CN115784934A - Synthetic method of tyrosine derivative - Google Patents
Synthetic method of tyrosine derivative Download PDFInfo
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- CN115784934A CN115784934A CN202211465437.3A CN202211465437A CN115784934A CN 115784934 A CN115784934 A CN 115784934A CN 202211465437 A CN202211465437 A CN 202211465437A CN 115784934 A CN115784934 A CN 115784934A
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- 150000003667 tyrosine derivatives Chemical class 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 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
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 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
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 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
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 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 description 8
- 239000002904 solvent Substances 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- CADXRZVJHPSEOI-JTQLQIEISA-N methyl (2r)-3-iodo-2-(phenylmethoxycarbonylamino)propanoate Chemical compound COC(=O)[C@H](CI)NC(=O)OCC1=CC=CC=C1 CADXRZVJHPSEOI-JTQLQIEISA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 2
- -1 2-methyl Chemical compound 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012071 phase 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of a tyrosine derivative, which mainly solves the technical problems of multiple synthesis steps and low efficiency of the existing synthesis method. The technical scheme of the invention is as follows: a method for synthesizing a tyrosine derivative, wherein the reaction formula is as follows:
Description
Technical Field
The invention relates to a rapid and simple synthesis method of a tyrosine derivative. The reaction route reported in the literature is shortened from 4 steps of reaction to 1 step of reaction, and the synthesis efficiency is improved.
Background
Tyrosine is an essential amino acid for human body, plays an important role in metabolism, growth and development of life, and is widely applied to industries such as food, feed, medicine, chemical engineering and the like. Tyrosine derivatives are also widely used in the biomedical field. The Journal of Medicinal Chemistry, 2006, 49,1585-1596 and J. Org. Chem. 1987,52, 5283-5286 documents report a process for the synthesis of tyrosine derivatives, as follows:
in related reports, the synthesis of a target product needs 4 steps of reaction to be completed, and the efficiency is low.
Disclosure of Invention
The invention aims to provide a rapid and simple synthesis method of a tyrosine derivative, which mainly solves the technical problems of multiple synthesis steps and low efficiency of the existing synthesis method. The method has the characteristics of simple and convenient operation and easy industrial production.
The technical scheme of the invention is as follows: a method for synthesizing a tyrosine derivative, wherein the reaction formula is as follows:
wherein: r is one of hydrogen atom, alkyl, benzyl or trityl; the alkyl group is preferably a methyl group or an ethyl group. X is a halogen atom selected from: cl, br or I.
The organic solvent is selected from one or more of the following solvents: ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyl, methyl acetate, ethyl formate, isopropyl acetate, tert-butyl acetate, methyl tert-butyl ether, diethyl ether, toluene, N-dimethylformamide. One of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran or toluene is preferred.
The metal palladium catalyst is Pd (PPh) 3 ) 4 Or Pd 2 (dba) 3 . The reaction temperature is from 0 to 120 ℃ and preferably from 40 to 80 ℃.
The invention has the beneficial effects that: the invention provides a rapid and simple synthesis method of a tyrosine derivative. The reaction route reported in the literature is shortened from 4 steps to 1 step, and the synthesis efficiency is improved.
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to these examples.
Example 1
A150 mL reaction flask was charged with DMF (20 mL), stirred, and charged with zinc powder (9.75g, 0.149mol), iodine (3.78 g,14.9 mmol), and N 2 The substitution was conducted 3 times, a solution of 2-benzyloxy-5-chloroacetophenone (14.3 g, 0.0547mol) in 30 ml of DMF was added dropwise, and after completion of the dropwise addition, (R) -methyl 2-benzyloxycarbonylamino-3-iodopropionate (18.0 g, 0.0497mol), tetrakis (triphenylphosphine) palladium (1.72 g, 1.49 mmol) and N 2 The displacement is carried out for 3 times, the temperature is increased to 50-60 ℃, the reaction is stirred for 12h, the reaction is completed, the reaction solution is poured into 100 mL of water, extraction is carried out by 200 mL of ethyl acetate, the organic phase is washed once by brine, the solvent is removed from the organic phase, and column chromatography purification (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio = 10. The yield is 70 percent, 1 H NMR（CDCl 3 , 400 MHz, ppm）: 7.70-7.76 (m, 14H), 5.16 (s, 2H), 5.05 (s,2H), 4.68 (t, 1H), 3.66 (s,3H), 2.98-3.23 ( t, 2H), 2.62 (s, 3H)。
example 2
Tetrahydrofuran (20 mL) was added to a 150mL reaction flask, stirring was turned on, and zinc powder (9.75g, 0.149mol), iodine (3.78 g,14.9 mmol), and N were added in that order 2 The substitution was conducted 3 times, a solution of 2-benzyloxy-5-chloroacetophenone (14.3 g, 0.0547mol) in 30 ml of tetrahydrofuran was added dropwise, and after completion of the dropwise addition, (R) -methyl 2-benzyloxycarbonylamino-3-iodopropionate (18.0 g, 0.0497mol), tetrakis (triphenylphosphine) palladium (1.72 g, 1.49mmol) and N 2 The displacement is carried out for 3 times, the temperature is raised to 40-50 ℃, the reaction is stirred for 12h, the reaction is completed, the reaction solution is poured into 100 mL of water, extraction is carried out by 200 mL of ethyl acetate, the organic phase is washed once by brine, the solvent is removed from the organic phase, and column chromatography purification (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio = 10. The yield thereof was found to be 67%, 1 H NMR（CDCl 3 , 400 MHz, ppm）: 7.70-7.76 (m, 14H), 5.16 (s, 2H), 5.05 (s,2H), 4.68 (t, 1H), 3.66 (s,3H), 2.98-3.23 ( t, 2H), 2.62 (s, 3H)。
example 3
A150 mL reaction flask was charged with ethyl acetate (20 mL), stirred, and charged with zinc powder (9.75g, 0.149mol), iodine (3.78 g,14.9 mmol), and N in that order 2 The substitution was conducted 3 times, a solution of 2-methoxy-5-iodoacetophenone (15.1 g, 0.0547mol) in 30 ml of ethyl acetate was added dropwise, and after completion of the addition, methyl (R) -2-benzyloxycarbonylamino-3-iodopropionate (18.0 g, 0.0497mol), tetrakis (triphenylphosphine) palladium (1.72 g, 1.49mmol) and N 2 The displacement is carried out for 3 times, the temperature is raised to 60-70 ℃, the reaction is stirred for 12h, the reaction is completed, the reaction solution is poured into 100 mL of water, extraction is carried out by 200 mL of ethyl acetate, the organic phase is washed once by brine, the solvent is removed from the organic phase, and column chromatography purification (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio = 10. The yield is 70 percent, 1 H NMR（CDCl 3 , 400 MHz, ppm）: 7.07-7.76 (m, 9H), 5.05 (s, 2H)， 4.68（m, 1H）, 3.83(s, 3H), 3.66(s, 3H), 2.98-3.23(m, 2H), 2.62(s, 3H)。
example 4
A150 mL reaction flask was charged with toluene (20 mL), stirred, and charged with zinc powder (9.75g, 0.149mol), iodine (3.78 g,14.9 mmol), and N in that order 2 The substitution was conducted 3 times, a solution of 2-ethoxy-5-bromoacetophenone (13.3 g, 0.0547mol) in 30 ml of toluene was added dropwise, and after completion of the dropwise addition, (R) -methyl 2-benzyloxycarbonylamino-3-iodopropionate (18.0 g, 0.0497mol), tetrakis (triphenylphosphine) palladium (1.72 g, 1.49 mmol) and N 2 Displacing for 3 times, heating to 70-80 deg.C, stirring for 12 hr, completely reacting, pouring the reaction solution into 100 mL water, extracting with 200 mL ethyl acetate, washing the organic phase with brine, removing solvent from the organic phase, and purifying by column chromatography (200-300 mesh silica gel, petroleum ether/ethyl acetateVolume ratio =10:1 mobile phase) yielded 13.5 g of the target product. The yield is 68 percent, 1 H NMR（CDCl 3 , 400 MHz, ppm）: 7.07-7.78 (m, 9H), 5.03 (s, 2H)， 4.68（m, 1H）, 4.05（m, 2H）, 3.66(s, 3H), 2.98-3.23(m, 2H), 2.62(s, 3H), 1.34(t, 3H)。
example 5
A150 mL reaction flask was charged with DMF (20 mL), stirred, and charged with zinc powder (9.75g, 0.149mol), iodine (3.78 g,14.9 mmol), and N 2 The substitution was carried out 3 times, a solution of 2-triphenylmethyloxy-5-bromoacetophenone (25.0 g 0.0547mol) in 30 ml of DMF was added dropwise, and after dropwise addition, (R) -methyl 2-benzyloxycarbonylamino-3-iodopropionate (18.0 g 0.0497mol), sphos (1.02 g 2.49 mmol), pd 2 (dba) 3 （1.36 g 1.49 mmol）, N 2 The displacement is carried out for 3 times, the temperature is increased to 50-60 ℃, the reaction is stirred for 12h, the reaction is completed, the reaction solution is poured into 100 mL of water, extraction is carried out by 200 mL of ethyl acetate, the organic phase is washed once by brine, the solvent is removed from the organic phase, and column chromatography purification (200-300 mesh silica gel, petroleum ether/ethyl acetate volume ratio = 10. The yield is 75 percent, 1 H NMR（CDCl 3 , 400 MHz, ppm）: 7.27-7.76 (m, 24H), 5.05 (s, 2H) , 4.68 (m, 1H) ,3.66 (s, 3H) , 2.98-3.23 (m, 2H) , 2.62 (s, 3H)。
Claims (7)
1. a method for synthesizing tyrosine derivative is characterized in that: the reaction formula is as follows:
wherein: r is one of hydrogen atom, alkyl, benzyl or trityl; x is a halogen atom selected from: cl, br or I.
2. A process according to claim 1, wherein the synthesis of a tyrosine derivative is as follows: the alkyl group is methyl or ethyl.
3. The method of claim 1 for synthesizing a tyrosine derivative, wherein: the organic solvent is selected from one or more of the following: ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl formate, isopropyl acetate, tert-butyl acetate, methyl tert-butyl ether, diethyl ether, toluene, N-dimethylformamide.
4. A process of synthesis of a tyrosine derivative according to claim 3, which comprises: the organic solvent is selected from one of N, N-dimethylformamide, ethyl acetate, tetrahydrofuran or toluene.
5. A process according to claim 1, wherein the synthesis of a tyrosine derivative is as follows: the metal palladium catalyst is Pd (PPh) 3 ) 4 Or Pd 2 (dba) 3 。
6. A process according to claim 1, wherein the synthesis of a tyrosine derivative is as follows: the reaction temperature is 0-120 ℃.
7. A process of synthesis of a tyrosine derivative according to claim 6, which comprises: the reaction temperature is 40-80 ℃.
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| CN202211465437.3A CN115784934A (en) | 2022-11-22 | 2022-11-22 | Synthetic method of tyrosine derivative |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105873932A (en) * | 2013-12-25 | 2016-08-17 | 卫材R&D管理有限公司 | (6S,9aS)-N-Benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-(methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound |
| CN107614504A (en) * | 2015-06-23 | 2018-01-19 | 卫材R&D管理有限公司 | (6S, 9aS) N benzyls 6 [(4 hydroxy phenyl) methyl] 4,7 dioxies 8 ({ base of 6 [base of 3 (base of piperazine 1) azetidine 1] pyridine 2 } methyl) 2 (the third 2 base of alkene 1) octahydro 1H pyrazines simultaneously [2,1 c] [1,2,4] crystal of the benzamide compound of triazine 1 |
| WO2022167656A1 (en) * | 2021-02-08 | 2022-08-11 | Bacoba Ag | Treatment of skin disorders |
-
2022
- 2022-11-22 CN CN202211465437.3A patent/CN115784934A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105873932A (en) * | 2013-12-25 | 2016-08-17 | 卫材R&D管理有限公司 | (6S,9aS)-N-Benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-(methyl)-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound |
| CN107614504A (en) * | 2015-06-23 | 2018-01-19 | 卫材R&D管理有限公司 | (6S, 9aS) N benzyls 6 [(4 hydroxy phenyl) methyl] 4,7 dioxies 8 ({ base of 6 [base of 3 (base of piperazine 1) azetidine 1] pyridine 2 } methyl) 2 (the third 2 base of alkene 1) octahydro 1H pyrazines simultaneously [2,1 c] [1,2,4] crystal of the benzamide compound of triazine 1 |
| WO2022167656A1 (en) * | 2021-02-08 | 2022-08-11 | Bacoba Ag | Treatment of skin disorders |
Non-Patent Citations (2)
| Title |
|---|
| DALE L. BOGER等: "Selectively Protected L-Dopa Derivatives: Application of the Benzylic Hydroperoxide Rearrangement", 《J. ORG. CHEM., VOL》, pages 5283 - 5286 * |
| YAN-LI SONG等: "Discovery of a Novel Nonphosphorylated Pentapeptide Motif Displaying High Affinity for Grb2-SH2 Domain by the Utilization of 3′-Substituted Tyrosine Derivatives", 《J. MED. CHEM.》, vol. 49, pages 1585 - 1596 * |
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