A process for the synthesis of (r)-3-(tert-butoxy carbonyl)amino-2-methylpropionic acid

Abstract

The application discloses a synthesis method of (R)-3-(t-butoxycarbonyl)amino-2-methylpropionic acid, and the (R)-3-(t-butoxycarbonyl)amino-2-methylpropionic acid is directly synthesized through chlorination, ammoniation, amide reduction, substitution and oxidation and the like steps by taking (S)-(+)-2-(4-isobutylphenyl)propionic acid as a starting material. The synthesis method avoids the current route which is prone to two methyl groups due to a C-alkylation step, and does not need to consider the separation and purification difficulties caused by a large number of disubstituted by-products and isomers, so that the total yield and purity are greatly improved. Compared with other existing technologies, the yield of the product obtained is greatly improved. The total yield of the synthesis route is 55.1%, which is about 6.2 times of the total yield 8.9% of the prior art, and is greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to pharmaceutical intermediates, particularly to a method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid, which has readily available starting materials with defined chirality, simple operation steps, and low synthesis cost. Background Technology

[0002] β-Amino acids are amino acids in which an amino group is substituted at the β-position of the carbon chain linked to the carboxyl group. The only common naturally occurring β-amino acid is β-alanine, which is often used as a component of bioactive macromolecules. However, β-peptides are generally not found in nature. For this reason, β-peptide antibiotics are being used to address the problem of antibiotic resistance. The principle behind this is the use of their unique "pseudo-mimicry," maintaining structural similarity to natural amino acids while adding a carbon atom between the carboxyl and amino groups. This prevents them from being specifically recognized by various enzymes in the body, thus slowing down or even preventing their hydrolysis and metabolism, thereby enhancing their efficacy.

[0003] β-amino acids are now used in various fields such as medicine, food, and agriculture. In the pharmaceutical field, many blockbuster drugs with huge market sales, such as β-lactam antibiotics, paclitaxel (an anticancer drug), sitagliptin (a diabetes drug), and vitamin B5, all require β-amino acids as important synthetic units.

[0004] Due to their wide range of applications, the synthesis of β-amino acids has gradually become an important topic in organic synthesis and pharmaceutical research. For a long time, synthesis has relied on assembling chiral cofactors through chiral induction or transition metal catalysis, such as the asymmetric hydroamination of acrylic acid compounds or the asymmetric hydrogenation of α-aminoacrylic acid compounds. These reactions often inevitably require expensive noble metal catalysts and intricately designed but difficult-to-synthesize chiral ligands. Other methods also suffer from cumbersome protection and deprotection steps and harsh reaction conditions. Therefore, designing novel synthetic routes for β-amino acids has become a major challenge in the field of synthesis.

[0005] (R)-3-(tert-Butoxycarbonyl)amino-2-methylpropionic acid is also a β-amino acid and is an important intermediate for the synthesis of treatments or prevention of rheumatoid arthritis, pemphigus vulgaris, systemic lupus erythematosus, lymphoma, and other diseases mediated by Sppl2a.

[0006] WO2020 / 016420A1 discloses a method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid. The disclosed technical solution involves methylation, cyano reduction, Boc anhydride substitution, ester hydrolysis, and chiral resolution of the starting material ethyl cyanoacetate to obtain the target compound. While ethyl cyanoacetate has a simple structure and is inexpensive, the methylation step suffers from severe selectivity issues. The main product is a disubstituted methylated product, meaning the target position is easily substituted with two methyl groups, resulting in an extremely low single-step yield of only 24.1% for the methylation step (Int-2). Furthermore, the separation step requires cumbersome and complex distillation, which is difficult to control. In addition, the resolution requires multiple steps with poor separation efficiency and low yield, resulting in an overall yield of only 8.9%. Moreover, the process uses the highly toxic and expensive alkylating agent iodomethane. Due to these problems, the synthetic route is not suitable for the industrial production of (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid. Other methods for preparing compound (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid (WO2020228729) all suffer from poor C-alkylation selectivity, poor chiral resolution, numerous resolution repetitions, and low yield. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid. Starting with readily available raw materials of defined chirality, this method achieves the target product conveniently and through simple operating steps, low synthesis cost, high yield, and high efficiency. The product obtained by this method not only possesses high purity but also meets the basic requirements for scalability, making it suitable for industrial production and thus possessing broad application prospects.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid, the method comprising the following steps:

[0010] a) The substance represented by formula I is chlorinated and ammonified to obtain the compound represented by formula II;

[0011] b) The compound represented by formula II is reduced with borane and substituted with Boc anhydride to obtain the compound represented by formula III;

[0012] c) The compound represented by formula III is oxidized with sodium periodate to obtain the compound represented by formula (IV);

[0013] Among them, the compound represented by formula I:

[0014] The compound represented by Formula II:

[0015] The compound represented by Formula III:

[0016] The compound represented by Formula IV:

[0017] In this invention, WO2020 / 016420A1 discloses a method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid, the synthetic route of which is as follows:

[0018]

[0019] Due to severe selectivity issues in the methylation step, the main products are disubstituted methylated products, meaning that the target position is easily replaced by two methyl groups. This results in an extremely low single-step yield of only 24.1% for the methylation step Int-2. Furthermore, the separation step requires cumbersome and complex distillation, which is difficult to control. In addition, the separation needs to be performed multiple times, resulting in poor separation efficiency and low yield. Consequently, the overall yield of the entire route is only 8.9%. Moreover, the process uses the highly toxic and expensive alkylating agent iodomethane.

[0020] This invention uses (S)-(+)-2-(4-isobutylphenyl)propionic acid as the starting material and directly synthesizes (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid through steps such as chlorination, amination, amide reduction, substitution, and oxidation.

[0021] The synthetic route of the present invention is as follows: Figure 1 As shown, it is:

[0022]

[0023] In this invention, the use of (S)-(+)-2-(4-isobutylphenyl)propionic acid replaces the process of adding a methyl group to the methylene group in the ethyl cyanoacetate structure. The new process directly avoids the selective methylation step in existing processes by chlorinating the carboxyl group with thionyl chloride and then ammonifying it. This directly avoids the poor selectivity of methylation and the generation of a large number of isomers, as well as the material loss caused by separation and purification, thus greatly improving the yield. This step is the key step in improving the overall yield of the synthetic route.

[0024] This invention avoids the use of highly toxic alkylating agents such as iodomethane and precious metal catalysts commonly used for cyano reduction, such as Raney nickel.

[0025] This invention utilizes sodium periodate and ruthenium chloride hydrate in combination, avoiding the need for specialized equipment such as high-pressure reactors, making the reaction faster and less labor-intensive.

[0026] Compared with other existing technologies, the product yield obtained by this invention is significantly improved. The total yield of the synthetic route of this invention is 55.1%, which is almost 6.2 times that of the total yield of 8.9% of the existing technology, representing a substantial improvement.

[0027] As a preferred embodiment of the present invention, the specific steps of the synthesis method are as follows:

[0028] a) Dissolve the substance shown in Formula I in a solvent, add thionyl chloride, react until the reaction is complete, add the reaction solution dropwise to ammonia water, wash with water, filter, and dry to obtain the compound shown in Formula II.

[0029] b) Add solvent to the substance shown in Formula II, replace with nitrogen and cool down, add 10.0 M borane dimethyl sulfide dropwise, stir the reaction until the reaction is complete, and wash, extract and concentrate the reaction solution to obtain the compound shown in Formula III.

[0030] c) Dissolve the substance shown in Formula III in a solvent, add sodium periodate and a catalyst, oxidize, and react until the reaction is complete. The reaction solution is repeatedly adjusted for pH, filtered, extracted, concentrated, and pulped to obtain the compound shown in Formula IV.

[0031] In a preferred embodiment of the present invention, in step a), the reaction temperature is 0–80°C, the amount of thionyl chloride is 1.5–2.5 equivalents, and the amount of ammonia is 4.0–5.0 wt.

[0032] In a preferred embodiment of the present invention, in step b), the amount of 10.0M borane dimethyl sulfide used is 2.5 to 4.0 equivalents, and the temperature is controlled at 0 to 5°C during the dropwise addition process; the temperature during the stirring reaction is 50 to 55°C.

[0033] In a preferred embodiment of the present invention, the reaction temperature in step c) is 20–30°C.

[0034] In a preferred embodiment of the present invention, in step c), the amount of sodium periodate used is 10.1 to 12.1 equivalents.

[0035] In a preferred embodiment of the present invention, in step c), the catalyst is ruthenium chloride hydrate, and the amount of catalyst used is 0.01 to 0.023 equivalents.

[0036] As a preferred embodiment of the present invention, adjusting the pH includes adjusting it to alkaline with an alkaline solution and adjusting it to acidic with an acidic solution.

[0037] As a preferred embodiment of the present invention, when adjusting to alkalinity, the alkaline solution used is a 15-20 wt% sodium carbonate aqueous solution, and the pH is adjusted to 9-10.

[0038] As a preferred embodiment of the present invention, when adjusting to acidity, the acidic solution used is a 15-20 wt% citric acid aqueous solution, with the pH adjusted to 3-4.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] 1) The synthesis method of the present invention uses relatively simple starting materials with readily available commercial-scale raw materials.

[0041] 2) The synthesis method of the present invention avoids the current route's tendency to add two methyl groups due to the C-alkylation step, and does not need to consider the difficulties in separation and purification caused by the presence of a large number of disubstituted byproducts and isomers. The overall yield and purity are greatly improved. Compared with other existing technologies, the product yield is significantly improved. The overall yield of the synthesis route of the present invention is 55.1%, which is almost 6.2 times that of the existing technology's overall yield of 8.9%, representing a significant improvement.

[0042] 3) The synthesis method of the present invention avoids the use of highly toxic and expensive alkylating reagents such as iodomethane and expensive and spontaneously combustible catalysts such as Raney nickel, as well as harsh conditions such as the need for hydrogenation reaction in a high-pressure reactor and cumbersome operations that are not conducive to scale-up production, such as the lack of chiral resolution.

[0043] 4) The synthesis method of the present invention has been verified by scale-up at the gram and kilogram levels. It has good repeatability and is a relatively economical, environmentally friendly, simple post-processing, and easy-to-scale production technical route. Attached Figure Description

[0044] Figure 1 This is the synthetic route of the present invention.

[0045] Figure 2 This is the spectrum of the compound represented by formula IV obtained in Example 9. Detailed Implementation

[0046] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0047] In this invention, all raw materials, reagents, or equipment used can be purchased from the market.

[0048] See Figure 1 This invention uses (S)-(+)-2-(4-isobutylphenyl)propionic acid as the starting material and directly synthesizes (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid through steps such as chlorination, amination, amide reduction, substitution, and oxidation.

[0049] The steps of the synthesis method of this invention are as follows:

[0050] a) Dissolve the substance shown in Formula I in a solvent, add thionyl chloride, react until the reaction is complete, add the reaction solution dropwise to ammonia water, wash with water, filter, and dry to obtain the compound shown in Formula II.

[0051] b) Add solvent to the substance shown in Formula II, replace with nitrogen and cool down, add 10.0 M borane dimethyl sulfide dropwise, stir the reaction until the reaction is complete, and wash, extract and concentrate the reaction solution to obtain the compound shown in Formula III.

[0052] c) Dissolve the substance shown in Formula III in a solvent, add sodium periodate and a catalyst, oxidize, and react until the reaction is complete. The reaction solution is repeatedly adjusted for pH, filtered, extracted, concentrated, and pulped to obtain the compound shown in Formula IV.

[0053] Example 1

[0054] See Figure 1 Synthesis of (S)-(+)-2-(4-isobutylphenyl)propionamide (II)

[0055] (S)-(+)-2-(4-isobutylphenyl)propionic acid (20 g, 0.097 mol, 1.0 eq) was added to a 250 mL three-necked flask, followed by thionyl chloride (28.84 g, 2.5 eq) and DMF (0.256 g, 0.0128 wt). The mixture was heated to 70-75 °C and stirred under reflux for 2 hours. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionic acid (I) was completed, excess thionyl chloride was removed from the reaction solution, and the solution was slowly added dropwise to ammonia water (80 g, 4 wt) that had been pre-cooled to -5-0 °C, with the addition temperature controlled not to exceed 10 °C, until the addition was complete. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionyl chloride was completed, the mixture was filtered. The filter cake was rinsed with 80 g (4 wt) of water and dried to obtain 18.1 g of compound (II), with a yield of 91.0% and a purity of 97.5%.

[0056] Example 2

[0057] See Figure 1 Synthesis of (S)-(+)-2-(4-isobutylphenyl)propionamide (II)

[0058] Add (S)-(+)-2-(4-isobutylphenyl)propionic acid (100g, 0.485mol, 1.0eq) to a 500mL three-necked flask, add thionyl chloride (86.51g, 1.5eq), add DMF (1.28g, 0.0128wt), heat to 70-75℃ and stir under reflux for 2 hours. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionic acid (I) is complete, remove excess thionyl chloride from the reaction solution and slowly add it dropwise to ammonia water (500g, 5wt) that has been cooled to -5-0℃ beforehand, controlling the dropwise temperature not to exceed 10℃, until the dropwise addition is complete. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionyl chloride is complete, filter. The filter cake was rinsed with 400 g (4 wt) of water and dried to obtain 93.0 g of compound (II), with a yield of 93.4% and a purity of 98.1%.

[0059] Example 3

[0060] See Figure 1 Synthesis of (S)-(+)-2-(4-isobutylphenyl)propionamide (II)

[0061] Add (S)-(+)-2-(4-isobutylphenyl)propionic acid (50g, 0.243mol, 1.0eq) to a 500mL three-necked flask, add thionyl chloride (43.3g, 1.5eq), add DMF (0.64g, 0.0128wt), heat to 70-75℃ and stir under reflux for 2 hours. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionic acid (I) is complete, remove excess thionyl chloride from the reaction solution and slowly add it dropwise to ammonia water (250g, 5wt) that has been cooled to -5-0℃ beforehand, controlling the dropwise temperature not to exceed 10℃, until the dropwise addition is complete. After the reaction of (S)-(+)-2-(4-isobutylphenyl)propionyl chloride is complete, filter. The filter cake was rinsed with 200 g (4 wt) of water and dried to obtain 46.1 g of compound (II), with a yield of 92.6% and a purity of 98.4%.

[0062] Example 4

[0063] See Figure 1 Synthesis of (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (III)

[0064] (S)-(+)-2-(4-isobutylphenyl)propionamide (10 g, 0.049 mol, 1.0 eq) and THF (50 mL, 5V) were mixed and stirred. After purging with nitrogen, the mixture was cooled to -5 to 0 °C. 10.0 M boron dimethyl sulfide (14.64 mL, 0.1461 mol, 3.0 eq) was slowly added dropwise at 0 to 5 °C until complete. The reaction temperature was controlled at 50 to 55 °C, and the reaction was allowed to proceed for 12 h. If the content of the raw material (S)-(+)-2-(4-isobutylphenyl)propionamide was ≤2.0%, post-treatment was possible. The reaction solution was cooled to 0 to 10 °C with stirring, and 12.2 g of 10% dilute hydrochloric acid was slowly added dropwise for quenching. Then, 10 g of water was added, followed by extraction with 20 mL of methyl tert-butyl ether. The mixture was separated, and the process was repeated twice. 30 mL of the aqueous phase was added. THF was added, followed by 32.0 g of 20% sodium carbonate aqueous solution to bring the system pH to 2-3. Then, di-tert-butyl dicarbonate (11.7 g, 0.0534 mol, 1.1 eq) was added, and then 126.0 g of 20% sodium carbonate aqueous solution was added to bring the system pH to 8-9. The temperature was raised to 25-30℃ and maintained for 2 hours. The raw material (S)-(+)-2-(4-isobutylphenyl)propylamine was kept ≤2.0% for post-processing. Extraction was performed by adding 30 mL of methyl tert-butyl ether, followed by separation and repeating twice. The combined organic phases were washed once with 20 mL of 10% citric acid aqueous solution, once with 20 mL of 20% sodium carbonate aqueous solution, once with 20 mL of semi-saturated brine, and once with 20 mL of saturated brine. Finally, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 12.8 g of solid III, with a yield of 90.5% and a purity of 98.2%.

[0065] Example 5

[0066] See Figure 1 Synthesis of (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (III)

[0067] (S)-(+)-2-(4-isobutylphenyl)propionamide (30 g, 0.146 mol, 1.0 eq) and THF (150 mL, 5V) were mixed and stirred. After nitrogen purging, the mixture was cooled to -5 to 0 °C. 10.0 M boron dimethyl sulfide (58.4 mL, 0.588 mol, 4.0 eq) was slowly added dropwise at 0 to 5 °C until the addition was complete. The reaction temperature was controlled at 50 to 55 °C, and the reaction was allowed to proceed for 12 h. If the content of the raw material (S)-(+)-2-(4-isobutylphenyl)propionamide was ≤2.0%, post-treatment was performed. The reaction solution was cooled to 0 to 10 °C with stirring, and 70.3 g of 18.5% dilute hydrochloric acid was slowly added dropwise for quenching. The mixture was then filtered, and the filter cake was rinsed three times with 90 mL of water, for a total of 270 mL. Extract the filtrate with 60 mL of methyl tert-butyl ether, separate the layers, and repeat twice. Add 90 mL of THF to the aqueous phase, then add 190.0 g of 20% sodium carbonate aqueous solution to bring the system pH to 2-3. Add di-tert-butyl dicarbonate (35.1 g, 0.161 mol, 1.1 eq), then add 260.0 g of 20% sodium carbonate aqueous solution to bring the system pH to 8-9. Heat to 25-30℃ and keep warm for 2 hours. If the raw material (S)-(+)-2-(4-isobutylphenyl)propylamine ≤ 2.0%, post-treatment can be performed. Extract with 90 mL of methyl tert-butyl ether, separate the layers, and repeat twice. Combine the organic phases and wash once with 60 mL of 10% citric acid aqueous solution, once with 60 mL of 20% sodium carbonate aqueous solution, once with 60 mL of semi-saturated saline solution, and once with 60 mL of saturated saline solution. Finally, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 40.4 g of product solid III, with a yield of 94.8% and a purity of 98.4%.

[0068] Example 6

[0069] See Figure 1 Synthesis of (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (III)

[0070] (S)-(+)-2-(4-isobutylphenyl)propionamide (75g, 0.365mol, 1.0eq) and THF (375mL, 5V) were mixed and stirred. After purging with nitrogen, the mixture was cooled to -5 to 0℃. 10.0M boron dimethyl sulfide (91.4mL, 0.913mol, 2.5eq) was slowly added dropwise at 0 to 5℃ until the addition was complete. The reaction temperature was controlled at 50 to 55℃, and the reaction was carried out for 12 hours. If the content of the raw material (S)-(+)-2-(4-isobutylphenyl)propionamide was ≤2.0%, post-treatment was performed. The reaction solution was cooled to 0 to 10℃ with stirring, and 175.8g of 18.5% dilute hydrochloric acid was slowly added dropwise for quenching. The mixture was then filtered, and the filter cake was washed three times with 225mL of water, for a total of 675mL. Extract the filtrate with 150 mL of methyl tert-butyl ether, separate the layers, and repeat twice. Add 225 mL of THF to the aqueous phase, then add 475.0 g of 20% sodium carbonate aqueous solution to bring the system pH to 2-3. Add di-tert-butyl dicarbonate (83.7 g, 0.384 mol, 1.05 eq), then add 650 g of 20% sodium carbonate aqueous solution to bring the system pH to 8-9. Heat to 25-30℃ and keep warm for 2 hours. If the raw material (S)-(+)-2-(4-isobutylphenyl)propylamine ≤ 2.0%, post-treatment can be performed. Extract with 225 mL of methyl tert-butyl ether, separate the layers, and repeat twice. Combine the organic phases and wash once with 150 mL of 10% citric acid aqueous solution, once with 150 mL of 20% sodium carbonate aqueous solution, once with 150 mL of semi-saturated saline solution, and once with 150 mL of saturated saline solution. Finally, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 101.1 g of solid III, with a yield of 94.9% and a purity of 98.7%.

[0071] Example 7

[0072] See Figure 1 Synthesis of (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid (IV)

[0073] (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (10 g, 0.034 mol, 1.0 eq) and sodium periodate (88.82 g, 0.415 mol, 12.1 eq) were added to a 500 mL three-necked flask. Acetonitrile (71.1 mL, 7.1 V) and water (109.0 mL, 10.9 V) were added and stirred. The mixture was cooled to -5 to 0 °C and maintained at 0 to 5 °C. At this temperature, ruthenium chloride hydrate (0.2 g, 0.79 mmol, 0.023 eq) was added in batches. After the addition was complete, the mixture was allowed to warm naturally to 20 to 30 °C and stirred. The reaction was monitored by total chromatographic chromatography (TLC) until complete. The mixture was then filtered through a diatomaceous earth liner. The filtrate was diluted with 30 mL of acetonitrile / water. Rinse thoroughly with a 1:1 ratio, combine the filtrates, concentrate the reaction solution, remove excess acetonitrile, and extract with 20 mL of methyl tert-butyl ether. Separate the layers. Extract the aqueous phase again with 20 mL of methyl tert-butyl ether. Separate the layers. Combine the organic phases, add 10 mL of water, and then add 50 g of 20% carbonic acid aqueous solution to adjust the pH to 9-10. Separate the layers. Extract the aqueous layer again with 20 mL of methyl tert-butyl ether. Separate the layers. Add 50 g of 20% citric acid aqueous solution to adjust the pH to 3-4. Extract with 20 mL of methyl tert-butyl ether. Separate the layers. Extract the aqueous phase again with 20 mL of methyl tert-butyl ether. Separate the layers. Combine the organic phases, dry, and remove the solvent to dryness to obtain 4.5 g of solid IV, yield 64.5%, purity 99.2%.

[0074] Example 8

[0075] See Figure 1 Synthesis of (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid (IV)

[0076] (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (50 g, 0.170 mol, 1.0 eq) and sodium periodate (444.1 g, 2.075 mol, 12.1 eq) were added to a 2000 mL three-necked flask. Acetonitrile (355.5 mL, 7.1 V) and water (545.0 mL, 10.9 V) were added and stirred. The mixture was cooled to -5 to 0 °C and maintained at 0 to 5 °C. At this temperature, ruthenium chloride hydrate (1.0 g, 3.95 mmol, 0.023 eq) was added in batches. After the addition was complete, the mixture was allowed to warm naturally to 20 to 30 °C and stirred. The reaction was monitored by total chromatographic chromatography (TLC) until complete. The mixture was then filtered through a diatomaceous earth bed. The filtrate was treated with 150 mL of acetonitrile / water at a ratio of 1:1. 1. Rinse thoroughly, combine the filtrates, concentrate the reaction solution, remove excess acetonitrile, and extract with 100 mL of methyl tert-butyl ether. The aqueous phase is extracted again with 100 mL of methyl tert-butyl ether, and the layers are separated. Combine the organic phases, add 50 mL of water, and then add 250 g of 20% carbonic acid aqueous solution to adjust the pH to 9-10. The layers are separated again, and the aqueous layer is extracted again with 100 mL of methyl tert-butyl ether. The layers are separated, and the aqueous phase is adjusted to 3-4 with 250 g of 20% citric acid aqueous solution. Extract with 100 mL of methyl tert-butyl ether, and the layers are separated. Combine the organic phases, dry, and remove the solvent to dryness to obtain 23.0 g of solid IV, yield 66.0%, purity 99.4%.

[0077] Example 9

[0078] See Figure 1 Synthesis of (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid (IV)

[0079] (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (20 g, 0.068 mol, 1.0 eq) and sodium periodate (177.6 g, 0.830 mol, 12.1 eq) were added to a 1000 mL three-necked flask. Acetonitrile (142.2 mL, 7.1 V) and water (218.0 mL, 10.9 V) were added and stirred. The mixture was cooled to -5 to 0 °C and maintained at 0 to 5 °C. At this temperature, ruthenium chloride hydrate (0.4 g, 1.58 mmol, 0.023 eq) was added in batches. After the addition was complete, the mixture was allowed to warm naturally to 20 to 30 °C and stirred. The reaction was monitored to completion by trans-polar chromatography (TLC). The mixture was then filtered through a diatomaceous earth liner. The filtrate was dilute with 60 mL of acetonitrile / water. Rinse thoroughly with a 1:1 ratio, combine the filtrates, concentrate the reaction solution, remove excess acetonitrile, and extract with 40 mL of methyl tert-butyl ether. Separate the layers. Extract the aqueous phase again with 40 mL of methyl tert-butyl ether. Separate the layers. Combine the organic phases, add 25 mL of water, and then add 100 g of 20% carbonic acid aqueous solution to adjust the pH to 9-10. Separate the layers. Extract the aqueous layer again with 40 mL of methyl tert-butyl ether. Separate the layers. Add 100 g of 20% citric acid aqueous solution to the aqueous phase to adjust the pH to 3-4. Extract with 40 mL of methyl tert-butyl ether. Separate the layers. Extract the aqueous phase again with 40 mL of methyl tert-butyl ether. Separate the layers. Combine the organic phases, dry, and remove the solvent to dryness to obtain 9.05 g of solid IV, yield 64.9%, purity 99.5%.

[0080] The spectrum of the compound represented by formula IV is as follows Figure 2 As shown.

[0081] Example 10

[0082] See Figure 1 Synthesis of (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid (IV)

[0083] (S)-(2-(4-isobutylphenyl)propyl)carbamate tert-butyl ester (70 g, 0.238 mol, 1.0 eq) and sodium periodate (518.9 g, 2.404 mol, 10.1 eq) were added to a 2000 mL three-necked flask. Acetonitrile (497.7 mL, 7.1 V) and water (763.0 mL, 10.9 V) were added and stirred. The mixture was cooled to -5 to 0 °C and maintained at 0 to 5 °C. At this temperature, ruthenium chloride hydrate (1.4 g, 5.53 mmol, 0.023 eq) was added in batches. After the addition was complete, the mixture was allowed to warm naturally to 20 to 30 °C and stirred. The reaction was carried out under controlled-volume chromatography (TLC) until complete. The mixture was then filtered through a diatomaceous earth liner. The filtrate was diluted with 210 mL of acetonitrile / water at a 1:1 ratio. Rinse thoroughly, combine the filtrates, concentrate the reaction solution, remove excess acetonitrile, and extract with 140 mL of methyl tert-butyl ether. The aqueous phase is extracted again with 140 mL of methyl tert-butyl ether, and the layers are separated. Combine the organic phases, add 87.5 mL of water, and then add 350 g of 20% carbonic acid aqueous solution to adjust the pH to 9-10. The layers are separated again, and the aqueous layer is extracted again with 140 mL of methyl tert-butyl ether. The resulting aqueous phase is then adjusted to pH 3-4 with 350 g of 20% citric acid aqueous solution, and extracted with 140 mL of methyl tert-butyl ether. The layers are separated again, and the organic phases are combined, dried, and desolventized to dryness to obtain 33.3 g of solid IV, yield 68.2%, purity 99.5%.

[0084] Therefore, this invention avoids the difficulties in separation and purification caused by the presence of a large number of disubstituted byproducts and isomers in the current route due to the easy addition of two methyl groups in the C-alkylation step, and greatly improves the overall yield and purity. Compared with other existing technologies, the product yield is significantly improved. The overall yield of the synthetic route of this invention is 55.1%, which is almost 6.2 times the overall yield of 8.9% of the existing technology, representing a significant improvement.

[0085] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid, characterized in that, The synthesis method includes the following steps: a) Dissolve the substance shown in Formula I in a solvent, add thionyl chloride, react until the reaction is complete, add the reaction solution dropwise to ammonia water, wash with water, filter, and dry to obtain the compound shown in Formula II; the reaction temperature is 0~80℃, the amount of thionyl chloride is 1.5~2.5 equivalents, and the amount of ammonia water is 4.0~5.0 wt. b) Add solvent to the substance shown in Formula II, replace with nitrogen and cool down, then add 10.0 M borane dimethyl sulfide dropwise, stir the reaction until the reaction is complete, and wash, extract and concentrate the reaction solution to obtain the compound shown in Formula III; the amount of 10.0 M borane dimethyl sulfide used is 2.5~4.0 equivalents, and the temperature is controlled at 0~5℃ during the dropwise addition; the temperature during the stirring reaction is 50~55℃; c) Dissolve the substance shown in Formula III in a solvent, add sodium periodate and a catalyst, oxidize, and react at 20-30°C until the reaction is complete. The reaction solution is repeatedly adjusted for pH, filtered, extracted, concentrated, and slurried to obtain the compound shown in Formula IV; wherein, the amount of sodium periodate is 10.1-12.1 equivalents, and the catalyst is ruthenium chloride hydrate, with a catalyst amount of 0.01-0.023 equivalents; Among them, the compound represented by formula I: ; The compound represented by Formula II: ; The compound represented by Formula III: ; The compound represented by Formula IV: .

2. The method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid according to claim 1, characterized in that, Adjusting pH involves using an alkaline solution to make it alkaline and using an acidic solution to make it acidic.

3. The method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid according to claim 2, characterized in that, When adjusting to alkalinity, the alkaline solution used is a 15-20 wt% sodium carbonate aqueous solution, and the pH is adjusted to 9-10.

4. The method for synthesizing (R)-3-(tert-butoxycarbonyl)amino-2-methylpropionic acid according to claim 2, characterized in that, When adjusting to acidity, the acidic solution used is a 15-20 wt% citric acid aqueous solution, and the pH is adjusted to 3-4.

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