CN112062705A - Synthesis method of 7-methyltryptophan - Google Patents
Synthesis method of 7-methyltryptophan Download PDFInfo
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- KBOZNJNHBBROHM-JTQLQIEISA-N (2s)-2-azaniumyl-3-(7-methyl-1h-indol-3-yl)propanoate Chemical compound CC1=CC=CC2=C1NC=C2C[C@H]([NH3+])C([O-])=O KBOZNJNHBBROHM-JTQLQIEISA-N 0.000 title claims abstract description 36
- 238000001308 synthesis method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 25
- 229940125904 compound 1 Drugs 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940125782 compound 2 Drugs 0.000 claims abstract description 9
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 3
- -1 7-methyl-3-indolyl-2-acetamidopropionic acid Chemical compound 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- KTUFZHVVJBHGKZ-UHFFFAOYSA-N 7-methyl-1h-indole-3-carbaldehyde Chemical compound CC1=CC=CC2=C1NC=C2C=O KTUFZHVVJBHGKZ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KBOZNJNHBBROHM-UHFFFAOYSA-N 2-azaniumyl-3-(7-methyl-1h-indol-3-yl)propanoate Chemical compound CC1=CC=CC2=C1NC=C2CC(N)C(O)=O KBOZNJNHBBROHM-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229930001118 polyketide hybrid Natural products 0.000 description 1
- 125000003308 polyketide hybrid group Chemical group 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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Abstract
The invention provides a method for synthesizing 7-methyltryptophan, which comprises the following steps: (1) reacting the compound a with the compound b to obtain a compound 1; (2) reacting the compound 1 with water to obtain a compound 2; (3) reacting the compound 2 with hydrogen to obtain a compound 3; (4) and (3) carrying out hydrolysis reaction on the compound to obtain the 7-methyltryptophan. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple equipment requirement and high safety index, and is suitable for large-scale commercial production. The total yield of the 7-methyl-tryptophan prepared by the method is up to 52.6 percent, and the purity is up to 98 percent. The invention provides a new choice for the commercial production process of the 7-methyl-tryptophan medicinal intermediate.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a synthetic method of 7-methyltryptophan.
Background
7-methyl-tryptophan, CAS No.: 17332-70-6, an important amino acid derivative, which is a key precursor for biosynthesis of many non-ribosomal peptide antibiotics, plays an important role in synthesis of high-efficiency antibacterial agents and analogues thereof, and therefore, 7-methyl-tryptophan is an important medical intermediate and has attracted wide attention in the medical field.
Currently, there are few reports on the synthesis of 7-methyl-tryptophan. Chou-Hsiung Chen et al (Organic & biological Chemistry,2014,12, 9764-. However, in the method, the use of a phosphorus reagent increases the difficulty of post-treatment, so that the target product is not easy to purify; and the strong alkali n-butyl lithium is harsh in use condition, and needs to react at the low temperature of minus 78 ℃ without water and oxygen, so that the requirement on equipment is increased, and the production cost is increased.
Therefore, the method for preparing the 7-methyl-tryptophan has low cost and simple operation and is suitable for large-scale commercial production, and has very important significance for popularization and application of the 7-methyl-tryptophan in the fields of medicines and the like.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a process which is low in cost, simple to operate and suitable for large-scale commercial production, and the 7-methyl-tryptophan with high purity and high yield is prepared.
The invention provides a method for synthesizing 7-methyltryptophan, which comprises the following steps:
(1) reacting the compound a with the compound b to obtain a compound 1;
(2) reacting the compound 1 with water to obtain a compound 2;
(3) reacting the compound 2 with hydrogen to obtain a compound 3;
(4) and (3) carrying out hydrolysis reaction on the compound to obtain the 7-methyltryptophan.
Further, in the step (1), the mass ratio of the compound a to the compound b is (1.0-2.0): 1, preferably 1.4: 1; the organic solvent of the solvent for the reaction is preferably acetic anhydride, and the mass ratio of the compound a to the acetic anhydride is (0.5-1.0): 1, preferably 0.8: 1; and/or the reaction is carried out in the presence of anhydrous sodium acetate, and the mass ratio of the acetic anhydride to the anhydrous sodium acetate is (2.0-3.0): 1, preferably 2.5: 1; and/or the reaction temperature is 80-120 ℃, preferably 100 ℃, the reaction time is 2-5 hours, preferably 3 hours, and the reaction is carried out under the protection of inert gas.
Further, the step (1) further comprises a step of purifying the system after the reaction is finished, wherein the purification treatment step comprises the following steps: and adding the system after the reaction into ice water, stirring and filtering, taking a filter cake, washing with water, and drying to obtain the product.
Further, in the step (2), the mass-to-volume ratio of the compound 1 to water is (0.1-0.6): 1 g/mL; the solvent for the reaction is an organic solvent, preferably acetonitrile or tetrahydrofuran, and the mass-volume ratio of the compound 1 to the organic solvent is (0.06-0.15): 1 g/mL; and/or the reaction temperature is 80-100 ℃, and the reaction time is 1-5 hours.
Further, in the step (2), the mass-to-volume ratio of the compound 1 to water is 0.3: 1 g/mL; the solvent of the reaction is acetonitrile, and the mass volume ratio of the compound 1 to the acetonitrile is 0.15: 1 g/mL.
Further, in the step (2), the temperature of the reaction is 80 ℃, and the time of the reaction is 3 hours.
Further, the step (2) further comprises a step of purifying the system after the reaction is finished, wherein the purification treatment step comprises the following steps: and adding the system after the reaction into methyl tert-butyl ether, stirring and filtering, taking a filter cake, washing with the methyl tert-butyl ether, and drying to obtain the product.
Further, in the step (3), the reaction is carried out in the presence of a catalyst which is Pd/C, preferably 5% Pd/C; the solvent for the reaction is an organic solvent, preferably an alcohol solvent, and more preferably methanol; the reaction temperature is room temperature, and the reaction time is 1-5 hours, preferably 3 hours.
Further, in the step (4), the reaction is carried out in a hydrochloric acid aqueous solution, wherein the concentration of the hydrochloric acid aqueous solution is 2-8 mol/L, and is preferably 6 mol/L; the mass-volume ratio of the compound 3 to the hydrochloric acid aqueous solution is 1: (4-8) g/mL, preferably 1: 6 g/mL; the reaction temperature is 70-150 ℃, preferably 100 ℃, and the reaction time is 2-5 hours, preferably 3 hours.
Further, the step (4) further comprises a step of purifying the system after the reaction is finished, wherein the purification treatment step comprises the following steps: and cooling the system after the reaction to room temperature, adjusting the pH value to 7-8, separating out solids, stirring, filtering, taking a filter cake, and drying to obtain the catalyst.
In the present invention, the concentration unit of the aqueous hydrochloric acid solution is "N", i.e., "mol/L", and for example, 6N aqueous hydrochloric acid solution is 6mol/L aqueous hydrochloric acid solution.
"Room temperature" means 25. + -. 2 ℃.
"5%" in "5% Pd/C" means that the mass fraction of Pd based on C is 5%.
The method for preparing 7-methyl-tryptophan provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, simple equipment requirements and high safety index, and is suitable for large-scale commercial production. The total yield of the 7-methyl-tryptophan prepared by the method is up to 52.6 percent, and the purity is up to 98 percent. The invention provides a new choice for the commercial production process of the 7-methyl-tryptophan medicinal intermediate.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 7-methyltryptophan obtained in example 1 of the present invention.
Detailed Description
The starting materials used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1: synthesis method of 7-methyl-tryptophan
7-methyl-tryptophan was prepared according to the following synthetic route:
(1) acetic anhydride (12.83g), anhydrous sodium acetate (5.16g,62.89mmol) and acetylglycine (compound b, 7.36g) were added to a three-necked flask in this order under stirring, 7-methylindole-3-carbaldehyde (compound a, 10g) was then added, the reaction mixture was heated to 100 ℃ under nitrogen protection for 3 hours, the temperature was lowered to 70 ℃, the reaction mixture was poured into 150mL of ice water, stirred for 1 hour and filtered, the filter cake was washed with water 3 times and dried to give 4- (7-methyl-1 'H-indol-3' -ylmethylene) -2-methyl-5 (4H) oxazolone as a pale yellow solid (compound 1, 12g, yield 75.2%).
(2) Acetonitrile (80mL), water (40mL) and the compound 4- (7-methyl-1 'H-indol-3' -ylmethylene) -2-methyl-5 (4H) oxazolone (12g) were added in this order to a three-necked flask with stirring, heated to 80 ℃ for reaction for 3 hours, cooled to room temperature, then 40mL of methyl tert-butyl ether was added to precipitate a solid, which was stirred for 1 hour, filtered, the filter cake was washed with 10mL of methyl tert-butyl ether, and dried to give 7-methyl-3-indolyl-2-acetamidoenepropionic acid as a solid (compound 2, 11g, yield 87.5%).
(3) Under the stirring condition, methanol (110mL) and 7-methyl-3-indolyl-2-acetamidopropionic acid (11g) are sequentially added into a three-necked flask, after 7-methyl-3-indolyl-2-acetamidopropionic acid is completely dissolved, 5% Pd/C (1g) is added, hydrogen is introduced, the mixture is stirred at room temperature for 3 hours, the Pd/C is removed by filtration, the filtrate is concentrated under reduced pressure, and solid 7-methyl-N-acetyltryptophan (compound 3, 10g, yield 92.5%) is obtained by drying.
(4) Under stirring, 5g of 7-methyl-N-acetyltryptophan was added to a three-necked flask, 30mL of 6N aqueous hydrochloric acid was added, the mixture was heated to 100 ℃ and stirred for 3 hours, the mixture was cooled to room temperature, the pH of the reaction mixture was adjusted to 7 to 8 with saturated aqueous sodium carbonate, a white solid was precipitated, the mixture was stirred for 2 hours at room temperature, filtered and dried to obtain 7-methyltryptophan (compound 4, 3.5g, yield 86.4%, purity 98%). The nuclear magnetic spectrum of the obtained 7-methyltryptophan is shown in FIG. 1.
The total yield of 7-methyltryptophan synthesized in this example was 52.6%.
The total yield of 7-methyltryptophan synthesized is the yield in step (1) × the yield in step (2) × the yield in step (3) × the yield in step (4).
Example 2: synthesis method of 7-methyl-tryptophan
(1) Acetic anhydride (6.4g), anhydrous sodium acetate (2.58g,31.45mmol) and acetylglycine (compound b, 3.68g) were added to a three-necked flask in this order under stirring, 7-methylindole-3-carbaldehyde (compound a, 5g) was then added, the reaction mixture was heated to 120 ℃ under nitrogen protection for 2 hours, the temperature was lowered to 80 ℃, the reaction mixture was poured into 80mL of ice water, stirred for 1 hour and filtered, the filter cake was washed with water 3 times and dried to give 4- (7-methyl-1 'H-indol-3' -ylmethylene) -2-methyl-5 (4H) oxazolone as a pale yellow solid (compound 1, 5.3g, yield 69.2%).
(2) Acetonitrile (80mL), water (20mL) and the compound 4- (7-methyl-1 'H-indol-3' -ylmethylene) -2-methyl-5 (4H) oxazolone (5g) were added to a three-necked flask in this order with stirring, heated to 100 ℃ for reaction for 3 hours, cooled to room temperature, then 20mL of methyl tert-butyl ether was added to precipitate a solid, which was stirred for 1 hour, filtered, the filter cake was washed with 10mL of methyl tert-butyl ether, and dried to give 7-methyl-3-indolyl-2-acetamidopropionic acid as a solid (compound 2, 4.1g, yield 80.6%).
(3) Under the stirring condition, methanol (50mL) and 7-methyl-3-indolyl-2-acetamidopropionic acid (4g) are sequentially added into a three-necked flask, after 7-methyl-3-indolyl-2-acetamidopropionic acid is completely dissolved, 5% Pd/C (1g) is added, hydrogen is introduced, the mixture is stirred at room temperature for 3 hours, the Pd/C is removed by filtration, the filtrate is concentrated under reduced pressure, and solid 7-methyl-N-acetyltryptophan (compound 3, 4.1g, yield 93.2%) is obtained by drying.
(4) Under stirring, 4g of 7-methyl-N-acetyltryptophan was added to a three-necked flask, 30mL of 6N aqueous hydrochloric acid was added, the mixture was heated to 150 ℃ and stirred for 2 hours, the mixture was cooled to room temperature, the pH of the reaction mixture was adjusted to 7 to 8 with saturated aqueous sodium carbonate, a white solid was precipitated, the mixture was stirred for 2 hours at room temperature, filtered and dried to obtain 7-methyltryptophan (compound 4, 2.6g, yield 82.4%, purity 98%).
The total yield of 7-methyltryptophan synthesized in this example was 42.8%.
Example 3: synthesis method of 7-methyl-tryptophan
(1) Same as in step (1) of example 1.
(2) Tetrahydrofuran (80mL), water (20mL) and the compound 4- (7-methyl-1 'H-indol-3' -ylmethylene) -2-methyl-5 (4H) oxazolone (12g) were added in this order to a three-necked flask with stirring, heated to 80 ℃ for reaction for 3 hours, cooled to room temperature, then 40mL of methyl tert-butyl ether was added to precipitate a solid, which was stirred for 1 hour, filtered, the filter cake was washed with 10mL of methyl tert-butyl ether and dried to give 7-methyl-3-indolyl-2-acetamidopropionic acid as a solid (compound 2, 8.6g, yield 70.6%).
(3) Ethanol (110mL) and 7-methyl-3-indolyl-2-acetamidopropionic acid (11g) were added to a three-necked flask in this order with stirring, and after 7-methyl-3-indolyl-2-acetamidopropionic acid was completely dissolved, 5% Pd/C (2g) was added, hydrogen was introduced, and the mixture was stirred at room temperature for 3 hours, and Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to obtain 7-methyl-N-acetyltryptophan as a solid (Compound 3, 10.3g, yield 93.4%).
(4) Under stirring, 5g of 7-methyl-N-acetyltryptophan was added to a three-necked flask, 30mL of 6N aqueous hydrochloric acid was added, the mixture was heated to 70 ℃ and stirred for 5 hours, the mixture was cooled to room temperature, the pH of the reaction mixture was adjusted to 7 to 8 with saturated aqueous sodium carbonate, a white solid was precipitated, the mixture was stirred at room temperature for 2 hours, filtered and dried to obtain 7-methyltryptophan (compound 4, 2.7g, yield 80.3%, purity 97%).
The total yield of 7-methyltryptophan synthesized in this example was 39.8%.
In conclusion, the invention provides a method for preparing 7-methyltryptophan, which has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple equipment requirements and high safety index, and is suitable for large-scale commercial production. The total yield of the 7-methyl-tryptophan prepared by the method is up to 52.6 percent, and the purity is up to 98 percent. The invention provides a new choice for the commercial production process of the 7-methyl-tryptophan medicinal intermediate.
Claims (10)
1. A method for synthesizing 7-methyltryptophan, which is characterized by comprising the following steps: the method comprises the following steps:
(1) reacting the compound a with the compound b to obtain a compound 1;
(2) reacting the compound 1 with water to obtain a compound 2;
(3) reacting the compound 2 with hydrogen to obtain a compound 3;
(4) and (3) carrying out hydrolysis reaction on the compound to obtain the 7-methyltryptophan.
2. The method of claim 1, wherein: in the step (1), the mass ratio of the compound a to the compound b is (1.0-2.0): 1, preferably 1.4: 1; the organic solvent of the solvent for the reaction is preferably acetic anhydride, and the mass ratio of the compound a to the acetic anhydride is (0.5-1.0): 1, preferably 0.8: 1; and/or the reaction is carried out in the presence of anhydrous sodium acetate, and the mass ratio of the acetic anhydride to the anhydrous sodium acetate is (2.0-3.0): 1, preferably 2.5: 1; and/or the reaction temperature is 80-120 ℃, preferably 100 ℃, the reaction time is 2-5 hours, preferably 3 hours, and the reaction is carried out under the protection of inert gas.
3. The method of claim 2, wherein: in the step (1), the method also comprises the step of purifying the system after the reaction is finished, wherein the purification treatment step is as follows: and adding the system after the reaction into ice water, stirring and filtering, taking a filter cake, washing with water, and drying to obtain the product.
4. The method of claim 1, wherein: in the step (2), the mass-to-volume ratio of the compound 1 to water is (0.1-0.6): 1 g/mL; the solvent for the reaction is an organic solvent, preferably acetonitrile or tetrahydrofuran, and the mass-volume ratio of the compound 1 to the organic solvent is (0.06-0.15): 1 g/mL; and/or the reaction temperature is 80-100 ℃, and the reaction time is 1-5 hours.
5. The method of claim 4, wherein: in the step (2), the mass-to-volume ratio of the compound 1 to water is 0.3: 1 g/mL; the solvent of the reaction is acetonitrile, and the mass volume ratio of the compound 1 to the acetonitrile is 0.15: 1 g/mL.
6. The method of claim 4, wherein: in the step (2), the reaction temperature is 80 ℃, and the reaction time is 3 hours.
7. The method according to any one of claims 1 to 6, wherein: in the step (2), the method also comprises the step of purifying the system after the reaction is finished, wherein the purification treatment step is as follows: and adding the system after the reaction into methyl tert-butyl ether, stirring and filtering, taking a filter cake, washing with the methyl tert-butyl ether, and drying to obtain the product.
8. The method according to any one of claims 1 to 6, wherein: in step (3), the reaction is carried out in the presence of a catalyst which is Pd/C, preferably 5% Pd/C; the solvent for the reaction is an organic solvent, preferably an alcohol solvent, and more preferably methanol; the reaction temperature is room temperature, and the reaction time is 1-5 hours, preferably 3 hours.
9. The method according to any one of claims 1 to 6, wherein: in the step (4), the reaction is carried out in a hydrochloric acid aqueous solution, wherein the concentration of the hydrochloric acid aqueous solution is 2-8 mol/L, and preferably 6 mol/L; the mass-volume ratio of the compound 3 to the hydrochloric acid aqueous solution is 1: (4-8) g/mL, preferably 1: 6 g/mL; the reaction temperature is 70-150 ℃, preferably 100 ℃, and the reaction time is 2-5 hours, preferably 3 hours.
10. The method of claim 9, wherein: in the step (4), the method also comprises the step of purifying the system after the reaction is finished, wherein the purification treatment step is as follows: and cooling the system after the reaction to room temperature, adjusting the pH value to 7-8, separating out solids, stirring, filtering, taking a filter cake, and drying to obtain the catalyst.
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| Title |
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| AMER MOUSSA等: "Chemoenzymatic routes to enantiomerically pure 2-azatyrosine and 2-, 3- and 4-pyridylalanine derivatives", 《AMINO ACIDS》 * |
| 姚其正: "《药物合成反应》", 31 December 2012 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113666861A (en) * | 2021-09-15 | 2021-11-19 | 长兴宜生药物科技有限公司 | Preparation method of non-natural L-tryptophan derivative |
| CN113666861B (en) * | 2021-09-15 | 2024-08-13 | 长兴宜生药物科技有限公司 | Preparation method of unnatural L-tryptophan derivative |
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