A method for efficiently preparing high-purity Fmoc-Tyr(Me)-OH

Abstract

The application discloses a kind of high-efficiency preparation methods of high-purity Fmoc-Tyr (Me)-OH, belong to the field of pharmaceutical intermediates, the method is first reacted with methanol and thionyl chloride after Tyr, with specific amount of di-tert-butyl dicarbonate reaction;Second, dissolved in solvent one, with specific amount of dimethyl carbonate reaction;Third, hydrolysis under alkaline condition;Then dissolved in solvent two, hydrolysis under acidic condition;Finally, with Fmoc-OSu reaction, obtain Fmoc-Tyr (Me)-OH.The application innovatively uses dimethyl carbonate, solvent one when synthesizing Boc-Tyr (Me)-OMe, and uses solvent two when synthesizing H-Tyr (Me)-OH, the three produce synergy under specific components, while guaranteeing product purity and maximum single impurity, reduce production cost and safety risk, greatly improve total yield, in addition, di-tert-butyl dicarbonate is used to pre-protect amino group, so that noble metal catalyst need not be used when removing protecting group, cost is significantly reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates, specifically relating to an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH. Background Technology

[0002] Fmoc-Tyr(Me)-OH, systematically named (S)-2-{[(9H-fluoren-9-yl)methoxy]carbonyl}-3-(4-methoxyphenyl)propionic acid, is a protected amino acid and also an organic synthesis intermediate and pharmaceutical intermediate. It can be used in biochemical research, organic synthesis, and pharmaceutical development. Its structural formula is shown below:

[0003] Because the hydroxyl and carboxyl groups in the tyrosine (L-configuration) molecule have similar chemical properties, to prevent side reactions and considering the solubility of the material, the amino and carboxyl groups are usually pre-protected, the hydroxyl group is methylated, the pre-protection is removed, and finally the desired protecting group is introduced onto the amino group. Currently, the mainstream method for industrial production includes the following steps: A. Starting with Tyr, it reacts with methanol (MeOH) to obtain H-Tyr-OMe·HCl (carboxyl preprotection). BH-Tyr-OMe·HCl reacts with benzyl chloroformate (Cbz-Cl) to give Z-Tyr-OMe (amino preprotected); CZ-Tyr-OMe reacts with a methylating agent [commonly dimethyl sulfate (Me2SO4)] to give Z-Tyr(Me)-OMe; DZ-Tyr(Me)-OMe hydrolyzes to obtain Z-Tyr(Me)-OH; EZ-Tyr(Me)-OH is hydrogenolyzed under palladium on carbon (Pd / C) catalysis to give H-Tyr(Me)-OH; FH-Tyr(Me)-OH reacts with 9-fluorenylmethyl-N-succinimide carbonate (Fmoc-OSu) to give Fmoc-Tyr(Me)-OH.

[0004] The reaction formula is shown below:

[0005] This method has the following drawbacks: long steps, low yield, long working time, and requires the use of highly toxic reagents and expensive precious metal catalysts, resulting in high safety risks and production costs, making it unsuitable for industrial production. Summary of the Invention

[0006] To address the above problems, this invention provides an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH.

[0007] Unless otherwise specified, the tyrosine (Tyr) and its derivatives involved in this invention are all L-configured, and the L-configuration is omitted in all molecular formulas. The technical solution of this invention is as follows: An efficient method for preparing high-purity Fmoc-Tyr(Me)-OH includes the following steps: After Tyr was mixed evenly with methanol, thionyl chloride (SOCl2) was added dropwise to react and give H-Tyr-OMe·HCl. H-Tyr-OMe·HCl was reacted with ditert-butyl dicarbonate [(Boc)2O] to obtain Boc-Tyr-OMe; Boc-Tyr-OMe is dissolved in an amide or sulfoxide polar aprotic solvent (solvent one) and reacted with dimethyl carbonate to obtain Boc-Tyr(Me)-OMe. Boc-Tyr(Me)-OMe was hydrolyzed under alkaline conditions to obtain Boc-Tyr(Me)-OH; Boc-Tyr(Me)-OH was dissolved in an ether solvent (solvent two) and hydrolyzed under acidic conditions to obtain H-Tyr(Me)-OH; H-Tyr(Me)-OH reacts with Fmoc-OSu to obtain Fmoc-Tyr(Me)-OH. The molar ratio of ditert-butyl dicarbonate to H-Tyr-OMe·HCl is (1.1~2):1; the mass ratio of amide or sulfoxide polar aprotic solvent to Boc-Tyr-OMe is (0.5~1):1; the molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2~3):1; and the mass ratio of ether solvent to Boc-Tyr(Me)-OH is (4~8):1.

[0008] This invention provides an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH, the reaction formula of which is as follows:

[0009] This invention innovatively uses dimethyl carbonate, which has low toxicity, as the methylating agent in the synthesis of Boc-Tyr(Me)-OMe, and selects amide or sulfoxide polar aprotic solvents. In the synthesis of H-Tyr(Me)-OH, an ether solvent is used. The three components produce a synergistic effect under specific conditions, which reduces safety risks and significantly improves the overall yield while ensuring product purity and minimizing single impurities, making it very suitable for industrial-scale production. At the same time, since di-tert-butyl dicarbonate is used instead of benzyl chloroformate for preprotection of the amino group, the costly noble metal catalyst (palladium on carbon) is not required when removing the protecting group, resulting in a significant reduction in cost.

[0010] Preferably, the amide or sulfoxide polar aprotic solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, or N,N-dimethylformamide.

[0011] Preferably, the ether solvent is one or more of dioxane, tetrahydrofuran, or ethylene glycol dimethyl ether.

[0012] Preferably, the molar ratio of di-tert-butyl dicarbonate to H-Tyr-OMe·HCl is (1.1~1.8):1; more preferably, the molar ratio of di-tert-butyl dicarbonate to H-Tyr-OMe·HCl is (1.2~1.5):1; and even more preferably, the molar ratio of di-tert-butyl dicarbonate to H-Tyr-OMe·HCl is (1.2~1.4):1.

[0013] Preferably, the mass ratio of amide or sulfoxide polar aprotic solvent to Boc-Tyr-OMe is (0.5~0.8):1; more preferably, the mass ratio of amide or sulfoxide polar aprotic solvent to Boc-Tyr-OMe is (0.5~0.6):1.

[0014] Preferably, the molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2.2~3):1; more preferably, the molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2.5~3):1; and even more preferably, the molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2.5~2.8):1.

[0015] Preferably, the mass ratio of the ether solvent to Boc-Tyr(Me)-OH is (4~6):1; more preferably, the mass ratio of the ether solvent to Boc-Tyr(Me)-OH is (4~5):1.

[0016] Preferably, the alkaline condition is an aqueous solution of alkali metal hydroxide; more preferably, the molar ratio of alkali metal oxide to Boc-Tyr(Me)-OMe is (1.2~2.5):1; even more preferably, the molar ratio of alkali metal oxide to Boc-Tyr(Me)-OMe is (1.3~1.5):1; particularly preferably, the alkali metal oxide is one or both of sodium hydroxide and potassium hydroxide.

[0017] Preferably, Boc-Tyr-OMe is dissolved in an amide or sulfoxide polar aprotic solvent, and the reaction temperature with dimethyl carbonate is 80~120℃; more preferably, the reaction temperature is 90~110℃; and even more preferably, the reaction temperature is 95~105℃.

[0018] Preferably, the hydrolysis temperature of Boc-Tyr(Me)-OMe under alkaline conditions is 10~30℃; more preferably, the hydrolysis temperature is 15~23℃; and even more preferably, the hydrolysis temperature is 18~20℃.

[0019] Preferably, the acidic condition is an aqueous solution of hydrogen chloride; more preferably, the concentration of the aqueous solution of hydrogen chloride is 1~4 mol / L; even more preferably, the concentration of the aqueous solution of hydrogen chloride is 2~3 mol / L.

[0020] The beneficial effects of this invention are as follows: (1) Innovatively, this invention uses dimethyl carbonate with low toxicity as a methylating agent in the synthesis of Boc-Tyr(Me)-OMe and selects amide or sulfoxide polar aprotic solvents, and uses ether solvents in the synthesis of H-Tyr(Me)-OH. The three components produce synergy under specific conditions. Compared with the mainstream method, it can reduce safety risks and significantly improve the overall yield while ensuring product purity and maximum single impurity. It is very suitable for industrial-scale production.

[0021] (2) In this invention, ditert-butyl dicarbonate is used instead of benzyl chloroformate to preprotect the amino group, so that no expensive precious metal catalyst (palladium on carbon) is needed when removing the protecting group, thus significantly reducing the cost. Detailed Implementation

[0022] The specific embodiments listed in this invention are merely examples, and the invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions to the embodiments described below are also within the scope of this invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of this invention should be covered within its scope. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. All reagents or instruments whose manufacturers are not specified are commercially available conventional products. To better illustrate this invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that this invention can be practiced even without certain specific details. In other embodiments, methods, means, equipment, and steps well known to those skilled in the art are not described in detail in order to highlight the main points of this invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise specified, all units used in this specification are International Standard Units (SI), and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors unavoidable in industrial production.

[0024] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0025] Except for Comparative Example 1, which used a 5000L glass-lined reactor, all other examples and comparative examples were synthesized in a 3000L glass-lined reactor, and the purity was detected by high performance liquid chromatography (HPLC).

[0026] Example 1 This embodiment provides an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH, the steps of which are as follows: S1. Synthesis of H-Tyr-OMe·HCl: Add 800 kg of methanol to 200 kg of Tyr, adjust the frequency converter to 50 Hz, and add 180 kg of thionyl chloride dropwise while controlling the temperature at 10-20 °C. After the addition is complete, raise the temperature to 40-45 °C for reaction. Monitor the Tyr reaction by thin layer chromatography (TCL) until complete, then concentrate under reduced pressure until no liquid distills off. Add 400 kg of ethyl acetate, adjust the frequency converter to 50 Hz, and slurry for 2 hours. Centrifuge and dry to obtain 245 kg of H-Tyr-OMe·HCl (off-white solid) with a molecular weight of 231.68 and a yield of 95.8%.

[0027] S2. Synthesis of Boc-Tyr-OMe: Add 1470 kg of water, 245 kg of acetone, and 292 kg of potassium carbonate to 245 kg of H-Tyr-OMe·HCl obtained in S1. Adjust the frequency converter to 50 Hz and control the temperature at 15-20℃. Add 277 kg of di-tert-butyl dicarbonate (molar ratio of 1.2:1 to H-Tyr-OMe·HCl). After the addition is complete, control the temperature at 15-20℃. After the reaction is complete (using a TCL monitor), add 490 kg of ethyl acetate. Adjust the pH of the system to 3 with a 20% citric acid aqueous solution. Allow the mixture to stand and separate the phases. Discard the aqueous phase and collect the organic phase. Wash repeatedly with a 20% sodium chloride aqueous solution until the pH reaches 6, using 50 kg each time. After drying with 25 kg of anhydrous sodium sulfate, concentrate under reduced pressure until no liquid distills off, yielding 312 kg of the product. Boc-Tyr-OMe (brownish-yellow oily substance) has a molecular weight of 295.33 and a yield of 100%.

[0028] S3. Synthesis of Boc-Tyr(Me)-OMe: 238 kg of dimethyl carbonate (molar ratio of Boc-Tyr-OMe to Boc-Tyr-OMe was 2.5:1) and 156 kg of dimethyl sulfoxide (mass ratio of Boc-Tyr-OMe to Boc-Tyr-OMe was 0.5:1) were added to 312 kg of Boc-Tyr-OMe obtained in S2. The frequency converter was adjusted to 50 Hz, and the temperature was raised to 90-95 °C for reaction. After the reaction of Boc-Tyr-OMe was completed by TCL monitoring, the temperature was lowered to 30 °C, and the product was extracted with a mixed solvent of ethyl acetate and n-hexane in a mass ratio of 1:3. The extraction endpoint was monitored by TLC. After drying with 25 kg of anhydrous sodium sulfate, the product was concentrated under reduced pressure until no liquid distilled off, yielding 327 kg of Boc-Tyr(Me)-OMe (light yellow oil) with a molecular weight of 309.36 and a yield of 100%.

[0029] S4. Synthesis of Boc-Tyr(Me)-OH: 630 kg of a 10% sodium hydroxide aqueous solution [molar ratio of sodium hydroxide to Boc-Tyr(Me)-OMe is 1.5:1] was added to 327 kg of Boc-Tyr(Me)-OMe obtained in S3. The frequency converter was adjusted to 50 Hz, and the reaction was controlled at 15-25℃. After the Boc-Tyr(Me)-OMe reaction was complete, the pH of the system was adjusted to 3 with a 20% citric acid aqueous solution. Then, 327 kg of ethyl acetate was added, and the mixture was allowed to stand and separate. The aqueous phase was discarded, and the organic phase was collected and repeatedly washed with a 20% sodium chloride aqueous solution until the pH reached 6, with 50 kg used each time. The organic phase was concentrated to dryness under reduced pressure, and then 654 kg of n-hexane was added and stirred for 2 hours. After centrifugation and drying, 234 kg of Boc-Tyr(Me)-OH (white solid) was obtained with a molecular weight of 295.33 and a yield of 75.0%.

[0030] S5. Synthesis of H-Tyr(Me)-OH: 1170 kg of dioxane [with a mass ratio of 5:1 to Boc-Tyr(Me)-OH] and 475 kg of a 2 mol / L aqueous solution of hydrogen chloride were added to 234 kg of Boc-Tyr(Me)-OH obtained in S4. The frequency converter was adjusted to 50 Hz. After the reaction of Boc-Tyr(Me)-OH was complete, the pH of the system was adjusted to 5 with a 20% sodium carbonate aqueous solution. After centrifugation and drying, 142 kg of H-Tyr(Me)-OH (white solid) was obtained with a molecular weight of 195.22 and a yield of 91.8%.

[0031] S6. Synthesis of Fmoc-Tyr(Me)-OH: Add 1136 kg of water and 426 kg of acetone to the 142 kg H-Tyr(Me)-OH obtained in S5. Adjust the frequency converter to 50 Hz, then add 141 kg of potassium carbonate. Control the temperature at 15-25℃ and add 258 kg of Fmoc-OSu in batches. After the H-Tyr(Me)-OH reaction is complete, monitor the TCL. Add 710 kg of ethyl acetate, then adjust the pH of the system to 3 with a 20% citric acid aqueous solution. Allow the mixture to stand and separate the phases. Discard the aqueous phase and collect the organic phase. Wash the organic phase repeatedly with a 20% sodium chloride aqueous solution until the pH reaches 6, using 200 kg each time. Concentrate the organic phase to dryness under reduced pressure, add 568 kg of n-hexane and slurry for 2 hours. Centrifuge and dry to obtain 267 kg of Fmoc-OSu. Fmoc-Tyr(Me)-OH (white solid) has a molecular weight of 417.45, an overall yield of 57.9%, a purity of 99.7%, and a maximum single impurity of 0.05%.

[0032] Example 2 This embodiment provides an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH, the steps of which are as follows: S1. Synthesis of H-Tyr-OMe·HCl: The process parameters are the same as in Example 1, and 248 kg of H-Tyr-OMe·HCl (off-white solid) is obtained with a molecular weight of 231.68 and a yield of 97.0%.

[0033] S2. Synthesis of Boc-Tyr-OMe: Add 1488 kg of water, 248 kg of acetone, and 293 kg of potassium carbonate to 248 kg of H-Tyr-OMe·HCl obtained in S1. Adjust the frequency converter to 50 Hz and control the temperature at 15-20℃. Add 304 kg of di-tert-butyl dicarbonate (molar ratio of 1.3:1 to H-Tyr-OMe·HCl). After the addition is complete, control the temperature at 15-20℃. After the reaction is complete (using a TCL monitor), add 496 kg of ethyl acetate. Adjust the pH of the system to 3 with a 20% citric acid aqueous solution. Allow the mixture to stand and separate the phases. Discard the aqueous phase and collect the organic phase. Wash the organic phase with a 20% sodium chloride aqueous solution until the pH reaches 6. Each wash is 50 kg. After drying with 25 kg of anhydrous sodium sulfate, concentrate under reduced pressure until no liquid distills off, yielding 316 kg of the product. Boc-Tyr-OMe (brownish-yellow oily substance) has a molecular weight of 295.33 and a yield of 100%.

[0034] S3. Synthesis of Boc-Tyr(Me)-OMe: 250 kg of dimethyl carbonate (molar ratio of Boc-Tyr-OMe to Boc-Tyr-OMe is 2.6:1) and 190 kg of N-methylpyrrolidone (mass ratio of Boc-Tyr-OMe to Boc-Tyr-OMe is 0.6:1) were added to 316 kg of Boc-Tyr-OMe obtained in S2. The frequency converter was adjusted to 50 Hz, and the temperature was raised to 97-103 °C for reaction. After the reaction of Boc-Tyr-OMe was complete as monitored by TCL, the temperature was lowered to 30 °C, and the product was extracted with a mixed solvent of ethyl acetate and n-hexane in a mass ratio of 1:3. The extraction endpoint was monitored by TLC. After drying with 25 kg of anhydrous sodium sulfate, the product was concentrated under reduced pressure until no liquid distilled off, yielding 331 kg of Boc-Tyr(Me)-OMe (light yellow oil) with a molecular weight of 309.36 and a yield of 100%.

[0035] S4. Synthesis of Boc-Tyr(Me)-OH: 840 kg of a 10% potassium hydroxide aqueous solution was added to 331 kg of Boc-Tyr(Me)-OMe obtained in S3 [the molar ratio of potassium hydroxide to Boc-Tyr(Me)-OMe was 1.4:1]. The frequency converter was adjusted to 50 Hz, and the reaction was controlled at 20-25℃. After the Boc-Tyr(Me)-OMe reaction was complete, the pH of the system was adjusted to 3 with a 20% citric acid aqueous solution. Then, 327 kg of ethyl acetate was added, and the mixture was allowed to stand and separate. The aqueous phase was discarded, and the organic phase was collected and washed with a 20% sodium chloride aqueous solution until the pH reached 6, with a volume of 50 kg each time. After the organic phase was concentrated to dryness under reduced pressure, 654 kg of n-hexane was added and the mixture was stirred for 2 hours. After centrifugation and drying, 259 kg of white solid Boc-Tyr(Me)-OH (white solid) was obtained, with a molecular weight of 295.33 and a yield of 82.0%.

[0036] S5. Synthesis of H-Tyr(Me)-OH: 1036 kg of tetrahydrofuran [with a mass ratio of 4:1 to Boc-Tyr(Me)-OH] and 350 kg of a 3 mol / L aqueous solution of hydrogen chloride were added to 259 kg of Boc-Tyr(Me)-OH obtained in S4. The frequency converter was adjusted to 50 Hz. After the reaction of Boc-Tyr(Me)-OH was complete, the pH of the system was adjusted to 5 with a 20% sodium carbonate aqueous solution. After centrifugation and drying, 160 kg of H-Tyr(Me)-OH (white solid) was obtained with a molecular weight of 195.22 and a yield of 93.5%.

[0037] S6. Synthesis of Fmoc-Tyr(Me)-OH: Add 1280 kg of water and 480 kg of acetone to 160 kg of H-Tyr(Me)-OH obtained in S5. Adjust the frequency converter to 50 Hz, then add 158 kg of potassium carbonate. Control the temperature at 15-25 ℃ and add 290 kg of Fmoc-OSu in batches. After the H-Tyr(Me)-OH reaction is complete, monitor the TCL. Add 800 kg of ethyl acetate, then adjust the pH of the system to 3 with a 20% citric acid aqueous solution. Allow the mixture to stand and separate the phases. Discard the aqueous phase and collect the organic phase. Wash the organic phase repeatedly with a 20% sodium chloride aqueous solution until the pH reaches 6, using 200 kg each time. Concentrate the organic phase to dryness under reduced pressure, add 640 kg of n-hexane and slurry for 2 hours. Centrifuge and dry to obtain 288 kg of Fmoc-OSu. Fmoc-Tyr(Me)-OH (white solid) has a molecular weight of 417.45, an overall yield of 62.5%, a purity of 99.6%, and a maximum single impurity of 0.06%.

[0038] Example 3 This embodiment provides an efficient method for preparing high-purity Fmoc-Tyr(Me)-OH, the steps of which are as follows: S1. Synthesis of H-Tyr-OMe·HCl: The process parameters are the same as in Example 1, and 252 kg of H-Tyr-OMe·HCl (off-white solid) is obtained with a molecular weight of 231.68 and a yield of 98.5%.

[0039] S2. Synthesis of Boc-Tyr-OMe: Add 1512 kg of water, 252 kg of acetone, and 300 kg of potassium carbonate to 252 kg of H-Tyr-OMe·HCl obtained in S1. Adjust the frequency converter to 50 Hz and control the temperature at 15-20℃. Add 332 kg of di-tert-butyl dicarbonate (molar ratio of 1.4:1 to H-Tyr-OMe·HCl). After the addition is complete, control the temperature at 15-20℃. After the reaction of H-Tyr-OMe·HCl is complete by TCL monitoring, add 504 kg of ethyl acetate. Adjust the pH to 3 with a 20% citric acid aqueous solution. Allow to stand and separate the liquids. Discard the aqueous phase and collect the organic phase. Wash repeatedly with a 20% sodium chloride aqueous solution until the pH reaches 6, using 50 kg each time. After drying with 25 kg of anhydrous sodium sulfate, concentrate under reduced pressure until no liquid distills off, yielding 321 kg of [the product is missing from the original text]. Boc-Tyr-OMe (brownish-yellow oily substance) has a molecular weight of 295.33 and a yield of 100%.

[0040] S3. Synthesis of Boc-Tyr(Me)-OMe: 274 kg of dimethyl carbonate (molar ratio of Boc-Tyr-OMe to Boc-Tyr-OMe was 2.8:1) and 161 kg of N,N-dimethylformamide (mass ratio of Boc-Tyr-OMe to Boc-Tyr-OMe was 0.5:1) were added to 321 kg of Boc-Tyr-OMe obtained in S2. The frequency converter was adjusted to 50 Hz, and the temperature was raised to 100-105 °C for reaction. After the reaction of Boc-Tyr-OMe was complete as monitored by TCL, the temperature was lowered to 30 °C, and the product was extracted with a mixed solvent of ethyl acetate and n-hexane in a mass ratio of 1:3. The extraction endpoint was monitored by TLC. After drying with 25 kg of anhydrous sodium sulfate, the product was concentrated under reduced pressure until no liquid distilled off, yielding 336 kg of Boc-Tyr(Me)-OMe (light yellow oil) with a molecular weight of 309.36 and a yield of 100%.

[0041] S4. Synthesis of Boc-Tyr(Me)-OH: 730 kg of 10% potassium hydroxide aqueous solution [molar ratio of potassium hydroxide to Boc-Tyr(Me)-OMe is 1.2:1] was added to 336 kg of Boc-Tyr(Me)-OMe obtained in S3. The frequency converter was adjusted to 50 Hz, and the temperature was controlled at 17~22℃. After the reaction of Boc-Tyr(Me)-OMe was complete, the pH of the system was adjusted to 3 with 20% citric acid aqueous solution. Then 336 kg of ethyl acetate was added, and the mixture was allowed to stand and separate. The aqueous phase was discarded, and the organic phase was collected and washed with 20% sodium chloride aqueous solution until the pH value was 6. The amount used each time was 50 kg. After the organic phase was concentrated to dryness under reduced pressure, 672 kg of n-hexane was added and stirred for 2 h. After centrifugation and drying, 261 kg of Boc-Tyr(Me)-OH (white solid) was obtained with a molecular weight of 295.33 and a yield of 81.3%.

[0042] S5. Synthesis of H-Tyr(Me)-OH: 1044 kg of ethylene glycol dimethyl ether [with a mass ratio of 4:1 to Boc-Tyr(Me)-OH] and 354 kg of a 3 mol / L aqueous solution of hydrogen chloride were added to 261 kg of Boc-Tyr(Me)-OH obtained in S4. The frequency converter was adjusted to 50 Hz. After the reaction of Boc-Tyr(Me)-OH was complete, the pH of the system was adjusted to 5 with a 20% sodium carbonate aqueous solution. After centrifugation and drying, 158 kg of H-Tyr(Me)-OH (white solid) was obtained with a molecular weight of 195.22 and a yield of 91.6%.

[0043] S6. Synthesis of Fmoc-Tyr(Me)-OH: Add 1264 kg of water and 474 kg of acetone to 158 kg of H-Tyr(Me)-OH obtained in S5. Adjust the frequency converter to 50 Hz, then add 157 kg of potassium carbonate. Control the temperature at 15-25 ℃ and add 287 kg of Fmoc-OSu in batches. After the H-Tyr(Me)-OH reaction is complete under TCL monitoring, add 790 kg of ethyl acetate and adjust the pH to 3 with 20% citric acid aqueous solution. After standing and separating, discard the aqueous phase and collect the organic phase. Wash repeatedly with 20% sodium chloride aqueous solution until the pH is 6, each time using 200 kg. After the organic phase is concentrated to dryness under reduced pressure, add 732 kg of n-hexane and stir for 2 hours. Centrifuge and dry to obtain 285 kg. Fmoc-Tyr(Me)-OH (white solid) has a molecular weight of 417.45, an overall yield of 61.9%, a purity of 99.7%, and a maximum single impurity of 0.04%.

[0044] Comparative Example 1 This comparative example provides a mainstream industrial method for preparing Fmoc-Tyr(Me)-OH, with the following steps: S1. Synthesis of H-Tyr-OMe·HCl: Add 1020kg of methanol to 200kg of Tyr, adjust the frequency converter to 50Hz, control the temperature at 10~20℃ and add 320kg of thionyl chloride dropwise. After the addition is complete, raise the temperature to 35~40℃ to react. After the reaction is complete, a methanol solution of H-Tyr-OMe·HCl is obtained.

[0045] S2. Synthesis of Z-Tyr-OMe: Cool to below 10℃, adjust the frequency converter to 50Hz, and slowly add 600kg of sodium carbonate to the methanol solution of H-Tyr-OMe·HCl obtained in S1, controlling the temperature to be below 20℃. After the addition is complete, add 200kg of water and 1080kg of ethyl acetate, and add 320kg of benzyl chloroformate dropwise while controlling the temperature to be below 20℃. After the addition is complete, monitor H-Tyr-OMe·HCl by TLC until the reaction is complete, and adjust the pH of the system to 6 with an aqueous solution of hydrogen chloride. Let stand and separate the liquids, discard the aqueous phase, collect the organic phase and dry it with 50kg of anhydrous sodium sulfate for 1h. After concentrating under reduced pressure until a large amount of solid precipitates, cool to 15~25℃ and add 810kg of petroleum ether, stir to crystallize, centrifuge and dry to obtain 405kg of Z-Tyr-OMe (white solid) with a molecular weight of 329.35.

[0046] S3. Synthesis of Z-Tyr(Me)-OMe: Add 3240 kg of acetonitrile to 405 kg of Z-Tyr-OMe obtained in S2, adjust the frequency converter to 50 Hz, and add 405 kg of Z-Tyr-OMe and 418 kg of potassium carbonate; after the addition is complete, add 382 kg of dimethyl sulfate dropwise at a controlled temperature of 10~20℃. After the addition is complete, control the temperature at 10~20℃ and react for 12 h. Add ethyl acetate for extraction and concentrate until no liquid distills out to obtain 295 kg of Z-Tyr(Me)-OMe.

[0047] S4. Synthesis of Z-Tyr(Me)-OH: Add 720 kg of water and 144 kg of sodium hydroxide to a glass-lined reactor and adjust the frequency converter to 50 Hz. After complete dissolution, cool to below 5 °C and add 295 kg of Z-Tyr(Me)-OMe obtained in S3. Stir at 5-15 °C for 3 hours, let stand and separate the liquids. Concentrate the organic phase under reduced pressure until no liquid distills out, then combine it with the aqueous phase and react at 5-15 °C. After the reaction is complete, adjust the pH of the system to 6 with an aqueous solution of hydrogen chloride. Then add 1200 kg of ethyl acetate, let stand and separate the liquids, discard the aqueous layer, and obtain 1500 kg of ethyl acetate solution of Z-Tyr(Me)-OH.

[0048] S5. Synthesis of H-Tyr(Me)-OH: 1500 kg of ethyl acetate solution of H-Tyr(Me)-OH obtained in S4 was transferred to a nitrogen-purged hydrogenolysis reactor, and 5 kg of 5% palladium on carbon was added. After sealing the reactor lid, hydrogen gas was introduced after purging with nitrogen, and the pressure was controlled at 0.15-0.20 MPa for hydrogenolysis. After the reaction was complete, 800 kg of water was added, the insoluble palladium on carbon was filtered off, the mixture was allowed to stand and separate into layers, the organic layer was discarded, and the aqueous layer was transferred to a 5000 L glass-lined reactor to obtain 970 kg of aqueous solution of H-Tyr(Me)-OH.

[0049] S6. Synthesis of Fmoc-Tyr(Me)-OH: Add 600 kg of acetone and 200 kg of sodium carbonate to 970 kg of aqueous solution of H-Tyr(Me)-OH. Adjust the frequency converter to 50 Hz and control the temperature at 10~20℃. Add 290 kg of Fmoc-OSu in batches. After the reaction is complete, 208 kg of Fmoc-Tyr(Me)-OH is obtained after post-processing. Its molecular weight is 417.45, the total yield is 45.1%, the purity is 99.5%, and the maximum single impurity is 0.06%.

[0050] Experimental results: Compared with Example 1, Comparative Example 1 used benzyl chloroformate to preprotect the amino group. When removing the preprotection, a more expensive noble metal catalyst (palladium on carbon) was used. At the same time, it used dimethyl sulfate, a highly toxic methylating agent, to react with Boc-Tyr-OMe. As a result, the cost was significantly increased and the overall yield was significantly reduced (57.9% in Example 1 → 45.1% in Comparative Example 1).

[0051] Comparative Example 2 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH, except that the solvent dimethyl sulfoxide in S3 is changed to dimethyl carbonate, and the other process parameters are the same as in Example 1.

[0052] Experimental results: Compared with Example 1, the conversion rate and total yield of Boc-Tyr-OMe were significantly reduced. After repeated experiments, the conversion rate of Boc-Tyr-OMe remained stable at around 50%, and the total yield remained stable at 30%~35%.

[0053] Comparative Example 3 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH, except that the dimethyl carbonate in S3 is replaced with dimethyl sulfate, and the other process parameters are the same as in Example 1.

[0054] Experimental results: TLC monitoring showed that the Boc-Tyr-OMe reaction was complete, and 235 kg of the final product Fmoc-Tyr(Me)-OH (white solid) was obtained, with an overall yield of 51.0%, a purity of 99.6%, and a maximum single impurity of 0.06%. The purity and maximum single impurity were comparable to those of Example 1, but the overall yield was lower than that of Example 1.

[0055] Comparative Example 4 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH, except that the mass ratio of dimethyl sulfoxide to Boc-Tyr-OMe in S3 is adjusted from 0.5:1 to 0.3:1, and the other process parameters are the same as in Example 1.

[0056] Experimental results: Compared with Example 1, the conversion rate and total yield of Boc-Tyr-OMe were significantly reduced. After repeated experiments, the conversion rate of Boc-Tyr-OMe remained stable at around 50%, and the total yield remained stable at 30%~35%.

[0057] Comparative Example 5 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH, except that the mass ratio of dimethyl sulfoxide to Boc-Tyr-OMe in S3 is adjusted from 0.5:1 to 3:1, and the other process parameters are the same as in Example 1.

[0058] Experimental results: TLC monitoring showed that the Boc-Tyr-OMe reaction was complete, ultimately yielding 271 kg of Fmoc-Tyr(Me)-OH (white solid). The overall yield was 58.8%, the purity was 99.5%, and the maximum single impurity was 0.05%. The overall yield, purity, and maximum single impurity were comparable to those in Example 1.

[0059] Comparative Example 6 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the molar ratio of dimethyl carbonate to Boc-Tyr-OMe in S3 from 2.5:1 to 1.5:1, all other process parameters are the same as in Example 1.

[0060] Experimental results: TLC monitoring showed that the Boc-Tyr-OMe reaction was incomplete, and the overall yield was significantly lower than that of Example 1. After repeated experiments, the overall yield was stabilized at 30%~40%.

[0061] Comparative Example 7 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the molar ratio of dimethyl carbonate to Boc-Tyr-OMe in S3 from 2.5∶1 to 4∶1, the other process parameters are the same as in Example 1.

[0062] Experimental results: TLC monitoring showed that the Boc-Tyr-OMe reaction was complete, ultimately yielding 275 kg of Fmoc-Tyr(Me)-OH (white solid). The overall yield was 59.7%, the purity was 99.7%, and the maximum single impurity was 0.05%. The overall yield, purity, and maximum single impurity were comparable to those in Example 1.

[0063] Comparative Example 8 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for changing the solvent dioxane in S5 to methanol, the other process parameters are the same as in Example 1.

[0064] Experimental results: Compared with Example 1, more impurities were generated during the synthesis of Fmoc-Tyr(Me)-OH, which required multiple purification processes to remove. After repeated experiments, the total yield of Fmoc-Tyr(Me)-OH remained stable at 25%~30%.

[0065] Comparative Example 9 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the mass ratio of S5 dioxane to Boc-Tyr(Me)-OH from 5:1 to 2:1, the other process parameters are the same as in Example 1.

[0066] Experimental results: TLC monitoring showed a small amount of incomplete reaction of Boc-Tyr(Me)-OH, ultimately yielding 240 kg of Fmoc-Tyr(Me)-OH (white solid), with an overall yield of 52.1%, a purity of 99.5%, and a maximum single impurity of 0.04%. The purity and maximum single impurity were comparable to those of Example 1, but the overall yield decreased.

[0067] Comparative Example 10 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the mass ratio of S5 dioxane to Boc-Tyr(Me)-OH from 5:1 to 10:1, the other process parameters are the same as in Example 1.

[0068] Experimental results: TLC monitoring showed that the Boc-Tyr(Me)-OH reaction was complete, and 278 kg of the final product Fmoc-Tyr(Me)-OH (white solid) was obtained. The overall yield was 60.3%, the purity was 99.6%, and the maximum single impurity was 0.04%. The overall yield, purity, and maximum single impurity were comparable to those in Example 1.

[0069] Comparative Example 11 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the molar ratio of ditert-butyl dicarbonate to H-Tyr-OMe·HCl in S2 from 1.2∶1 to 1∶1, all other process parameters are the same as in Example 1.

[0070] Experimental results: TLC monitoring showed that the H-Tyr-OMe reaction was incomplete, and the yield was significantly lower than that of Example 1. The final overall yield was only 46.8%.

[0071] Comparative Example 12 This comparative example provides a method for preparing Fmoc-Tyr(Me)-OH. Except for adjusting the molar ratio of ditert-butyl dicarbonate to H-Tyr-OMe·HCl in S2 from 1.2∶1 to 2.2∶1, all other process parameters are the same as in Example 1.

[0072] Experimental results: TLC monitoring showed that the H-Tyr-OMe reaction was complete, and 277 kg of Fmoc-Tyr(Me)-OH (white solid) was finally obtained. The overall yield was 60.1%, the purity was 99.5%, and the maximum single impurity was 0.05%. The overall yield, purity, and maximum single impurity were comparable to those in Example 1.

[0073] In summary, compared to the mainstream industrial method for preparing Fmoc-Tyr(Me)-OH (Comparative Example 1), this method significantly improves the overall yield (45.1% in Comparative Example 1 → 57.9% in Example 1) by using dimethyl carbonate instead of dimethyl sulfate as the methylating agent, employing amide or sulfoxide polar aprotic solvents in S3, and using ether solvents in S5, while ensuring product purity and minimizing single impurities. Furthermore, the use of ditert-butyl dicarbonate instead of benzyl chloroformate in S2 further enhances this method. The ester pre-protects the amino group, thus eliminating the need for a noble metal catalyst (palladium on carbon) during the removal of the protecting group in S5, significantly reducing costs. Simultaneously, in this invention, amide or sulfoxide polar aprotic solvents, dimethyl carbonate, and ether solvents exhibit synergy within specific ratio ranges: using only dimethyl carbonate and ether solvents (Comparative Example 2), or only amide or sulfoxide polar aprotic solvents and ether solvents (Comparative Example 3), or only amide or sulfoxide polar aprotic solvents and dimethyl carbonate (Comparative Example 8)... The overall yield of Fmoc-Tyr(Me)-OH was lower than that of the three solvents used in combination (Example 1); when the amount of amide or sulfoxide polar aprotic solvent was too low (Comparative Example 4), the overall yield was low, only 30%~35%, while when the amount was too high (Comparative Example 5), although the purity, overall yield and maximum single impurity of Fmoc-Tyr(Me)-OH were comparable to those of the present invention (Example 1), the material consumption increased; when the amount of dimethyl carbonate was too low (Comparative Example 6), the overall yield was low, only 30%~40%, while... When the dosage is high (Comparative Example 7), although the purity, total yield, and maximum single impurity of Fmoc-Tyr(Me)-OH are comparable to those of the present invention (Example 1), the material consumption increases; when the dosage of ether solvent is low (Comparative Example 9), the total yield decreases (57.9% of Example 1 → 52.1% of Comparative Example 9), while when the dosage is too high (Comparative Example 10), although the purity, total yield, and maximum single impurity of Fmoc-Tyr(Me)-OH are comparable to those of the present invention (Example 1), the material consumption increases.

[0074] The embodiments described above merely illustrate specific implementation methods of this application, and while the descriptions are detailed, they should not be construed as limiting the scope of protection of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the technical solution of this application, and these modifications and improvements all fall within the scope of protection of this application.

Claims

1. A highly efficient method for preparing high-purity Fmoc-Tyr(Me)-OH, characterized in that, Includes the following steps: After Tyr was mixed evenly with methanol, thionyl chloride was added dropwise to react and give H-Tyr-OMe·HCl. The H-Tyr-OMe·HCl was reacted with ditert-butyl dicarbonate to obtain Boc-Tyr-OMe; The Boc-Tyr-OMe was dissolved in an amide or sulfoxide polar aprotic solvent and reacted with dimethyl carbonate to obtain Boc-Tyr(Me)-OMe. The Boc-Tyr(Me)-OMe was hydrolyzed under alkaline conditions to obtain Boc-Tyr(Me)-OH; The Boc-Tyr(Me)-OH was dissolved in an ether solvent and hydrolyzed under acidic conditions to obtain H-Tyr(Me)-OH; The H-Tyr(Me)-OH was reacted with Fmoc-OSu to obtain Fmoc-Tyr(Me)-OH. The molar ratio of ditert-butyl dicarbonate to H-Tyr-OMe·HCl is (1.1~2):1; the mass ratio of the amide or sulfoxide polar aprotic solvent to Boc-Tyr-OMe is (0.5~1):1; the molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2~3):1; and the mass ratio of the ether solvent to Boc-Tyr(Me)-OH is (4~8):

1.

2. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The amide or sulfoxide polar aprotic solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, or N,N-dimethylformamide.

3. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The ether solvent is one or more of dioxane, tetrahydrofuran, or ethylene glycol dimethyl ether.

4. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The molar ratio of the ditert-butyl dicarbonate to the H-Tyr-OMe·HCl is (1.1~1.8):

1.

5. The efficient preparation method of high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The mass ratio of the amide or sulfoxide polar aprotic solvent to the Boc-Tyr-OMe is (0.5~0.8):

1.

6. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The molar ratio of dimethyl carbonate to Boc-Tyr-OMe is (2.2~3):

1.

7. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The mass ratio of the ether solvent to the Boc-Tyr(Me)-OH is (4~6):

1.

8. The efficient preparation method for high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The alkaline condition is an aqueous solution of alkali metal hydroxide, and the molar ratio of the alkali metal oxide to Boc-Tyr(Me)-OMe is (1.2~2.5):

1.

9. The efficient preparation method of high-purity Fmoc-Tyr(Me)-OH according to claim 8, characterized in that, The alkali metal oxide is one or both of sodium hydroxide and potassium hydroxide.

10. The efficient preparation method of high-purity Fmoc-Tyr(Me)-OH according to claim 1, characterized in that, The acidic condition is an aqueous solution of hydrogen chloride, and the concentration of the aqueous solution of hydrogen chloride is 1~4 mol / L.

Images