a 20L kettle protected by nitrogen, and stir at room temperature for 30min. Slowly add a solution of N,N-carbonyldiimidazole 1.22Kg (7.5mol) dissolved in 2L tetrahydrofuran dropwise when the temperature drops to 0-5°C. During the dropping process, the temperature of the solution is kept below 20°C. After the drop is complete, the solution is kept at 40°C React for 14 hours, after the reaction is complete, add 500ml of 10mol/L hydrogen chloride tetrahydrofuran solution dropwise, recover the solution, add 2L of dichloromethane to the residue, heat to reflux for 30min, filter while hot, add 10L of methyl tert-butyl ether to the filtrate, After stirring for 30 minutes, filter, the filtrate was cooled to -10°C and stirred for 2 hours, a large amount of white solid was precipitated, filtered with suction, the filter residue was washed with cold methyl tert-butyl ether, and dried in vacuo to obtain a white powdery solid (S)-3-benzyloxycarbonyl - 838 g of 4-isopropyl-2,5-oxazolidinedione, the yield is 60.5%, the purity is 98.0% (HPLC), and the optical rotation is +62.9° (C=1, tetrahydrofuran, T=25°C).

Claims (13)

1. The preparation technology of (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione is characterized in that it comprises the following operations: S1. get L-valine and benzyl chloroformate to react under alkaline conditions to generate N-benzyloxycarbonyl-L-valine, and the synthetic method comprises dissolving L-valine in sodium hydroxide solution, Add benzyl chloroformate or 1,4-dioxane solution containing benzyl chloroformate dropwise during the reaction, and react at normal temperature; S2. Extraction and separation, discarding the organic phase, retaining the water, adjusting the pH of the water to acidity, and then extracting with a reaction solvent, taking the organic phase and transferring it to a kettle under a nitrogen protection environment to mix with an alkaline accelerator and cooling, then Add dropwise the reaction solvent containing N,N-carbonyldiimidazole, and react for 6~14 hours in a neutral to slightly alkaline environment and reaction temperature to generate (S)-3-benzyloxycarbonyl-4-isopropyl-2 , the reaction solvent of 5-oxazolidinedione; the pH of the neutral and slightly alkaline environment is 7.3-9.0. 2. The preparation process according to claim 1, characterized in that: in step S2, the reaction solvent is selected from dichloromethane, tetrahydrofuran, N,N-dimethylformamide, formamide, 1,4-dioxane , acetonitrile or a combination of two or more. 3. The preparation process according to claim 1, characterized in that: in step S2, the reaction solvent is selected from the combination of dichloromethane and tetrahydrofuran, N,N-dimethylformamide or dichloromethane and acetonitrile, N,N - combination of dimethylformamide. 4. The preparation process according to claim 1, characterized in that: when the reaction solvent in step S2 is a combination of dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, the reaction temperature is 0-25°C. 5. The preparation process according to claim 1, characterized in that: when the reaction solvent in step S2 is a combination of dichloromethane, acetonitrile and N,N-dimethylformamide, the reaction temperature is 0-40°C. 6. The preparation process according to claim 1, characterized in that: in step S2, the alkaline accelerator is selected from at least one of 4-dimethylaminopyridine, pyridine, and piperidine. 7. The preparation process according to claim 1, characterized in that: 4-dimethylaminopyridine is selected as the alkaline accelerator in step S2. 8. The preparation process according to claim 1, characterized in that: in step S2, the molar dosage ratio of the alkaline accelerator to N-benzyloxycarbonyl-L-valine is (0.05~0.2):1. 9. The preparation process according to claim 1, characterized in that: in step S2, the molar ratio of N-benzyloxycarbonyl-L-valine to N,N-carbonyldiimidazole is 1: (1~2) . 10. The preparation process according to any one of claims 1 to 9, characterized in that: after the reaction in step S2 is completed, a purification step is also included: Add hydrogen chloride tetrahydrofuran solution or hydrogen chloride ethyl acetate solution dropwise to the reaction solvent containing (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione or pass through dry hydrogen chloride gas to neutralize And the alkaline substances in the reaction solution, so that the entire system is kept in an acidic environment during the post-treatment process to protect the product; First add a good solvent to (S)-3-benzyloxycarbonyl-4-isopropyl-2,5-oxazolidinedione to filter and remove impurities, and then add a poor solvent to the filtrate to freeze and precipitate; The poor solvent is selected from at least one of methyl tert-butyl ether, toluene, n-hexane, sherwood oil; Described good solvent is selected from at least one in methylene chloride, ethyl acetate; The impurity refers to the impure components included in the target compound, including but not limited to imidazole, a by-product produced by the reaction, and incompletely reacted reaction materials. 11. The preparation process according to claim 1, characterized in that, before step S2 is extracted with the reaction solvent, it also includes the step of purifying N-benzyloxycarbonyl-L-valine: extracting the aqueous liquid with the reaction solvent, and extracting The layer was dried, and then the reaction solvent was distilled under reduced pressure to obtain N-benzyloxycarbonyl-L-valine; Or adjust the acidity of the water solution to crystallize and dry to obtain N-benzyloxycarbonyl-L-valine. 12. The preparation process according to claim 1, characterized in that, after step S2 is extracted with a reaction solvent, it also includes an organic phase removal step: after washing with saturated brine, drying with anhydrous sodium sulfate, filtering, An anhydrous, salt-free organic phase is obtained. 13. A method for synthesizing N-benzyloxycarbonyl-α-amino acid-NCA with α-amino acid as raw material, characterized in that it comprises the following steps

Formula 10 Formula 8 Formula 12

Formula 12 Formula 9 Formula 13 Take the α-amino acid shown in formula 10, react with benzyl chloroformate under alkaline conditions to generate the compound of formula 12, then separate the compound of formula 12, turn it into the reaction solvent under acidic conditions, and combine with the basic promoter, React with N,N-carbonyldiimidazole in a neutral slightly alkaline environment and reaction temperature to generate the compound of formula 13, the α-amino acid includes: glycine, alanine, valine, leucine, Isoleucine, Phenylalanine, Tryptophan, Serine, Methionine, Histidine.

Images