CN115784922A - Preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid - Google Patents
Preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid Download PDFInfo
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- CN115784922A CN115784922A CN202211401302.0A CN202211401302A CN115784922A CN 115784922 A CN115784922 A CN 115784922A CN 202211401302 A CN202211401302 A CN 202211401302A CN 115784922 A CN115784922 A CN 115784922A
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- amino
- cyclopropyl
- cyclobutyl
- tert
- butoxycarbonyl
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 title claims abstract description 37
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid Chemical compound 0.000 claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 12
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 8
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000007259 addition reaction Methods 0.000 claims abstract description 3
- 230000008878 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- 238000003379 elimination reaction Methods 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- COERJHDMQUPDCV-UHFFFAOYSA-N [K].FB(F)F Chemical compound [K].FB(F)F COERJHDMQUPDCV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- FKTLISWEAOSVBS-UHFFFAOYSA-N 2-prop-1-en-2-yloxyprop-1-ene Chemical compound CC(=C)OC(C)=C FKTLISWEAOSVBS-UHFFFAOYSA-N 0.000 description 1
- SIQJIBZPKVVKHX-UHFFFAOYSA-N FB(F)F.[K]C1CC1 Chemical compound FB(F)F.[K]C1CC1 SIQJIBZPKVVKHX-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid, belonging to the technical field of medical intermediates. The method comprises the steps of taking N-Boc-L-vinyl glycine as a raw material, performing addition reaction with bromine to obtain (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid, eliminating the (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid with potassium tert-butoxide/2, 6-tetramethylpiperidine, coupling the (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride with cyclopropyl/cyclobutyl trifluoroborate potassium salt Suzuki, and finally performing Pd/C catalytic hydrogenation to obtain the (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid.
Description
Technical Field
The invention relates to a preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid, belonging to the technical field of medical intermediates.
Background
(2S) -2-amino-4-cyclopropylbutyric acid, CAS:1336542-19-8, english name: (2S) -2-Amino-4-cyclopropybutanoic acid; (2S) -2-amino-4-cyclobutylbutyric acid, CAS:1932829-31-6, english name: (2S) -2-Amino-4-cyclobutylbutanoid acid. (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid is a non-natural alpha-amino acid which can form a polypeptide by an amide bond, the nature of which is determined by its basic unit as an amino acid. As the result of intensive research, many unnatural alpha-amino acids have unique biological functions and application values, and can be used as precursors for synthesizing other nitrogen-containing compounds, such as hormones, alkaloids, antibiotics, antitumor drugs, etc., as components constituting bacterial cell walls, and as chiral inducers.
At present, no literature report exists on the synthetic methods of (2S) -2-amino-4-cyclopropyl butyric acid and (2S) -2-amino-4-cyclobutyl butyric acid, so that the corresponding synthetic methods need to be developed to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid. N-Boc-L-vinylglycine is used as a raw material and is added with bromine to obtain (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid, then the (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyl-3-olefine acid is eliminated with potassium tert-butoxide/2, 6-tetramethylpiperidine to obtain (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] butyl-3-olefine acid, then the (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyl-3-olefine acid hydrochloride is obtained by Suzuki coupling with cyclopropyl/cyclobutyl trifluoroborate, and then Pd/C catalytic hydrogenation is carried out to obtain (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid.
The invention relates to a preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid, wherein a reaction equation is expressed as follows:
the method comprises the following steps:
step one, addition reaction: reacting N-Boc-L-vinyl glycine with bromine in chloroalkane to obtain (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid;
second, elimination reaction: mixing (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid with an organic solvent, and adding potassium tert-butoxide/2, 6-tetramethylpiperidine for reaction to obtain (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid;
step three, suzuki coupling: mixing (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid, cyclopropyl/cyclobutyl potassium trifluoroborate, inorganic base, water and an organic solvent, adding (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride for coupling, and performing post-treatment for removing Boc to obtain (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride;
step four, catalytic hydrogenation: mixing (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride, palladium-carbon and alcohol solvent, and carrying out catalytic hydrogenation reaction to obtain (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid.
Further, in the above technical scheme, in the first step, the molar ratio of N-Boc-L-vinylglycine to bromine is 1.01-1.05; the chloralkane solvent is selected from dichloromethane and dichloroethane.
Further, in the above technical solution, in the second step, the organic solvent is selected from a mixed solvent of THF/DMSO or THF/sulfolane.
Further, in the above technical scheme, in the second step, the molar ratio of the (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid, potassium tert-butoxide, to 2, 6-tetramethylpiperidine is 1.
Further, in the above technical solution, in the third step, the inorganic base is selected from cesium carbonate or potassium carbonate.
Further, in the above technical solution, in the third step, the organic solvent is selected from THF or a THF/DME mixed solvent.
Further, in the above technical scheme, in the third step, the molar ratio of (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid, cyclopropyl/cyclobutyl trifluoroborate, inorganic base, (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium is 1.05-1.10.
Further, in the above technical solution, in the third step, hydrogen chloride gas is used for the Boc removal in the post-treatment.
Further, in the above technical solution, in the fourth step, the alcohol solvent is selected from ethanol or isopropanol, the hydrogenation pressure is 0.1-0.3MPa, and the amount of palladium carbon is 2.5-5.0% of the weight of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride.
Advantageous effects of the invention
1. The elimination through bromination addition to obtain the compound 2 is more economical, and the elimination yield is high through potassium tert-butoxide/2, 6-tetramethylpiperidine and almost no isomer exists.
2. The Suzuki coupling is carried out by utilizing cyclopropyl/cyclobutyl potassium trifluoroborate and other organic potassium trifluoroborates, so that the conversion rate and yield are higher, and the product is easier to purify.
3. The method has the advantages of simple operation, low requirement on equipment, high yield and good continuity, and can meet the increasing market demand.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid
Example 1
Adding 40.2g (0.2mol, 1.0eq) of N-Boc-L-vinyl glycine and 220mL of dichloromethane into a four-port reaction kettle under the protection of nitrogen, cooling to-5 ℃, dropwise adding 32.6g (0.204mol, 1.02eq)/dichloromethane solution, reacting for 1 hour at 0 ℃, sampling, detecting by TLC, adding 5% sodium thiosulfate aqueous solution for quenching, washing an organic phase for 2 times, concentrating under reduced pressure to the residual 1 volume, adding N-hexane for precipitating a solid, and filtering to obtain (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino group]Butyric acid 67.3g, yield 93.2%, purity 96.7%. 1 HNMR(400MHz,CDCl 3 )δ:11.83(s,1H),5.73(s,1H),5.53-5.45(m,2H),3.74-3.69(m,1H),3.52-3.45(m,1H),1.39(s,9H).
Example 2
Adding (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino) into a four-port reaction kettle under the protection of nitrogen]36.1g (0.1mol, 1.0eq) of butyric acid, 350mL of tetrahydrofuran and 40mL of sulfolane, cooling to 0 ℃, slowly adding a mixed solution of potassium tert-butoxide (28.0g, 0.25mol)/2, 6-tetramethylpiperidine (42.4g, 0.30mol) at the controlled temperature of 0-10 ℃, then heating to 40-45 ℃ for reaction for 5 hours, detecting that no raw material remains in TLC (thin layer chromatography), cooling to 0 ℃, adding hydrochloric acid to adjust the pH value to be 7.5-8.5, concentrating under reduced pressure to remove tetrahydrofuran, adding ethyl acetate, adjusting the pH value to be 3.0-3.5 by using hydrochloric acid, carrying out layering, washing an organic phase for 2 times, concentrating under reduced pressure to the remaining 2 volumes, adding n-hexane to obtain (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino-n-hexane]22.9g of but-3-enoic acid, 81.6% yield and 98.7% HPLC. 1 HNMR(400MHz,CDCl 3 )δ:12.13(s,1H),7.31(s,1H),6.29-6.25(m,1H),4.67-4.63(m,1H),1.40(s,9H).
Example 3
Under the protection of nitrogen, adding (2S) -4-bromine-2- [ (tert-butoxycarbonyl) amino into a four-port reaction kettle]22.4g (80mmol, 1.0eq) of butane-3-olefine acid, 180mL of tetrahydrofuran and 40mL of water are added after stirring uniformly, 91.2g (0.28mol, 3.5eq) of cesium carbonate, 13g (88mmol, 1.1eq) of cyclopropyl potassium trifluoroborate and 1.74g (2.4mmol, 0.03eq) of (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride are added, the temperature is increased to 65-70 ℃ for reaction for 5 hours, HPLC detection shows that no raw materials are left, the mixture is filtered by diatomite, the filtrate is concentrated under reduced pressure, methyl tert-butyl ether and 4M hydrochloric acid are added to adjust the pH to be =3.0-3.5, water washing is carried out for 2 times, anhydrous sodium sulfate and silica gel are added to stir, the filtrate is cooled to 0 ℃ after filtration, 17.5g (0.48mol, 6.0eq) of hydrogen chloride are introduced, boc is removed at room temperature, the mixture is concentrated under reduced pressure, a methyl tert-butyl ether product is added to precipitate, and the mixture is filtered to obtain (2S) -2-amino-4- (cyclopropyl) butane-olefine acid hydrochloride, the yield is 12.5, 99.87%, and HPLC is obtained. 1 HNMR(400MHz,DMSO-d 6 )δ:14.12(s,1H),9.12(s,1H),6.13-6.05(m,2H),5.23-5.19(m,1H),4.23-4.17(m,1H),1.83-1.55(m,2H),0.52-0.31(m,4H).
Example 4
Under the protection of nitrogen, adding (2S) -4-bromine-2- [ (tert-butoxycarbonyl) amino into a four-port reaction kettle]22.4g (80mmol, 1.0eq) of butyl-3-olefine acid, 150mL of tetrahydrofuran, 45mL of ethylene glycol dimethyl ether and 40mL of water are added after stirring uniformly, 44.2g (0.32mol, 4.0eq) of potassium carbonate, 14.9g (92mmol, 1.15eq) of cyclobutyl trifluoroborate and 2.3g (3.2mmol, 0.04eq) of (1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride are added, the temperature is increased to 70-75 ℃ for reaction for 7 hours, no raw materials are remained through HPLC detection, the raw materials are filtered through kieselguhr, the filtrate is concentrated under reduced pressure, methyl tert-butyl ether and 4M hydrochloric acid are added to adjust the pH to be =2.5-3.5, the mixture is washed for 2 times, anhydrous sodium sulfate and silica gel are added into the organic phase for stirring, the filtrate is cooled to 0 ℃ after filtration, 20.4g (0.56mol, 7.0eq) of hydrogen chloride is introduced, the concentration is carried out at room temperature, the reduced pressure is carried out, the mixture is added, an isopropenyl ether product is separated out, and the filtrate is filtered to obtain 12.4- (2S) -2-amino-4- (cyclobutyl) hydrochloride, 12- (3.0eq) hydrochloride, the Boc 3.9-9.9 percent, the yield is 99 percent of HPLC yield is obtained through HPLC detection by HPLC, and the HPLC detection is obtained. 1 HNM R(400MHz,DMSO-d 6 )δ:13.97(s,1H),8.95(s,1H),7.12-7.02(m,2H),5.72-5.63(m,1H),5.26-5.21(m,1H),4.19-4.13(m,1H),2.98-2.90(m,1H),2.16-1.82(m,6H).
Example 5
Adding 8.9g (0.05mol, 1eq) of (2S) -2-amino-4- (cyclopropyl) but-3-enoic acid hydrochloride, 10% Pd/C0.22g and 90mL ethanol/10 mL water into a high-pressure reaction kettle, replacing with hydrogen, pressurizing at room temperature 0.2MPa until TLC detection reaction is completed, filtering with diatomaceous earth, concentrating the filtrate under reduced pressure to a constant solution, adding MTBE and 5% aqueous sodium hydroxide solution to adjust pH =6.7-6.8, layering, washing the organic phase with water for 2 times, drying with anhydrous magnesium sulfate, concentrating the filtrate under reduced pressure to the remaining 3 volumes, adding n-propyl-3Hexane, the product precipitated out and was filtered to give 6.6g of (2S) -2-amino-4-cyclopropylbutyric acid as the product in 91.6% yield, 99.4% HPLC and 99.7% Cbz-derived ee. 1 HNMR(400MHz,DMSO-d 6 )δ:12.29(s,1H),8.83(s,2H),3.29-3.26(m,1H),1.85-1.77(m,2H),1.37-1.11(m,3H),0.31-0.05(m,4H).
Example 6
Adding 9.6g (0.05mol, 1eq) of (2S) -2-amino-4- (cyclopropyl) but-3-enoic acid hydrochloride, 10% Pd/C0.24g and 100mL of ethanol/20 mL of water into a high-pressure reaction kettle, replacing with hydrogen, pressurizing at room temperature by 0.15MPa until the TLC detection reaction is complete, filtering through diatomite, concentrating the filtrate under reduced pressure to a constant solution, adding MTBE and 5% aqueous sodium hydroxide solution to adjust the pH to be 6.7-6.8, layering, washing the organic phase with water for 2 times, drying anhydrous magnesium sulfate, concentrating the filtrate under reduced pressure to the residual 3.5 volume, adding n-hexane to precipitate the product, filtering to obtain 7.1g of the product (2S) -2-amino-4-cyclobutyl butyric acid, the yield is 90.9%, 99.5% by HPLC, and the Cbz derivative ee is 99.8%. 1 HNMR(400MHz,DMSO-d 6 )δ:12.28(s,1H),8.80(s,2H),3.18-3.13(m,1H),2.09-2.05(m,1H),1.94-1.72(m,8H),1.19-1.07(m,2H).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (9)
1. A method for preparing (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid, comprising the steps of:
step one, addition reaction: reacting N-Boc-L-vinyl glycine with bromine in chloroalkane solvent to obtain (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid;
second, elimination reaction: mixing (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid with an organic solvent, and adding potassium tert-butoxide/2, 6-tetramethylpiperidine to react to obtain (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid;
step three, suzuki coupling: (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid, (cyclopropyl/cyclobutyl) potassium trifluoroborate, inorganic base, water and an organic solvent are mixed, and (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium is added for coupling, and after post-treatment, boc removal is carried out to obtain (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride.
Step four, catalytic hydrogenation: mixing (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-enoic acid hydrochloride, palladium-carbon and alcohol solvent, and carrying out catalytic hydrogenation reaction to obtain (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid.
2. A method of producing (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the first step, the molar ratio of N-Boc-L-vinyl glycine to bromine is 1.01-1.05.
3. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the second step, the organic solvent is selected from a mixed solvent of THF/DMSO or THF/sulfolane.
4. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the second step, the molar ratio of the (2R) -3, 4-dibromo-2- [ (tert-butoxycarbonyl) amino ] butyric acid, potassium tert-butoxide, and 2, 6-tetramethylpiperidine is 1.
5. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the third step, the inorganic base is selected from cesium carbonate or potassium carbonate.
6. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the third step, the organic solvent is selected from THF or a THF/DME mixed solvent.
7. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the third step, the molar ratio of (2S) -4-bromo-2- [ (tert-butoxycarbonyl) amino ] but-3-enoic acid, potassium (cyclopropyl/cyclobutyl) trifluoroborate, inorganic base, and (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium is 1.05-1.10.
8. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the third step, hydrogen chloride gas is used for removing Boc in the post-treatment.
9. The process for the preparation of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butanoic acid according to claim 1, wherein: in the fourth step, the alcohol solvent is ethanol or isopropanol, the hydrogenation pressure is 0.1-0.3MPa, and the dosage of palladium carbon is 2.5-5.0% of the weight of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) but-3-olefine acid hydrochloride.
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| CN103387510A (en) * | 2013-08-08 | 2013-11-13 | 苏州永健生物医药有限公司 | Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride |
| CN110072855A (en) * | 2016-10-17 | 2019-07-30 | 基因泰克公司 | Therapeutic compound and its application method |
| CN114644635A (en) * | 2020-12-21 | 2022-06-21 | 上海济煜医药科技有限公司 | Triazole tricyclic derivative and preparation method and application thereof |
| CN115160158A (en) * | 2022-07-27 | 2022-10-11 | 泰州天鸿生化科技有限公司 | Preparation method of chiral tert-leucinol |
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| CN103387510A (en) * | 2013-08-08 | 2013-11-13 | 苏州永健生物医药有限公司 | Synthesis method of beta-amino-alpha-hydroxycyclohexyl butyl aluminum hydrochloride |
| CN110072855A (en) * | 2016-10-17 | 2019-07-30 | 基因泰克公司 | Therapeutic compound and its application method |
| CN114644635A (en) * | 2020-12-21 | 2022-06-21 | 上海济煜医药科技有限公司 | Triazole tricyclic derivative and preparation method and application thereof |
| CN115160158A (en) * | 2022-07-27 | 2022-10-11 | 泰州天鸿生化科技有限公司 | Preparation method of chiral tert-leucinol |
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