CN116655534A - Synthetic method of Boc-3- (3-pyrazole) -L-alanine - Google Patents
Synthetic method of Boc-3- (3-pyrazole) -L-alanine Download PDFInfo
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- CN116655534A CN116655534A CN202310666907.0A CN202310666907A CN116655534A CN 116655534 A CN116655534 A CN 116655534A CN 202310666907 A CN202310666907 A CN 202310666907A CN 116655534 A CN116655534 A CN 116655534A
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- 229960003767 alanine Drugs 0.000 title claims abstract description 22
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract 19
- 230000002194 synthesizing effect Effects 0.000 claims abstract 9
- 125000005843 halogen group Chemical group 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- UGZBFCCHLUWCQI-LURJTMIESA-N methyl (2r)-3-iodo-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)[C@H](CI)NC(=O)OC(C)(C)C UGZBFCCHLUWCQI-LURJTMIESA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- 239000007787 solid Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- YQFFHPXGRDVLLR-UHFFFAOYSA-N (2,3,4-triphenylphenyl)phosphane Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC=CC=2)C(P)=CC=C1C1=CC=CC=C1 YQFFHPXGRDVLLR-UHFFFAOYSA-N 0.000 description 1
- ICFGFAUMBISMLR-UHFFFAOYSA-N 1h-pyrazole-5-carbaldehyde Chemical compound O=CC=1C=CNN=1 ICFGFAUMBISMLR-UHFFFAOYSA-N 0.000 description 1
- -1 2-methyl Chemical compound 0.000 description 1
- SITJXRWLFQGWCB-UHFFFAOYSA-N 3-iodo-1-methylpyrazole Chemical compound CN1C=CC(I)=N1 SITJXRWLFQGWCB-UHFFFAOYSA-N 0.000 description 1
- XHZWFUVEKDDQPF-UHFFFAOYSA-N 5-bromo-1h-pyrazole Chemical compound BrC1=CC=NN1 XHZWFUVEKDDQPF-UHFFFAOYSA-N 0.000 description 1
- IJPFBRONCJOTTA-UHFFFAOYSA-N 5-chloro-1h-pyrazole Chemical class ClC1=CC=NN1 IJPFBRONCJOTTA-UHFFFAOYSA-N 0.000 description 1
- RUKDVLFJSMVBLV-UHFFFAOYSA-N 5-iodo-1h-pyrazole Chemical compound IC1=CC=NN1 RUKDVLFJSMVBLV-UHFFFAOYSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004896 polypeptide structure Anatomy 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method of Boc-3- (3-pyrazole) -L-alanine, which mainly solves the technical problems of complex synthesis process, high cost and high-pressure hydrogenation danger in the prior art. The technical scheme of the invention is as follows: a method for synthesizing Boc-3- (3-pyrazole) -L-alanine, which has the following reaction formula:
Description
Technical Field
The invention relates to a synthetic method of Boc-3- (3-pyrazole) -L-alanine.
Background
Amino acids are the most basic substances of vital proteins and are involved in the vital activities of living organisms. Amino acids include natural amino acids and unnatural amino acids. With the development needs of polypeptide drugs and the wide application of combinatorial chemistry technologies, common protein amino acids cannot meet the needs of special structures, but unnatural amino acids can be designed according to the needs of human beings. Alanine containing pyrazole group has similar group with natural amino acid histidine in structure, and the introduction of the alanine into polypeptide structure can have great influence on organisms, and is always a hot spot for research in the field of polypeptides. Patent WO2007/70826, 2007, A1 and patent WO2008/157162, 2008, A1 report a synthesis method of 3- (3-pyrazole) -L-alanine, specifically as follows:
the route uses pyrazole-3-formaldehyde as a starting material, and an asymmetric high-pressure hydrogenation reaction is needed, and an expensive rhodium metal catalyst and an expensive chiral ligand are needed.
Disclosure of Invention
The invention provides a rapid and simple synthesis method of Boc-3- (3-pyrazole) -L-alanine, which mainly solves the technical problems of multiple reaction steps, high cost and high-pressure hydrogenation danger of the existing synthesis method.
The technical scheme of the invention is as follows: a synthetic method of Boc-3- (3-pyrazole) -L-alanine comprises the following steps:
step one, adding a metal palladium catalyst into N-Boc-3-iodoalanine methyl ester and 3-halogenated pyrazole in an organic solvent, and obtaining an intermediate through a coupling reaction; and step two, hydrolyzing the intermediate through lithium hydroxide to obtain a target product Boc-3- (3-pyrazole) -L-alanine. The specific reaction route related by the invention is as follows:
wherein: x is halogen selected from: one of Cl, br or I; r is one of a hydrogen atom, an alkyl group or a benzyl group, wherein the alkyl group is one of a methyl group, an ethyl group and a C3-C10 linear or branched alkyl group, and R is preferably one of a hydrogen atom, a methyl group or an ethyl group, and most preferably a hydrogen atom or a methyl group.
The organic solvent is selected from one or more of the following: ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyl, tetrahydrofuran, methyl acetate, ethyl formate, isopropyl acetate, t-butyl acetate, methyl t-butyl ether, diethyl ether, toluene, DMF, preferably one of DMF, ethyl acetate or tetrahydrofuran; DMF is further preferred.
The metal palladium catalyst is selected from tetra (triphenyl)Phenylphosphine) palladium, or Pd 2 (dba) 3 。
The reaction temperature in the first step is 0-100 ℃, preferably 40-80 ℃.
The invention has the beneficial effects that: the invention provides a rapid and simple synthesis method of Boc-3- (3-pyrazole) -L-alanine. The reaction route reported in the literature is shortened from 3 steps to 2 steps, the use of expensive metal rhodium catalyst and dangerous high-pressure hydrogenation reaction are avoided, the synthesis operation is simplified, and the synthesis efficiency is improved.
Detailed Description
The invention will be further illustrated with reference to specific embodiments, to which the invention is not limited.
Example 1
Step one 500 mL reaction flask was charged with DMF (150 ml), stirring was turned on, zinc powder (24 g,0.36 mol), iodine (4.6 g,18 mmol) and N were added sequentially 2 3-iodopyrazole (23.3 g, 0.12 mol) in 50 ml DMF was added dropwise after 3-displacement, methyl (R) -2-tert-butoxycarbonylamino-3-iodopropionate (34.4 g,0.108 mol) and tetrakis (triphenylphosphine) palladium (4.2 g, 3.6 mmol) N were added 2 3 times of replacement, heating to 40-50 ℃ and stirring for 12 h, completely reacting, pouring the reaction liquid into 800 mL water, extracting with 200 mL ethyl acetate, washing an organic phase once with brine, removing the solvent from the organic phase, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio=10:1 mobile phase) to obtain 20.4 g intermediate with the yield of 70%.
Step two, taking a 500 ml reaction bottle, adding the intermediate (20.4 g,75.8 mmol) of the previous step, THF (200 ml), starting stirring, dropwise adding a 1M lithium hydroxide aqueous solution (114 ml,113.7 mmol), stirring at room temperature for 1 hour after the addition, concentrating at 40 ℃ under reduced pressure to remove THF, extracting an aqueous phase with petroleum ether 200 ml for 2 times, adjusting the pH of the aqueous phase to 4 with solid citric acid, precipitating solids, filtering to obtain a solid 12.6 g, and obtaining the yield of 65%; HPLC purity 97.0%.1H-NMR (400 MHz, DMSO): delta (ppm) =12.55 (br, 2H), 7.49 (s, 1H), 7.01 (d, 1H), 6.05 (s, 1H), 4.15 (m, 1H), 2.80-3.00 (m, 2H), 1.35 (s, 9H).
Example 2
Step one 500 mL reaction flask was charged with ethyl acetate (150 ml), stirring was turned on, zinc powder (24 g,0.36 mol), iodine (4.6 g,18 mmol), N were added sequentially 2 3-Bromopyrazole (17.6 g, 0.12 mol) in 50 ml ethyl acetate was added dropwise after 3-displacement, methyl (R) -2-t-butoxycarbonylamino-3-iodopropionate (34.4 g,0.108 mol), tetrakis (triphenylphosphine) palladium (4.2 g, 3.6 mmol) N was added 2 3 times of replacement, heating to 50-60 ℃ and stirring for 12 h, completely reacting, pouring the reaction liquid into 800 mL water, extracting with 200 mL ethyl acetate, washing an organic phase once with brine, removing the solvent from the organic phase, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio=10:1 mobile phase) to obtain 17.5 g intermediate with the yield of 60%.
Step two, taking a 500 ml reaction bottle, adding the intermediate (17.5 g,65.0 mmol) of the previous step, THF (175 ml), starting stirring, dropwise adding a 1M lithium hydroxide aqueous solution (98 ml,97.5 mmol), stirring for 1 hour at room temperature after the addition is finished, concentrating under reduced pressure at 40 ℃ to remove THF, extracting an aqueous phase with petroleum ether 175 ml for 2 times, regulating the pH of the aqueous phase with solid citric acid to 4, precipitating solids, filtering to obtain a solid 13.3 g, and obtaining the yield of 80%; HPLC purity 98.0%.1H-NMR (400 MHz, DMSO): delta (ppm) =12.55 (br, 2H), 7.49 (s, 1H), 7.01 (d, 1H), 6.05 (s, 1H), 4.15 (m, 1H), 2.80-3.00 (m, 2H), 1.35 (s, 9H).
Example 3
Step one 500 mL reaction flask was charged with tetrahydrofuran (150 ml), stirring was turned on, zinc powder (24 g,0.36 mol), iodine (4.6 g,18 mmol), N were added sequentially 2 3-Chloropyrazoles (12.3. 12.3 g, 0.12 mol) in 50 ml tetrahydrofuran were added dropwise after 3-displacement, methyl (R) -2-t-butoxycarbonylamino-3-iodopropionate (34.4 g,0.108 mol), sphos (2.5 g,6.0 mmol), pd 2 (dba) 3 （3.3 g，3.6 mmol）N 2 3 times of replacement, heating to 60-70deg.C, stirring for 12 h, reacting completely, pouring the reaction solution into 800 mL water, extracting with 200 mL ethyl acetate, washing the organic phase with saline, removing solvent from the organic phase, purifying by column chromatography (200-300 mesh silica gel,petroleum ether/ethyl acetate volume ratio = 10:1 mobile phase) yields 20.4 g intermediates in 70%.
Step two, taking a 500 ml reaction bottle, adding the intermediate (20.4 g,75.8 mmol) of the previous step, THF (204 ml), starting stirring, dropwise adding a 1M lithium hydroxide aqueous solution (114 ml,113.7 mmol), stirring at room temperature for 1 hour after the addition, concentrating at 40 ℃ under reduced pressure to remove THF, extracting an aqueous phase with petroleum ether 204 ml for 2 times, adjusting the pH of the aqueous phase to 4 with solid citric acid, precipitating solids, filtering to obtain a solid 17.4 g, and obtaining the yield of 90%; HPLC purity 98.1%.1H-NMR (400 MHz, DMSO): delta (ppm) =12.55 (br, 2H), 7.49 (s, 1H), 7.01 (d, 1H), 6.05 (s, 1H), 4.15 (m, 1H), 2.80-3.00 (m, 2H), 1.35 (s, 9H).
Example 4
Step one 500 mL reaction flask was charged with toluene (150 ml), stirring was turned on, zinc powder (24 g,0.36 mol), iodine (4.6 g,18 mmol), N were added sequentially 2 1-methyl-3-iodopyrazole (24.96 g, 0.12 mol) in 50 ml toluene was added dropwise after 3-displacement, methyl (R) -2-t-butoxycarbonylamino-3-iodopropionate (34.4 g,0.108 mol), tetrakis (triphenylphosphine) palladium (4.2 g, 3.6 mmol) N was added 2 3 times of replacement, heating to 70-80 ℃ and stirring for 12 h, completely reacting, pouring the reaction liquid into 800 mL water, extracting with 200 mL ethyl acetate, washing an organic phase once with brine, removing the solvent from the organic phase, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio=10:1 mobile phase) to obtain 21.4 g intermediate with the yield of 70%.
Step two, taking a 500 ml reaction bottle, adding the intermediate (21.4 g,75.5 mmol) of the previous step, THF (214 ml), starting stirring, dropwise adding a 1M lithium hydroxide aqueous solution (113 ml,113.3 mmol), stirring for 1 hour at room temperature after the addition is finished, concentrating under reduced pressure at 40 ℃ to remove THF, extracting an aqueous phase with petroleum ether 220 ml for 2 times, regulating the pH of the aqueous phase with solid citric acid to 4, precipitating solids, filtering to obtain a solid 16.3 g, and obtaining the yield of 80%; HPLC purity 98.2%.1H-NMR (400 MHz, DMSO): delta (ppm) =12.55 (br, 2H), 7.49 (s, 1H), 7.01 (d, 1H), 6.05 (s, 1H), 4.15 (m, 1H), 3.92 (s, 1H), 2.80-3.00 (m, 2H), 1.35 (s, 9H).
Claims (9)
1. A synthetic method of Boc-3- (3-pyrazole) -L-alanine is characterized in that: the method comprises the following two steps: step one, adding a metal palladium catalyst into N-Boc-3-iodoalanine methyl ester and 3-halogenated pyrazole in an organic solvent, and obtaining an intermediate through a coupling reaction; step two, the intermediate is hydrolyzed by lithium hydroxide to obtain a target product Boc-3- (3-pyrazole) -L-alanine; the reaction formula is as follows:
wherein: x is halogen selected from: one of Cl, br or I; r is one of hydrogen atom, alkyl or benzyl.
2. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 1, wherein the method comprises the following steps: the alkyl is one of methyl, ethyl and C3-C10 straight-chain or branched-chain alkyl.
3. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 1, wherein the method comprises the following steps: r is selected from one of hydrogen atom, methyl or ethyl.
4. A method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 3, wherein the method comprises the steps of: r is selected from hydrogen atom or methyl.
5. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 1, wherein the method comprises the following steps: the organic solvent in the first step is selected from one or more of the following: ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl formate, isopropyl acetate, t-butyl acetate, methyl t-butyl ether, diethyl ether, toluene, DMF.
6. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 5, wherein the method comprises the following steps: the organic solvent in the step one is selected from one of DMF, ethyl acetate or tetrahydrofuran.
7. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 1, wherein the method comprises the following steps: the metal palladium catalyst in the first step is tetra (triphenylphosphine) palladium or Pd 2 (dba) 3 。
8. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 1, wherein the method comprises the following steps: the reaction temperature of the first step is 0-100 ℃.
9. The method for synthesizing Boc-3- (3-pyrazole) -L-alanine according to claim 8, wherein the method comprises the following steps: the reaction temperature of the first step is 40-80 ℃.
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