CN116178214B - Preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester - Google Patents
Preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester Download PDFInfo
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- CN116178214B CN116178214B CN202211569699.4A CN202211569699A CN116178214B CN 116178214 B CN116178214 B CN 116178214B CN 202211569699 A CN202211569699 A CN 202211569699A CN 116178214 B CN116178214 B CN 116178214B
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- glutamic acid
- tert
- butyl ester
- fluorenylmethoxycarbonyl
- methyl ester
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- GOPWHXPXSPIIQZ-FQEVSTJZSA-N (4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-FQEVSTJZSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 trifluoroacetyl glutamic acid-5-methyl ester Chemical compound 0.000 claims abstract description 19
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 14
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZGEYCCHDTIDZAE-BYPYZUCNSA-N L-glutamic acid 5-methyl ester Chemical compound COC(=O)CC[C@H](N)C(O)=O ZGEYCCHDTIDZAE-BYPYZUCNSA-N 0.000 claims abstract description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 8
- 239000004220 glutamic acid Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 5
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 5
- 239000012467 final product Substances 0.000 claims abstract description 3
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 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 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims 4
- 229960002989 glutamic acid Drugs 0.000 claims 3
- 229930182847 D-glutamic acid Natural products 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229920001184 polypeptide Polymers 0.000 abstract 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
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
- 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
- C07C227/20—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 by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
Abstract
The invention aims to provide a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester, which mainly solves the problems of high operation difficulty and expensive reagent of the existing synthesis method. The technical scheme of the invention is as follows: a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester comprises the following steps: glutamic acid is catalyzed by a dehydrating agent to generate glutamic acid-5-methyl ester hydrochloride, the glutamic acid-5-methyl ester hydrochloride reacts with an acylating agent to generate trifluoroacetyl glutamic acid-5-methyl ester, the trifluoroacetyl glutamic acid-5-methyl ester reacts with isobutene in a solvent to generate trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester, the trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester is hydrolyzed by inorganic base to obtain glutamic acid-1-tert-butyl ester, and then the glutamic acid-1-tert-butyl ester is protected by 9-fluorenylmethyl-N-succinimidyl carbonic ester to obtain a final product N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester. The product of the invention has important application in the field of polypeptide medicaments.
Description
Technical Field
The invention relates to a preparation method of a glutamic acid derivative, in particular to a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester.
Background
N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester (Fmoc-Glu-OtBu) is a commonly used amino acid protecting reagent, cas number of Fmoc-Glu-OtBu: 84793-07-7. The synthetic route in the prior art is as follows:
defects in the prior art: the synthesis route is complex to operate, the required reagents (Z-Osu, pd/C, etc.) are expensive, so that the cost of the product is high, the method is not suitable for industrial production, and the yield of the reaction intermediate in the prior art is relatively low, for example, the yield in the fourth step of hydrogenation is only 44%.
Disclosure of Invention
The invention aims to provide a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester, which mainly solves the technical problems of complex operation, low yield and expensive reagent in the existing synthesis method.
The technical scheme of the invention is as follows: a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester comprises the following steps:
glutamic acid is catalyzed by a dehydrating agent to generate glutamic acid-5-methyl ester hydrochloride, the glutamic acid-5-methyl ester hydrochloride reacts with an acylating agent to generate trifluoroacetyl glutamic acid-5-methyl ester, the trifluoroacetyl glutamic acid-5-methyl ester reacts with isobutene in a solvent to generate trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester, the trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester is hydrolyzed by inorganic base to obtain glutamic acid-1-tert-butyl ester, and then the glutamic acid-1-tert-butyl ester is protected by 9-fluorenylmethyl-N-succinimidyl carbonic ester to obtain a final product N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester. The reaction formula is as follows:
the dehydrating agent is one of thionyl chloride and acetyl chloride.
The acylating agent is one of trifluoroacetic anhydride and ethyl trifluoroacetate, preferably trifluoroacetic anhydride.
The solvent is one of tetrahydrofuran, dichloromethane, methyl tertiary butyl ether and dioxane, preferably dichloromethane or methyl tertiary butyl ether.
The acid is one of concentrated sulfuric acid and p-toluenesulfonic acid, preferably concentrated sulfuric acid.
The inorganic base is one of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like.
The beneficial effects of the invention are as follows: the invention provides a preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester, which utilizes the advantages that a trifluoroacetyl group can protect glutamic acid amino under alkaline conditions and can also simultaneously deprotect with carboxymethyl ester of glutamic acid under alkaline conditions, shortens reaction steps, is simple to operate, and avoids expensive metal palladium catalysts in the old route.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of example 1.
FIG. 2 is an infrared spectrum of example 1.
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of example 2.
FIG. 4 is an infrared spectrum of example 2.
Detailed Description
Example 1:
100 g of glutamic acid (molecular weight 147,0.68 mol) is added into 600 ml of methanol, the temperature is reduced to minus 10 ℃, 110 ml of thionyl chloride is added dropwise, after the completion of the reaction, the reaction is carried out at room temperature, the thin plate chromatography monitoring reaction is carried out, diethyl ether is added for crystallization after the reaction is completed, 110 g of glutamic acid-5-methyl ester hydrochloride is obtained through suction filtration, and the yield is 83%.
Dissolving 110 g of glutamic acid-5-methyl ester hydrochloride (molecular weight 197.5,0.56 mol) obtained in the previous step in 1000 ml of tetrahydrofuran, cooling to below 10 ℃, and dropwise adding 170 ml of triethylamine (molecular weight 101,1.25 mol) to finish; cooling the periphery by ice water bath, slowly dropwise adding 99 ml of trifluoroacetic anhydride (molecular weight 210,0.7 mol), finishing the reaction after the dropwise addition, washing the reaction system once by water, washing the reaction system twice by saturated sodium bicarbonate solution, washing the reaction system by saturated salt water to be neutral, drying, basically evaporating ethyl acetate, adding petroleum ether for crystallization, and obtaining 97 g of trifluoroacetyl glutamic acid-5-methyl ester with the yield of 92%.
97 g of trifluoroacetyl glutamic acid-5-methyl ester (molecular weight 188.5,0.52 mol) obtained in the previous step is dissolved in 970 ml of dichloromethane, the temperature is reduced to 15 ℃, 77 g of concentrated sulfuric acid (molecular weight 98,0.77 mol, mass fraction is 98%) is added dropwise, 75 g of isobutene (molecular weight 56,1.34 mol) is introduced after completion, the temperature is controlled to be about 0 ℃ after completion, the reaction is carried out overnight, thin plate chromatography monitoring is carried out, excessive isobutene is pumped out after the reaction is completed, the reaction system is washed three times by saturated sodium bicarbonate solution, saturated salt is washed once, the solvent is dried, and 128 g of oily trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester is obtained after evaporation, and the yield is 95%.
128 g (molecular weight 261.5,0.49 mol) of the oily matter obtained in the last step is dissolved in 1.2L of ethanol, 640 ml of sodium hydroxide solution (3 mol/L) is added dropwise at the temperature of 0-5 ℃, the reaction is finished for 4 hours, the temperature of 0-5 ℃ is still controlled, the pH of the system is adjusted to 6-7 by using 50% citric acid solution, solids are gradually separated out from the system, 74 g of glutamic acid-1-tert-butyl ester is obtained by suction filtration, and the yield is 69%.
74 g of glutamic acid-1-tert-butyl ester (molecular weight 220,0.34 mol) obtained in the above step is suspended in a mixed solution of 600 ml of acetone and 600 ml of water, 110 g of sodium bicarbonate (molecular weight 84,1.34 mol) is added, 113 g of 9-fluorenylmethyl-N-succinimidyl carbonate solid (molecular weight 337,0.34 mol) is added in batches, the pH of the system is kept between 8 and 9 by using concentrated alkali, the reaction is monitored by thin plate chromatography, after the reaction is finished, 1.4L of ethyl acetate is added into the system, the pH of the system is adjusted to between 2 and 3 by using citric acid, layering, removing the water phase, washing the oil phase to be neutral by using saturated salt water, drying, basically evaporating the solvent, adding petroleum ether for crystallization, and carrying out suction filtration, thus obtaining 130 g of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester with the yield of 90%. The nuclear magnetic resonance hydrogen spectrum of the product is shown in figure 1, and the infrared spectrum is shown in figure 2.
Example 2:
100 g of glutamic acid (molecular weight 147,0.68 mol) is added into 600 ml of methanol, the temperature is reduced to minus 10 ℃, 120 ml of acetyl chloride is added dropwise, after the completion of the reaction, the reaction is carried out at room temperature, the thin plate chromatography monitoring reaction is carried out, diethyl ether is added for crystallization after the reaction is completed, 113 g of glutamic acid-5-methyl ester hydrochloride is obtained by suction filtration, and the yield is 85 percent
113 g of glutamic acid-5-methyl ester hydrochloride (molecular weight 197.5,0.57 mol) obtained in the previous step is dissolved in 1000 ml of tetrahydrofuran, cooled to below 10 ℃, and 177 ml of triethylamine (molecular weight 101,1.27 mol) is added dropwise to finish the process; and (3) cooling the periphery by using an ice water bath, slowly dropwise adding 101 milliliters of trifluoroacetic anhydride (molecular weight 210,0.7 mol), finishing the reaction after the dropwise addition, washing the reaction system once by using saturated sodium bicarbonate solution twice, washing the reaction system with saturated saline water to be neutral, drying, basically evaporating ethyl acetate, adding petroleum ether for crystallization, and obtaining 93 grams of trifluoroacetyl glutamic acid-5-methyl ester with the yield of 86 percent.
93 g of trifluoroacetyl glutamic acid-5-methyl ester (molecular weight 188.5,0.49 mol) obtained in the previous step is dissolved in 930 ml of methyl tertiary butyl ether, the temperature is reduced to 15 ℃, 74 g of concentrated sulfuric acid (molecular weight 98,0.74 mol) is dripped, 72 g of isobutene (molecular weight 56,1.28 mol) is introduced after the completion of the reaction, the temperature is controlled to be about 0 ℃ after the completion of the reaction, the reaction is carried out overnight, thin plate chromatography monitoring is carried out, the excessive isobutene is pumped out after the reaction is completed, the reaction system is washed three times by saturated sodium bicarbonate solution, saturated salt is washed once, the mixture is dried, and the solvent is evaporated to obtain 125 g of oily trifluoroacetyl glutamic acid-5-methyl ester-1-tertiary butyl ester, and the yield is 98%.
125 g (molecular weight 261.5,0.48 mol) of the oily matter obtained in the last step is dissolved in 1.2L of ethanol, the temperature is controlled to be 0-5 ℃, a sodium carbonate solution (102 g of sodium carbonate is dissolved in 600 ml of water) is dropwise added, the reaction is finished for 4 hours, the temperature is still controlled to be 0-5 ℃, the pH value of the system is adjusted to be 6-7 by using 50% citric acid solution, solids are gradually separated out from the system, 63 g of glutamic acid-1-tert-butyl ester is obtained by suction filtration, and the yield is 59%.
63 g of glutamic acid-1-tert-butyl ester (molecular weight 220,0.286 mol) obtained in the above step is suspended in a mixed solution of 600 ml of acetone and 600 ml of water, 96 g of sodium bicarbonate (molecular weight 84,1.14 mol) is added, 96 g of 9-fluorenylmethyl-N-succinimidyl carbonate solid (molecular weight 337,0.286 mol) is added in batches, the pH of the system is kept between 8 and 9 by using concentrated alkali, the reaction is monitored by thin plate chromatography, 1.2L of ethyl acetate is added to the system after the reaction is finished, the pH of the system is adjusted to between 2 and 3 by using citric acid, layering, removing the water phase, washing the oil phase to be neutral by using saturated salt water, drying, basically evaporating the solvent, adding petroleum ether for crystallization, and carrying out suction filtration, thus obtaining 105 g of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester with the yield of 86%. The nuclear magnetic resonance hydrogen spectrum of the product is shown in figure 3, and the infrared spectrum is shown in figure 4.
Claims (7)
1. A preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester is characterized by comprising the following steps: the specific operation steps are as follows:
firstly, glutamic acid is catalyzed by a dehydrating agent to generate glutamic acid-5-methyl ester hydrochloride;
secondly, reacting glutamic acid-5-methyl ester hydrochloride with an acylating reagent to generate trifluoro acetyl glutamic acid-5-methyl ester;
thirdly, reacting trifluoroacetyl glutamic acid-5-methyl ester with isobutene in a solvent under the catalysis of acid to generate trifluoroacetyl glutamic acid-5-methyl ester-1-tert-butyl ester;
fourthly, hydrolyzing the trifluoro acetyl glutamic acid-5-methyl ester-1-tert-butyl ester by inorganic alkali to obtain glutamic acid-1-tert-butyl ester;
and fifthly, protecting the glutamic acid-1-tert-butyl ester by using 9-fluorenylmethyl-N-succinimidyl carbonate to obtain a final product N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester.
2. The method for preparing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the dehydrating agent is one of thionyl chloride and acetyl chloride.
3. The method for preparing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the acylating reagent is one of trifluoroacetic anhydride and ethyl trifluoroacetate.
4. The method for preparing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the solvent is one of tetrahydrofuran, methyl tertiary butyl ether and dioxane.
5. The method for preparing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the acid is one of concentrated sulfuric acid and p-toluenesulfonic acid.
6. The method for preparing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the inorganic base is one of sodium hydroxide, potassium hydroxide and sodium carbonate.
7. The method for producing N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester according to claim 1, wherein: the glutamic acid is one of L-glutamic acid, D-glutamic acid and DL-glutamic acid.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5140104A (en) * | 1982-03-09 | 1992-08-18 | Cytogen Corporation | Amine derivatives of folic acid analogs |
| CN106008271A (en) * | 2016-05-27 | 2016-10-12 | 成都郑源生化科技有限公司 | Preparation method of 1-tert-butyl glutamate derivative |
| WO2019243825A1 (en) * | 2018-06-21 | 2019-12-26 | Curadev Pharma Limited | Small molecule modulators of human sting, conjugates and therapeutic applications |
| CN111704566A (en) * | 2020-06-16 | 2020-09-25 | 吉尔生化（上海）有限公司 | Preparation method of N-fluorenylmethoxycarbonyl-gamma- (S-trityl-cysteamine) -L-glutamic acid |
| WO2022204412A1 (en) * | 2021-03-24 | 2022-09-29 | Bristol-Myers Squibb Company | Immunomodulators |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5140104A (en) * | 1982-03-09 | 1992-08-18 | Cytogen Corporation | Amine derivatives of folic acid analogs |
| CN106008271A (en) * | 2016-05-27 | 2016-10-12 | 成都郑源生化科技有限公司 | Preparation method of 1-tert-butyl glutamate derivative |
| WO2019243825A1 (en) * | 2018-06-21 | 2019-12-26 | Curadev Pharma Limited | Small molecule modulators of human sting, conjugates and therapeutic applications |
| CN111704566A (en) * | 2020-06-16 | 2020-09-25 | 吉尔生化（上海）有限公司 | Preparation method of N-fluorenylmethoxycarbonyl-gamma- (S-trityl-cysteamine) -L-glutamic acid |
| WO2022204412A1 (en) * | 2021-03-24 | 2022-09-29 | Bristol-Myers Squibb Company | Immunomodulators |
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