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WO2010053050A1 - O-alkylsérine et procédé de production de n-benzyl-o-alkysérine - Google Patents

O-alkylsérine et procédé de production de n-benzyl-o-alkysérine Download PDF

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Publication number
WO2010053050A1
WO2010053050A1 PCT/JP2009/068657 JP2009068657W WO2010053050A1 WO 2010053050 A1 WO2010053050 A1 WO 2010053050A1 JP 2009068657 W JP2009068657 W JP 2009068657W WO 2010053050 A1 WO2010053050 A1 WO 2010053050A1
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Prior art keywords
alkylserine
formula
acid
benzyl
compound
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English (en)
Japanese (ja)
Inventor
啓明 直原
章 西山
進 天野
雅俊 大貫
増俊 野尻
直明 田岡
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Kaneka Corp
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Kaneka Corp
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    • 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
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • 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
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • 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

Definitions

  • the present invention relates to an O-alkylserine useful as a pharmaceutical intermediate and a method for producing N-benzyl-O-alkylserine useful for its production.
  • N-benzyl-O-methylserine amide is prepared by optical resolution of racemic 1-benzylaziridine-2-carboxamide with amidase and then treatment with methanol in the presence of Lewis acid catalyst. To do. Subsequently, a method of producing (S) -O-methylserine hydrochloride by debenzylation by hydrogenation in the presence of a palladium catalyst and further hydrolysis (Non-patent Document 2). (3) (R) -N-chloroacetyl-O-methylserine is produced by chloroacetylating racemic O-methylserine and asymmetric hydrolysis using N-acetylamino acid amide hydrolase derived from pig kidney.
  • Patent Document 1 a method for producing (R) -O-methylserine hydrochloride by hydrolysis with hydrochloric acid (Patent Document 1). (4) N-tritylation of serine benzyl ester followed by O-tosylation followed by treatment with triethylamine to produce 1-tritylaziridine-2-carboxylic acid benzyl ester. Subsequent detritylation is followed by benzyloxycarbonyl protection on the nitrogen to produce 1-benzyloxycarbonylaziridine-2-carboxylic acid benzyl ester.
  • Non-Patent Document 1 has a problem in that methylation is performed using expensive silver and highly toxic methyl iodide, and the reaction requires a long time.
  • the method described in Non-Patent Document 2 is not suitable for implementation on an industrial scale because it uses expensive starting materials and the process is long.
  • N-chloroacetyl-O-methylserine has a high water solubility, and therefore has a problem in that a large amount of extraction solvent is required.
  • the method described in Patent Document 2 is unsuitable for implementation on an industrial scale because it involves a multi-step process.
  • the method described in Non-Patent Document 3 is based on an industrial scale because alkylation is performed using a large excess of ignitable sodium hydride and highly toxic alkyl iodide. Issues remain in implementation.
  • the object of the present invention is to provide an O-alkylserine useful as a pharmaceutical intermediate and an N-benzyl-O-alkylserine useful for its production from an easily available starting material using an inexpensive reagent.
  • the object is to provide a method which can be carried out efficiently on an industrial scale.
  • the present invention has the following formula (1):
  • R 1 represents an alkyl group having 1 to 5 carbon atoms
  • R 1 represents an alkyl group having 1 to 5 carbon atoms
  • N-benzyl-O—alkylserine represented by the formula (1) is produced, and the compound represented by the formula (1) is obtained as a crystal directly from the reaction solution. It is related with the manufacturing method characterized by separating.
  • the present invention is characterized by further debenzylating the compound represented by the formula (1) obtained above, wherein the following formula (2):
  • R 1 is the same as defined above, and a method for producing O-alkylserine or a salt thereof.
  • R 1 represents an alkyl group having 1 to 5 carbon atoms
  • N-benzyl-O-alkylserine or a salt thereof
  • O-alkylserine useful as a pharmaceutical intermediate can be easily and efficiently produced on an industrial scale using a readily available and inexpensive reagent.
  • N-benzyl-O-alkylserine derivative which is the starting compound of the present invention, has the following formula (3):
  • the compound represented by the formula (3) may be referred to as the compound (3).
  • R 1 represents an alkyl group having 1 to 5 carbon atoms.
  • Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.
  • Preferably they are a methyl group, an ethyl group, and an isopropyl group, More preferably, it is a methyl group.
  • R 2 represents NH 2 or OR 3 .
  • R 3 represents an alkyl group having 1 to 5 carbon atoms.
  • Specific examples of R 2 include an amino group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, a tert-butoxy group, and an n-pentyloxy group.
  • Etc An amino group, a methoxy group, an ethoxy group, or an isopropoxy group is preferable, and an amino group or a methoxy group is more preferable.
  • N-benzyl-O-alkylserine derivative represented by the above formula (3) is, for example, the following formula (4):
  • N-benzyl-O-alkylserine or a salt thereof obtained by hydrolyzing compound (3) has the following formula (1):
  • R 1 in the above formula (1) is the same as described above.
  • the salt include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, perchlorate; formate, acetate, pivalate, oxalate, Salts with organic acids such as lactate, mandelate, tartrate, dibenzoyl tartrate, methanesulfonate, p-toluenesulfonate, camphorsulfonate; lithium salt, sodium salt, potassium salt, magnesium salt, Metal salts such as calcium salts; ammonium salts such as ammonium salts, benzylamine salts, 1-phenethylamine salts, dicyclohexylamine salts, cinchonidine salts, and phenylglycinamide salts.
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, perchlorate
  • formate acetate, pivalate, oxalate
  • Salts with organic acids such as lactate, mandelate, tartrate,
  • Compound (1) is a novel compound not described in the literature.
  • O-alkylserine or a salt thereof obtained by debenzylation of compound (1) has the following formula (2):
  • the present inventors similarly use a Bronsted acid in place of the boron trifluoride / ethyl ether complex, that is, even when the compound (4) is allowed to act on the alcohol (5) and Bronsted acid. It has been found that high regioselectivity can be achieved, and industrial implementation has become possible.
  • Examples of the alcohol (5) include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, isopentanol, and cyclopentanol.
  • Methanol, ethanol, n-propanol, isopropanol, and n-butanol are preferable, and methanol is more preferable.
  • the amount of the alcohol (5) used is preferably 50 times or less, more preferably 3 to 20 times the weight of the compound (4).
  • Bronsted acid examples include sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid; hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, Inorganic acids such as phosphoric acid and boric acid; Carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, oxalic acid, tartaric acid, mandelic acid, aspartic acid, glutamic acid An acid etc. are mentioned. Sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid are preferable, and sulfuric acid and methanesulfonic acid are more preferable.
  • the amount of Bronsted acid used is preferably 1 to 10 times the molar amount, more preferably 1 to 2 times the molar amount relative to the compound (4).
  • the reaction temperature is preferably 0 to 120 ° C., more preferably 30 to 80 ° C. from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 5 minutes to 20 hours, more preferably 30 minutes to 6 hours, from the viewpoint of improving the yield.
  • a method for adding compound (4), alcohol (5), and Bronsted acid during the reaction is not particularly limited, but a method for adding compound (4) to a mixture of alcohol (5) and Bronsted acid. Alternatively, a method of simultaneously adding the Bronsted acid and the compound (4) to the alcohol (5) is preferable.
  • the reaction solution obtained in this step is preferably used as it is in the next step, but may be post-treated as necessary.
  • a general treatment for obtaining a product from the reaction solution may be performed.
  • the reaction solution after completion of the reaction is neutralized by adding water or an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate or the like.
  • a general extraction solvent such as ethyl acetate, diethyl ether, methyl tert-butyl ether, methylene chloride, toluene, hexane or the like is added to carry out the extraction operation.
  • the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.
  • the target product thus obtained has a sufficient purity, but may be purified by a general purification method such as crystallization, fractional distillation, column chromatography or the like for the purpose of further increasing the purity.
  • salt formation crystallization may be performed by forming a salt with an acid such as hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, or methanesulfonic acid.
  • the compound (4) in which R 2 is OR 3 is Tetrahedron Asymmetry, Vol. 3, No. 1, 1992, 51. or Organic Process Research & Development, Vol. 11, No. 4, 2007, 711.
  • the compound (4) in which R 2 is NH 2 can be easily produced by reacting acrylamide and bromine to produce 2,3-dibromopropionic acid amide, followed by reaction with benzylamine. Furthermore, it can be produced by reacting the compound (4) in which R 2 is OR 3 with ammonia by the method described in Organic Process Research & Development, Vol. 11, No. 4, 2007, 711. is there.
  • the method for producing the N-benzyl-O-alkylserine derivative used in this step is not particularly limited, but the method obtained from compound (4) is preferred from the viewpoint of the availability of the compound and the simplicity of the method.
  • Hydrolysis is preferably performed by adding an acid or alkali for the purpose of accelerating the reaction.
  • the acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoroacetic acid or the like, and more preferably hydrochloric acid or sulfuric acid.
  • the alkali is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium carbonate or the like, more preferably sodium hydroxide or potassium hydroxide.
  • the amount of acid or alkali used is preferably 0.5 to 30 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (3).
  • the amount of water used for hydrolysis is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (3).
  • a solvent compatible with water may be added.
  • the solvent include methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofuran and the like. Methanol or ethanol is preferred.
  • the amount of solvent used is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (3).
  • the reaction temperature is preferably ⁇ 10 to 120 ° C., more preferably 0 to 80 ° C. from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 5 minutes to 48 hours from the viewpoint of improving the yield, and more preferably 30 minutes to 24 hours.
  • the addition method and order of addition of the compound (3), acid or alkali, water, and solvent during the reaction are not particularly limited.
  • the hydrolysis may be performed by adding a microorganism-derived enzyme source for the purpose of accelerating the reaction.
  • a microorganism-derived enzyme source for the purpose of accelerating the reaction.
  • optically active N-benzyl-O-alkylserine can be easily obtained by using an enzyme source having the ability to selectively hydrolyze one of the three-dimensional structures.
  • microorganism-derived enzyme source examples include esterase, lipase, amidase, protease and the like. From the viewpoint of usefulness of the compound, etc., it is preferably hydrolysis using an enzyme source having the ability to hydrolyze R selectively, and more preferably, R 2 of compound (3) is R 2 selectively when NH 2 is NH 2 . Hydrolysis using an enzyme source that has the ability to hydrolyze.
  • the “enzyme source” includes not only the enzyme having the hydrolysis activity but also the culture of microorganisms and the treated product thereof as long as the enzyme has the hydrolysis activity.
  • “Microbial culture” means a culture solution or culture containing cells
  • “processed product” means, for example, a crude extract, freeze-dried microorganism, acetone-dried microorganism, or these bacteria. It means a crushed body and the like, as long as it has the hydrolysis activity.
  • they can be used by immobilizing them by known means with the enzyme itself or cells. Immobilization can be performed by methods well known to those skilled in the art (for example, a crosslinking method, a physical adsorption method, a comprehensive method, etc.).
  • the depository organization includes an organization corresponding to a deposit number for identifying each microorganism.
  • the microorganism specified by the NBRC number is available from the National Institute of Technology and Evaluation Biological Genetic Resources Division.
  • the R 2 is NH 2 the compound (3), as the enzyme source having an R selectively hydrolyzing ability, Rhodococcus (Rhodococcus) enzyme derived from the genus source of the like, preferably, Rhodococcus rhodochrous (Rhodococcus rhodochrous ) Derived enzyme source. More preferably Rhodococcus rhodochrous (Rhodococcusrhodochrous) NBRC15564.
  • microorganism having the ability to produce a hydrolase derived from the microorganism may be either a wild strain or a mutant strain.
  • microorganisms derived by genetic techniques such as cell fusion or gene manipulation can also be used.
  • a microorganism that produces the genetically engineered enzyme is, for example, a process described in WO 98/35025 for isolating and / or purifying these enzymes to determine part or all of the amino acid sequence of the enzyme, this amino acid sequence
  • a method comprising a step of obtaining a DNA sequence encoding an enzyme based on the above, a step of obtaining a recombinant microorganism by introducing this DNA into another microorganism, and a step of culturing the recombinant microorganism to obtain the enzyme, etc. (WO 98/35025).
  • the recombinant microorganism as described above include a transformed microorganism transformed with a plasmid having a DNA encoding the hydrolase.
  • the host microorganism is preferably Escherichia coli .
  • the culture medium for the microorganism used as the enzyme source is not particularly limited as long as the microorganism can grow.
  • a carbon source carbohydrates such as glucose and sucrose, alcohols such as ethanol and glycerol, fatty acids such as oleic acid and stearic acid and esters thereof, oils such as rapeseed oil and soybean oil, and ammonium sulfate as a nitrogen source , Sodium nitrate, peptone, casamino acid, corn steep liquor, bran, yeast extract, etc.
  • Inorganic salts such as magnesium sulfate, sodium chloride, calcium carbonate, potassium hydrogen phosphate, potassium dihydrogen phosphate, etc.
  • a normal liquid medium containing an extract, meat extract or the like can be used.
  • an inducer may be added to the medium in order to induce microbial enzyme production.
  • the inducer include nitriles, lactam compounds, amides and the like.
  • nitriles include acetonitrile, isovaleronitrile, propionitrile, pivalonitrile, n-butyronitrile, isobutyronitrile, n-capronitrile, 3-pentenenitrile, and the like.
  • lactam compounds include ⁇ -butyrolactam, ⁇ -Valerolactam, ⁇ -caprolactam, etc.
  • amides include crotonamide, benzamide, propionamide, acetamide, n-butyramide, isobutyramide, n-valeramide, n-capronamide, methacrylamide, phenylacetamide, cyclohexanecarboxamide Etc.
  • the amount of these inducers added to the medium is 0.05% to 2.0%, preferably 0.1% to 1.0%. Cultivation is carried out aerobically. Usually, the cultivation time is about 1 to 5 days, the pH of the medium is 3 to 9, and the cultivation temperature is 10 to 50 ° C.
  • the hydrolysis reaction using an enzyme source derived from a microorganism is performed by adding the compound (3) as a substrate and the culture or treated product of the microorganism to a suitable solvent, and stirring under pH adjustment. Can do.
  • the reaction conditions vary depending on the enzyme, microorganism or processed product thereof, substrate concentration, etc., but the substrate concentration is usually about 0.1 to 99% by weight, preferably 1 to 60% by weight, and the reaction temperature is 10 to 60%. C., preferably 20 to 50.degree. C., the reaction pH is 4 to 11, preferably 6 to 9, and the reaction time is 1 to 120 hours, preferably 1 to 72 hours.
  • the substrate can be added in a batch or continuously. The reaction can be carried out batchwise or continuously.
  • Examples of the method for isolating the compound (1) directly from the reaction solution as a crystal include a cooling crystallization method, a concentrated crystallization method, and a neutralization crystallization method.
  • the compound (1) when the compound (3) is acid-hydrolyzed in the above step, the compound (1) can be isolated as a salt crystal with an acid by cooling or concentrating the reaction solution.
  • the compound (3) when the compound (3) is alkali-hydrolyzed, it can also be isolated as a crystal in which the carboxylic acid of the compound (1) is converted into a salt by cooling or concentrating the reaction solution.
  • an organic solvent such as methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofuran or the like may be added.
  • the neutralization crystallization method is preferable from the viewpoint of removing impurities.
  • the reaction liquid obtained by hydrolyzing the compound (3) with an acid or alkali is neutralized by adding an alkali or acid, and in some cases, further concentrated to precipitate the compound (1) as crystals.
  • the mixed impurities can be removed in the mother liquor, and a method of isolating the compound (1) with improved purity can be employed.
  • inorganic salts precipitate at the time of neutralization they may be separated before crystallization, or crystals may be precipitated together with inorganic salts and separated together.
  • the isolation of compound (1) as a crystal directly from the reaction solution means that the compound (3) is hydrolyzed and then crystallized using this reaction solution as it is. It means to isolate (1).
  • the alkali is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium carbonate or the like, more preferably sodium hydroxide or potassium hydroxide.
  • the acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoroacetic acid or the like, and more preferably hydrochloric acid or sulfuric acid.
  • the amount of alkali or acid used varies depending on the pH of the reaction solution.
  • the pH is preferably 3 to 10, and more preferably 5 to 9.
  • the temperature during crystallization is preferably 50 ° C. or less, more preferably 0 to 30 ° C.
  • the solvent may be distilled off under reduced pressure to increase the crystallization concentration.
  • an inorganic salt such as sodium chloride or sodium sulfate may be added to increase the salt concentration.
  • the crystals of compound (1) can be separated and obtained by a method such as vacuum filtration, pressure filtration, or centrifugation. Further, when the mother liquor remains in the acquired crystal and the purity of the crystal is lowered, the quality can be improved by washing with water or an organic solvent as necessary. As a method for drying the crystals, it is desirable to dry under reduced pressure (vacuum drying) at about 60 ° C. or less while avoiding thermal decomposition and melting.
  • the content of the impurity (6) is usually 5% by weight or less, and in some cases, it can be 1% by weight or less.
  • the same operation as the neutralization crystallization may be performed. That is, by adding and neutralizing an alkali or an acid according to the pH after completion of the reaction, the absolute configuration is S by precipitating and separating the compound (1) having the absolute configuration R as a crystal. The compound (3) is removed from the mother liquor, and the compound (1) having an absolute configuration R can be isolated.
  • the use amount, pH, crystallization temperature, separation method, drying method and the like of the alkali or acid are the same as described above.
  • Examples of the debenzylation method include a hydrogenation method in the presence of a transition metal catalyst.
  • the transition metal catalyst is preferably palladium, rhodium, or platinum, and more preferably palladium.
  • Palladium is preferably palladium black, palladium / carbon, palladium hydroxide / carbon, and more preferably palladium / carbon.
  • the amount of the transition metal catalyst used is not more than 0.1 times the molar amount relative to the compound (1), more preferably 0.05 to 0.0001 times the molar amount.
  • the hydrogen pressure in this step is preferably 1 to 100 kg / cm 2 , more preferably 1 to 30 kg / cm 2 .
  • reaction solvent water; alcohol solvents such as methanol, ethanol and isopropanol; ether solvents such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; ester solvents such as ethyl acetate and isopropyl acetate; benzene, toluene, Hydrocarbon solvents such as hexane; halogen solvents such as methylene chloride and chloroform; amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; dimethylpropylene urea and the like Urea solvents; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide may be used, and these may be used alone or in combination of two or more.
  • Preferred is water; alcohol-based solvents such as methanol, ethanol, isopropanol, and more preferred are water, water
  • the amount of the solvent used is preferably 50 times or less, more preferably 5 to 20 times the weight of the compound (1).
  • the reaction temperature is preferably 0 to 100 ° C., more preferably 10 to 60 ° C. from the viewpoint of shortening the reaction time and improving the yield.
  • the reaction time is preferably 30 minutes to 48 hours, more preferably 1 to 24 hours, from the viewpoint of improving the yield.
  • a general process for obtaining a product from the reaction solution may be performed.
  • the reaction solvent is distilled off by an operation such as heating under reduced pressure to obtain the desired product.
  • the target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization,
  • the purity may be further increased by a general purification method such as fractional distillation or column chromatography.
  • Example 1 Production of N-benzyl-O- methylserine methyl ester A solution consisting of 52.1 g (540 mmol) of methanesulfonic acid and 900 mL of methanol was cooled to 2 ° C., and 154.7 g of 1-benzylaziridine-2-carboxymethyl ester was obtained. A solution consisting of (540 mmol) and 100 mL of methanol was added over 0.5 hours, and then the temperature was raised to 40 ° C. After stirring for 6 hours, the reaction solution (40.7 g out of the total amount of 980.1 g) was concentrated under reduced pressure, and toluene was added.
  • Example 2 Preparation of N-benzyl-O- methylserine methyl ester In a solution consisting of 230.98 g (2.36 mol) of sulfuric acid and 2061.50 g of methanol, 79% by weight of 1-benzylaziridine-2-carboxymethyl ester 378. A solution consisting of 49 g (1.57 mol) and 291.39 g of methanol was added dropwise over 1 hour, and then the temperature was raised to 50 ° C. After stirring for 2.5 hours, the mixture was cooled to 25 ° C., and 628.00 g (4.71 mol) of a 30 wt% aqueous sodium hydroxide solution was added dropwise over 1 hour.
  • Example 3 Preparation of N-benzyl-O-methylserine Methanol solution containing 5.99 g (27 mmol) of N-benzyl-O-methylserine methyl ester prepared in Example 1 and 5.25 g (55 mmol) of methanesulfonic acid To 26 g, 7.29 g (55 mmol) of a 30% by weight aqueous sodium hydroxide solution was added, and the mixture was concentrated to 44.57 g under reduced pressure. To this solution were added 10.00 g of water and 7.15 g (54 mmol) of a 30% by weight aqueous sodium hydroxide solution, and the mixture was stirred at 25 ° C. for 2 hours, and then concentrated to 25.71 g under reduced pressure.
  • Example 4 Production of N-benzyl-O-methylserine 30% by weight of hydroxide was added to 2516.40 g of an aqueous solution containing 285.06 g (1.28 mol) of N-benzyl-O-methylserine methyl ester produced in Example 2. 209.33 g (1.57 mol) of an aqueous sodium solution was added dropwise over 20 minutes. After stirring at 25 ° C. for 2 hours, 829.48 g of water was added to the reaction solution.
  • Example 5 Production of N-benzyl-O-methylserine To 14.8 g of an aqueous solution containing 1.07 g (4.78 mmol) of N-benzyl-O-methylserine methyl ester, 0.78 g of 30% by weight aqueous sodium hydroxide solution ( 5.83 mmol) was added dropwise, followed by stirring at 25 ° C. for 2 hours. When 163 mg (1.66 mol) of sulfuric acid was added to this aqueous solution and the pH was adjusted to 7, crystals were precipitated. When the crystals were dissolved at 80 ° C. and cooled to 0 ° C., the title compound containing 2.2% by weight of 3-benzylamino-2-methoxypropionic acid was obtained as white crystals (489 mg, purity 74% by weight, recovered) Rate 36%).
  • Example 6 Production of N-benzyl-O- methylserinamide From 600 mg (3.4 mmol) of 1-benzylaziridine-2-carboxamide produced in Reference Example 3, 6 mL of methanol, and 327 mg (3.4 mmol) of methanesulfonic acid The resulting solution was stirred at 60 ° C. for 3 hours. Methanol was distilled off, 6 mL of water and 471 mg (3.4 mmol) of potassium carbonate were added to the residue, and the mixture was stirred at 25 ° C. for 1 hour, and then extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography (mobile phase: ethyl acetate) to give the title compound as a pale yellow oil (391 mg, yield 55%).
  • Example 7 Production of N-benzyl-O-methylserine hydrochloride A solution consisting of 439 mg (1.96 mmol) of N-benzyl-O-methylserine methyl ester produced in Example 1 and 5 mL of 6N hydrochloric acid at 90 ° C. Stir for 18 hours. The reaction mixture was concentrated to give the title compound as white crystals (498 mg, yield 100%).
  • Example 8 Production of (R) -N-benzyl-O-methylserine Rhodococcus rhodochrous NBRC15564 was sterilized in a Sakaguchi flask (glycerol 1.0%, peptone 0.5%, malt extract 0.3). %, Yeast extract 0.3%, isovaleronitrile 0.1%, pH 7.0), and cultured with shaking at 30 ° C. for 72 hours. After completion of the culture, the cells were collected by centrifugation and suspended in 100 mM phosphate buffer (pH 7.0) to obtain a 20-fold concentrated cell suspension.
  • Example 9 Preparation of O-methylserine A solution consisting of 3.14 g (14 mmol) of N-benzyl-O-methylserine, 14.13 g of methanol, 14.13 g of water, 314 mg of 10 wt% palladium / carbon (50% water-containing product) The mixture was stirred at 25 ° C. for 17 hours under a pressurized hydrogen atmosphere. Palladium was filtered off under reduced pressure, washed with a solution consisting of 4.95 g of methanol and 4.95 g of water, and the filtrate was concentrated to 3.31 g under reduced pressure. When 1.84 g of water and 12.72 g of ethanol were added to the residue, crystals were precipitated. After stirring at 25 ° C.
  • Example 11 Production of O-methylserine A solution consisting of 19 g (9 mmol) of N-benzyl-O-methylserine, 171 g of methanol, 47.5 g of water, 1.9 g of 10% by weight palladium / carbon (containing 50% water) was obtained at atmospheric pressure. The mixture was stirred at 25 ° C. for 24 hours under an atmosphere. The palladium was filtered off under reduced pressure, washed with a mixed solvent of methanol and water (3.5 / 1 (v / v), 19 g), and the filtrate was concentrated to 24.6 g.
  • Example 12 Production of O-methylserine From 14.1 g (6.7 mmol) of N-benzyl-O-methylserine, 127.1 g of methanol, 20.1 g of water, 1.4 g of 10 wt% palladium / carbon (50% water-containing product) The resulting solution was stirred at 25 ° C. for 13 hours under a normal pressure hydrogen atmosphere. The palladium was filtered off under reduced pressure, washed with a mixed solvent of methanol and water (3.5 / 1 (v / v), 14 g), and the filtrate was concentrated to 18.9 g. 10.8 g of methanol was added to 17.9 g of this concentrated liquid, and the temperature was raised to 70 ° C.

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Abstract

La présente invention concerne une O-alkylsérine qui peut être utilisée en tant qu'intermédiaire pharmaceutique. L'invention concerne également un procédé de production d'une N-benzyl-O-alkylsérine, qui est un composé pouvant être utilisé pour la production, à l'échelle industrielle, de ladite O-alkylsérine, à partir d'un matériau de départ facilement disponible et en utilisant un réactif peu onéreux, et ce de façon simple et très efficace. Un composé de formule (3) est hydrolysé pour donner une solution réactionnelle. La N-benzyl-O-alkylsérine est isolée sous la forme de cristaux directement à partir de la solution réactionnelle. De façon particulièrement préférée, un dérivé de la 1-benzylaziridine, qui est un composé facilement disponible, est soumis à une réaction d'ouverture de cycle avec un alcool et un acide de Brönsted pour obtenir un composé de formule (3). La N-benzyl-O-alkysérine est débenzylée pour obtenir la O-alkysérine.
PCT/JP2009/068657 2008-11-04 2009-10-30 O-alkylsérine et procédé de production de n-benzyl-o-alkysérine Ceased WO2010053050A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020095983A1 (fr) 2018-11-07 2020-05-14 中外製薬株式会社 Procédé de production d'un dérivé de sérine o-substitué
US11492369B2 (en) 2017-12-15 2022-11-08 Chugai Seiyaku Kabushiki Kaisha Method for producing peptide, and method for processing bases
US11542299B2 (en) 2017-06-09 2023-01-03 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11732002B2 (en) 2018-11-30 2023-08-22 Chugai Seiyaku Kabushiki Kaisha Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound
WO2024024965A1 (fr) 2022-07-29 2024-02-01 中外製薬株式会社 Procédé de production d'un dérivé de sérine o-substitué
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US12071396B2 (en) 2019-03-15 2024-08-27 Chugai Seiyaku Kabushiki Kaisha Method for preparing aromatic amino acid derivative
US12163134B2 (en) 2015-03-13 2024-12-10 Chugai Seiyaku Kabushiki Kaisha Modified aminoacyl-tRNA synthetase and use thereof
US12371454B2 (en) 2019-11-07 2025-07-29 Chugai Seiyaku Kabushiki Kaisha Cyclic peptide compound having Kras inhibitory action
US12391971B2 (en) 2017-01-31 2025-08-19 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptides in cell-free translation system

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4927858B1 (fr) * 1968-12-14 1974-07-22
JPS57159747A (en) * 1981-03-27 1982-10-01 Kenji Okawa Synthesis of amino acid derivative
JPS58172352A (ja) * 1982-04-05 1983-10-11 Mitsui Toatsu Chem Inc セリンの分離方法
JPH10251209A (ja) * 1997-03-07 1998-09-22 Nof Corp （メタ）アクリル酸セリンエステル、製造方法、共重合体および生体適合性材料
JP2006115729A (ja) * 2004-10-20 2006-05-11 Daicel Chem Ind Ltd 光学活性β−ヒドロキシアミノ酸の晶析方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4927858B1 (fr) * 1968-12-14 1974-07-22
JPS57159747A (en) * 1981-03-27 1982-10-01 Kenji Okawa Synthesis of amino acid derivative
JPS58172352A (ja) * 1982-04-05 1983-10-11 Mitsui Toatsu Chem Inc セリンの分離方法
JPH10251209A (ja) * 1997-03-07 1998-09-22 Nof Corp （メタ）アクリル酸セリンエステル、製造方法、共重合体および生体適合性材料
JP2006115729A (ja) * 2004-10-20 2006-05-11 Daicel Chem Ind Ltd 光学活性β−ヒドロキシアミノ酸の晶析方法

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12415835B2 (en) 2011-12-28 2025-09-16 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
US12163134B2 (en) 2015-03-13 2024-12-10 Chugai Seiyaku Kabushiki Kaisha Modified aminoacyl-tRNA synthetase and use thereof
US12391971B2 (en) 2017-01-31 2025-08-19 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptides in cell-free translation system
US11542299B2 (en) 2017-06-09 2023-01-03 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11787836B2 (en) 2017-06-09 2023-10-17 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US12281141B2 (en) 2017-06-09 2025-04-22 Chugai Seiyaku Kabushiki Kaisha Method for synthesizing peptide containing N-substituted amino acid
US11492369B2 (en) 2017-12-15 2022-11-08 Chugai Seiyaku Kabushiki Kaisha Method for producing peptide, and method for processing bases
US12312297B2 (en) 2018-11-07 2025-05-27 Chugai Seiyaku Kabushiki Kaisha O-substituted serine derivative production method
KR20210088619A (ko) 2018-11-07 2021-07-14 추가이 세이야쿠 가부시키가이샤 O-치환 세린 유도체의 제조 방법
WO2020095983A1 (fr) 2018-11-07 2020-05-14 中外製薬株式会社 Procédé de production d'un dérivé de sérine o-substitué
KR20250119653A (ko) 2018-11-07 2025-08-07 추가이 세이야쿠 가부시키가이샤 O-치환 세린 유도체의 제조 방법
US11732002B2 (en) 2018-11-30 2023-08-22 Chugai Seiyaku Kabushiki Kaisha Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound
US12331072B2 (en) 2018-11-30 2025-06-17 Chugai Seiyaku Kabushiki Kaisha Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound
US12071396B2 (en) 2019-03-15 2024-08-27 Chugai Seiyaku Kabushiki Kaisha Method for preparing aromatic amino acid derivative
US12371454B2 (en) 2019-11-07 2025-07-29 Chugai Seiyaku Kabushiki Kaisha Cyclic peptide compound having Kras inhibitory action
KR20250044666A (ko) 2022-07-29 2025-04-01 추가이 세이야쿠 가부시키가이샤 O-치환 세린 유도체를 제조하는 방법
WO2024024965A1 (fr) 2022-07-29 2024-02-01 中外製薬株式会社 Procédé de production d'un dérivé de sérine o-substitué

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