CN108017552B - Synthetic method of alpha-hydroxy-beta-amino acid single stereoisomer - Google Patents
Synthetic method of alpha-hydroxy-beta-amino acid single stereoisomer Download PDFInfo
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Abstract
The invention relates to a synthetic method of an alpha-hydroxy-beta-amino acid single stereoisomer. Mainly solves the technical problem that the prior synthesis method uses expensive chiral ligand or highly toxic raw materials and is not suitable for industrial production. The preparation method comprises the following steps: (1) synthesizing a substituted alpha-hydroxy-beta-amino acid racemate according to a literature method; (2) the penicillin G acylase is used for stereoselectively synthesizing the alpha-hydroxy-beta-amino acid single isomer with (S, S) configuration and the alpha-hydroxy-beta-amino acid single isomer with (R, R) configuration. The method is suitable for preparing the alpha-hydroxy-beta-amino acid with single isomer at low cost and high efficiency.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of an alpha-hydroxy-beta-amino acid single stereoisomer.
Background
The single isomer alpha-hydroxy-beta-amino acid is an important building block of some medicines, and is widely applied to screening of polypeptide medicines in synthesis of taxol and analogues thereof and ubenimex. The synthesis of the single isomer α -hydroxy- β -amino acids has been reported in the literature: chiral amine hydroxylation methods as reported in (1) document synth. commu. 1998, 28, 4463: sharpless et al hydroxylate alpha, beta-unsaturated amide with asymmetric amine under the catalysis of chiral ligand, and then synthesize single isomer alpha-hydroxy-beta-amino acid by several steps. (2) The cyanation process reported in the literature Tetrahedron: Asymmetry, 2001, 12, 347-353-: jose M, Andresl et al use sodium cyanide to attack chiral amino aldehyde, and then acid hydrolysis to obtain a single isomer of alpha-hydroxy-beta-amino acid. In the first method, expensive chiral ligand is used, so that the method is not suitable for industrial production; and the second method uses a virulent sodium cyanide raw material, has strict limitation on the environment, and is not suitable for large-scale use.
Disclosure of Invention
The invention aims to provide a synthetic method of a single stereoisomer of alpha-hydroxy-beta-amino acid, which mainly solves the technical problem that the existing synthetic method uses expensive chiral ligands or highly toxic raw materials and is not suitable for industrial production.
The idea of the invention is to firstly adopt a literature method (Tetrahedron, 2004, 60, 9043-.
The technical scheme of the invention is as follows: a synthetic method of single stereoisomer of alpha-hydroxy-beta-amino acid comprises the following steps:
(1) preparation of trans-epoxides
Adding trans-2-olefine acid ester into a container with a reflux condensing device, adding a solvent dichloroethane into the container, then adding m-chloroperoxybenzoic acid with the amount of substances 1.3-1.5 times of that of the trans-2-olefine acid ester into the container, reacting for 3-6 h at 40-65 ℃, cooling and filtering after the reaction is finished, washing the filtrate with a saturated sodium sulfite aqueous solution, and concentrating to obtain trans-epoxide a;
(2) preparation of oxazoline rings
Adding trans-epoxide, phenylacetonitrile and boron trifluoride diethyl etherate into a solvent, reacting completely, adding water for quenching, and extracting and concentrating an organic solvent to obtain oxazoline ring b;
(3) ring opening and hydrolysis
Adding oxazoline ring and hydrochloric acid solution into solvent, reacting until no raw material exists, adding sodium hydroxide aqueous solution for complete hydrolysis, filtering generated solid, suspending the solid in ethyl acetate, adding diluted hydrochloric acid, stirring, separating organic phase, and concentrating to obtain a product c;
(4) stereoselective synthesis of penicillin G acylase
Adding a compound c into a certain amount of water, adjusting the pH value with inorganic base, stirring until the compound c is dissolved, adding penicillin G acylase, controlling the pH value to be 7-9, controlling the reaction temperature to be 20-40 ℃ until the reaction is finished, removing the penicillin G acylase, adjusting the pH value of a filtrate to be 1-2, extracting twice with an organic solvent, concentrating the extracted water phase, and purifying with ion exchange resin to obtain the (S, S) -configuration alpha-hydroxy-beta-amino acid d; combining the organic phases, and concentrating to obtain the phenylacetyl protected alpha-hydroxy-beta-amino acid f with the (R, R) configuration;
(5) hydrolyzing to obtain (R, R) configuration alpha-hydroxy-beta-amino acid
Adding phenylacetyl protected alpha-hydroxy-beta-amino acid f with (R, R) configuration into 6N hydrochloric acid, refluxing to react completely, concentrating to remove hydrochloric acid, adding water, washing twice with organic solvent, and concentrating the water phase to obtain alpha-hydroxy-beta-amino acid hydrochloride g with (R, R) configuration. The reaction route of the step (1-5) is as follows:
in the formula: r1= alkyl or aryl. The alkyl group is preferably one of methyl, ethyl, propyl, butyl or benzyl. The aryl group is preferably a phenyl group or a substituted phenyl group.
The water used in the step (4) is deionized water, and the pH value of the solution is preferably adjusted to 7.5-8.5 by using inorganic base; the inorganic base is one of sodium hydroxide, lithium hydroxide, potassium hydroxide or sodium carbonate, preferably sodium hydroxide and lithium hydroxide, the acid is hydrochloric acid, and the organic solvent is ethyl acetate. The penicillin G acylase used in the step (4) is penicillin G acylase aqueous solution or immobilized penicillin G acylase, preferably immobilized penicillin G acylase. The preferable reaction temperature in the step (4) is 35-38 ℃. The dosage of the 6N hydrolyzed hydrochloric acid in the step (5) is 5-30 times, preferably 8-12 times of that of the phenylacetyl protected alpha-hydroxy-beta-amino acid with the (R, R) configuration. The reflux reaction temperature is controlled to be 100-120 ℃, and preferably 105-110 ℃.
The invention has the beneficial effects that: the invention relates to a method for stereoselectively synthesizing alpha-hydroxy-beta-amino acid single isomer with (S, S) configuration and alpha-hydroxy-beta-amino acid single isomer with (R, R) configuration by using penicillin G acylase which is commonly used in industry to produce penicillin medicaments and has large use cost and low price. The raw materials used have low cost, the penicillin G acylase can be recycled and reused, the process is simple, the reaction condition requirement is common, the synthesis period is short, and the method is suitable for industrial mass production.
Detailed Description
The invention is further illustrated by the following examples, which should not be construed as limiting the invention.
Example 1: preparation of (2S,3S) -3-amino-2-hydroxyhexanoic acid and (2R,3R) -3-amino-2-hydroxyhexanoic acid hydrochloride
(1) Preparation of trans-epoxides
Adding trans-2-hexenoic acid ester (90g, 0.70 mol), dichloroethane (500mL) and m-chloroperoxybenzoic acid (85% by mass, 142g, 0.91 mol) into a 1L three-necked bottle, heating at 50 ℃ for 3 hours, and completing the reaction. After cooling, filtration was carried out, and the filtrate was washed with saturated sodium hydrogencarbonate and saturated sodium sulfite, dried over anhydrous sodium sulfate, and concentrated to give an oily substance. The oil was distilled under reduced pressure to give trans-epoxide a (88 g, 88% yield);
(2) preparation of oxazoline rings
A2-liter three-necked flask was charged with trans-epoxide a (88 g, 0.61 mol), phenylacetonitrile (254 g, 2.38mol) and dichloromethane (880 mL). Boron trifluoride diethyl etherate (308 g, 2.38mol) was added dropwise at 0 ℃. After the addition, the reaction is carried out for 18 hours at room temperature, ice water (500mL multiplied by 2) is added for washing, then saturated sodium bicarbonate is used for washing, and the compound b (containing excessive benzyl cyanide and directly put into the next step) is obtained by drying and concentrating;
(3) ring opening and hydrolysis
The trans-epoxide b (obtained in the previous step) was added to a 2-liter three-necked flask, tetrahydrofuran (700 mL) was added to dissolve the trans-epoxide b, 6N hydrochloric acid (40 mL) was added thereto, and the mixture was stirred for 3 hours, then 6N sodium hydroxide solution (120 mL) was added thereto, the reaction was carried out for 16 hours, the precipitated white solid was filtered, the white solid was suspended in ethyl acetate (500mL), and 1N diluted hydrochloric acid (300 mL) was added thereto and the mixture was stirred until the solid was dissolved. The ethyl acetate phase was separated, dried and concentrated to give compound c (87 g, 54% yield);
(4) stereoselective synthesis of (2S,3S) -3-amino-2-hydroxycaproic acid with penicillin G acylase
Deionized distilled water (300 mL) was added to a 1L three-necked flask, and then compound c (15 g) was added thereto, and the pH was adjusted to 8 to 9 with 3N lithium hydroxide solution, followed by stirring to dissolve the mixture. Immobilized penicillin G acylase (3G) was added. And (3) heating to 35-38 ℃, stirring for 54 hours, reducing the pH in the splitting process, and adjusting by using a 3N lithium hydroxide solution to keep the pH at 8-9. Sampling analysis shows that the resolution conversion rate is 98.8%. Cooling to room temperature, adjusting the pH value to 11-12, and filtering to remove the immobilized penicillin G acylase. Acidifying the filtrate with 6N hydrochloric acid until the pH value is 2-3, and then adding ethyl acetateThe extraction was performed twice. The ethyl acetates were combined, dried and concentrated to obtain compound e (10.1 g, containing phenylacetic acid). After the aqueous phase was concentrated, inorganic salts were removed by cation exchange resin, amino acids were eluted with 10% by mass of aqueous ammonia, and compound d (3.5 g) in the aqueous ammonia eluate was concentrated. The results of the nuclear magnetic resonance measurement were as follows:1H NMR (400 MHz, DMSO-d 6 ) 5.40 (Br, 3H), 3.16 (s, 1H), 2.81 (Br s, 1H), 1.45 (m, 2H), 1.31 (m, 2H),0.85 (t, 3H). The results of the LC-MS were as follows: LC-MS (ESI):m/z147.90 [M+H]+；
(5) hydrolyzing to obtain (2R,3R) 3-amino-2-hydroxy caproate
Compound e (10.1 g) was suspended in 6N hydrochloric acid solution (100 mL), heated to reflux at 105 ℃ for 16 hours, concentrated to remove hydrochloric acid, diluted with water, washed twice with ethyl acetate to remove phenylacetic acid, and the aqueous phase was concentrated to give g (4.7 g) of dry compound. The results of the nuclear magnetic resonance measurement were as follows:1H NMR (400 MHz, DMSO-d 6 ) 13.10 (br, 1H), 8.18 (br s,3H), 4.39 (s, 1H), 3.38 (s, 1H), 1.35 (m, 4H), 0.85 (t, 3H) in combination with liquid chromatography-mass spectrometry, the results are as follows: LC-MS (ESI):m/z147.70 [M+H]+。
example 2: r1Adjusting the pH value to 7.5-8.5 by using 3N sodium hydroxide solution, wherein the penicillin G acylase is penicillin G acylase aqueous solution, the pH value of filtrate is acidified to 1-2 by using 6N hydrochloric acid, the reaction temperature in the step (4) is 20-25 ℃, the dosage of the 6N hydrochloric acid hydrolyzed in the step (5) is 8 times of that of α -hydroxy- β -amino acid protected by phenylacetyl in the (R, R) configuration, the reaction temperature is 110 ℃, and the rest is the same as that in the example 1.
Example 3: r1Adjusting the pH value to 7.5-8.5 by using 3N sodium carbonate solution for benzyl, using immobilized penicillin G acylase as penicillin G acylase, using 6N hydrochloric acid to acidify the pH value of filtrate to 1-2, and using the 6N hydrochloric acid to carry out the reaction at the temperature of 30-35 ℃ in the step (4), wherein the dosage of the 6N hydrochloric acid hydrolyzed in the step (5) is 10 times of that of α -hydroxy- β -amino acid protected by phenylacetyl in the (R, R) configuration, and the reaction temperature is 108 ℃, and the rest is the same as in the example 1.
Example 4: r1Adjusting the pH value of phenyl to 8.5-9 by using 3N potassium hydroxide solution; acylation of penicillin GThe enzyme is immobilized penicillin G acylase, the pH value of filtrate is acidified to 1-2 by 6N hydrochloric acid, the reaction temperature in the step (4) is 35-38 ℃, the dosage of the 6N hydrochloric acid for hydrolysis in the step (5) is 12 times of that of α -hydroxy- β -amino acid protected by phenylacetyl in (R, R) configuration, the reaction temperature is 115 ℃, and the rest is the same as that in the example 1.
Example 5: r1Adjusting the pH of toluene to 7.5-8.5 with 3N sodium hydroxide solution, preparing immobilized penicillin G acylase as penicillin G acylase, acidifying the filtrate to pH 1-2 with 6N hydrochloric acid, and adjusting the reaction temperature of step (4) to 35-40 ℃, wherein the amount of 6N hydrochloric acid hydrolyzed by step (5) is 25 times of that of α -hydroxy- β -amino acid protected by phenylacetyl in (R, R) configuration, and the reaction temperature is 100 ℃, and the rest is the same as in example 1.
Claims (8)
1. A synthetic method of single stereoisomer of alpha-hydroxy-beta-amino acid is characterized in that: the method comprises the following steps:
(1) adding alpha-hydroxy-beta-amino acid racemate into water, adjusting the pH value of the solution to 7-9 by using inorganic base, adding penicillin G acylase, controlling the reaction temperature to be 20-40 ℃, removing the penicillin G acylase after the resolution is finished, adjusting the pH value of filtrate to 1-2 by using acid, extracting twice by using an organic solvent, concentrating the extracted water phase, and purifying by using ion exchange resin to obtain the alpha-hydroxy-beta-amino acid of the single isomer with the (S, S) configuration; concentrating the organic phase after extraction to obtain phenylacetyl protected alpha-hydroxy-beta-amino acid with (R, R) configuration;
(2) adding the phenylacetyl protected alpha-hydroxy-beta-amino acid with the (R, R) configuration into 6N hydrochloric acid, refluxing to react completely, concentrating to remove hydrochloric acid, adding water, washing twice with an organic solvent, concentrating a water phase to obtain alpha-hydroxy-beta-amino acid hydrochloride with the (R, R) configuration, and purifying with ion exchange resin to obtain single isomer alpha-hydroxy-beta-amino acid with the (R, R) configuration; the reaction formula is as follows:
in the formula: r1Is one of methyl, ethyl, propyl, butyl or benzyl; or a phenyl group.
2. The method of claim 1, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: the water used in the step (1) is deionized water, the pH value of the solution is adjusted to be 7.5-8.5 by using inorganic base, the inorganic base is one of sodium hydroxide, lithium hydroxide, potassium hydroxide or sodium carbonate, the acid is hydrochloric acid, and the organic solvent is ethyl acetate.
3. The method of claim 2, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: the inorganic bases are sodium hydroxide and lithium hydroxide.
4. The method of claim 1, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: the penicillin G acylase used in the step (1) is penicillin G acylase aqueous solution or immobilized penicillin G acylase.
5. The method for synthesizing a single stereoisomer of an α -hydroxy- β -amino acid according to claim 4, wherein: the penicillin G acylase used in the step (1) is immobilized penicillin G acylase.
6. The method of claim 1, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: and (1) controlling the reaction temperature to be 35-38 ℃.
7. The method of claim 1, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: the reflux reaction temperature is controlled to be 100-120 ℃.
8. The method of claim 7, wherein the single stereoisomer of the α -hydroxy- β -amino acid is selected from the group consisting of: the reflux reaction temperature is controlled to be 105-110 ℃.
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