A method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine

Abstract

The present invention provides a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine, which relates to the field of organic synthesis. The preparation method of the present invention comprises the following steps: (1) reacting compound 1, a base, and di-tert-butyl dicarbonate in a solvent to obtain compound 2; (2) reacting compound 2, a base, and dimethyl sulfate in a solvent to obtain compound 3; (3) reacting compound 3 with thionyl chloride in a solvent to obtain compound 4; (4) reacting compound 4 with benzyl chloroformate in an alkaline environment in a solvent to obtain compound 5; (5) reacting compound 5 with a base in a solvent to obtain. The raw materials used in the present invention are easily available and low-priced, the reaction conditions are mild, the intermediate reaction steps do not require purification, and column chromatography separation is not required, and the steps are simple; and the reaction steps of the present invention are safe, non-toxic, and environmentally friendly. The product obtained by the preparation method of the present invention has high purity, high yield, low cost, is suitable for scale-up production, and has broad application prospects. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine. Background Art

[0002] Research indicates that diol-based HIV protease inhibitors containing novel P2 substituents are potential drugs for treating AIDS (J. Adrian Meredith et al. Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors. European Journal of Medicinal Chemistry 45 (2010) 160–170). The document mentions O-methyl-L-homoserine derivatives as important intermediates for preparing these novel P2 substituents. The document discloses a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine, the synthetic route of which is as follows:

[0003]

[0004] The above-mentioned method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine has a total of three steps. The yield of step 1 (Step: 1) is only 50%, the yield of step 2 (Step: 2) is only 44%, and the yield of step 3 is only 58%, with an overall yield of only 13%, which is a very low yield. In addition, step 2 uses expensive reagents such as 2,6-di-tert-butyl-4-methylpyridine and methyl trifluoromethanesulfonate, which is relatively costly. In addition, both steps 2 and 3 require column chromatography separation, which is not conducive to scale-up production. Summary of the Invention

[0005] In order to solve the above problems, the present invention provides a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine.

[0006] The present invention provides a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine, which comprises the following steps:

[0007]

[0008] Step 1: Compound 1, a base and di-tert-butyl dicarbonate react in a solvent to obtain compound 2;

[0009] Step 2: Compound 2, a base and dimethyl sulfate react in a solvent to obtain compound 3;

[0010] Step 3: Compound 3 reacts with thionyl chloride in a solvent to obtain compound 4;

[0011] Step 4: In a solvent, compound 4 and benzyl chloroformate react under alkaline conditions to obtain compound 5;

[0012] Step 5: Compound 5 reacts with a base in a solvent to obtain O-methyl-N-benzyloxycarbonyl-L-homoserine.

[0013] Furthermore,

[0014] In step 1, the base is one or a mixture of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, triethylamine, diisopropylethylamine, and pyridine;

[0015] And / or, in step 1, the solvent is one or a mixture of water, methanol, ethanol, tetrahydrofuran, dioxane, and dimethylformamide;

[0016] And / or, in step 2, the base is one or a mixture of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, and potassium carbonate;

[0017] And / or, in step 2, the solvent is one or a mixture of tetrahydrofuran, acetone, dioxane, and methyl tert-butyl ether;

[0018] And / or, in step 3, the solvent is methanol;

[0019] And / or, in step 4, the solvent is one or a mixture of water, tetrahydrofuran, dioxane, dichloromethane, and methyl tert-butyl ether;

[0020] And / or, in step 4, the alkaline environment is an environment with a pH of 8 to 9;

[0021] And / or, in step 5, the base is one or a mixture of sodium hydroxide, potassium hydroxide, and lithium hydroxide;

[0022] And / or, in step 5, the solvent is one or a mixture of water, tetrahydrofuran, dioxane, dichloromethane, and methyl tert-butyl ether.

[0023] Furthermore,

[0024] In step 1, the base is potassium carbonate;

[0025] And / or, in step 1, the solvent is methanol;

[0026] And / or, in step 2, the base is sodium hydroxide;

[0027] And / or, in step 2, the solvent is tetrahydrofuran, acetone or dioxane;

[0028] And / or, in step 4, the solvent is a mixed solution of water and tetrahydrofuran;

[0029] And / or, in step 4, the alkaline environment is an environment with a pH of 8;

[0030] And / or, in step 5, the base is sodium hydroxide;

[0031] And / or, in step 5, the solvent is a mixed solution of water and methyl tert-butyl ether or a mixed solution of water and dichloromethane.

[0032] Furthermore,

[0033] In step 4, the volume ratio of water to tetrahydrofuran is 1:1;

[0034] And / or, in step 4, the alkaline environment is adjusted to pH=8 using sodium bicarbonate;

[0035] And / or, in step 5, the volume ratio of water to methyl tert-butyl ether is 1:1 or the volume ratio of water to dichloromethane is 1:1.

[0036] Furthermore,

[0037] In step 1, the molar ratio of compound 1, base and di-tert-butyl dicarbonate is 1:1-5:1-5;

[0038] and / or, in step 2, the molar ratio of the compound 2, the base and dimethyl sulfate is 1:1-5:1-5;

[0039] And / or, in step 3, the molar ratio of compound 3 to thionyl chloride is 1:1 to 5;

[0040] And / or, in step 4, the molar ratio of benzyl chloroformate to compound 3 in step 3 is 1 to 5:1;

[0041] And / or, in step 5, the molar ratio of the base to the compound 3 in step 3 is 1 to 5:1.

[0042] Furthermore,

[0043] In step 1, the molar ratio of compound 1, base and di-tert-butyl dicarbonate is 1:1:1.1;

[0044] And / or, in step 2, the molar ratio of compound 2, base and dimethyl sulfate is 1:1:2;

[0045] And / or, in step 3, the molar ratio of compound 3 to thionyl chloride is 1:1.3;

[0046] and / or, in step 4, the molar ratio of benzyl chloroformate to compound 3 in step 3 is 1.5:1;

[0047] And / or, in step 5, the molar ratio of the base to the compound 3 in step 3 is 1.5:1.

[0048] Furthermore,

[0049] In step 1, the reaction temperature is 25-35°C;

[0050] And / or, in step 2, the reaction temperature is 0 to 10°C;

[0051] And / or, in step 3, the reaction is a reflux reaction;

[0052] And / or, in step 4, the reaction temperature is 25-35°C;

[0053] And / or, in step 4, the reaction temperature is 25-35°C.

[0054] Furthermore,

[0055] In step 1, after the reaction, water is added to the reaction solution, the temperature is lowered to 0-10° C., the pH is adjusted to 3-4, a solid is precipitated, and the solid is filtered and dried to obtain compound 2;

[0056] And / or, in step 2, after the reaction, water is added to the reaction solution to adjust the pH to 3-4, extraction is performed, the organic phase is dried, filtered, and concentrated under reduced pressure to remove the solvent to obtain compound 3;

[0057] And / or, in step 3, after the reaction, the reaction solution is concentrated to dryness under reduced pressure and directly used in the reaction of step 4;

[0058] And / or, in step 4, after the reaction, the reaction solution is extracted, the organic phase is dried, filtered, concentrated to dryness, and directly used in the reaction of step 5;

[0059] Preferably,

[0060] In step 1, hydrochloric acid is used to adjust the pH;

[0061] And / or, in step 2, the pH is adjusted using hydrochloric acid;

[0062] And / or, in step 2, the extraction is performed using dichloromethane or methyl tert-butyl ether;

[0063] And / or, in step 4, the extraction is carried out using dichloromethane or methyl tert-butyl ether.

[0064] Furthermore,

[0065] In step 5, after the reaction, the reaction solution is separated, the aqueous phase is extracted, the pH of the extracted aqueous phase is adjusted to 2-3, extracted again, and the organic phase is dried, filtered, and concentrated to obtain O-methyl-N-benzyloxycarbonyl-L-homoserine.

[0066] Furthermore,

[0067] In step 5, the aqueous phase is extracted with dichloromethane or methyl tert-butyl ether;

[0068] And / or, in step 5, the pH is adjusted using hydrochloric acid;

[0069] And / or, in step 5, the extraction is performed again using dichloromethane.

[0070] In the present invention, the room temperature is 25 to 35°C.

[0071] Compared with the prior art, the present invention has the following beneficial effects:

[0072] The present invention provides a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine. The preparation method uses readily available and inexpensive raw materials, has mild reaction conditions, requires no purification in intermediate reaction steps, and does not require column chromatography separation, resulting in a simple process. Furthermore, the reaction steps involved are safe, non-toxic, and environmentally friendly. The product obtained by the preparation method has high purity (over 98%), high yield (over 60%), low cost, is suitable for scale-up production, and has broad application prospects.

[0073] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0074] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0075] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0076] The route for synthesizing O-methyl-N-benzyloxycarbonyl-L-homoserine of the present invention is as follows:

[0077]

[0078] The synthetic route of the present invention comprises 5 steps, wherein the yield of step 1 is 95.6%. In steps 2-5, the intermediate is not purified and the crude product is used directly, and the total yield of the 4 steps is 70%. No expensive reagents are used, the yield is high, column chromatography separation is not required, the cost is low, and scale-up is facilitated.

[0079] Example 1: Preparation of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0080] Step 1: Synthesis of N-Boc-L-homoserine

[0081] L-homoserine (11.9 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were dissolved in 120 mL of methanol. Di-tert-butyl dicarbonate (24 g, 0.11 mol) was slowly added dropwise at room temperature. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 120 mL of tap water was added, the temperature was lowered to 0-10°C, and the pH was adjusted to 3-4 with 3N hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 20.8 g of N-Boc-L-homoserine with a yield of 95%.

[0082] Step 2: Synthesis of O-methyl-N-Boc-L-homoserine

[0083] N-Boc-L-homoserine (22.0 g, 0.1 mol) was dissolved in 220 mL of tetrahydrofuran, and sodium hydroxide (4.0 g, 0.1 mol) was added in batches. The temperature was lowered to 0-10°C, and dimethyl sulfate (25.0 g, 0.2 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the starting material disappeared on TLC. 220 mL of tap water was added, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The product was extracted twice with 110 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 24 g of an oily crude product, which was directly carried out to the next step without purification.

[0084] Step 3: Synthesis of O-methyl-L-homoserine methyl ester hydrochloride

[0085] Dissolve O-methyl-N-Boc-L-homoserine (24.0 g, 0.1 mol) in 240 mL of methanol. Slowly add thionyl chloride (15.5 g, 0.13 mol) dropwise at room temperature. After the addition is complete, heat the mixture to reflux and continue the reaction until the intermediate disappears on TLC. Cool the mixture and concentrate under reduced pressure to dryness, then proceed directly to the next step.

[0086] Step 4: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine methyl ester

[0087] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of tetrahydrofuran. The pH was adjusted to 8 with sodium bicarbonate at room temperature. Benzyl chloroformate (25.5 g, 0.15 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the raw material disappeared on TLC. The reaction solution was extracted three times with 360 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and directly proceeded to the next step.

[0088] Step 5: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0089] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of methyl tert-butyl ether. Sodium hydroxide (6.0 g, 0.15 mol) was added at room temperature and the reaction was continued until the starting material disappeared on TLC. The liquid was separated and the aqueous phase was extracted three times with 120 mL of methyl tert-butyl ether. The pH of the aqueous phase was adjusted to 2-3 with 6N hydrochloric acid and extracted twice with 240 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 18.7 g of a light yellow oil with a purity of 98.9% as determined by HPLC and a yield of 70%.

[0090] [M-1]: 266.2; HNMR (400M, DMSO): δ=7.54-7.55(d,1H),7.30-7.38(m,5H),5.02(s, 2H),4.03(m,1H),3.33(d,2H),3.19(s,3H),1.90-1.96(m,1H),1.70-1.78(m,1H).

[0091] Example 2: Preparation of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0092] Step 1: Synthesis of N-Boc-L-homoserine

[0093] L-homoserine (11.9 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were dissolved in 120 mL of methanol. Di-tert-butyl dicarbonate (24 g, 0.11 mol) was slowly added dropwise at room temperature. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 120 mL of tap water was added, the temperature was lowered to 0-10°C, and the pH was adjusted to 3-4 with 3N hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 20.8 g of N-Boc-L-homoserine with a yield of 95%.

[0094] Step 2: Synthesis of O-methyl-N-Boc-L-homoserine

[0095] N-Boc-L-homoserine (22.0 g, 0.1 mol) was dissolved in 220 mL of acetone, and sodium hydroxide (4.0 g, 0.1 mol) was added in batches. The temperature was lowered to 0-10°C, and dimethyl sulfate (25.0 g, 0.2 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 220 mL of tap water was added, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The product was extracted twice with 110 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 24 g of an oily crude product. The product was directly processed into the next step without purification.

[0096] Step 3: Synthesis of O-methyl-L-homoserine methyl ester hydrochloride

[0097] Dissolve O-methyl-N-Boc-L-homoserine (24.0 g, 0.1 mol) in 240 mL of methanol. Slowly add thionyl chloride (15.5 g, 0.13 mol) dropwise at room temperature. After the addition is complete, heat the mixture to reflux and continue the reaction until the intermediate disappears on TLC. Cool the mixture and concentrate under reduced pressure to dryness, then proceed directly to the next step.

[0098] Step 4: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine methyl ester

[0099] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of tetrahydrofuran. The pH was adjusted to 8 with sodium bicarbonate at room temperature. Benzyl chloroformate (25.5 g, 0.15 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the raw material disappeared on TLC. The reaction solution was extracted three times with 360 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and directly proceeded to the next step.

[0100] Step 5: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0101] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of methyl tert-butyl ether. Sodium hydroxide (6.0 g, 0.15 mol) was added at room temperature and the reaction was continued until the starting material disappeared by TLC. The layers were separated and the aqueous phase was extracted three times with 120 mL of methyl tert-butyl ether. The pH of the aqueous phase was adjusted to 2-3 with 6N hydrochloric acid and extracted twice with 240 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 17.6 g of a light yellow oil with a purity of 98.5% as determined by HPLC and a yield of 66%.

[0102] [M-1]: 266.2; HNMR (400M, DMSO): δ=7.54-7.55(d,1H),7.30-7.38(m,5H),5.02(s, 2H),4.03(m,1H),3.33(d,2H),3.19(s,3H),1.90-1.96(m,1H),1.70-1.78(m,1H).

[0103] Example 3: Preparation of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0104] Step 1: Synthesis of N-Boc-L-homoserine

[0105] L-homoserine (11.9 g, 0.1 mol) and potassium carbonate (13.8 g, 0.1 mol) were dissolved in 120 mL of methanol. Di-tert-butyl dicarbonate (24 g, 0.11 mol) was slowly added dropwise at room temperature. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 120 mL of tap water was added, the temperature was lowered to 0-10°C, and the pH was adjusted to 3-4 with 3N hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 20.8 g of N-Boc-L-homoserine with a yield of 95%.

[0106] Step 2: Synthesis of O-methyl-N-Boc-L-homoserine

[0107] N-Boc-L-homoserine (22.0 g, 0.1 mol) was dissolved in 220 mL of dioxane, and sodium hydroxide (4.0 g, 0.1 mol) was added in batches. The temperature was lowered to 0-10°C, and dimethyl sulfate (25.0 g, 0.2 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 220 mL of tap water was added, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The product was extracted twice with 110 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 24 g of an oily crude product, which was directly carried out to the next step without purification.

[0108] Step 3: Synthesis of O-methyl-L-homoserine methyl ester hydrochloride

[0109] Dissolve O-methyl-N-Boc-L-homoserine (24.0 g, 0.1 mol) in 240 mL of methanol. Slowly add thionyl chloride (15.5 g, 0.13 mol) dropwise at room temperature. After the addition is complete, heat the mixture to reflux and continue the reaction until the intermediate disappears on TLC. Cool the mixture and concentrate under reduced pressure to dryness, then proceed directly to the next step.

[0110] Step 4: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine methyl ester

[0111] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of tetrahydrofuran. The pH was adjusted to 8 with sodium bicarbonate at room temperature. Benzyl chloroformate (25.5 g, 0.15 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the raw material disappeared on TLC. The reaction solution was extracted three times with 360 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and directly proceeded to the next step.

[0112] Step 5: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0113] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of dichloromethane. Sodium hydroxide (6.0 g, 0.15 mol) was added at room temperature and the reaction was continued until the starting material disappeared on TLC. The layers were separated and the aqueous phase was extracted three times with 120 mL of dichloromethane. The pH of the aqueous phase was adjusted to 2-3 with 6N hydrochloric acid and extracted twice with 240 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 17.6 g of a light yellow oil with a purity of 98.0% as determined by HPLC and a yield of 65%.

[0114] [M-1]: 266.2; HNMR (400M, DMSO): δ=7.54-7.55(d,1H),7.30-7.38(m,5H),5.02(s, 2H),4.03(m,1H),3.33(d,2H),3.19(s,3H),1.90-1.96(m,1H),1.70-1.78(m,1H).

[0115] Example 4: Preparation of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0116] Step 1: Synthesis of N-Boc-L-homoserine

[0117] L-homoserine (1.5 kg, 12.6 mol) and potassium carbonate (1.74 kg, 12.6 mol) were dissolved in 15 L of methanol. Di-tert-butyl dicarbonate (2.75 kg, 13.8 mol) was slowly added dropwise at room temperature. After the addition was completed, the reaction was continued until the starting material disappeared by TLC. 15 L of tap water was added, the temperature was lowered to 0-10°C, and the pH was adjusted to 3-4 with 3N hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 2.6 kg of N-Boc-L-homoserine with a yield of 95%.

[0118] Step 2: Synthesis of O-methyl-N-Boc-L-homoserine

[0119] N-Boc-L-homoserine (2.6 kg, 11.8 mol) was dissolved in 26 L of tetrahydrofuran, and sodium hydroxide (0.47 kg, 11.8 mol) was added in batches. The temperature was lowered to 0-10°C, and dimethyl sulfate (3.0 kg, 23.6 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the TLC raw material disappeared. 26 L of tap water was added, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The mixture was extracted twice with 13 L of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 2.7 kg of an oily crude product, which was directly carried out to the next step without purification.

[0120] Step 3: Synthesis of O-methyl-L-homoserine methyl ester hydrochloride

[0121] Dissolve O-methyl-N-Boc-L-homoserine (2.7 kg, 11.8 mol) in 27 L of methanol. Slowly add thionyl chloride (1.82 kg, 15.3 mol) dropwise at room temperature. After the addition is complete, raise the temperature to reflux and continue the reaction until the intermediate disappears on TLC. Cool the mixture and concentrate to dryness under reduced pressure before proceeding directly to the next step.

[0122] Step 4: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine methyl ester

[0123] The concentrate from the previous step was dissolved in 21 L of water and 21 L of tetrahydrofuran. The pH was adjusted to 8 with sodium bicarbonate at room temperature. Benzyl chloroformate (3.0 kg, 17.7 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the starting material disappeared on TLC. The reaction solution was extracted three times with 30 L of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and directly proceeded to the next step.

[0124] Step 5: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0125] The concentrate from the previous step was dissolved in 21 L of water and 21 L of methyl tert-butyl ether. Sodium hydroxide (0.7 kg, 17.7 mol) was added at room temperature and the reaction was continued until the starting material disappeared by TLC. The layers were separated and the aqueous phase was extracted three times with 10 L of methyl tert-butyl ether. The pH of the aqueous phase was adjusted to 2-3 with 6N hydrochloric acid and extracted twice with 21 L of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.2 kg of a light yellow oil with a purity of 99.0% as determined by HPLC and a yield of 70%.

[0126] [M-1]: 266.2; HNMR (400M, DMSO): δ=7.54-7.55(d,1H),7.30-7.38(m,5H),5.02(s, 2H),4.03(m,1H),3.33(d,2H),3.19(s,3H),1.90-1.96(m,1H),1.70-1.78(m,1H).

[0127] Comparative Example 1

[0128] Step 1: Synthesis of N-Boc-L-homoserine

[0129] L-homoserine (11.9 g, 0.1 mol) and sodium hydroxide (4.0 g, 0.1 mol) were dissolved in 120 mL of methanol. Di-tert-butyl dicarbonate (24 g, 0.11 mol) was slowly added dropwise at room temperature. After the addition was completed, the reaction was continued for 24 hours. 120 mL of tap water was added, the temperature was lowered to 0-10°C, and the pH was adjusted to 3-4 with 3N hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 17.5 g of N-Boc-L-homoserine with a yield of 80%.

[0130] Step 2: Synthesis of O-methyl-N-Boc-L-homoserine

[0131] N-Boc-L-homoserine (22.0 g, 0.1 mol) was dissolved in 220 mL of methyl tert-butyl ether, and sodium hydroxide (4.0 g, 0.1 mol) was added in batches. The temperature was lowered to 0-10°C, and dimethyl sulfate (25.0 g, 0.2 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the starting material disappeared on TLC. 220 mL of tap water was added, and the pH was adjusted to 3-4 with 3N hydrochloric acid. The product was extracted twice with 110 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 24 g of an oily crude product. The product was directly subjected to the next step without purification.

[0132] Step 3: Synthesis of O-methyl-L-homoserine methyl ester hydrochloride

[0133] Dissolve O-methyl-N-Boc-L-homoserine (24.0 g, 0.1 mol) in 240 mL of methanol. Slowly add thionyl chloride (15.5 g, 0.13 mol) dropwise at room temperature. After the addition is complete, heat the mixture to reflux and continue the reaction until the intermediate disappears on TLC. Cool the mixture and concentrate under reduced pressure to dryness, then proceed directly to the next step.

[0134] Step 4: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine methyl ester

[0135] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of methyl tert-butyl ether. The pH was adjusted to 8 with sodium bicarbonate at room temperature. Benzyl chloroformate (25.5 g, 0.15 mol) was slowly added dropwise. After the addition was completed, the reaction was continued until the TLC raw material disappeared. The reaction solution was extracted three times with 360 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and directly proceeded to the next step.

[0136] Step 5: Synthesis of O-methyl-N-benzyloxycarbonyl-L-homoserine

[0137] The concentrate from the previous step was dissolved in 240 mL of water and 240 mL of dichloromethane. Sodium hydroxide (6.0 g, 0.15 mol) was added at room temperature and the reaction was continued until the starting material disappeared on TLC. The liquid was separated and the aqueous phase was extracted three times with 120 mL of methyl tert-butyl ether. The pH of the aqueous phase was adjusted to 2-3 with 6N hydrochloric acid and extracted twice with 240 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 12.0 g of a light yellow oil with a purity of 98.9% as determined by HPLC and a yield of 45%.

[0138] [M-1]: 266.2; HNMR (400M, DMSO): δ=7.54-7.55(d,1H),7.30-7.38(m,5H),5.02(s, 2H),4.03(m,1H),3.33(d,2H),3.19(s,3H),1.90-1.96(m,1H),1.70-1.78(m,1H).

[0139] In summary, the present invention provides a method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine. The preparation method utilizes readily available and inexpensive raw materials, operates under mild reaction conditions, requires no purification in intermediate reaction steps, and requires no column chromatography separation, resulting in a simple process. Furthermore, the reaction steps involved are safe, non-toxic, and environmentally friendly. The product obtained by the preparation method has high purity (over 98%), high yield (over 60%), low cost, is suitable for scale-up production, and has broad application prospects.

Claims

1. A method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine, characterized in that: It includes the following steps: Step 1: Compound 1, a base and di-tert-butyl dicarbonate react in a solvent to obtain compound 2; Step 2: Compound 2, a base and dimethyl sulfate react in a solvent to obtain compound 3; Step 3: Compound 3 reacts with thionyl chloride in a solvent to obtain compound 4; Step 4: In a solvent, compound 4 and benzyl chloroformate react under alkaline conditions to obtain compound 5; Step 5: Compound 5 reacts with a base in a solvent to obtain O-methyl-N-benzyloxycarbonyl-L-homoserine; In step 1, the base is potassium carbonate; In step 1, the solvent is methanol; In step 2, the base is sodium hydroxide; In step 2, the solvent is tetrahydrofuran, acetone or dioxane; In step 3, the solvent is methanol; In step 4, the solvent is a mixed solution of water and tetrahydrofuran; In step 4, the alkaline environment is an environment with a pH of 8; In step 5, the base is sodium hydroxide; In step 5, the solvent is a mixed solution of water and methyl tert-butyl ether or a mixed solution of water and dichloromethane.

2. The method according to claim 1, wherein: In step 4, the volume ratio of water to tetrahydrofuran is 1:1; Alternatively, in step 4, the alkaline environment is adjusted to pH 8 using sodium bicarbonate; Alternatively, in step 5, the volume ratio of water to methyl tert-butyl ether is 1:1 or the volume ratio of water to dichloromethane is 1:

1.

3. The method according to claim 1, wherein: In step 1, the molar ratio of compound 1, base and di-tert-butyl dicarbonate is 1:1-5:1-5; Or, in step 2, the molar ratio of the compound 2, the base and dimethyl sulfate is 1:1-5:1-5; Or, in step 3, the molar ratio of compound 3 to thionyl chloride is 1:1 to 5; Alternatively, in step 4, the molar ratio of benzyl chloroformate to compound 3 in step 3 is 1 to 5:1; Alternatively, in step 5, the molar ratio of the base to the compound 3 in step 3 is 1 to 5:

1.

4. The method according to claim 3, wherein: In step 1, the molar ratio of compound 1, base and di-tert-butyl dicarbonate is 1:1:1.1; Alternatively, in step 2, the molar ratio of compound 2, base and dimethyl sulfate is 1:1:2; Or, in step 3, the molar ratio of compound 3 to thionyl chloride is 1:1.3; Alternatively, in step 4, the molar ratio of benzyl chloroformate to compound 3 in step 3 is 1.5:1; Alternatively, in step 5, the molar ratio of the base to the compound 3 in step 3 is 1.5:

1.

5. The method according to claim 1, wherein: In step 1, the reaction temperature is 25-35°C; Or, in step 2, the reaction temperature is 0-10°C; Or, in step 3, the reaction is a reflux reaction; Alternatively, in step 4, the reaction temperature is 25-35°C; Alternatively, in step 4, the reaction temperature is 25-35°C.

6. The method according to claim 1, wherein: In step 1, after the reaction, water is added to the reaction solution, the temperature is lowered to 0-10° C., the pH is adjusted to 3-4, a solid is precipitated, and the solid is filtered and dried to obtain compound 2; Alternatively, in step 2, after the reaction, water is added to the reaction solution to adjust the pH to 3-4, extraction is performed, the organic phase is dried, filtered, and concentrated under reduced pressure to remove the solvent to obtain compound 3; Alternatively, in step 3, after the reaction, the reaction solution is concentrated to dryness under reduced pressure and directly used in the reaction of step 4; Alternatively, in step 4, after the reaction, the reaction solution is extracted, the organic phase is dried, filtered, concentrated to dryness, and directly used in the reaction of step 5.

7. The method according to claim 6, characterized in that: In step 1, hydrochloric acid is used to adjust the pH; Or, in step 2, the pH is adjusted using hydrochloric acid; Or, in step 2, the extraction is performed using dichloromethane or methyl tert-butyl ether; Alternatively, in step 4, the extraction is performed using dichloromethane or methyl tert-butyl ether.

8. The method according to claim 1, wherein: In step 5, after the reaction, the reaction solution is separated, the aqueous phase is extracted, the pH of the extracted aqueous phase is adjusted to 2-3, extracted again, and the organic phase is dried, filtered, and concentrated to obtain O-methyl-N-benzyloxycarbonyl-L-homoserine.

9. The method according to claim 8, characterized in that: In step 5, the aqueous phase is extracted with dichloromethane or methyl tert-butyl ether; Alternatively, in step 5, the pH is adjusted using hydrochloric acid; Alternatively, in step 5, the extraction is performed again using dichloromethane.

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