CN111187793A - Method for synthesizing L-2-methyl norleucine - Google Patents
Method for synthesizing L-2-methyl norleucine Download PDFInfo
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- CN111187793A CN111187793A CN202010069254.4A CN202010069254A CN111187793A CN 111187793 A CN111187793 A CN 111187793A CN 202010069254 A CN202010069254 A CN 202010069254A CN 111187793 A CN111187793 A CN 111187793A
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- CBDGLHGPNJMCQK-UHFFFAOYSA-N 2-bromo-2-methylhexanoic acid Chemical compound CCCCC(C)(Br)C(O)=O CBDGLHGPNJMCQK-UHFFFAOYSA-N 0.000 claims abstract description 8
- CVKMFSAVYPAZTQ-UHFFFAOYSA-N 2-methylhexanoic acid Chemical compound CCCCC(C)C(O)=O CVKMFSAVYPAZTQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims description 3
- 108010073038 Penicillin Amidase Proteins 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 8
- 238000005804 alkylation reaction Methods 0.000 abstract description 5
- 150000001413 amino acids Chemical class 0.000 abstract description 5
- 238000007059 Strecker synthesis reaction Methods 0.000 abstract description 3
- 230000031709 bromination Effects 0.000 abstract description 3
- 238000005893 bromination reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- WOCIAKWEIIZHES-UHFFFAOYSA-N ruthenium(iv) oxide Chemical compound O=[Ru]=O WOCIAKWEIIZHES-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical class OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/04—Alpha- or beta- amino acids
- C12P13/06—Alanine; Leucine; Isoleucine; Serine; Homoserine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing L-2-methyl norleucine. Mainly solves the technical problems that optical pure amino acid is obtained through asymmetric Strecker reaction or asymmetric alkylation reaction controlled by chiral auxiliary three-dimensionally, the existing reaction conditions are harsh, the operation is complicated, and the like, and the method is not suitable for amplification production. The synthesis of the invention comprises four steps, (1) bromination of 2-methyl caproic acid; (2) ammonolysis of 2-bromo-2-methylhexanoic acid; (3) phenylacetylation of DL-2-methylnorleucine; (4) and carrying out enzymolysis and resolution on DL-phenylacetyl-2-methyl norleucine to obtain a final product. The target product with the optical purity of more than 99 percent is obtained through four-step reaction. The method has the advantages of high selectivity, high yield, low cost, simple and convenient operation and purification, good economic benefit and more suitability for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing L-2-methyl norleucine. L-2-methyl norleucine is a raw material for synthesizing polypeptide drugs, and belongs to the technical field of drug synthesis chemical industry.
Background
α -methyl amino acids are important compounds, which are important raw materials for peptide drugs and are often introduced into peptide drugs to modify peptide chain structures because of their metabolic stability and rigidity, they may reduce the conformational freedom of peptides containing these amino acids and thus alter their biological properties.
A chemical report (chem. Ber. 106, 2291-2297, 1973, Klaus Weinges) et al report a synthetic method for L-2-methylnorleucine by subjecting 2-hexanone as a starting material to an asymmetric Strecker reaction with a chiral amine followed by acid and base hydrolysis in sequence. The chiral amine is not easy to obtain, and sodium cyanide is extremely toxic and inconvenient to use, so that the chiral amine is not suitable for industrial production.
The synthesis route is as follows:
german applied chemistry (Angewandte Chemie, 92(9), 753-one 754, 1980, Michael Kolb) et al report a synthetic method for L-2-methyl-norleucine starting from propargylamine by asymmetric alkylation using a prolinol derivative as chiral prosthetic group, followed by hydrolysis and finally oxidation of the alkynyl group to a carboxyl group with ruthenium dioxide and sodium periodate. The n-butyl lithium is used in three continuous steps, the reaction conditions are harsh, and the method is not suitable for industrial production.
The synthesis route is as follows:
asymmetric Tetrahedron (Tetrahedron Asymmetry, 4(6), 1081-. The raw materials are not easy to obtain, and diazomethane is used, so that the method is not suitable for industrial production.
The synthesis route is as follows:
tetrahedron Letters, 37(15), 2573, 2576, 1996, ImogaiHassan, and the like, report a synthetic method for synthesizing L-2-methyl-norleucine, wherein the method uses special raw materials, needs ozone oxidation, is inconvenient to operate and is not suitable for industrial production.
The synthesis route is as follows:
journal of organic chemistry (j. org. chem., 65(25), 2000, Franklin a. Davis) et al report a synthetic method for the synthesis of L-2-methylnorleucine, which uses 2-hexanone as a starting material to react with an asymmetric Strecker of a chiral sulfinamide and cyanide, followed by acid hydrolysis. The chiral amine is not easy to obtain, and cyanide is extremely toxic and inconvenient to use, and reaction conditions are harsh, so that the method is not suitable for industrial production.
The synthesis route is as follows:
the Amino acid journal (Amino Acids, 2010, 38, 829-one 837, Daniele Balducci) and others report a synthetic method for synthesizing L-2-methyl-norleucine, which uses chloroacetyl chloride as a raw material and forms a chiral prosthetic group, and then the chiral prosthetic group is subjected to stereoscopically controlled asymmetric alkylation and finally hydrolysis. The stereoselectivity is not high when the first chiral center is produced, so column chromatography is used for separating diastereoisomers, three-step low-temperature alkylation reaction is continuously used, the reaction conditions are harsh, and the method is not suitable for industrial production.
The synthesis route is as follows:
disclosure of Invention
The invention aims to disclose a method for synthesizing L-2-methyl norleucine, which is simple, efficient, mild in condition and suitable for industrial production. Mainly solves the technical problems of harsh conditions, complex operation and unsuitability for amplification production in the process of obtaining optically pure amino acid by asymmetric Strecker reaction or asymmetric alkylation reaction controlled by chiral auxiliary group in a three-dimensional way.
The technical scheme of the invention is as follows: a method for synthesizing L-2-methyl norleucine is characterized by comprising the following steps: the method comprises the following steps:
step 1: adding NBS into 2-methylhexanoic acid in an organic solvent in the presence of a catalyst, and brominating to obtain 2-bromo-2-methylhexanoic acid;
step 2: carrying out ammonolysis on the 2-bromo-2-methylhexanoic acid obtained in the step 1 in a methanol solution of ammonia to obtain DL-2-methyl norleucine;
and step 3: reacting the DL-2-methyl norleucine obtained in the step (2) with phenylacetyl chloride to obtain DL-phenylacetyl-2-methyl norleucine;
and 4, step 4: resolving DL-phenylacetyl-2-methyl norleucine obtained in the step (3) by using enzyme to obtain L-2-methyl norleucine;
the reaction formula is as follows:
in the above reaction, in the first step, the organic solvent is one of chlorobenzene or benzotrifluoride, and preferably the solvent is benzotrifluoride; the catalyst in the first step is one of azobisisobutyronitrile or benzoyl peroxide, and the preferable catalytic solvent is azobisisobutyronitrile; the reaction temperature in the first step is 80 ℃ or 90 ℃, preferably 90 ℃. The enzyme in the fourth step is Penicillin G acylase (Penicilin G acylase) in an amount of 10% (Wt%) of the substrate.
NBS is N-bromosuccinimide.
The invention has the beneficial effects that: the invention takes 2-methylhexanoic acid as a raw material to prepare chiral L-2-methyl norleucine with high optical purity through NBS bromination, ammonolysis, phenylacetylation and subsequent enzymolysis resolution. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple method, high efficiency, high mass yield, economy and effectiveness, and is suitable for industrial mass production.
Detailed Description
Example 1:
first, bromination of 2-methylhexanoic acid
2-methylhexanoic acid (90 g, 0.69 mol) and trifluorotoluene (900 mL) were added to a 2L three-necked flask, replacing the nitrogen. NBS (129 g, 0.72 mol) and azobisisobutyronitrile (5.67 g, 34.5 mmol) were added at room temperature. After the addition, the temperature was raised to 90 ℃. After 2 hours of reaction, LC-MS analysis showed no starting material. Filtration and direct spin-drying of the filtrate yielded 2-bromo-2-methylhexanoic acid (144 g).
Second step, aminolysis of 2-bromo-2-methylhexanoic acid
2-bromo-2-methylhexanoic acid (144 g, 0.69 mol) and methanol (150 mL) were added to a 2L three-necked flask, stirred, and 5M ammonia in methanol (580 mL, 2.9 mol) was added. The reaction was heated to 50 ℃ for 12 hours. Directly spin-drying, adding 500mL of absolute ethanol, heating to 50 ℃, and stirring for 1 hour. Suction filtration was carried out, and the filtrate was directly spin-dried to give DL-2-methylnorleucine (101 g).
Third step, phenylacetation of DL-2-methylnorleucine
DL-2-methylnorleucine (100, 0.69 mol) was added to a 2L three-necked flask, followed by 4 mol/L aqueous sodium hydroxide solution (500 mL) and acetone (500 mL). The temperature was reduced to 0 ℃ and phenylacetyl chloride (213 g, 1.38 mol) was added dropwise and stirred at room temperature overnight. The next day, washed with ethyl acetate (3 × 400 mL), the aqueous phase was adjusted to pH = 3 with 3N hydrochloric acid and filtered. The filtrate was extracted with ethyl acetate (500 mL), and the organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was slurried with methyl tert-ether, filtered and dried to give the product DL-phenylacetyl-2-methylnorleucine (89.3 g, 49% yield over three steps).
The fourth step, enzymatic resolution of DL-phenylacetyl-2-methylnorleucine
DL-phenylacetyl-2-methylnorleucine (45.0 g, 0.17 mol) and water (1500 mL) were added to a 3L three-necked flask, and the pH was adjusted to 8.5 with a 1M aqueous solution of sodium hydroxide. Heating to 37 deg.C, adding penicillin G acylase (4.5G, available from Shunheng Heidel Co., Ltd., Zhejiang), maintaining pH to 8.5, and stirring at 37 deg.C for 16 hr. pH = 6 was adjusted with 3N hydrochloric acid and extracted with ethyl acetate (3 x 500 mL). The aqueous phase was adjusted to pH 6 with 1M aqueous sodium hydroxide and concentrated to a small volume. The precipitated solid was collected by filtration, washed with anhydrous ethanol, and dried to obtain the product L-2-methylnorleucine (10.3 g, yield 83%).
1H NMR (D2O): δ1.77-1.67 (m, 2H), 1.33 (s, 3H), 1.29-1.11 (m, 4H),1.24 (t,J= 14 Hz, 3H)。
Example 2, the first step was conducted using chlorobenzene as the organic solvent, benzoyl peroxide as the catalyst, and the reaction temperature was 80 ℃.
Example 3, the first step organic solvent was trifluorotoluene, the catalyst was benzoyl peroxide, the reaction temperature was 80 ℃, and the rest of example 1.
Example 4, the first step was conducted in the same manner as in example 1 except that chlorobenzene was used as the organic solvent, azobisisobutyronitrile was used as the catalyst, and the reaction temperature was 90 ℃.
Claims (8)
1. A method for synthesizing L-2-methyl norleucine is characterized by comprising the following steps: comprises the following steps:
step 1: adding NBS into 2-methylhexanoic acid in an organic solvent in the presence of a catalyst, and brominating to obtain 2-bromo-2-methylhexanoic acid;
step 2: carrying out ammonolysis on the 2-bromo-2-methylhexanoic acid obtained in the step 1 in a methanol solution of ammonia to obtain DL-2-methyl norleucine;
and step 3: reacting the DL-2-methyl norleucine obtained in the step (2) with phenylacetyl chloride to obtain DL-phenylacetyl-2-methyl norleucine;
and 4, step 4: resolving DL-phenylacetyl-2-methyl norleucine obtained in the step (3) by using enzyme to obtain L-2-methyl norleucine;
the reaction formula is as follows:
2. the method for synthesizing L-2-methylnorleucine according to claim 1, wherein: the organic solvent in the first step is one of chlorobenzene or benzotrifluoride.
3. The method for synthesizing L-2-methylnorleucine according to claim 2, wherein: the organic solvent in the first step is trifluorotoluene.
4. The method for synthesizing L-2-methylnorleucine according to claim 1, wherein: the catalyst in the first step is one of azobisisobutyronitrile or benzoyl peroxide.
5. The method for synthesizing L-2-methylnorleucine according to claim 4, wherein: the catalyst in the first step is azobisisobutyronitrile.
6. The method for synthesizing L-2-methylnorleucine according to claim 1, wherein: the reaction temperature of the first step is 80 ℃ or 90 ℃.
7. The method for synthesizing L-2-methylnorleucine according to claim 6, wherein: the reaction temperature in the first step was 90 ℃.
8. The method for synthesizing L-2-methylnorleucine according to claim 1, wherein: the enzyme in the fourth step is penicillin G acylase, and the dosage of the enzyme is 10 percent of the weight percentage of the substrate.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB811103A (en) * | 1955-08-25 | 1959-04-02 | Parke Davis & Co | Amino acid compounds and methods for producing the same |
| CN1616411A (en) * | 2004-10-11 | 2005-05-18 | 温州师范学院 | Novel chiral amino acid derivative and its synthetic method and use |
| CN102533888A (en) * | 2010-12-29 | 2012-07-04 | 浙江九洲药物科技有限公司 | Continuous enzymatic method for producing L-tert-leucine |
| CN102628075A (en) * | 2012-02-24 | 2012-08-08 | 上海瀚鸿化工科技有限公司 | Method for producing chiral amino acid by penicillin acylase resolution and product thereof |
| CN103074409A (en) * | 2011-10-25 | 2013-05-01 | 张家港九木科技有限公司 | Method for splitting halogenated alpha-amino acid |
-
2020
- 2020-01-21 CN CN202010069254.4A patent/CN111187793A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB811103A (en) * | 1955-08-25 | 1959-04-02 | Parke Davis & Co | Amino acid compounds and methods for producing the same |
| CN1616411A (en) * | 2004-10-11 | 2005-05-18 | 温州师范学院 | Novel chiral amino acid derivative and its synthetic method and use |
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