A process for the synthesis of (2S,3S)-3-t-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid

Abstract

The application discloses a synthesis method of (2S, 3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid and belongs to the field of pharmaceutical intermediates. The synthesis method comprises the following steps: (R)-glyceraldehyde acetonide is condensed with (S)-tert-butylsulfonamide in a Lewis acid to obtain an intermediate A, then nucleophilic addition is performed on the intermediate A with o-tolylmagnesium bromide to obtain an intermediate B, deprotection is performed on the intermediate B to obtain an intermediate C, then amino protection is performed on the intermediate C with di-tert-butyl dicarbonate to obtain an intermediate D, and finally, the intermediate D is oxidized under the catalysis of TEMPO to obtain a target product. The (R)-glyceraldehyde acetonide and the (S)-tert-butylsulfonamide are used as raw materials, and the target product is obtained through a condensation reaction, an addition reaction, an acidolysis reaction, a Boc protection reaction and an oxidation reaction in sequence, the synthesis route has the advantages of low cost, low cost, simple operation and meeting the requirement of process amplification.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid. Background Technology

[0002] (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid is a non-natural amino acid derivative belonging to the β-substituted isoserine class of compounds. This compound possesses important biological activities and is suitable for peptide synthesis and drug design. Its structural characteristics make it an ideal intermediate for peptide modification, conformational constraint, and the construction of bioactive molecules.

[0003] In the prior art, the synthesis of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid mainly includes the following methods: A. Using (S)-2-tert-butoxycarbonylamino-2-o-tolylacetic acid as a starting material, the corresponding aldehyde is obtained by reducing it with a reducing agent. This aldehyde is then added to an aqueous sodium cyanide solution, and sodium bisulfite is added dropwise to replace the cyano group. Hydrolysis and resolution then yield the target compound. This method has a low yield and uses hazardous sodium cyanide.

[0004] Its synthetic route is shown in the following equation:

[0005] B. Using (S)-2-tert-butoxycarbonylamino-2-o-tolylacetic acid as a starting material, the corresponding aldehyde is selectively reduced by a reducing agent. Subsequently, it undergoes a Wittig reaction with methyltriphenylphosphine bromide in the presence of potassium tert-butoxide to yield the corresponding olefin. This olefin is then selectively oxidized with sodium hypochlorite under the catalysis of a chiral Mn(III)-salen complex to obtain an epoxide, followed by ring-opening and re-oxidation to obtain the target compound. This method suffers from drawbacks such as high raw material costs, low yield, and difficulty in storing the intermediates, making it unsuitable for industrial-scale production.

[0006] Its synthetic route is shown in the following equation:

[0007] In conclusion, it is crucial to develop a synthetic route that uses inexpensive, readily available, and high-yield raw materials. Summary of the Invention

[0008] To address the limitations of existing methods for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid, including limited technical routes, low economic efficiency, poor reaction selectivity, and safety and environmental risks, this invention aims to provide a method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid. After process optimization, this method can selectively prepare amino acid structures with four configurations.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid, which is carried out according to the following synthetic route:

[0010] The synthesis method includes the following steps: Step 1: Mix (R)-glyceraldehyde acetal and (S)-tert-butyl sulfinamide in an organic solvent, and condense them under the action of Lewis acid and dehydrating agent to obtain intermediate A; Step 2: Mix intermediate A with an organic solvent and react it with o-tolyl Grignard reagent at low temperature to obtain intermediate B; Step 3: Mix intermediate B with an organic solvent and react with hydrogen chloride gas to obtain intermediate C; Step 4: Mix intermediate C, di-tert-butyl dicarbonate, and an organic solvent, and react them in the presence of an organic base to obtain intermediate D; Step 5: In the presence of TMEPO, air is introduced and the mixture is heated to undergo an oxidation reaction to obtain (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid.

[0011] Preferably, in step 1, the molar ratio of (R)-glyceraldehyde acetal to (S)-tert-butyl sulfinamide, Lewis acid to desiccant is 1.05-1.07:1:0.05:2.0-3.5.

[0012] Preferably, in step 1, the organic solvent is selected from dichloromethane or tetrahydrofuran; the Lewis acid is selected from p-toluenesulfonic acid or anhydrous ketone sulfate; and the desiccant is selected from anhydrous magnesium sulfate or anhydrous copper sulfate.

[0013] Preferably, in step 1, the intermediate A is prepared by: adding Lewis acid and desiccant to (R)-glyceraldehyde acetal and (S)-tert-butyl sulfinamide in a reaction solvent and reacting at 25-40°C for 5-8 hours, cooling to 0-20°C, filtering, concentrating under reduced pressure, and then directly using it in the next step.

[0014] Preferably, in step 2, the molar ratio of intermediate A to o-tolyl Grignard reagent is 1.0~1.1-1.2.

[0015] Preferably, in step 2, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is -40~10℃, and the reaction time is 3-4h.

[0016] Preferably, in step 2, the intermediate B is prepared by mixing intermediate A with an organic solvent, cooling the mixture, adding o-tolyl Grignard reagent solution dropwise, reacting for 3-4 hours after the addition is complete, quenching with saturated ammonium chloride aqueous solution, washing the organic phase with water, concentrating the organic phase under reduced pressure, and recrystallizing with toluene and n-heptane to obtain intermediate B.

[0017] Preferably, in step 3, the organic solvent is selected from tetrahydrofuran, ethyl acetate, or dichloromethane; the molar ratio of intermediate B to hydrogen chloride is 1:2-8.0.

[0018] Preferably, in step 4, the organic solvent is selected from methanol or ethanol; the organic base is selected from triethylamine or diisopropylethylamine.

[0019] Preferably, in step 4, the molar ratio of intermediate C, ditert-butyl dicarbonate, and organic base is 1:1.08-1.10:2.05-2.15.

[0020] Preferably, in step 5, the molar ratio of intermediate D to TMEPO is 1:0.02-0.04.

[0021] Compared with the prior art, the present invention has achieved the following technical advancements: 1. This invention uses (R)-glyceraldehyde acetal and (S)-tert-butyl sulfinamide to condense in a Lewis acid to obtain intermediate A, which then undergoes nucleophilic addition with o-tolyl magnesium bromide to obtain intermediate B. After deprotection, intermediate C is obtained, which is then protected with di-tert-butyl dicarbonate to obtain intermediate D. Finally, the target product is obtained by oxidation under TEMPO catalysis. The overall route is smooth, and all reagents used are conventional and readily available.

[0022] 2. This invention uses (R)-glyceraldehyde acetal and (S)-tert-butyl sulfinamide as raw materials, and proceeds through condensation reaction, addition reaction, acid hydrolysis reaction, Boc protection reaction and oxidation reaction in sequence to obtain the target product with high yield and purity. It has low cost, simple operation and is suitable for industrial scale-up.

[0023] 3. Since both tert-butyl sulfinamide and glyceraldehyde acetal (R and S) are readily available in the market, four different configurations can be selectively obtained by controlling the synthesis method of this invention. Replacing (S)-tert-butyl sulfinamide with (R)-tert-butyl sulfinamide, while keeping everything else unchanged, yields the 2S,3R configuration product. Similarly, replacing (R)-glyceraldehyde acetal with (S)-glyceraldehyde acetal, while keeping everything else unchanged, yields the 2R,3S configuration product. Simultaneously, replacing (S)-tert-butyl sulfinamide with (R)-tert-butyl sulfinamide and (R)-glyceraldehyde acetal with (S)-glyceraldehyde acetal results in the 2R,3R configuration product. Attached Figure Description

[0024] Figure 1 The image shows the HNMR spectrum of the product obtained in Example 8. Detailed Implementation

[0025] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0026] Example 1: Synthesis of Compound A

[0027] Under nitrogen protection, 136.6 g (1.05 mol) of (R)-glyceraldehyde acetal, 121.2 g (1.0 mol) of (S)-tert-butylsulfinamide, and 600 mL of tetrahydrofuran were mixed and stirred for 10 minutes until the mixture was completely dissolved. 8.6 g (50 nmol) of p-toluenesulfonic acid and 240.7 g (2.0 mol) of anhydrous magnesium sulfate were added, and the mixture was heated to 40 °C and reacted for 6 hours. TLC analysis showed almost no (S)-tert-butylsulfinamide remaining. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran. Toluene was added, and the mixture was completely dissolved. The mixture was then rapidly passed through silica gel, and the filtrate was concentrated under reduced pressure to remove the toluene, yielding intermediate A 203.5 g, with a yield of 87.2%.

[0028] Example 2: Synthesis of Compound A

[0029] Under nitrogen protection, 136.6 g (1.05 mol) of (R)-glyceraldehyde acetal, 121.2 g (1.0 mol) of (S)-tert-butyl sulfinamide and 1200 mL of dichloromethane were mixed and stirred for 10 minutes until the mixture was completely dissolved. 558.6 g (3.5 mol) of anhydrous copper sulfate was added, and the mixture was heated to 40 °C and reacted for 8 hours. TLC analysis showed that almost no (S)-tert-butyl sulfinamide remained. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove dichloromethane, yielding intermediate A 217.5 g, with a yield of 93.2%.

[0030] Example 3: Synthesis of Compound B

[0031] Under nitrogen protection, 186.7 g (800 nmol) of intermediate A was mixed with 1120 mL of tetrahydrofuran and stirred. The mixture was cooled to -40 °C, and 440 mL (880 nmol) of 2 M / L o-tolyl magnesium bromide tetrahydrofuran solution was slowly added dropwise. The reaction was then carried out at this temperature for 1 hour, followed by a slow increase to 10 °C and stirring for 2 hours. The mixture was quenched with saturated ammonium chloride aqueous solution, allowed to stand for separation, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure below 30 °C to remove the tetrahydrofuran. The solution was then dissolved again with ethyl acetate, washed with water, and the organic phase was concentrated under reduced pressure to remove the ethyl acetate. The solution was replaced with toluene until the water content was ≤0.1%. The mixture was recrystallized with n-heptane to obtain intermediate B with a dr = 98.3%. The solution was then recrystallized with toluene and n-heptane to obtain 198.1 g of intermediate B with a dr = 99.8%, yielding 76.1%.

[0032] Example 4: Synthesis of Compound B

[0033] Under nitrogen protection, 186.7 g (800 nmol) of intermediate A was mixed with 1500 mL of 2-methyltetrahydrofuran and stirred. The mixture was cooled to -40 °C, and 440 mL (880 mol) of 2 M / L o-tolyl magnesium bromide tetrahydrofuran solution was slowly added dropwise. The reaction was then carried out at this temperature for 2 hours, followed by a slow increase to 10 °C and stirring for 2 hours. The mixture was then quenched with a saturated ammonium chloride aqueous solution, allowed to stand for separation, and the aqueous phase was extracted with 2-methyltetrahydrofuran. The organic phases were combined, heated to 35 °C, washed with water, and the organic phase was concentrated under reduced pressure to remove 2-methyltetrahydrofuran. The organic phase was then replaced with toluene until the water content was ≤0.1%. Recrystallization with n-heptane yielded intermediate B (dr=98.8%). Recrystallization with toluene and n-heptane yielded 196.1 g of intermediate B (dr=99.9%) (HPLC 99.3%, yield 75.3%).

[0034] Example 5: Synthesis of Compound C

[0035] Compound B1 95.3 g (600 nmol) was mixed with 2000 mL of dichloromethane and stirred. The mixture was cooled to -5 °C and hydrogen chloride 175.2 g (4.8 mol) was slowly passed through while maintaining the temperature between -5 and 10 °C. The HPLC sample was completely removed. The dichloromethane and HCl were concentrated under reduced pressure at 25 °C. MTBE was added, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with MTBE to give intermediate C 117 g. The HPLC yield was 99.4%, and the recovery rate was 89.6%.

[0036] Example 6: Synthesis of Compound D

[0037] Under nitrogen protection, 87.1 g (400 nmol) of compound C, 94.3 g (432 nmol) of di-tert-butyl dicarbonate, and 260 mL of ethanol were mixed and stirred. The mixture was cooled to 10 °C, and 87 g (860 nmol) of triethylamine was added dropwise while maintaining the temperature below 35 °C. After the triethylamine was completely removed, the mixture was reacted at 30-35 °C for 5 hours. The ethanol and tert-butanol were concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with 5% hydrochloric acid solution, 6% sodium bicarbonate solution, and water, respectively. The organic phase was concentrated under reduced pressure to remove ethyl acetate, and n-heptane was added. The mixture was first heated to 60 °C and then cooled to 0-5 °C, resulting in the precipitation of a large amount of solid. The solid was filtered to give intermediate D 103.9 g (HPLC 99.8%, yield 92.3%).

[0038] Example 7: Synthesis of Compound D

[0039] Under nitrogen protection, 87.1 g (400 nmol) of compound C, 94.3 g (432 nmol) of di-tert-butyl dicarbonate, and 175 mL of methanol were mixed and stirred. The mixture was cooled to 10 °C, and 111.1 g (860 nmol) of DIPEA was added dropwise while maintaining the temperature below 35 °C. After the DIPEA was completely removed, the mixture was reacted at 30-35 °C for 5 hours. The methanol and tert-butanol were concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with 5% hydrochloric acid solution, 6% sodium bicarbonate solution, and water, respectively. The organic phase was concentrated under reduced pressure to remove ethyl acetate, and n-heptane was added. The mixture was first heated to 60 °C and then cooled to 0-5 °C, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain intermediate D 105.9 g (HPLC 99.7%, yield 94.1%).

[0040] Example 8: Synthesis of (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid

[0041] Intermediate D 56.3 g (200 nmol), 2,2,6,6-tetramethylpiperidine oxide 0.94 g (6 nmol), acetonitrile 280 mL, and water 280 mL were mixed and stirred. The mixture was heated to 45-50 °C, and compressed air was introduced during stirring for a total of 10 hours. HPLC analysis showed that the remaining raw material was <2%. The mixture was cooled to room temperature, and the pH was adjusted to 3.4-4.0 with 15% citric acid. Acetic acid was used for extraction, and the organic phase was dried over anhydrous magnesium sulfate. The mixture was filtered, and the filter cake was washed with ethyl acetate. Most of the ethyl acetate was concentrated under reduced pressure. Isopropyl ether was added, and the mixture was first heated to 60 °C, then cooled to 5 °C. A large amount of white solid precipitated out. The solid was filtered to obtain the target product (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid 52.1 g (HPLC 99.3%, yield 88.2%).

[0042] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid, characterized in that, The synthesis route is as follows: ； The synthesis method includes the following steps: Step 1: Mix (R)-glyceraldehyde acetal and (S)-tert-butyl sulfinamide in an organic solvent, and condense them under the action of Lewis acid and dehydrating agent to obtain intermediate A; Step 2: Mix intermediate A with an organic solvent and react it with o-tolyl Grignard reagent at low temperature to obtain intermediate B; Step 3: Mix intermediate B with an organic solvent and react with hydrogen chloride gas to obtain intermediate C; Step 4: Mix intermediate C, di-tert-butyl dicarbonate, and an organic solvent, and react them in the presence of an organic base to obtain intermediate D; Step 5: In the presence of TMEPO, air is introduced and the mixture is heated to undergo an oxidation reaction to obtain (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid.

2. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 1, the molar ratio of (R)-glyceraldehyde acetal to (S)-tert-butyl sulfinamide, Lewis acid to desiccant is 1.05-1.07:1:0.05:2.0-3.

5.

3. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 1, the organic solvent is selected from dichloromethane or tetrahydrofuran; the Lewis acid is selected from p-toluenesulfonic acid or anhydrous ketone sulfate; and the desiccant is selected from anhydrous magnesium sulfate or anhydrous copper sulfate.

4. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 2, the molar ratio of intermediate A to o-tolyl Grignard reagent is 1.0~1.1-1.

2.

5. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 2, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is -40~10℃, and the reaction time is 3-4h.

6. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 3, the organic solvent is selected from tetrahydrofuran, ethyl acetate, or dichloromethane; the molar ratio of intermediate B to hydrogen chloride is 1:2-8.

7. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 4, the organic solvent is selected from methanol or ethanol; the organic base is selected from triethylamine or diisopropylethylamine.

8. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 4, the molar ratio of intermediate C, ditert-butyl dicarbonate, and organic base is 1:1.08-1.10:2.05-2.

15.

9. The method for synthesizing (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-o-tolylpropionic acid according to claim 1, characterized in that: In step 5, the molar ratio of intermediate D to TMEPO is 1:0.02-0.04.

Images