CN116082190A - Industrial production method of efficient Fmoc-Ser (tBu) -OH - Google Patents
Industrial production method of efficient Fmoc-Ser (tBu) -OH Download PDFInfo
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- CN116082190A CN116082190A CN202211711146.8A CN202211711146A CN116082190A CN 116082190 A CN116082190 A CN 116082190A CN 202211711146 A CN202211711146 A CN 202211711146A CN 116082190 A CN116082190 A CN 116082190A
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- serine
- fmoc
- tbu
- ser
- methyl ester
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- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000009776 industrial production Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 16
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 10
- DDCPKNYKNWXULB-YFKPBYRVSA-N (2s)-2-azaniumyl-3-[(2-methylpropan-2-yl)oxy]propanoate Chemical compound CC(C)(C)OC[C@H]([NH3+])C([O-])=O DDCPKNYKNWXULB-YFKPBYRVSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 229960001153 serine Drugs 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 4
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000007127 saponification reaction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000000605 extraction Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of organic synthesis, in particular to an efficient Fmoc-Ser (tBu) -OH industrial production method, which comprises the following steps: in the first step, methanol and L-serine are added into a reaction vessel, and SOCl is added dropwise after cooling 2 Heating to react after the addition to obtain L-serine methyl ester hydrochloride; secondly, dissolving L-serine methyl ester hydrochloride in a solvent, adding sulfuric acid as a catalyst, introducing isobutene to react, and directly adding NaOH to saponify after the reaction is finished to obtain an O-tert-butyl L-serine aqueous solution; thirdly, adding ethyl acetate and alkali into the aqueous solution of O-tertiary butyl L-serine, adding 9-fluorenylmethyl-N-succinimidyl carbonate, adjusting pH to 8-9 for reactionAnd (3) performing post-acidification extraction to obtain a final product Fmoc-Ser (tBu) -OH. The invention avoids the purification of the intermediate, and the reaction process is relatively well controlled. The industrial production method of Fmoc-Ser (tBu) -OH provided by the invention can efficiently and stably produce high-quality Fmoc-Ser (tBu) -OH, the purity is more than 99.5%, and single impurity is less than 0.1%.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to an industrial production method of high-efficiency Fmoc-Ser (tBu) -OH.
Background
Fmoc-Ser (tBu) -OH, chinese alias: FMOC-O-tert-butyl-L-serine
Molecular formula C 22 H 25 NO 5 Molecular weight: 383.44.
the chemical structural formula:
Fmoc-Ser (tBu) -OH is an important intermediate in the synthesis of polypeptides, particularly in solid phase methods. The method is widely applied to the synthesis of various products such as medicines, biochemistry, foods, cosmetics and the like, and is commonly used for the synthesis of various medicines. Chinese patent No. CN109265370A discloses a method for preparing Fmoc-Ser (tBu) -OH. According to the method, tert-butyl is introduced through perchloric acid/tert-butyl acetate, the perchloric acid has strong acidity and strong oxidizing property, and has a large potential safety hazard, so that the purchase and the use are limited.
The Fmoc-Ser (tBu) -OH demand of the domestic and foreign markets is large, and the current domestic production targets can not meet the demands of high-end drug synthesis. In addition, the traditional Fmoc-Ser (tBu) -OH preparation method also has the problems of high manufacturing cost, insufficient purity of the obtained product and the like. Therefore, how to optimize the Fmoc-Ser (tBu) -OH production process, reduce the production cost and obtain a high-purity product is a problem to be solved at present.
Disclosure of Invention
The invention aims to solve the technical problems that: provides an industrial production method of high-efficiency Fmoc-Ser (tBu) -OH.
In order to solve the problems, the technical scheme provided by the invention is as follows:
an industrial production method of high-efficiency Fmoc-Ser (tBu) -OH comprises the following steps:
(1) Adding methanol and L-Serine, cooling and drop-adding SOCl 2 Heating to react after the addition to obtain L-serine methyl ester hydrochloride;
(2) Dissolving L-serine methyl ester hydrochloride in a solvent, adding acid as a catalyst, introducing isobutene for reaction, and directly adding NaOH for saponification after the reaction is finished to obtain an O-tert-butyl L-serine aqueous solution;
(3) Adding ethyl acetate and alkali into the aqueous solution of O-tert-butyl L-serine, adding 9-fluorenylmethyl-N-succinimidyl carbonate, adjusting pH, and acidifying and extracting after reaction to obtain a final product Fmoc-Ser (tBu) -OH;
the chemical reaction equation is as follows:
preferably, the catalyst in step (2) is selected from sulfuric acid or p-toluene sulfonic acid.
Preferably, the solvent in the step (2) is selected from dichloromethane or ethylene glycol dimethyl ether. The dosage of the solvent is 3-10 times of the weight of the L-serine methyl ester hydrochloride; further, the solvent is used in an amount of 5 to 10 times by weight of L-serine methyl ester hydrochloride.
Preferably, in the step (2), the molar ratio of L-serine methyl ester hydrochloride, isobutene and the catalyst is 1:1 to 8:1 to 5. Further, the molar ratio of L-serine methyl ester hydrochloride, isobutene to the catalyst is 1:2 to 4:1 to 3.
Preferably, the liquid alkali in the step (2) is an aqueous solution of NaOH with the mass fraction of 20% -40%, and the saponification temperature is 10-30 ℃.
Preferably, the alkaline conditions in step (3) are achieved by adjusting the pH of the system by adding a base, preferably an inorganic base such as sodium carbonate, potassium carbonate; specifically, the alkaline condition means that the pH is in the range of 8 to 9.
Preferably, the molar ratio of Fmoc-OSU in the step (3) to L-serine methyl ester hydrochloride in the step (2) is 0.8-1.2: 1.
preferably, the target product in the step (3) is purified by recrystallization, and the solvent used in the recrystallization purification is petroleum ether, ethanol, methanol, isopropanol or n-propanol.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The industrial production method of Fmoc-Ser (tBu) -OH provided by the invention can efficiently and stably produce high-quality Fmoc-Ser (tBu) -OH, the purity is more than 99.5%, single impurity is less than 0.1%, the purification of intermediates is avoided, and the reaction process is relatively well controlled; compared with the prior art, the method has the characteristics of high process safety, environment friendliness, mild reaction conditions, easiness in operation and high purity of the prepared product, and is suitable for industrial mass production.
Drawings
FIG. 1 shows the hydrogen spectrum of Fmoc-Ser (tBu) -OH obtained according to an embodiment of the invention.
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1:
synthesis of L-serine methyl ester hydrochloride
And (3) pumping 500Kg of methanol into a dried and clean 1000L reaction kettle, adding 50Kg of L-serine, cooling to 0 ℃ under stirring, dropwise adding 85Kg of thionyl chloride, heating to 50-60 ℃ after the dropwise adding is finished, reacting for 5-6 hours, and concentrating under reduced pressure until the L-serine methyl ester hydrochloride is dried to obtain 75Kg of L-serine methyl ester hydrochloride.
Synthesis of O-tert-butyl L-serine
Into a 2000L reaction kettle which is clean and dry, 600Kg of dichloromethane is pumped, 75Kg of L-serine methyl ester hydrochloride is added under stirring, 51Kg of sulfuric acid is added, the temperature is reduced to 0-5 ℃, 60Kg of isobutene is introduced, the stirring reaction is completed, and the temperature is slowly increased to 10-20 ℃ for reaction for 10 hours. After the reaction is finished, 250Kg of 30% liquid alkali is dripped at the temperature of 10-20 ℃, the reaction is continued to be stirred for 2 hours after the dripping is finished, the mixture is stood for layering, and a water layer is collected.
Synthesis of Fmoc-Ser (tBu) -OH
The aqueous layer was added with 400Kg of ethyl acetate, the pH was controlled to 8-9 with sodium carbonate, and 145Kg of Fmoc-OSU was added to complete the reaction until O-t-butyl L-serine was reacted. After the reaction, the pH value is adjusted to 4-5 by hydrochloric acid, the mixture is stood for layering, an organic layer is collected, the aqueous layer is extracted twice by using 400kg of ethyl acetate, and the organic layers are combined. Washing with 300kg of saline to pH 6-7, concentrating the organic phase under reduced pressure until solid is separated out, adding 500kg of petroleum ether, stirring for crystallization, centrifuging, and collecting solid. The product 132Kg is obtained after drying, the purity of the product is 99.8 percent, and single impurity is 0.05 percent.
Example 2:
synthesis of L-serine methyl ester hydrochloride
And (3) pumping 500Kg of methanol into a dried and clean 1000L reaction kettle, adding 100Kg of L-serine, cooling to 0 ℃ under stirring, dropwise adding 140Kg of thionyl chloride, heating to 50-60 ℃ after the dropwise adding is finished, reacting for 5-6 hours, and concentrating under reduced pressure until the L-serine methyl ester hydrochloride is dried to obtain 149Kg.
Synthesis of O-tert-butyl L-serine
1300Kg of methylene dichloride is pumped into a dry and clean 2000L reaction kettle, 149Kg of L-serine methyl ester hydrochloride is added under stirring, 300Kg of p-toluenesulfonic acid monohydrate is added, the temperature is reduced to 0-5 ℃, 250Kg of isobutene is introduced, the stirring reaction is completed, and the temperature is slowly increased to 10-20 ℃ for reaction for 10 hours. After the reaction is finished, 500Kg of 30% liquid alkali is added dropwise at the temperature of 10-20 ℃, the reaction is continued to be stirred for 2 hours after the dripping is finished, the mixture is kept stand for layering, and a water layer is collected.
Synthesis of Fmoc-Ser (tBu) -OH
The aqueous layer was added with 800Kg of ethyl acetate, the pH was controlled to 8-9 with sodium carbonate, and 290Kg of Fmoc-OSU was added to complete the reaction until O-t-butyl L-serine was reacted. After the reaction, the pH value is adjusted to 4-5 by hydrochloric acid, the mixture is stood for layering, an organic layer is collected, the aqueous layer is extracted twice by using 800kg of ethyl acetate, and the organic layers are combined. Washing with 600kg of saline to pH 6-7, concentrating under reduced pressure until solid is separated out, adding 1000kg of petroleum ether, stirring for crystallization, centrifuging, and collecting solid. The product 273Kg is obtained after drying, the purity of the product is 99.9%, and the single impurity is less than 0.05%.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (9)
1. The industrial production method of the high-efficiency Fmoc-Ser (tBu) -OH is characterized by comprising the following steps of:
(1) Adding methanol and L-serine into a reaction vessel, cooling and dropwise adding SOCl 2 Heating to react after the addition to obtain L-serine methyl ester hydrochloride;
(2) Dissolving L-serine methyl ester hydrochloride in a solvent, adding acid as a catalyst, introducing isobutene for reaction, and directly adding NaOH for saponification after the reaction is finished to obtain an O-tert-butyl L-serine aqueous solution;
(3) Adding ethyl acetate and alkali into the aqueous solution of O-tert-butyl L-serine, adding 9-fluorenylmethyl-N-succinimidyl carbonate, adjusting pH, and acidifying and extracting after reaction to obtain a final product Fmoc-Ser (tBu) -OH;
the chemical reaction equation is as follows:
2. the process according to claim 1, wherein the catalyst in step (2) is selected from sulfuric acid or p-toluene sulfonic acid.
3. The process according to claim 1, wherein the solvent in step (2) is selected from dichloromethane or ethylene glycol dimethyl ether. The dosage of the solvent is 3-10 times of the weight of the L-serine methyl ester hydrochloride.
4. The process according to claim 1, wherein the molar ratio of L-serine methyl ester hydrochloride, isobutylene to catalyst of step (2) is 1:1 to 8:1 to 5.
5. The process according to claim 4, wherein the molar ratio of L-serine methyl ester hydrochloride, isobutylene and catalyst in step (2) is 1:2 to 4:1 to 3.
6. The production method according to claim 1, wherein the NaOH in the step (2) is 20% -40% by mass of aqueous NaOH solution, and the saponification temperature is 10-30 ℃.
7. The production method according to claim 1, wherein the pH in the step (3) is in the range of 8 to 9, the alkaline condition is achieved by adding an alkali to adjust the pH of the system, and the alkali is selected from one or two of inorganic alkali sodium carbonate and potassium carbonate.
8. The method according to claim 1, wherein the molar ratio of Fmoc-OSU in step (3) to L-serine methyl ester hydrochloride in step (2) is 0.8 to 1.2:1.
9. the production method according to claim 1, wherein the target product in the step (3) is further purified by recrystallization, and the solvent used for the recrystallization purification is one or more of petroleum ether, ethanol, methanol, isopropanol or n-propanol.
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|---|---|---|---|---|
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| CN112094205A (en) * | 2019-06-18 | 2020-12-18 | 成都郑源生化科技有限公司 | Method for preparing Fmoc-Ser (tBu) -OH |
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2022
- 2022-12-29 CN CN202211711146.8A patent/CN116082190A/en active Pending
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