CN117865829A - Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester - Google Patents
Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester Download PDFInfo
- Publication number
- CN117865829A CN117865829A CN202410049902.8A CN202410049902A CN117865829A CN 117865829 A CN117865829 A CN 117865829A CN 202410049902 A CN202410049902 A CN 202410049902A CN 117865829 A CN117865829 A CN 117865829A
- Authority
- CN
- China
- Prior art keywords
- aspartic acid
- tert
- butyl ester
- fluorenylmethoxycarbonyl
- methyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VZXQYACYLGRQJU-IBGZPJMESA-N (3s)-3-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 VZXQYACYLGRQJU-IBGZPJMESA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 19
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 14
- PUWCNJZIFKBDJQ-YFKPBYRVSA-N (3s)-3-azaniumyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC(O)=O PUWCNJZIFKBDJQ-YFKPBYRVSA-N 0.000 claims abstract description 10
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 9
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 4
- 239000012467 final product Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 32
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 13
- 229960005261 aspartic acid Drugs 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group 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 8
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 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
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 abstract 1
- 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
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- 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
- 238000001704 evaporation 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
- 239000003208 petroleum Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229920006395 saturated elastomer Polymers 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
- 238000001035 drying Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012071 phase Substances 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
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 carboxyl methyl Chemical group 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
- 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
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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) -aspartic 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) -aspartic acid-1-tert-butyl ester comprises the following steps: aspartic acid is catalyzed by a dehydrating agent to generate aspartic acid-5-methyl ester hydrochloride, the aspartic acid-5-methyl ester hydrochloride reacts with an acylating agent to generate trifluoroacetyl aspartic acid-5-methyl ester, the trifluoroacetyl aspartic acid-5-methyl ester reacts with isobutene in a solvent to generate trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester, the trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester is hydrolyzed by inorganic base to obtain aspartic acid-1-tert-butyl ester, and then the aspartic acid-1-tert-butyl ester is protected by 9-fluorenylmethyl-N-succinimidyl carbonic ester to obtain the final product N- (9-fluorenylmethoxycarbonyl) -aspartic 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 an aspartic acid derivative, in particular to a preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester.
Background
N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester (Fmoc-Asp-OtBu) is a commonly used amino acid protecting reagent, cas number of Fmoc-Asp-OtBu: 129460-09-9, the synthetic route of 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) -aspartic 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) -aspartic acid-1-tert-butyl ester comprises the following steps:
aspartic acid is catalyzed by a dehydrating agent to generate aspartic acid-5-methyl ester hydrochloride, the aspartic acid-5-methyl ester hydrochloride reacts with an acylating agent to generate trifluoroacetyl aspartic acid-5-methyl ester, the trifluoroacetyl aspartic acid-5-methyl ester reacts with isobutene in a solvent to generate trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester, the trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester is hydrolyzed by inorganic base to obtain aspartic acid-1-tert-butyl ester, and then the aspartic acid-1-tert-butyl ester is protected by 9-fluorenylmethyl-N-succinimidyl carbonic ester to obtain the final product N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester. The reaction formula is as follows:
。
the aspartic acid is one of L-aspartic acid, D-aspartic acid or DL-aspartic acid.
The dehydrating agent is thionyl chloride or acetyl chloride.
The acylating agent is trifluoroacetic anhydride or ethyl trifluoroacetate, preferably trifluoroacetic anhydride.
The solvent is one of tetrahydrofuran, dichloromethane, methyl tertiary butyl ether or dioxane, preferably dichloromethane or methyl tertiary butyl ether.
The acid is concentrated sulfuric acid with the mass percentage concentration of 98% or p-toluenesulfonic acid, and preferably concentrated sulfuric acid with the mass percentage concentration of 98%.
The inorganic base is one of sodium hydroxide, potassium hydroxide or sodium carbonate.
The beneficial effects of the invention are as follows: the invention provides a preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester, which utilizes the advantages that a trifluoroacetyl group can protect aspartic acid amino under alkaline conditions and can also simultaneously deprotect with carboxyl methyl ester of aspartic 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
90 g of aspartic acid (molecular weight 133,0.68 mol) is added into 600 ml of methanol, the temperature is reduced to-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, 105 g of aspartic acid-5-methyl ester hydrochloride is obtained through suction filtration, and the yield is 85%.
105 g of aspartic acid-5-methyl ester hydrochloride (molecular weight 183.5,0.57 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 is 210,0.7 mol), finishing the reaction after the dropwise adding, washing the reaction system once by using water, washing the reaction system twice by using a saturated sodium bicarbonate solution, washing the reaction system by using saturated saline water until the reaction system is neutral, drying the reaction system, basically evaporating ethyl acetate, adding petroleum ether for crystallization, and obtaining 86 g of trifluoroacetyl aspartic acid-5-methyl ester with the yield of 86%.
86 g of trifluoroacetyl aspartic acid-5-methyl ester (molecular weight 174.5,0.49 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 added dropwise, 72 g of isobutene (molecular weight 56,1.28 mol) is introduced, the temperature is controlled to be about 0 ℃ after the introduction, the reaction is carried out overnight, thin plate chromatography monitoring is carried out, the reaction is finished, excessive isobutene is pumped out, 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 119 g of oily trifluoroacetyl aspartic acid-5-methyl ester-1-tertiary butyl ester, and the yield is 98%.
119 g (molecular weight 247.5,0.48 mol) of oily matter in the last step is dissolved in 1.2L of ethanol, the temperature is controlled to be 0-5 ℃, 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, solid is gradually separated out from the system, 59 g of aspartic acid-1-tert-butyl ester is obtained by suction filtration, and the yield is 59%.
59 g of aspartic acid-1-tert-butyl ester (molecular weight 206,0.286 mol) obtained in the above step was 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) was added, 96 g of 9-fluorenylmethyl-N-succinimidyl carbonate solid (molecular weight 337,0.286 mol) was added in portions, the pH of the system was kept at 8 to 9 by using a concentrated base, the reaction was monitored by thin plate chromatography, 1.2 l of ethyl acetate was added to the system after the reaction was completed, the pH of the system was adjusted to 2 to 3 by using citric acid, the layers were separated, the aqueous phase and the oil phase were washed to neutrality by using saturated brine, dried, the solvent was evaporated basically, and petroleum ether was added for crystallization, suction filtration to obtain 101 g of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester (molecular weight: 411.5), and the yield was 86%. 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
90 g of aspartic acid (molecular weight 133,0.68 mol) is added into 600 ml of methanol, the temperature is reduced to-10 ℃, 110 ml of thionyl chloride is added dropwise, after the completion of the reaction, the reaction is monitored by thin plate chromatography, diethyl ether is added for crystallization after the completion of the reaction, 103 g of aspartic acid-5-methyl ester hydrochloride is obtained by suction filtration, and the yield is 83%.
Dissolving 103 g of aspartic acid-5-methyl ester hydrochloride (molecular weight 183.5,0.56 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 adding, 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 91 g of trifluoroacetyl aspartic acid-5-methyl ester with the yield of 92%.
91 g of trifluoroacetyl aspartic acid-5-methyl ester (molecular weight 174.5,0.52 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 the oily trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester 121 g is obtained after evaporation, and the yield is 95%.
121 g (molecular weight 247.5,0.49 mol) of oily matter 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 value of the system is adjusted to 6-7 by using 50% citric acid solution, solid is gradually separated out from the system, 70 g of aspartic acid-1-tert-butyl ester is obtained by suction filtration, and the yield is 69%.
70 g of aspartic acid-1-tert-butyl ester (molecular weight 206,0.34 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 portions, the pH of the system is kept between 8 and 9 by using concentrated alkali, the reaction is monitored by thin plate chromatography, 1.4 l of ethyl acetate is added to the system after the reaction, 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, thereby obtaining 126 g of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester (molecular weight: 411.5), and the yield is 90%. 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) -aspartic acid-1-tert-butyl ester is characterized by comprising the following steps: the specific operation steps are as follows:
firstly, aspartic acid is catalyzed by a dehydrating agent to generate aspartic acid-5-methyl ester hydrochloride;
secondly, reacting aspartic acid-5-methyl ester hydrochloride with an acylating agent to generate trifluoroacetyl aspartic acid-5-methyl ester;
thirdly, reacting trifluoroacetyl aspartic acid-5-methyl ester with isobutene in a solvent under the catalysis of acid to generate trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester;
fourthly, hydrolyzing the trifluoroacetyl aspartic acid-5-methyl ester-1-tert-butyl ester by inorganic alkali to obtain aspartic acid-1-tert-butyl ester;
fifthly, protecting the aspartic acid-1-tert-butyl ester by using 9-fluorenylmethyl-N-succinimidyl carbonate to obtain a final product N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester; the reaction formula is as follows:
。
2. the process for producing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, wherein: the aspartic acid in the first step is one of L-aspartic acid, D-aspartic acid or DL-aspartic acid.
3. The method for preparing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the dehydrating agent in the first step is thionyl chloride or acetyl chloride.
4. The method for preparing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, which is characterized in that: in the second step, the acylating reagent is trifluoroacetic anhydride or ethyl trifluoroacetate.
5. The method for preparing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the solvent in the third step is one of tetrahydrofuran, methyl tertiary butyl ether or dioxane.
6. The method for preparing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the acid in the third step is one of concentrated sulfuric acid and p-toluenesulfonic acid.
7. The method for preparing N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester according to claim 1, which is characterized in that: the inorganic base in the fourth step is one of sodium hydroxide, potassium hydroxide or sodium carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410049902.8A CN117865829A (en) | 2024-01-13 | 2024-01-13 | Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410049902.8A CN117865829A (en) | 2024-01-13 | 2024-01-13 | Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117865829A true CN117865829A (en) | 2024-04-12 |
Family
ID=90582709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410049902.8A Pending CN117865829A (en) | 2024-01-13 | 2024-01-13 | Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117865829A (en) |
-
2024
- 2024-01-13 CN CN202410049902.8A patent/CN117865829A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101077609B1 (en) | Process for preparing tricyclic derivatives | |
| JP2021527703A (en) | Bribalacetam intermediate, its manufacturing method and bribalacetam manufacturing method | |
| CN107501112A (en) | A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate | |
| CN110054574B (en) | Synthesis method of fluorenylmethyloxycarbonyl-2, 3-dehydro-valine | |
| CN116178214B (en) | Preparation method of N- (9-fluorenylmethoxycarbonyl) -glutamic acid-1-tert-butyl ester | |
| CN117865829A (en) | Preparation method of N- (9-fluorenylmethoxycarbonyl) -aspartic acid-1-tert-butyl ester | |
| EP0080229A1 (en) | Salicylic derivatives of N-acetylcysteine | |
| CN111548356B (en) | Process for preparing tert-butyl-1, 8-dioxa-4, 11-diazaspiro [5.6] dodecane-11-carboxylic acid ester | |
| CN113501771B (en) | Preparation method of N- (2-aminoethyl) glycine derivative | |
| CN114105800B (en) | Preparation method of 2, 3-diaminomethyl benzoate | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN109574860B (en) | Method for preparing vilanterol | |
| JPH04364188A (en) | Production of 3-alkoxymethyl-cefalosporin derivative | |
| US3880919A (en) | Process for the production of alpha-amino-2-hydroxy-phenylacetic acids | |
| CN112479876B (en) | Oxazepane spiro compounds, intermediates and process for their preparation | |
| CN113387959B (en) | Synthesis method of thieno [3,2-c ] pyridine-6-carboxylic acid methyl ester | |
| CN102911085A (en) | Synthesis process of compound D-2- aminoxy-3-methylbutyric acid | |
| CN115925511B (en) | Synthesis method of intermediate 4, 4-difluorocyclohexanol | |
| CN109912410B (en) | Method for preparing tricyclodecenyl alcohol, reaction intermediate and preparation method thereof | |
| CN112552200B (en) | Preparation method of optical pure 4- (1-amino) ethyl benzoate and salt thereof | |
| CN117088830A (en) | Synthesis method of 2-amino-2- (furan-3-yl) acetic acid compound | |
| CN114736146A (en) | Preparation method of novel 1-methylpyrrolidine-2-acrylic acid | |
| CN117247335A (en) | Preparation method and application of nafamostat intermediate | |
| CN115572289A (en) | Synthesis method of tesofensine | |
| CN116621789A (en) | Synthesis method of (4S) -3- [2- [ [ fluorenylmethoxycarbonyl ] amino ] acetyl ] -2, 2-dimethyl-4-oxazolidinecarboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |