Synthesis method of high-purity (2S)-(1-tetrahydropyrimidine-2-ketone)-3-methylbutyric acid
By using L-valine methyl ester hydrochloride as the raw material, avoiding the use of highly toxic methyl chloroformate, the problems of environmental pollution and by-product generation in the prior art were solved, and the synthesis of (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid was achieved with high purity and low cost.
Patent Information
- Application Number
- CN202411668542.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-21
- Publication Date
- 2025-02-25
AI Technical Summary
The prior art requires the use of highly drug methyl chloroformate and a large amount of ammonia water when synthesizing (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, resulting in environmental pollution and by-product generation, affecting product purity and cost.
L-valine methyl ester hydrochloride is used as raw material, and through condensation reaction, reduction reaction, cyclosynthesis reaction and hydrolysis deesterization reaction, avoid the use of highly toxic methyl chloroformate, reduce the generation of by-products and improve the purity of the product.
The synthesis of high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid is achieved, which avoids environmental pollution, reduces production costs, and is suitable for large-scale production.
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] The present application relates to the field of chemical medicine, and more specifically to a method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid. Background Art
[0002] (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid is an important intermediate of the anti-AIDS drug lopinavir, molecular formula: C 9 H 15 O 3 N 2 , whose structural formula is as follows:
[0003]
[0004] At present, the main methods for synthesizing (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid are:
[0005]
[0006] The compound N-(2-cyanoethyl)-L-valine is generated by condensation reaction of L-valine and acrylonitrile, and then acylated with methyl chloroformate to generate the compound N-(2-cyanoethyl)-N-(2-alkoxycarbonyl)-L-valine, and then hydrogenated, reduced and cyclized under the catalysis of Raney nickel to obtain the compound (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid. This method requires the use of highly toxic methyl chloroformate and a large amount of ammonia water. During post-treatment, a viscous inorganic precipitate is generated, which needs to be filtered by adding diatomaceous earth. In addition, industrial ammonia water is volatile and causes environmental pollution.
[0007] In view of this, the inventors have designed a method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid. The synthetic route of the method of the present invention is as follows:
[0008] Summary of the invention
[0009] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, which has the advantages of avoiding the use of highly toxic methyl chloroformate, using L-valine methyl ester hydrochloride as a raw material, reducing the generation of by-products, making the product purer, and having low cost, green and environmental protection, easy large-scale production, etc., and having good application prospects.
[0010] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, comprising the following steps:
[0011] S1. Take L-valine methyl ester hydrochloride (II) as a raw material and react with acrylonitrile in an alkaline aqueous solution to undergo condensation reaction, extract with an organic solvent, and concentrate to obtain compound III:
[0012]
[0013] S2. Compound III in step S1 is reduced in an organic solvent in the presence of a base and under Raney nickel catalysis by introducing hydrogen, filtered and concentrated to obtain compound IV:
[0014]
[0015] S3. Compound IV in step S2 is subjected to a cyclization reaction with triphosgene in an organic solvent under alkaline conditions, and then washed, extracted, and concentrated to obtain compound V:
[0016]
[0017] S4. Compound V in step S3 is added to an alkaline aqueous solution in an organic solvent for hydrolysis and deesterification reaction, concentrated, impurity-removed, added with an inorganic acid to adjust the pH, extracted, and concentrated again, and then added with a mixed solvent for pulping, cooled, filtered, and dried to obtain (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid (Compound I):
[0018]
[0019] The alkali in step S1 is sodium hydroxide, potassium hydroxide or a mixture of the two.
[0020] The organic solvent in step S1 is one of ethyl acetate, dichloromethane, and diethyl ether, or a mixture of two or more thereof.
[0021] The alkali in step S2 is potassium carbonate, ammonia water or a mixture of the two.
[0022] The organic solvent in step S2 is one of methanol, ethanol, and isopropanol, or a mixture of two or more thereof.
[0023] The organic solvent in step S3 is one of dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, 1,2-dichloroethane, tetrahydrofuran, 1,4-dichlorohexacyclopentane, or a mixture of two or more thereof.
[0024] The base in step S3 is one of trimethylamine, triethylamine, tripropylamine and pyridine, or a mixture of two or more thereof.
[0025] The organic solvent in step S4 is one of methanol, ethanol, isopropanol, and n-butanol, or a mixture of two or more thereof.
[0026] The inorganic acid in step S4 is one of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture of two or more thereof.
[0027] The mixed solvent in step S4 is a mixture of ethyl acetate and methanol, ethanol, isopropanol and n-butanol. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figure 1 The present invention is a synthetic route diagram of the synthetic method of (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid. DETAILED DESCRIPTION
[0029] A method for synthesizing (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid of the present invention comprises the following steps:
[0030] Step S1, preparation of compound III, the reaction route is as follows:
[0031]
[0032] Example 1: Add (18.5g, 0.33mol) potassium hydroxide, add 43ml water, stir to dissolve, and cool to 0°C; slowly add (50g, 0.3mol) L-valine methyl ester hydrochloride in batches, stir for 30 minutes, add acrylonitrile (16.5g, 0.31mol) dropwise, and after the dropwise addition, heat to 75-80°C and react for 3.5 hours; after the reaction is complete, cool to room temperature (25-30°C), add 300ml ethyl acetate to extract, and separate the layers; add 120ml ethyl acetate to the water layer, extract the layers, and separate the layers; combine the organic layers, stir with 9% saline (16.8g sodium chloride dissolved and mixed with 168g water) for 30 minutes, let stand for 30 minutes, and separate the layers; heat the organic phase in a water bath at ≤55°C, and concentrate to dryness under reduced pressure to obtain 52g of compound III with a yield of 94.1% (light yellow oil), (purity 99.1%).
[0033] Example 2: Add (13.2g, 0.33mol) of sodium hydroxide, add 30ml of water, stir to dissolve, and cool to 0°C; slowly add (50g, 0.3mol) of L-valine methyl ester hydrochloride in batches, stir for 30 minutes, add acrylonitrile (17.5g, 0.33mol) dropwise, and after the addition, heat to 60-65°C and react for 4 hours; after the reaction is complete, cool to room temperature (25-30°C), add 300ml of ethyl acetate for extraction, and separate the layers; add 120ml of ethyl acetate to the aqueous layer for extraction, and separate the layers; combine the organic layers, stir with 9% saline (16.8g of sodium chloride dissolved in 168g of water) for 30 minutes, let stand for 30 minutes, and separate the layers; heat the organic phase in a water bath at ≤55°C, and concentrate to dryness under reduced pressure to obtain 50g of compound III with a yield of 90.5% (light yellow oil), (purity 99.0%).
[0034] Example 3: Add (18.5 g, 0.33 mol) potassium hydroxide, add 43 ml water, stir to dissolve, and cool to 0°C; slowly add (50 g, 0.3 mol) L-valine methyl ester hydrochloride in batches, stir for 30 minutes, add acrylonitrile (15.92 g, 0.3 mol) dropwise, and after the addition, heat to 40-45°C for reaction for 5 hours; after the reaction is complete, cool to room temperature (25-30°C), add 300 ml dichloromethane for extraction, and separate the layers; add 120 ml dichloromethane to the aqueous layer for extraction, and separate the layers; combine the organic layers, stir with 9% saline (16.8 g sodium chloride dissolved in 168 g water) for 30 minutes, let stand for 30 minutes, and separate the layers; heat the organic phase in a water bath at ≤40°C, and concentrate to dryness under reduced pressure to obtain 49.5 g of compound III with a yield of 89.6% (light yellow oil), (purity 99.2%).
[0035] Step S2, preparation of compound IV, the specific route is as follows:
[0036]
[0037] Example 1 Compound III (52 g, 0.28 mol) was dissolved in 208 g of methanol, 96 g of aqueous ammonia was added, 8 g of W4 type Raney nickel was added, hydrogen was introduced to 0.5 MPa, the temperature was raised to 50-55°C, and the reaction was carried out for 6 hours; after the reaction was complete, the temperature was cooled to room temperature, filtered, and the filtrate was heated in a water bath at ≤55°C and distilled to dryness under reduced pressure to obtain 45 g of compound IV with a yield of 85.5% (light yellow oil) (purity 98.8%).
[0038] Example 2 Compound III (52 g, 0.28 mol) was dissolved in 300 g of ethanol, 96 g of aqueous ammonia was added, 8 g of W4 type Raney nickel was added, hydrogen was introduced to 0.5 MPa, the temperature was raised to 55-60°C and the reaction was carried out for 8 hours; after the reaction was complete, the temperature was cooled to room temperature, filtered, and the filtrate was heated in a water bath at ≤55°C and distilled to dryness under reduced pressure to obtain 44.5 g of compound IV with a yield of 84.5% (light yellow oil) (purity 99.2%).
[0039] Example 3 Compound III (52 g, 0.28 mol) was dissolved in 208 g of methanol, 39 g of potassium carbonate and 8 g of W4 type Raney nickel were added, hydrogen was introduced to 0.5 MPa, the temperature was raised to 50-55°C and the reaction was carried out for 6 hours; after the reaction was complete, the temperature was cooled to room temperature, filtered, and the filtrate was heated in a water bath at ≤55°C and distilled to dryness under reduced pressure to obtain 43 g of compound IV with a yield of 81.7% (light yellow oil) (purity 99.0%).
[0040] Step S3, preparation of compound V, the specific route is as follows:
[0041]
[0042] Example 1 Compound IV (45 g, 0.24 mol) was added to 300 ml of dichloromethane, stirred and cooled to 0°C; triethylamine (29 g, 0.29 mol) was first added dropwise, and then a dichloromethane solution of triphosgene (28.5 g, 0.096 mol) was added dropwise, and the reaction was maintained at 0-5°C for 2 hours; after the reaction was complete, water (2 x 500 ml) was added for washing; the aqueous layers were combined, and dichloromethane (2 x 125 ml) was added for extraction, and the layers were separated; the organic phase was heated in a water bath at 5-20°C and concentrated to dryness under reduced pressure to obtain compound V43 g, with a yield of 83.6% and a light yellow oily substance with a purity of 98.7%
[0043] Example 2 Compound IV (45 g, 0.24 mol) was added to 500 ml of 1,2-dichloroethane, stirred and cooled to 0°C; pyridine (25.6 g, 0.324 mol) was first added dropwise, and then a dichloromethane solution of triphosgene (32 g, 0.108 mol) was added dropwise, and after the addition was completed, the temperature was kept at 0-5°C for 2 hours; after the reaction was complete, water (2x500 ml) was added for washing; the water layers were combined, and dichloromethane (2x125 ml) was added for extraction, and the layers were separated; the organic phase was heated in a water bath at 25-30°C and concentrated to dryness under reduced pressure to obtain compound V42 g, with a yield of 81.7% as a light yellow oil. (Purity 98.8%)
[0044] Example 3 Compound IV (45 g, 0.24 mol) was added to 350 ml of chloroform, stirred and cooled to 0°C; trimethylamine (17.7 g, 0.3 mol) was first added dropwise, and then a dichloromethane solution of triphosgene (30 g, 0.1 mol) was added dropwise, and after the addition was completed, the temperature was kept at 0-5°C for 2 hours; after the reaction was complete, water (2x500 ml) was added for washing; the aqueous layers were combined, dichloromethane (2x125 ml) was added for extraction, and the layers were separated; the organic phase was heated in a water bath at 30-40°C and concentrated to dryness under reduced pressure to obtain compound V41.3 g, with a yield of 80.3% and a pale yellow oil (purity 99.1%)
[0045] Step S4, preparation of compound I, the specific route is as follows:
[0046]
[0047] Example 1 Compound V (43 g, 0.2 mol) and 800 ml of methanol were added to a reaction flask, stirred to dissolve, and cooled to 0°C; 2.4% lithium hydroxide aqueous solution (18 g of lithium hydroxide and 730 g of water were dissolved and mixed), and the mixture was kept warm at 0°C for 3 hours; after the reaction was complete, the methanol was concentrated under reduced pressure in a water bath at ≤55°C, the residual liquid was cooled to room temperature, (2x150 ml) of dichloromethane was added, extracted, and layered; 300 ml of dichloromethane was added to the water, the temperature was cooled to 10-15°C, concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2.0-3.0, and the layers were separated; 150 ml of dichloromethane was added to the water for extraction, and the layers were separated; the organic phases were combined, heated in a water bath at ≤40°C, concentrated to dryness under reduced pressure, 40 g of isopropanol and 110 g of ethyl acetate were added, the temperature was raised to 55°C, the temperature was kept warm and stirred for 2 hours, the temperature was slowly cooled to 0-5°C, filtered, and dried to obtain 36.2 g of compound I as a white solid with a yield of 90.4% (purity 99.7%).
[0048] Example 2 Compound V (43g, 0.2mol) and 800ml of ethanol were added to a reaction flask, stirred to dissolve, and cooled to 0°C; 4.3% lithium hydroxide aqueous solution (18g lithium hydroxide and 400g water dissolved and mixed) was added, and the reaction was kept at 0°C for 3.5 hours; after the reaction was complete, the methanol was concentrated under reduced pressure in a water bath at ≤55°C, the residual liquid was cooled to room temperature, (2x150ml) of dichloromethane was added, extracted, and layered; 300ml of dichloromethane was added to the water, the temperature was cooled to 10-15°C, concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2.0-3.0, and the layers were separated; 150ml of dichloromethane was added to the water for extraction, and the layers were separated; the organic phases were combined, heated in a water bath at ≤40°C, concentrated to dryness under reduced pressure, 40g of ethanol, 100g of ethyl acetate were added, the temperature was raised to 55°C, the temperature was kept stirred for 2 hours, the temperature was slowly reduced to 0-5°C, suction filtered, and dried to obtain 35.5g of compound I as a white solid with a yield of 88.7% (purity 99.5%).
[0049] Example 3 Compound V (43 g, 0.2 mol) and 800 ml of methanol were added to a reaction flask, stirred to dissolve, and cooled to 0°C; 5.66% lithium hydroxide aqueous solution (18 g of lithium hydroxide and 300 g of water were dissolved and mixed), and the mixture was kept warm at 0°C for 3 hours; after the reaction was complete, the methanol was concentrated under reduced pressure in a water bath at ≤55°C, the residual liquid was cooled to room temperature, (2x150 ml) of dichloromethane was added, extracted, and layered; 300 ml of dichloromethane was added to the water, the temperature was cooled to 10-15°C, 30% sulfuric acid was slowly added dropwise to adjust the pH to 2.0-3.0, and the layers were separated; 150 ml of dichloromethane was added to the water for extraction, and the layers were separated; the organic phases were combined, heated in a water bath at ≤40°C, concentrated to dryness under reduced pressure, 40 g of isopropanol and 80 g of ethyl acetate were added, the temperature was raised to 55°C, the temperature was kept warm and stirred for 2 hours, the temperature was slowly reduced to 0-5°C, suction filtered, and dried to obtain 35 g of compound I as a white solid with a yield of 87.4% (purity 99.5%).
[0050] The beneficial effects of the present invention are as follows:
[0051] The invention has the advantages of avoiding the use of highly toxic methyl chloroformate, reducing by-products by using L-valine methyl ester hydrochloride as a raw material, making the product purity higher, and having the advantages of low cost, being green and environmentally friendly, being easy for large-scale production, and having good application prospects.
[0052] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the design concept of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid, characterized in that: The following steps are involved: S1. In an alkaline solution, L-valine methyl ester hydrochloride (Compound II) and acrylonitrile are reacted at 0-80°C for 2-6 hours, and the solvent is extracted and the solvent is evaporated under reduced pressure to obtain N-(2-cyanoethyl)-L-valine methyl ester (Compound III), wherein the molar ratio of L-valine methyl ester hydrochloride to acrylonitrile is 1:1-1.1; the base is one of sodium hydroxide and potassium hydroxide or a mixture of two of them; the solvent is one of ethyl acetate, dichloromethane and diethyl ether or a mixture of two or more thereof; S2. Under alkaline Raney Ni catalytic conditions, hydrogen is introduced into a solvent containing N-(2-cyanoethyl)-L-valine methyl ester (compound III) to a pressure of 0.3-0.6 MPa, and the reaction is carried out at 40-70° C. for 5-10 hours. The solvent is filtered and the solvent is evaporated under reduced pressure to obtain N-(3-aminopropyl)-L-valine methyl ester (compound IV); wherein the base is potassium carbonate, ammonia water, or a mixture of two of the two, and the molar ratio of the base to N-(2-cyanoethyl)-L-valine methyl ester is 1-10:1; the solvent is methanol, ethanol, isopropanol, or a mixture of two or more thereof; the amount of the Raney Ni catalyst is 10% to 20% by weight of the N-(2-cyanoethyl)-L-valine methyl ester; S3. Triphosgene and N-(3-aminopropyl)-L-valine methyl ester (Compound IV) are reacted in an organic solvent at -5 to 10°C under the action of an acid-binding agent, and post-treated to obtain (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid methyl ester (Compound V); the acid-binding agent is one of trimethylamine, triethylamine, tripropylamine, and pyridine, or a mixture of two or more thereof; the organic solvent is one of dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, 1,2-dichloroethane, tetrahydrofuran, and 1,4-dichlorohexacyclopentane, or a mixture of two or more thereof; S4. Methyl (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutanoate (Compound V) is hydrolyzed under alkaline conditions to give (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutanoic acid (Compound I).
2. A method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 1, characterized in that: In the step S3, the reaction time is 1 to 2 hours.
3. The method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 1, characterized in that: The specific process of the post-treatment of step S3 is: adding water to the reaction solution for washing twice, then adding dichloromethane to the water layer for extraction twice, heating the organic layer in a water bath, and concentrating under reduced pressure at less than 40 degrees to obtain (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid methyl ester.
4. The method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 1, characterized in that: In step S3, the molar ratio of triphosgene to N-(3-aminopropyl)-L-valine methyl ester is 0.33 to 1:1; the molar ratio of N-(3-aminopropyl)-L-valine methyl ester to the acid binding agent is 1:1 to 1.5; and the amount of the organic solvent used is 5 to 20 times that of N-(3-aminopropyl)-L-valine methyl ester.
5. The method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 1, characterized in that: The specific process of step S4 is: adding a lithium hydroxide aqueous solution dropwise to a solvent containing (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid methyl ester, reacting at 0-5°C for 2-4 hours after the addition, concentrating the solvent under reduced pressure to obtain a hydrolyzate, adding an organic solvent to the hydrolyzate for extraction, discarding the organic layer, cooling to 10-15°C, adding an inorganic acid dropwise to adjust the pH to 2.0-3.0, precipitating white crystals, filtering and drying to obtain a crude product, adding ethyl acetate and an alcohol mixed solvent to the crude product, cooling to 0-5°C, filtering with suction, and drying at 50-55°C to obtain (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid.
6. A method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 5, characterized in that: The concentration of the lithium hydroxide aqueous solution is 1% to 10%; the organic solvent is one of dichloromethane, chloroform, and carbon tetrachloride, or a mixture of two or more thereof.
7. A method for synthesizing high-purity (2S)-(1-tetrahydropyrimidin-2-one)-3-methylbutyric acid according to claim 5, characterized in that: The alcohol solvent is one of methanol, ethanol, isopropanol, and n-butanol, or a mixture of two or more thereof; the mass ratio of ethyl acetate to the alcohol solvent is 2 to 3:1.