CN114561440A - Preparation method of high-purity (R) - (+) -1- (4-methoxyphenylethyl amine monomer - Google Patents
Preparation method of high-purity (R) - (+) -1- (4-methoxyphenylethyl amine monomer Download PDFInfo
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- CN114561440A CN114561440A CN202210453117.XA CN202210453117A CN114561440A CN 114561440 A CN114561440 A CN 114561440A CN 202210453117 A CN202210453117 A CN 202210453117A CN 114561440 A CN114561440 A CN 114561440A
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- 239000000178 monomer Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 title claims description 9
- 238000000034 method Methods 0.000 claims abstract description 25
- JTDGKQNNPKXKII-SSDOTTSWSA-N (1r)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@@H](C)N)C=C1 JTDGKQNNPKXKII-SSDOTTSWSA-N 0.000 claims abstract description 19
- 230000008569 process Effects 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000004296 chiral HPLC Methods 0.000 claims description 12
- 230000003287 optical effect Effects 0.000 claims description 12
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- JTDGKQNNPKXKII-UHFFFAOYSA-N 1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C(C(C)N)C=C1 JTDGKQNNPKXKII-UHFFFAOYSA-N 0.000 claims description 7
- XYXFJNIUUWEUIJ-UHFFFAOYSA-N propan-2-yl 2-methoxyacetate Chemical compound COCC(=O)OC(C)C XYXFJNIUUWEUIJ-UHFFFAOYSA-N 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 6
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 108010084311 Novozyme 435 Proteins 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012455 biphasic mixture Substances 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- -1 4-methoxyphenylethyl Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims 1
- 239000002440 industrial waste Substances 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 108090001060 Lipase Proteins 0.000 description 4
- 239000004367 Lipase Substances 0.000 description 4
- 102000004882 Lipase Human genes 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019421 lipase Nutrition 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QRMHDGWGLNLHMN-UHFFFAOYSA-N Methyl methoxyacetate Chemical compound COCC(=O)OC QRMHDGWGLNLHMN-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BAIIKJGHGGFAKN-UHFFFAOYSA-N anisole;ethanamine Chemical compound CCN.COC1=CC=CC=C1 BAIIKJGHGGFAKN-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- PXKLMJQFEQBVLD-UHFFFAOYSA-N bisphenol F Chemical compound C1=CC(O)=CC=C1CC1=CC=C(O)C=C1 PXKLMJQFEQBVLD-UHFFFAOYSA-N 0.000 description 1
- IWPATTDMSUYMJV-UHFFFAOYSA-N butyl 2-methoxyacetate Chemical compound CCCCOC(=O)COC IWPATTDMSUYMJV-UHFFFAOYSA-N 0.000 description 1
- JDJWQETUMXXWPD-UHFFFAOYSA-N butyl 2-methoxypropanoate Chemical compound CCCCOC(=O)C(C)OC JDJWQETUMXXWPD-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- JLEKJZUYWFJPMB-UHFFFAOYSA-N ethyl 2-methoxyacetate Chemical compound CCOC(=O)COC JLEKJZUYWFJPMB-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- FIABMSNMLZUWQH-UHFFFAOYSA-N propyl 2-methoxyacetate Chemical compound CCCOC(=O)COC FIABMSNMLZUWQH-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
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- C07—ORGANIC CHEMISTRY
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/001—Amines; Imines
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Abstract
The invention discloses a preparation method of a high-purity (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer, which avoids the defects of the traditional process, reduces the occurrence of side reactions, improves the product purity specification and reduces the generation of industrial waste.
Description
Technical Field
The technology relates to a preparation method of a high-purity (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer, belongs to the field of biochemistry, and is particularly used for synthesis, resolution and purification of the (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer.
Background
The (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer is a chiral auxiliary agent with high activity and high selectivity, is widely used for synthesizing chiral drugs, determining the purity of acid enantiomers and fully synthesizing natural products, and is an important chiral amine compound;
in the prior art, the preparation method of the (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer comprises an asymmetric reduction method and a racemate chiral resolution method: for example, patent CN109851506A discloses that ketone and ammonium salt RCOONH4 are subjected to reductive amination with hydrogen gas under the action of ruthenium-chiral diphosphine catalyst, and then acid is added for heating hydrolysis, and (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer is prepared by one-pot method, which requires the use of noble metal catalyst and special equipment, generates by-products, has low ee value, and cannot meet the production of products with high specification requirements; the chiral resolution method is more suitable for producing and preparing high-purity (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer due to the advantages of easily available raw materials, simple production process, no byproduct generation and the like, and the patent CN106632368A, the patent WO2021/58754A1 and the patent EP2258696A1 respectively disclose and introduce a method for chiral resolution by using reagents such as 4, 11-diethyl-4, 9-dihydroxy-1H-pyrano [3',4':6,7] indolizine [1,2-B ] quinoline-3, 14(4H,12H) -diketone and the like as resolution aids, and the used resolution reagents are high in price, low in atom economy, large in industrial waste generation amount and poor in applicability.
Patent document US6387692B1 discloses a method for preparing (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer, which uses racemate 1- (4-methoxyphenyl) ethylamine as a raw material, 2-methoxy methyl acetate as a resolution aid, and uses biological enzyme Novozyme 435 to catalyze and perform acylation reaction on the (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer to generate ((R) - (+) -1- (4-methoxyphenyl) ethyl) -2-methoxyacetamide, however, the optical purity of the product prepared by the method is 95%, and still can not meet the requirements of medicines.
During the research process, the inventor of the present invention surprisingly found that when isopropyl 2-methoxyacetate is used as a resolution aid, a product with optical purity of more than 99% can be obtained, and the requirement of the optical purity of the medicine can be met.
In order to avoid the defects of the traditional process, reduce the occurrence of side reactions, improve the product purity specification and reduce the generation of industrial waste, the invention provides the preparation method of the high-purity (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer, and the production period is shortened. Effectively saving the production cost and being beneficial to enlarging the production scale.
Disclosure of Invention
1. The invention aims to obtain the (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer by efficiently separating 1- (4-methoxyphenyl) ethylamine racemate by adopting a biological enzyme separation method instead of the traditional process.
2. The biological enzyme resolution technology is concerned about because of the advantages of few by-products, simple and convenient operation, environmental protection and the like, and the application of the biological enzyme method chiral medicine resolution technology is broken through along with the development of structure biology and modern molecular biology and the continuous and deep research of the enzyme method chiral medicine resolution. The method adopts isopropyl 2-methoxyacetate as a resolution aid, uses a biological enzyme Novozyme 435 to catalyze in a diisopropyl ether system solvent, leads an (R) - (+) -1- ((4-methoxybenzene) ethylamine monomer to carry out acylation reaction, carries out salt formation separation on the system to obtain an (S) - (-) -1- (4-methoxybenzene) ethylamine monomer, carries out chemical hydrolysis on the ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer to obtain the (R) - (+) -1- (4-methoxybenzene) ethylamine monomer, obtains the optimum condition of resolution efficiency by controlling the degree of enzyme catalytic reaction, has no side reaction in the process, avoids the use of chiral acid compared with the conventional chemical resolution method, the atom utilization rate is obviously improved;
in order to solve the technical problem, the invention adopts the following technical scheme:
a preparation method of a high-purity (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer is characterized by comprising the following steps:
step (1): using racemate 1- (4-methoxybenzene) ethylamine as a raw material, using isopropyl 2-methoxyacetate as a resolution aid, and catalyzing by using a biological enzyme Novozyme 435 in an organic solvent to perform acylation reaction on a (R) - (+) -1- (4-methoxybenzene) ethylamine monomer to generate ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide;
step (2): and (2) hydrolyzing the ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer obtained in the step (1) by a chemical method to obtain a (R) - (+) -1- (4-methoxybenzene) ethylamine monomer.
In a preferred embodiment of the present invention, the organic solvent is one or more of diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxahexane, acetone, and ethyl acetate.
In a preferred embodiment of the present invention, the organic solvent is diisopropyl ether or methyl tert-butyl ether.
In a preferable technical scheme of the invention, the weight ratio of the racemate 1- (4-methoxyphenyl) ethylamine to the biological enzyme is 30:1-5: 1.
In a preferable technical scheme of the invention, the weight ratio of the racemate 1- (4-methoxyphenyl) ethylamine to the biological enzyme is 20:1-10: 1.
In a preferred embodiment of the present invention, wherein the acylation is monitored by chiral HPLC, the reaction is stopped when the optical purity of the unreacted (S) - (-) -1- (4-methoxyphenylethyl amine is >99.9% ee.
In a preferred embodiment of the invention, wherein the hydrolysis is carried out by heating a mixture of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide and triethanolamine to 115 ℃, adding 50% aqueous NaOH and vigorously stirring the biphasic mixture at 120 ℃ until the reaction is complete.
In a preferred embodiment of the present invention, the mass ratio of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide to triethanolamine is 1:0.5 to 1:5, and the mass ratio of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide to 50% aqueous NaOH solution is 1: 1-3.
Drawings
FIG. 1 shows Chiral HPLC chromatogram of 1- (4-methoxybenzene) ethyl-2-methoxyacetamide racemate and ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer;
FIG. 2 shows Chiral HPLC chromatogram of 1- (4-methoxybenzene) ethyl) -2-methoxyacetamide racemate and (R) - (+) -1- (4-methoxybenzene) ethylamine monomer;
FIG. 3 shows a Chiral HPLC chromatogram of 1- (4-methoxybenzene) ethyl-2-methoxyacetamide racemate and ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer;
FIG. 4 shows Chiral HPLC chromatogram of 1- (4-methoxybenzene) ethyl) -2-methoxyacetamide racemate and (R) - (+) -1- (4-methoxybenzene) ethylamine monomer.
Detailed Description
Example 1
A preparation method of a high-purity (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer comprises the following steps:
24g of racemic 1- (4-methoxybenzene) ethylamine and 40g of isopropyl 2-methoxyacetate were dissolved in diisopropyl ether (400 mL). Novozyme 435 (1 g) of immobilized lipase was added and the resulting solution was stirred overnight at room temperature. The progress of the reaction was monitored by chiral HPLC as the optical purity of the unreacted (S) - (-) -1- (4-methoxyphenylethyl amine>The reaction was stopped at 99.9% ee. Filtering to remove solid substances, and recovering and temporarily storing at low temperature; the residue was washed with diisopropyl ether (50mL) and the combined filtrates were stirred with 5% aqueous HCl (50 mL). Separating the two phases and using H2The organic phase was washed with O (100 mL). The combined aqueous phases were re-extracted with diisopropyl ether (3X 70 mL) and the combined organic extracts were dried (Na)2SO4). Evaporation of the solvent gave ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer as a colorless solid, 17 g. Analytically and optically pure samples were obtained by recrystallization from cyclohexane as shown in fig. 1, where the column: unicral CMO 5 μm 4.6 × 250 mm; mobile phase: n-hexane: 30-60% of ethanol; temperature: 24 ℃; flow rate: 1.0 ml/min; sample introduction amount: 5.0. mu.l.
The aqueous phase was cooled in an ice bath and the aqueous extract was made alkaline (pH 13) by the addition of 50% aqueous NaOH. Diisopropyl ether (75mL) was added and the phases were separated. The aqueous phase was extracted with diisopropyl ether (2X 75mL) and the combined extracts were dried (Na2SO 4). The solvent was removed by concentration and the remaining 11.2g of (S) - (-) -1- (4-methoxyphenylethyl amine was purified by distillation under reduced pressure as a colorless liquid with an optical purity of >99% ee as indicated by chiral HPLC.
A mixture of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide 250g and triethanolamine (125 g) was heated to 115 ℃. 250g of 50% aqueous NaOH solution were added and the biphasic mixture was brought to 120 ℃Followed by vigorous stirring. After 6 hours, GC detection was complete. Addition of H2The mixture was diluted with O (300mL) and cooled to room temperature. Diisopropyl ether (500ml) was introduced and the phases were separated. The aqueous phase was extracted with diisopropyl ether (2X 200mL) and the combined organic extracts were extracted with H2O (200mL), concentrated to remove the solvent, and purified by distillation under reduced pressure to give (R) - (+) -1- (4-methoxyphenyl) ethylamine 220 g having a purity of 99.40% ee by chiral HPLC, as shown in FIG. 2, wherein the column: unicral CMO 5 μm 4.6 × 250 mm; mobile phase: n-hexane: ethanol 50-60%; temperature: 24 ℃; flow rate: 1.0 ml/min; sample introduction amount: 5.0. mu.l.
Example 2
A preparation method of a high-purity (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer comprises the following steps:
Racemic 1- (4-methoxyphenyl) ethylamine 12g and isopropyl 2-methoxyacetate 20g were dissolved in methyl tert-butyl ether (200 mL). 1g of recovered lipase was added and the cloudy solution was stirred at room temperature overnight. The progress of the reaction was monitored by chiral HPLC as the optical purity of the unreacted (S) - (-) -1- (4-methoxyphenylethyl amine>The reaction was stopped at 99.9% ee. Filtering to remove solid substances, and recovering and temporarily storing at low temperature; the residue was washed with methyl tert-butyl ether (50mL) and the combined filtrates were stirred with 5% aqueous HCl (50 mL). Separating the two phases and using H2The organic phase was washed with O (100 mL). The combined aqueous phases were re-extracted with methyl tert-butyl ether (3X 70 mL) and the combined organic extracts were dried (Na2SO 4). Evaporation of the solvent gave ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer as a colorless solid, 8.1 g. Analytically and optically pure samples were obtained by recrystallization from cyclohexane as shown in fig. 3, where the column: unicral CMO 5 μm 4.6 × 250 mm; mobile phase: n-hexane: 30-60% of ethanol; temperature: 24 ℃; flow rate: 1.0 ml/min; sample introduction amount: 5.0. mu.l.
The aqueous phase was cooled in an ice bath and the aqueous extract was made alkaline (pH 13) by the addition of 50% aqueous NaOH. Methyl tert-butyl ether (75mL) was added and the phases separated. The aqueous phase was extracted with methyl tert-butyl ether (2X 75mL) and the combined extracts were dried (Na2SO 4). The solvent was removed by concentration and the remaining 5.75 g of (R) - (+) -1- (4-methoxyphenylethyl amine was purified by distillation under reduced pressure as a colorless liquid with an optical purity of >99% ee as indicated by chiral HPLC.
A mixture of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide 12g and triethanolamine (60 g) was heated to 115 ℃. 30g of 50% aqueous NaOH solution were added and the biphasic mixture was stirred vigorously at 120 ℃. After 6 hours, GC detected complete conversion of the feedstock. Addition of H2The mixture was diluted with O (300mL) and cooled to room temperature. Methyl tert-butyl ether (500ml) was introduced and the phases separated. The aqueous phase was extracted with methyl tert-butyl ether (2X 200mL) and the combined organic extracts were extracted with H2O (200mL), concentrated to remove the solvent, and purified by distillation under reduced pressure to give (R) - (+) -1- (4-methoxyphenyl) ethylamine 10.8 g with a purity of 98.26% ee by chiral HPLC, as shown in FIG. 4, wherein the column: unicral CMO 5 μm 4.6 × 250 mm; mobile phase: n-hexane: ethanol 50-60%; temperature: 24 ℃; flow rate: 1.0 ml/min; sample introduction amount: 5.0. mu.l.
It can be seen that the invention still obtains the target product with ee value of more than 98% even if the recovered lipase is used, and the recovery and use of the lipase can reduce the production cost, and is suitable for industrial production.
Comparative example
1. This experiment is the same as example 1, differing only in the starting materials used, as shown in the following table:
2. this experiment is the same as example 1, differing only in the solvent used in step 1, as shown in the following table:
3. this experiment is identical to example 1, except that the mass ratio of 1- (4-methoxyphenylethyl) amine (RS) -1 to enzyme in step 1 is different:
4. a comparative example, identical to example 1, differing only in the type of chiral resolving agent in step 1, compares the effect on the optical purity of intermediate R) - (+) -1- (4-methoxyphenylethyl amine:
as can be seen from the results of comparative example 4, the resolving assistant has a very important influence on the optical chirality of the final product, and when isopropyl 2-methoxyacetate of the present invention is selected as the resolving assistant, it has higher optical activity than other resolving assistants (methyl 2-methoxyacetate, ethyl 2-methoxyacetate, n-propyl 2-methoxyacetate, n-butyl 2-methoxyacetate, methyl 2-methoxypropionate, n-butyl 2-methoxypropionate).
As can be seen from the results of the above comparative experiments, the present invention obtains significant beneficial technical effects by selecting specific substrates, reagents and material ratios, and it can be confirmed from the above results that there is a certain synergistic effect among the substrates, the reagents and the material ratios, and the technical effects are significantly deteriorated regardless of any factor of substitution.
It will be understood by those skilled in the art that the present invention is not limited to the embodiments illustrated herein, and that various obvious changes, rearrangements and substitutions may be made therein by those skilled in the art without departing from the scope of the invention. Therefore, although the present invention has been described in greater detail by the above embodiments, the present invention is not limited to the above embodiments, and may include other equivalent embodiments without departing from the spirit of the present invention, and the scope of the present invention is determined by the scope of the appended claims.
Claims (8)
1. A preparation method of a high-purity (R) - (+) -1- (4-methoxy phenyl) ethylamine monomer is characterized by comprising the following steps:
step 1: using racemate 1- (4-methoxybenzene) ethylamine as a raw material, using isopropyl 2-methoxyacetate as a resolution aid, and catalyzing by using a biological enzyme Novozyme 435 in an organic solvent to perform acylation reaction on a (R) - (+) -1- (4-methoxybenzene) ethylamine monomer to generate ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide;
step 2: and (2) hydrolyzing the ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide monomer obtained in the step (1) by a chemical method to obtain a (R) - (+) -1- (4-methoxybenzene) ethylamine monomer.
2. The method for preparing a high-purity (R) - (+) -1- (4-methoxyphenylethyl amine monomer according to claim 1, wherein the organic solvent is one or more of diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxahexane, acetone, and ethyl acetate.
3. The method for preparing a high purity (R) - (+) -1- (4-methoxyphenylethyl) amine monomer according to claim 2, wherein the organic solvent is diisopropyl ether or methyl tert-butyl ether.
4. The method for preparing the high-purity (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer according to claim 3, wherein the weight ratio of the racemate 1- (4-methoxyphenyl) ethylamine to the biological enzyme is 30:1-5: 1.
5. The method for preparing the high-purity (R) - (+) -1- (4-methoxyphenyl) ethylamine monomer according to claim 4, wherein the weight ratio of the racemate 1- (4-methoxyphenyl) ethylamine to the biological enzyme is 20:1-10: 1.
6. The process of claim 5, wherein the acylation is performed by chiral HPLC, and the reaction is stopped when the optical purity of the unreacted (S) - (+) -1- (4-methoxyphenylamine is >99.9% ee.
7. The method of preparing a highly pure (R) - (+) -1- (4-methoxybenzene) ethylamine monomer as claimed in any one of claims 1 to 6, wherein the hydrolysis is carried out by heating a mixture of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide and triethanolamine to 115 ℃, adding 50% aqueous NaOH solution and vigorously stirring the biphasic mixture at 120 ℃ until the reaction is complete.
8. The method for preparing a highly pure (R) - (+) -1- (4-methoxybenzene) ethylamine monomer according to claim 7, wherein the mass ratio of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide to triethanolamine is 1:0.5 to 1:5, and the mass ratio of ((R) - (+) -1- (4-methoxybenzene) ethyl) -2-methoxyacetamide to 50% aqueous NaOH solution is 1: 1-3.
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| CN103012170A (en) * | 2012-11-29 | 2013-04-03 | 张家港市大伟助剂有限公司 | Preparation method of 4-methoxyphenethylamine |
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| CN1771328A (en) * | 2003-02-26 | 2006-05-10 | 巴斯福股份公司 | Enzymatic production of (meth)acrylic acid esters |
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