WO2015146882A1 - トリ-カルボベンゾキシ-アルギニンの製造方法 - Google Patents
トリ-カルボベンゾキシ-アルギニンの製造方法 Download PDFInfo
- Publication number
- WO2015146882A1 WO2015146882A1 PCT/JP2015/058672 JP2015058672W WO2015146882A1 WO 2015146882 A1 WO2015146882 A1 WO 2015146882A1 JP 2015058672 W JP2015058672 W JP 2015058672W WO 2015146882 A1 WO2015146882 A1 WO 2015146882A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- arginine
- carbobenzoxy
- tri
- group
- formula
- Prior art date
Links
- 0 *C(CCCNC(*)=*)C(O)=O Chemical compound *C(CCCNC(*)=*)C(O)=O 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
Definitions
- the present invention relates to a method for producing tri-carbobenzoxy-arginine useful for peptide production.
- Tri-carbobenzoxy-arginine is one of the important starting compounds in the production of peptides containing arginine as a constituent.
- tri-carbobenzoxy-arginine is obtained by dissolving commercially available arginine in an aqueous NaOH solution and adding carbobenzoyl chloride and NaOH to react to convert to tri-carbobenzoxy-arginine sodium salt.
- Non-patent document 1 tri-carbobenzoxy-arginine sodium salt is obtained by filtration, then neutralized with sulfuric acid, and extracted with ethyl acetate to synthesize tri-carbobenzoxy-arginine ( Non-patent document 1) has been reported.
- the problem to be solved by the present invention is to provide a method capable of producing high-purity tri-carbobenzoxy-arginine efficiently on an industrial scale.
- the present inventors have used an organic solvent in addition to water as a conventional reaction solvent in a reaction in which tri-carbobenzoxylation is caused by reacting carbobenzoxyl chloride with a base using arginine, It has been found that by carrying out the reaction in a two-layer system of water / organic solvent, the reaction solution has a good fluidity and can be produced on an industrial scale.
- the obtained tri-carbobenzoxy-arginine can be obtained as a solid with good filterability by forming a salt with dicyclohexylamine, and can be obtained as a high-purity tri-carbobenzoxy-arginineamine salt. I found it.
- high-purity tri-carbobenzoxy-arginine can be obtained by adding acid to the resulting tri-carbobenzoxy-arginine amine salt and extracting the tri-carbobenzoxy-arginine into the organic layer. I found.
- the present invention provides the following formula (1); (In the formula, A 1 and A 2 each represent an amino group protecting group or a hydrogen atom.
- R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a substituent.
- the arginine or arginine derivative (1) represented by the formula (1) or a salt thereof is carbobenzoxylated by adding the following formula (2); (Where Cbz represents a benzyloxycarbonyl group)
- the present invention relates to a method for producing tri-carbobenzoxy-arginine represented by the formula:
- the addition of carbobenzoxyl chloride and base in a two-layer system is preferably carried out in the presence of a surfactant.
- the base is preferably an alkali metal hydroxide
- the compound represented by the formula (1) is preferably arginine or arginine hydrochloride.
- a 1 or A 2 is an amino group protecting group, it is preferably deprotected and carbobenzoxylated.
- each of R 2 , R 3 and R 4 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or 7 to 7 carbon atoms which may have a substituent. Represents an aralkyl group of 15).
- the present invention also provides the following formula (2);
- An amine is added to tri-carbobenzoxy-arginine represented by the following formula (3): (Wherein R 2 , R 3 and R 4 represent the same groups as described above), and relates to a production method for obtaining a tri-carbobenzoxy-arginineamine salt represented by a solid form.
- the present invention also provides a high-purity tri-carbobenzo, characterized in that an acid is added to the obtained tri-carbobenzoxy-arginine amine salt to extract tri-carbobenzoxy-arginine into an organic layer.
- the present invention relates to a method for producing xy-arginine.
- the reaction solution has a good fluidity, and tri-carbobenzoxy-arginine can be efficiently produced on an industrial scale.
- tri-carbobenzoxy-arginineamine salt can be obtained as a solid with good filterability by forming a salt with amine, and further extracted to an organic layer under acidic conditions to obtain high-purity tri-carbobenzobenzoate.
- Xy-arginine can be produced efficiently and simply on an industrial scale.
- arginine of formula (1) or an arginine derivative or a salt thereof (hereinafter collectively referred to as arginine raw material (1)) is a water / organic solvent two-layer system, and carbobenzoxyl chloride and a base are added.
- carbobenzoxylation is carried out while maintaining excellent fluidity of the reaction solution that can withstand production on an industrial scale.
- the resulting tri-carbobenzoxy-arginine is a salt of carboxylic acid, and this salt is extracted into an organic solvent under acidic conditions, for example, to obtain a salt-free form of tri-carbobenzoxy-arginine.
- a surfactant is present during the carbobenzoxylation, which makes it possible to efficiently convert di-carbobenzoxy-arginine to tri-carbobenzoxy-arginine, The yield is greatly improved.
- a 1 and A 2 each represent an N protecting group (amino protecting group) or a hydrogen atom.
- the amino group-protecting group is usually selected from known amino-protecting groups other than the benzyloxycarbonyl group, for example, acyl-type protection such as formyl group, acetyl group, trifluoroacetyl group, benzoyl group, pivaloyl group, phthaloyl group, etc.
- urethane type (carbamate type) protecting groups such as carbobenzoxy group, t-butoxycarbonyl group, isopropoxycarbonyl group, ethoxycarbonyl group, methoxycarbonyl group; benzyl group, p-methoxybenzyl group, triphenylmethyl group, etc.
- p-toluenesulfonyl group, benzenesulfonyl group, trifluoromethanesulfonyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triphenylsilyl group and the like can be exemplified.
- a 1 and A 2 are preferably hydrogen atoms. When A 1 and A 2 are N protecting groups, it is preferred to deprotect them before carbobenzoxylation.
- R 1 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group having 7 to 15 carbon atoms, preferably It is a hydrogen atom.
- alkyl group include a methyl group and an ethyl group
- aralkyl group include a benzyl group and a phenethyl group.
- the arginine raw material (1) may be a racemate or an optically active substance exhibiting optical rotation.
- the arginine raw material (1) may be a salt with an acid.
- the acid include mineral acid, sulfonic acid, and carboxylic acid. Although it does not specifically limit as a mineral acid, For example, acids (hydrochloric acid, hydrobromic acid, etc.) containing hydrogen halides, such as hydrogen chloride and hydrogen bromide, a sulfuric acid, phosphoric acid, etc. are mentioned.
- the sulfonic acid is not particularly limited, and examples thereof include methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 1-phenylethanesulfonic acid and the like. Can be mentioned.
- the carboxylic acid is not particularly limited, and examples thereof include formic acid, acetic acid, trifluoroacetic acid, non-optically active carboxylic acid such as benzoic acid, and optically active carboxylic acid such as tartaric acid.
- a preferred acid is a mineral acid, more preferably hydrochloric acid or sulfuric acid.
- Preferable arginine raw material (1) is arginine or arginine salt in which A 1 and A 2 are hydrogen atoms, more preferably arginine or arginine hydrochloride.
- the organic solvent used in the reaction is not particularly limited as long as it is a solvent that forms a two-layer system with water during the reaction and can maintain the fluidity of the reaction solution, and does not contain a solute.
- a solvent that can be freely mixed with water in all proportions is also included as long as it does not contain a solute.
- Preferred solvents are those in which generated tri-carbobenzoxy-arginine is precipitated and released out of the system, such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertbutyl acetate, etc.
- ethers such as tert-butyl methyl ether and ethylene glycol dibutyl ether
- halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
- aromatic hydrocarbons such as toluene, chlorobenzene and xylene Is mentioned.
- tert-butyl methyl ether, dichloromethane, and toluene are preferable. Needless to say, these organic solvents may be used alone or in combination of two or more.
- the amount of the organic solvent used for the reaction solvent is not particularly limited, but is, for example, 32 parts by weight or less, preferably 16 parts by weight or less, and more preferably 8 parts by weight with respect to 1 part by weight of the arginine raw material (1). It is as follows. Although a minimum is not specifically limited, For example, 1 weight part or more, Preferably it is 2 weight part or more, More preferably, it is 4 weight part or more.
- the amount of water used in the above reaction is, for example, 1 part by weight or more, preferably 2 parts by weight or more, more preferably 3 parts by weight or more with respect to 1 part by weight of the organic solvent.
- an upper limit is not specifically limited, For example, it is 10 weight part or less, Preferably it is 8 weight part or less, More preferably, it is 6 weight part or less.
- the origin of water is not ask
- the temperature in the above reaction is not particularly limited as long as it is not lower than the temperature at which the reaction solvent does not solidify, but is 100 ° C. or lower, preferably 80 ° C. or lower, more preferably 50 ° C. or lower.
- the lower limit is ⁇ 50 ° C. or higher, preferably ⁇ 30 ° C. or higher, more preferably ⁇ 10 ° C. or higher.
- An upper limit is 32 mol or less with respect to 1 mol of arginine raw materials (1), Preferably it is 16 mol or less, More preferably, it is 8 mol or less.
- the lower limit is not particularly limited.
- a 1 and A 2 are hydrogen atoms, 3 mol or more, preferably 4 mol or more, more preferably 4.3 mol per 1 mol of arginine. More than moles.
- the base is not particularly limited and may be an organic base or an inorganic base.
- inorganic bases such as alkali metals such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates, etc.
- Metal or alkaline earth metal-containing compounds are mentioned. Specific examples include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate, calcium hydrogen carbonate and the like.
- Alkali metal hydroxides are preferable, lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferable, and sodium hydroxide and potassium hydroxide are still more preferable.
- the amount of the base used is not particularly limited, but is 36 times mol or less, preferably 20 times mol or less, more preferably 12 times mol or less with respect to arginine or an arginine derivative.
- a salt of arginine or an arginine derivative is used as a raw material, it is necessary to neutralize the salt with a base, so that the amount of the base used is preferably 1 mol more than the above range.
- the lower limit is not particularly limited.
- the necessary amount (1 times mole) and triglyceride for neutralizing the carboxylic acid of arginine considering the necessary amount (3 times mol) for neutralizing hydrochloric acid produced by carbobenzoxylation, it is 4 times mol with respect to the arginine raw material (1) (preferably arginine or arginine derivative).
- the above base may be added as an aqueous solution as necessary.
- the base concentration in the aqueous solution is not particularly limited, but is 80 wt% or less, preferably 60 wt% or less, and more preferably 40 wt% or less.
- the lower limit is not particularly limited, but from the viewpoint of productivity, it is preferable that the amount of the reaction solution is not extremely increased, and is 1 wt%, preferably 3 wt%, more preferably 5 wt%.
- the method for adding the carbobenzoxyl chloride and the base is not particularly limited, and after adding the arginine raw material (1) and a predetermined amount of base, carbobenzoxyl chloride may be added.
- carbobenzoxyl chloride may be added simultaneously while controlling the pH.
- the pH range is, for example, about 8 to 14, preferably about 9 to 13, and more preferably about 10 to 12.
- a raw material mixture containing arginine raw material (1), a part of a base, an organic solvent and water is prepared, and then all the rest of the base and all of the carbobenzoxyl chloride are added thereto.
- the adding step is performed.
- the amount of the base in the raw material mixture is, for example, 0.5 mol or more, preferably 1.0 mol or more, more preferably 1.5 mol or more, with respect to 1 mol of the arginine raw material (1). 4 mol or less, preferably 3 mol or less, more preferably 2.5 mol or less.
- the base and carbobenzoxyl chloride may be added sequentially or continuously. Moreover, you may add alternately and may add simultaneously. Preferably, the base and carbobenzoxyl chloride are added simultaneously and continuously.
- this addition step may be performed in two or more stages. For example, the first addition step until two benzyloxycarbonyl groups (Cbz) are bonded to the arginine raw material (1) and the second addition step in which one benzyloxycarbonyl group (Cbz) is further bonded are added.
- a process may be implemented and the said 1st addition process and the 2nd addition process may each be divided and implemented.
- the amount of the base added in the first addition step is, for example, 2 mol or more, preferably 3 mol or more, more preferably 4 mol or more, for example, 15 mol or less, relative to 1 mol of the arginine raw material (1).
- it is 12 mol or less, More preferably, it is 8 mol or less, More preferably, it is 6 mol or less, More preferably, it is 5 mol or less.
- the amount of carbobenzoxyl chloride added in the first addition step is, for example, 2.5 mol or more, preferably 3.0 mol or more, more preferably 3.5 mol, per 1 mol of the arginine raw material (1).
- it is 10 mol or less, preferably 8.0 mol or less, more preferably 6.0 mol or less, and further preferably 5.0 mol or less.
- the proportion of di-carbobenzoxy-arginine (hereinafter referred to as disubstituted product) at the end of the first addition step is determined as mono-carbobenzoxy-arginine (hereinafter referred to as monosubstituted product), disubstituted product, and tri-carbohydrate.
- mono-carbobenzoxy-arginine hereinafter referred to as monosubstituted product
- disubstituted product disubstituted product
- tri-carbohydrate tri-carbohydrate.
- 25% or more, preferably 30% or more, more preferably 35% or more, still more preferably 42% or more with respect to 100% of the total of benzoxy-arginine (hereinafter referred to as trisubstituted products), for example, It is 70% or less, preferably 60% or less, more preferably 55% or less.
- the amount of base added in the second addition step is, for example, 2.0 mol or more, preferably 2.5 mol or more, more preferably 2.8 mol or more, with respect to 1 mol of the arginine raw material (1).
- it is 7.0 mol or less, preferably 6.0 mol or less, more preferably 5.0 mol or less, still more preferably 4.0 mol or less.
- the amount of carbobenzoxyl chloride added in the first addition step is, for example, 1.0 mol or more, preferably 1.5 mol or more, more preferably 1.8 mol, per 1 mol of the arginine raw material (1).
- it is 4.0 mol or less, preferably 3.5 mol or less, more preferably 3.0 mol or less.
- the addition amount of each of the base and carbobenzoxyl chloride is less than that of the first addition step, while the addition time is longer than that of the first addition step.
- the addition time of the second addition step is, for example, 1 or more, preferably 2 or more, more preferably 2.5 or more, for example, 10 or less, preferably 6 when the addition time of the first addition step is 1. Below, more preferably 4 or less.
- the ratio of the trisubstituted product at the end of the second addition step is, for example, 85% or more, preferably 90% or more, and more preferably 92% with respect to 100% of the total of the monosubstituted product, the disubstituted product, and the trisubstituted product. % Or more, for example, 98% or less, preferably 97% or less, more preferably 96% or less.
- the ratio of the monosubstituted product at the end of the second addition step is, for example, 5% or less, preferably 3.5% or less, with respect to the total of 100% of the monosubstituted product, the disubstituted product, and the trisubstituted product. Preferably it is 2% or less.
- the ratio of the disubstituted product is, for example, 10% or less, preferably 8% or less, more preferably 5% or less.
- a surfactant may be added as necessary to improve the yield of the tri-carbobenzoxylation reaction.
- the surfactant is not particularly limited, but is a carboxylic acid type surfactant (particularly a fatty acid type having about 6 to 30 carbon atoms) such as sodium hexanoate, sodium heptanoate, sodium octoate, sodium decanoate, and the like.
- -Sulphonic acid types such as sodium hexanesulfonate, sodium 1-heptanesulfonate, sodium 1-octanesulfonate, sodium 1-decanesulfonate, sodium 1-dodecanesulfonate (particularly linear fatty acids having about 6 to 30 carbon atoms)
- Sulfonic acid type surfactants, and sulfate type surfactants such as sodium lauryl sulfate and ammonium lauryl sulfate (particularly sulfate type having a straight aliphatic hydrocarbon group of about 6 to 30 carbon atoms), and lauryl Lithium phosphate, sodium lauryl phosphate, potassium lauryl phosphate, etc.
- Surfactants of acid ester type (particularly phosphate ester type having a straight aliphatic hydrocarbon group of about 6 to 30 carbon atoms), tetrabutylammonium chloride, tetramethylammonium hydroxide, hexadecyltrimethylammonium bromide, etc.
- Quaternary ammonium salt type surfactants alkylamine salt type surfactants such as monomethylamine hydrochloride and trimethylamine hydrochloride, and substances having a pyridine ring such as butylpyridinium chloride and cetylpyridinium chloride, and lauric acid
- Nonionic surfactants such as glycerin and polyoxyethylene polyoxypropylene glycol
- amphoteric surfactants such as lauryldimethylaminoacetic acid betaine and oleyldimethylamine N-oxide can be used.
- a preferred surfactant is a surfactant having a long chain (straight chain) aliphatic hydrocarbon group having about 6 to 30 carbon atoms, more preferably a sulfonic acid type surfactant.
- the timing of the use of the surfactant is not particularly limited as long as it is before the reaction is completed, but preferably the reaction solution at the start of the reaction (that is, at the start of coexistence of the three components of the arylidine raw material (1), the carboxylic benzochloride and the base). It is recommended that it be present in the raw material mixture, particularly preferably.
- the amount of the surfactant used is not particularly limited, but is 0.01 times mol or more, preferably 0.05 times mol or more, more preferably 0.1 times mol or more with respect to the arginine raw material (1). is there. Although there is no restriction
- Tri-carbobenzoxy-arginine produced as described above is produced in a water / organic solvent system, so it does not become agglomerated and has excellent agitation properties, and is excellent in terms of reaction selectivity and reaction yield. ing.
- the reaction yield of tri-carbobenzoxy-arginine is, for example, 20% or more, preferably 30% or more, more preferably 45% or more.
- the upper limit is preferably 100%, but 80% is excellent.
- tri-carbobenzoxy-arginine may be isolated as necessary, or may be appropriately treated or purified while maintaining the solution or slurry state.
- tri-carbobenzoxy-arginine forms a salt with a base (particularly an inorganic base), and this salt is inferior in filterability. Therefore, it is preferable to process or refine
- a reaction solution containing a salt of tri-carbobenzoxy-arginine with a base can be treated with an acid and then extracted with an organic solvent to remove inorganic impurities and water-soluble impurities.
- the purity of carbobenzoxy-arginine can be improved.
- the extraction after the completion of the reaction may be carried out only with the organic solvent and water used during the reaction, or water or an organic solvent may be appropriately added after the completion of the reaction.
- the organic solvent to be added may be the same as or different from the solvent used in the reaction, and is not particularly limited.
- Acetic esters such as tert-butyl methyl ether and ethylene glycol dibutyl ether; Halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; Aromatic hydrocarbons such as toluene, chlorobenzene and xylene Etc.
- tert-butyl methyl ether, dichloromethane, and toluene are preferable. Needless to say, these organic solvents may be used alone or in combination of two or more.
- Examples of the acid used for acidification during extraction include mineral acid, sulfonic acid, and carboxylic acid. Although it does not specifically limit as a mineral acid, For example, hydrogen halides, such as hydrogen chloride and hydrogen bromide, a sulfuric acid, phosphoric acid, etc. are mentioned.
- the sulfonic acid is not particularly limited, and examples thereof include methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 1-phenylethanesulfonic acid and the like. Can be mentioned.
- the carboxylic acid is not particularly limited, and examples thereof include formic acid, acetic acid, trifluoroacetic acid, non-optically active carboxylic acid such as benzoic acid, and optically active carboxylic acid such as tartaric acid.
- carboxylic acid examples thereof include formic acid, acetic acid, trifluoroacetic acid, non-optically active carboxylic acid such as benzoic acid, and optically active carboxylic acid such as tartaric acid.
- these acids hydrogen chloride, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, benzoic acid, particularly hydrogen chloride, hydrogen bromide, and sulfuric acid are preferable, and hydrogen chloride and sulfuric acid are particularly preferable.
- the amount of the acid used is not particularly limited as long as the target tri-carbobenzoxy-arginine can be adjusted to a pH at which it can be extracted into the organic layer, and is, for example, 1.5 or less.
- extraction temperature is not specifically limited, It can implement above the temperature which a reaction solvent does not solidify.
- the upper limit is 100 ° C, preferably 80 ° C, more preferably 50 ° C.
- the lower limit is not particularly limited, but is ⁇ 50 ° C., preferably ⁇ 30 ° C., more preferably ⁇ 10 ° C.
- the present invention is also characterized in that a tri-carbobenzoxy-arginine amine salt is produced by adding an amine to a tri-carbobenzoxy-arginine solution to be solidified and filtering the obtained solid.
- a tri-carbobenzoxy-arginine amine salt is produced by adding an amine to a tri-carbobenzoxy-arginine solution to be solidified and filtering the obtained solid.
- an amine is added to the tri-carbobenzoxy-arginine solution to solidify, the filterability of the resulting solid is remarkably improved, and the purification efficiency can be increased.
- the tri-carbobenzoxy-arginine used may be obtained by the above method or may be synthesized separately.
- the tri-carbobenzoxy-arginine solution may be a solution obtained by adjusting the pH of a reaction solution obtained by tricarbobenzoxylation of arginine to obtain a tri-carbobenzoxy-arginine solution, or an extract obtained by extraction from the solution. Alternatively, a separately prepared solution may be used.
- the tri-carboxy-arginine solution is usually an organic solvent solution.
- the organic solvent is not particularly limited, but acetates such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertbutyl acetate; tetrahydrofuran, 1,4-dioxane, tert-butyl Ethers such as methyl ether and ethylene glycol dibutyl ether; Halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; Aromatic hydrocarbons such as toluene, chlorobenzene and xylene; N, N-dimethylformamide and the like Amides; nitriles such as acetonitrile and the like.
- Preferred examples include tert-butyl methyl ether, dichloromethane, toluene, ethyl acetate, and tetrahydrofuran. Needless to say, these organic solvents may be used alone or in combination of two or more. Further, an extract of tri-carbobenzoxy-arginine obtained by the above method may be used.
- the amount of the organic solvent is not particularly limited, but the upper limit is 120 times weight, preferably 60 times weight, more preferably 30 times weight with respect to tri-carbobenzoxy-arginine. Although a minimum is not specifically limited, It can implement by the usage-amount which can ensure the fluidity
- R 2 , R 3 and R 4 in the above general formula are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon. Represents an aralkyl group of formula 7-15.
- alkyl group having 1 to 6 carbon atoms examples include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, sec-butyl group, tertbutyl group, A cyclobutyl group, an n-pentyl group, a cyclopentyl group, an n-hexyl group, a cyclohexyl group and the like can be mentioned, and a cycloalkyl group such as a cyclohexyl group is preferable.
- a substituent is not specifically limited, For example, alkyl groups, such as a methyl group and an ethyl group, a halogen atom, an amino group, a hydroxyl group etc. can be mentioned.
- Examples of the aralkyl group having 7 to 15 carbon atoms which may have a substituent include a benzyl group, a p-chlorobenzyl group, a p-hydroxybenzyl group, a p-fluorobenzyl group, and an m, m-difluorobenzyl group. , Phenylethyl group, naphthyl group and the like.
- R 2 , R 3 and R 4 is preferably a combination in which NR 2 R 3 R 4 is a secondary amine, more preferably one is hydrogen and the remaining two are cycloalkyl such as a cyclohexyl group. It is a group.
- the amount of the amine used is not particularly limited, but in order to ensure the yield, the carboxylic acid of tri-carbobenzoxy-arginine needs to form an amine salt, and this tri-carbobenzoxy-arginine It is 0.25 mol or more, preferably 0.5 mol or more, more preferably 1 mol or more with respect to 1 mol.
- the upper limit of the amount used is not limited, but it is 8 mol or less, preferably 4 mol or less, more preferably 2 mol or less with respect to 1 mol of tri-carbobenzoxy-arginine.
- the solidification temperature can be carried out above the temperature at which the reaction solvent does not solidify.
- an upper limit is not specifically limited, 100 degreeC, Preferably it is 70 degreeC, More preferably, it is 50 degreeC.
- the lower limit is not particularly limited, but is ⁇ 50 ° C., preferably ⁇ 30 ° C., more preferably ⁇ 10 ° C.
- Solidified and aging is carried out with stirring, agitation intensity per unit volume is not particularly limited, for example, 0.05 kW / m 3 or higher, preferably 0.1 kW / m 3 or more, more preferably 0. 2 kW / m 3 or more.
- the present invention also provides the production of tri-carbobenzoxy-arginine by extracting the tri-carbobenzoxy-arginine amine salt into an organic solvent using an acid in an organic solvent or water / organic solvent two-layer system. It is characterized by.
- the tri-carbobenzoxy-arginineamine salt preferably includes the solid obtained in the above-mentioned “Preparation of tri-carbobenzoxy-arginineamine salt”, and this solid is acid-treated with an organic solvent or water / organic What is necessary is just to extract to an organic solvent after melt
- tri-carbobenzoxy-arginine it is possible to purify tri-carbobenzoxy-arginine by repeatedly carrying out the above-mentioned method for producing tri-carbobenzoxy-arginineamine salt and the method for producing tri-carbobenzoxy-arginine. High purity tri-carbobenzoxy-arginine can be obtained.
- the organic solvent used for extraction is not particularly limited, but acetates such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertbutyl acetate; tert-butyl methyl ether, ethylene glycol di- Ethers such as butyl ether; Halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; Aromatic hydrocarbons such as toluene, chlorobenzene and xylene. More preferred are tert-butyl methyl ether, dichloromethane, toluene and ethyl acetate. Needless to say, these organic solvents may be used alone or in combination of two or more.
- the amount of water used for the extraction is not particularly limited as long as it is an amount that dissolves the salt of the acid and amine added during extraction.
- the upper limit of the amount of the organic solvent used for the extraction is not particularly limited, but is, for example, 40 times the weight, preferably 20 times the weight, more preferably the tri-carbobenzoxy-arginineamine salt. 10 times the weight.
- the lower limit is not particularly limited, but is, for example, 1-fold weight, preferably 3-fold weight, more preferably 5-fold weight with respect to the tri-carbobenzoxy-arginineamine salt.
- Examples of the acid used for acidification at the time of extraction include mineral acid, sulfonic acid, and carboxylic acid.
- the mineral acid is not particularly limited, and examples thereof include an aqueous solution of hydrogen halide such as hydrogen chloride and hydrogen bromide (hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, phosphoric acid and the like.
- the sulfonic acid is not particularly limited, and examples thereof include methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 1-phenylethanesulfonic acid and the like. Can be mentioned.
- the carboxylic acid is not particularly limited, and examples thereof include formic acid, acetic acid, trifluoroacetic acid, non-optically active carboxylic acid such as benzoic acid, and optically active carboxylic acid such as tartaric acid.
- carboxylic acid examples thereof include formic acid, acetic acid, trifluoroacetic acid, non-optically active carboxylic acid such as benzoic acid, and optically active carboxylic acid such as tartaric acid.
- hydrogen chloride, hydrogen bromide, p-toluenesulfonic acid, benzoic acid, particularly hydrogen chloride, hydrogen bromide, and sulfuric acid are preferable, and hydrogen chloride and sulfuric acid are particularly preferable.
- the temperature at which the acid is added and the temperature at which the acid is extracted are not particularly limited, but the reaction can be performed at a temperature at which the reaction solvent does not solidify.
- an upper limit is not specifically limited, It is 100 degreeC, Preferably it is 70 degreeC, More preferably, it is 50 degreeC.
- the lower limit is not particularly limited, but is ⁇ 50 ° C., preferably ⁇ 30 ° C., more preferably ⁇ 10 ° C.
- the purity of the obtained tri-carbobenzoxy-arginine by high performance liquid chromatography is, for example, 80 area% or more, preferably 85 area% or more, more preferably 90 area% or more, for example, 99.9 area%. It is also possible to do.
- the yield and production ratio of each compound were analyzed using high performance liquid chromatography.
- the purity (area%) refers to the area of the object peak relative to the total peak area after subtracting the peak shape (hereinafter referred to as blank) resulting from the disturbance of the solvent peak and the waveform derived from the system.
- the yield and production ratio of each compound were analyzed under the conditions described below using high performance liquid chromatography.
- Example 1 Method for producing tri-carbobenzoxy-arginine (2) D-arginine hydrochloride (10 g, 47.47 mmol), sodium 1-octanesulfonate (3.10 g, 14.3 mmol, 0.30 eq), H 2 O ( After mixing 10.00 g), the internal temperature was cooled to 0 ° C. 10% aqueous KOH solution (53.27 g, 94.94 mmol, 2.0 eq) and tert-butyl methyl ether (50.00 g) were added.
- Carbobenzoxyl chloride 32.40 g, 189.9 mmol, 4.0 eq
- 10% aqueous KOH solution 159.81 g, 284.8 mmol, 6.0 eq
- Example 2 To the organic layer of tri-carbobenzoxy-arginine obtained in Example 1 (139.42 g, pure content 15.46 g, 26.81 mmol, 31.3 area%) was added tert-butyl methyl ether (81.00 g). Later, dicyclohexylamine (7.29 g, 40.2 mmol, 1.5 eq) was added over 2 hrs to precipitate the tri-carbobenzoxy-arginine dicyclohexylamine salt.
- the filterability of the solid is very good (about 5 min using a 60 mm Kiriyama funnel), and it is washed with tert-butyl methyl ether (70.00 g) to obtain a wet solid of a tri-carbobenzoxy-arginine dicyclohexylamine salt (18. 72 g, 91.0 area%).
- Water (106.38 g) and ethyl acetate (159.57 g) were added to the obtained wet solid (17.73 g, 91.0 area%) of tri-carbobenzoxy-arginine dicyclohexylamine salt, and the internal temperature was cooled to 0 ° C. .
- Example 3 to 12 Carbobenzoxylation of arginine was performed in the same manner as in Example 1 under the conditions shown in Table 1.
- the organic solvent / water ratio in the reaction solvent is also the same as in Example 1 (however, the water here refers only to the added water and does not include the water entering from the KOH aqueous solution).
- the reaction yield is shown in Table 1.
- Example 13 to 20 In Examples 14 to 17, high-purity tri-carbobenzoxy-arginine solutions were obtained from the tri-carbobenzoxy-arginine reaction organic layer in the same manner as in Example 2 under the conditions shown in Table 2. In Examples 13 and 18 to 20, purification of the tri-carbobenzoxy-arginine solution was repeated under the conditions shown in Table 2 to obtain a higher purity tri-carbobenzoxy-arginine solution.
- Example 21 The tri-carbobenzoxy-arginine solution obtained in Example 14 was concentrated at a jacket temperature of 40 ° C. and 10 mmHg for 1 hr, and then vacuum-dried at a jacket temperature of 40 ° C. for 12 hr to obtain tri-carbobenzoxy-arginine (89.1 wt. %, 92.7 area%).
- the present invention can be used for the production of peptides.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
従来、トリ-カルボベンゾキシ-アルギニンを得る方法としては、市販のアルギニンをNaOH水溶液に溶解し、カルボベンゾキシクロリド及びNaOHを加えて反応することにより、トリ-カルボベンゾキシ-アルギニンナトリウム塩に変換した後、濾過することによりトリ-カルボベンゾキシ-アルギニンナトリウム塩を取得し、次いで、硫酸を用いて中和した後、酢酸エチルで抽出することによりトリ-カルボベンゾキシ-アルギニンを合成する方法(非特許文献1)が報告されている。
また、得られたトリ-カルボベンゾキシ-アルギニンは、ジシクロヘキシルアミンと塩を形成させることにより、濾過性の良い固体として取得できること、また高純度のトリ-カルボベンゾキシ-アルギニンアミン塩として取得できることを見出した。
また、得られたトリ-カルボベンゾキシ-アルギニンアミン塩に酸を添加して、トリ-カルボベンゾキシ-アルギニンを有機層に抽出することにより、高純度のトリ-カルボベンゾキシ-アルギニンを取得できることを見出した。
で表されるトリ-カルボベンゾキシ-アルギニンの製造方法に関する。
前記カルボベンゾキシ化工程において、二層系でのカルボベンゾキシクロリドおよび塩基の添加を、界面活性剤存在下で実施することが好ましい。前記塩基としては、アルカリ金属水酸化物が好ましく、式(1)で表される化合物としては、アルギニン又はアルギニン塩酸塩が好ましい。前記A1又はA2がアミノ基保護基の場合、脱保護し、カルボベンゾキシ化する事が好ましい。
なおA1及びA2としては、水素原子が好ましい。A1及びA2がN保護基の場合、それを脱保護してから、カルボベンゾキシ化することが好ましい。
前記アルキル基には、例えば、メチル基、エチル基などが含まれ、前記アラルキル基には、例えば、ベンジル基、フェネチル基などが含まれる。
抽出温度は、特に限定されないが、反応溶媒が固化しない温度以上で実施する事ができる。上限は、100℃、好ましくは80℃、より好ましくは50℃である。下限は、特に限定されないが、-50℃、好ましくは-30℃、より好ましくは-10℃である。
R2、R3及びR4の組み合わせとして好ましくは、NR2R3R4が2級アミンになる組み合わせであり、より好ましくはいずれか一つが水素であり、残り二つがシクロヘキシル基等のシクロアルキル基である。
上記抽出に用いる有機溶媒の使用量としては、上限は、特に限定されないが、トリ-カルボベンゾキシ-アルギニンアミン塩に対して、例えば、40倍重量であり、好ましくは20倍重量、より好ましくは10倍重量である。下限は、特に限定されないが、トリ-カルボベンゾキシ-アルギニンアミン塩に対して、例えば、1倍重量であり、好ましくは3倍重量、より好ましくは5倍重量である。
本実施例において、各化合物の収率および生成比は、高速液体クロマトグラフィーを用いて分析した。また純度(area%)は、溶媒ピーク及びシステム由来の波形の乱れに起因するピーク形状(以下、ブランクという)を差し引いた後の全ピーク面積に対する対象物ピークの面積をいう。
本実施例において、各化合物の収率、生成比は高速液体クロマトグラフィーを用いて以下に記載の条件で分析した。
〔高速液体クロマトグラフィー分析条件〕
カラム:Zorbax Eclipse Plus C18, 50x4.6mm;1.8μm
移動相A:0.1重量%リン酸水溶液、移動相B:アセトニトリル
流速:1.0mL/min
〔グラジエント条件〕
0.00分 移動相A:移動相B=90:10
15.00分 移動相A:移動相B=10:90
25.00分 移動相A:移動相B=10:90
25.01分 移動相A:移動相B=90:10
30.00分 STOP
カラム温度:40度
検出波長:210nm
トリ-カルボベンゾキシ-アルギニンナトリウム塩の製造方法
D-アルギニン(300mg、1.72mmol)に1N NaOH水溶液(1.72mL、1.72mmol、1.0eq)を加えて溶解後、内温0℃に冷却した。2N NaOH水溶液(0.86mL、1.72mmol、1.0eq)及びカルボベンゾキシクロリド(293mg、1.72mmol、1.0eq)を5回ずつ交互に0.5hrかけて添加すると、2回目添加終了時点で固体が析出して塊状となり、全量添加終了時点で撹拌不可能となった。反応液を桐山ロートで濾過したところ、濾過性が非常に悪かった(21mm桐山ロートを用いて1hr程度)。湿固体を真空乾燥することによりトリ-カルボベンゾキシ-アルギニンナトリウム塩の乾燥固体(149mg、0.258mmol、15.0%yield)を取得した。
トリ-カルボベンゾキシ-アルギニンナトリウム塩の製造方法
L-アルギニン(20.00g、114.8mmol)に水(50.00g)、30%KOH水溶液(21.47g、114.8mmol、1.0eq)を加えて溶解後、内温0℃に冷却した。30%KOH水溶液(21.47g、114.8mmol、1.0eq)及びカルボベンゾキシクロリド(19.58g、114.8mmol、1.0eq)を5回ずつ交互に4.5hrかけて添加すると、2回目添加終了時点で固体が析出して塊状となり、全量添加終了時点で比較例1と同様に撹拌不可能となった。
トリ-カルボベンゾキシ-アルギニン(2)の製造方法
D-アルギニン塩酸塩(10g、47.47mmol)、1-オクタンスルホン酸ナトリウム(3.10g、14.3mmol、0.30eq)、H2O(10.00g)を混合後、内温0℃に冷却した。10%KOH水溶液(53.27g、94.94mmol、2.0eq)とtert-ブチルメチルエーテル(50.00g)を加えた。カルボベンゾキシクロリド(32.40g、189.9mmol、4.0eq)及び10%KOH水溶液(159.81g、284.8mmol、6.0eq)を5hrかけて同時に添加(第1添加)した(この時点でトリ-カルボベンゾキシ-アルギニン100area%に対するモノ-カルボベンゾキシ-アルギニンは10.9area%、ジ-カルボベンゾキシ-アルギニンは96.7area%)。
続いて、内温15℃に温調した後、カルボベンゾキシクロリド(21.87g、128.2mmol、2.7eq)及び10%KOH水溶液(98.55g、175.6mmol、3.7eq)をpH11~12に維持しながら15hrかけて同時に添加(第2添加)した(この時点でモノ-カルボベンゾキシ-アルギニンは1.3area%、ジ-カルボベンゾキシ-アルギニンは4.3area%)。反応液の流動性は終始良好であり、問題なく撹拌できた。反応終了後、35%塩酸(22.06g、211.8mmol、4.5eq)を加えてpH1.1に調整し、分液した。有機層をH2O(30g)で二回洗浄し、トリ-カルボベンゾキシ-アルギニンの有機層(144.46g、純分16.0g、27.7mmol、58.4%yield、31.3area%)を取得した。
実施例1で取得したトリ-カルボベンゾキシ-アルギニンの有機層(139.42g、純分15.46g、26.81mmol、31.3area%)にtert-ブチルメチルエーテル(81.00g)を加えた後、ジシクロヘキシルアミン(7.29g、40.2mmol、1.5eq)を2hrで添加すると、トリ-カルボベンゾキシ-アルギニンジシクロヘキシルアミン塩が析出した。固体の濾過性は非常によく(60mm桐山ロートを用いて5min程度)、tert-ブチルメチルエーテル(70.00g)で洗浄することによりトリ-カルボベンゾキシ-アルギニンジシクロヘキシルアミン塩の湿固体(18.72g、91.0area%)を取得した。
取得したトリ-カルボベンゾキシ-アルギニンジシクロヘキシルアミン塩の湿固体(17.73g、91.0area%)に水(106.38g)、酢酸エチル(159.57g)を加え、内温0℃に冷却した。97%H2SO4(1.3g、12.9mmol)を添加してpH1.7に調整した。水層を除去した後、水(106.00g)で有機層を洗浄し、トリ-カルボベンゾキシ-アルギニンの有機層(163.89g、純分12.40g、21.51mmol、84.7%yield、90.5area%)を取得した。
実施例1と同様にして、表1に示す条件で、アルギニンのカルボベンゾキシ化を実施した。なお、反応溶媒における有機溶媒/水比も実施例1と同じである(但し、ここでいう水は添加した水のみを指し、KOH水溶液から入ってくる水は含まない)。反応収率を表1に示す。
実施例14~17は表2に示す条件で、実施例2と同様にしてトリ-カルボベンゾキシ-アルギニン反応有機層から高純度のトリ-カルボベンゾキシ-アルギニン溶液を取得した。実施例13、18~20は表2に示す条件で、トリ-カルボベンゾキシ-アルギニン溶液の精製を繰り返してさらに高純度のトリ-カルボベンゾキシ-アルギニン溶液を取得した。
実施例14で取得したトリ-カルボベンゾキシ-アルギニン溶液をジャケット温度40℃、10mmHgで1hr濃縮した後、ジャケット温度40℃、12hr真空乾燥することにより、トリ-カルボベンゾキシ-アルギニン(89.1wt%、92.7area%)を取得した。
Claims (9)
- 前記カルボベンゾキシ化工程において、二層系でのカルボベンゾキシクロリドおよび塩基の添加を、界面活性剤存在下で実施することを特徴とする、請求項1に記載の製造方法。
- 前記塩基が、アルカリ金属水酸化物である、請求項1または2に記載の製造方法。
- 前記式(1)で表される化合物がアルギニン又はアルギニン塩酸塩である、請求項1~3のいずれかに記載の製造方法。
- 前記A1又はA2で表されるアミノ基保護基を脱保護及びカルボベンゾキシ化する工程を含む、請求項1~4に記載の製造方法。
- 請求項7又は8に記載の製造方法にて得られるトリ-カルボベンゾキシ-アルギニンアミン塩に酸を添加して、トリ-カルボベンゾキシ-アルギニンを有機層に抽出することを特徴とする、トリ-カルボベンゾキシ-アルギニンの製造方法。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201580017051.8A CN106132926B (zh) | 2014-03-28 | 2015-03-23 | 三苄氧羰基精氨酸的制造方法 |
US15/129,927 US10202337B2 (en) | 2014-03-28 | 2015-03-23 | Method for producing tri-carbobenzoxy-arginine |
EP15769421.7A EP3124470B1 (en) | 2014-03-28 | 2015-03-23 | Method for producing tri-carbobenzoxy-arginine |
JP2016510323A JP6484220B2 (ja) | 2014-03-28 | 2015-03-23 | トリ−カルボベンゾキシ−アルギニンの製造方法 |
SG11201608114QA SG11201608114QA (en) | 2014-03-28 | 2015-03-23 | Method for producing tri-carbobenzoxy-arginine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014-068838 | 2014-03-28 | ||
JP2014068838 | 2014-03-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015146882A1 true WO2015146882A1 (ja) | 2015-10-01 |
Family
ID=54195396
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2015/058672 WO2015146882A1 (ja) | 2014-03-28 | 2015-03-23 | トリ-カルボベンゾキシ-アルギニンの製造方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US10202337B2 (ja) |
EP (1) | EP3124470B1 (ja) |
JP (1) | JP6484220B2 (ja) |
CN (1) | CN106132926B (ja) |
SG (1) | SG11201608114QA (ja) |
WO (1) | WO2015146882A1 (ja) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1171335A (ja) * | 1997-08-27 | 1999-03-16 | Fuji Photo Film Co Ltd | 芳香族カルボンアミド類の製造方法 |
JP2001199943A (ja) * | 2000-01-21 | 2001-07-24 | Kemikurea:Kk | 2,6−ジブロモ−4−トリフルオロメトキシアニリンの製造方法 |
JP2002173457A (ja) * | 2000-12-05 | 2002-06-21 | Daicel Chem Ind Ltd | ケトン化合物の製造方法 |
WO2003066563A1 (fr) * | 2002-02-04 | 2003-08-14 | Kaneka Corporation | Procede d'obtention d'acides 2-halogeno-carboxyliques optiquement actifs |
JP2003300926A (ja) * | 2002-04-08 | 2003-10-21 | Nippon Shokubai Co Ltd | α−ヒドロキシカルボン酸又はα−オキソカルボン酸の製造方法 |
JP2011526910A (ja) * | 2008-06-30 | 2011-10-20 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 置換ピリミジン誘導体の製造方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3856848A (en) * | 1973-12-26 | 1974-12-24 | Lilly Co Eli | Process for preparing a protected arginine |
SE9301912D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | Process for the production of aminoalkylguandines |
DE19518073A1 (de) * | 1995-05-17 | 1996-11-21 | Hoechst Ag | Substituierte Benzyloxycarbonylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US6072075A (en) * | 1997-05-22 | 2000-06-06 | The Regents Of The University Of California | Guanidinylation reagents |
CN1107668C (zh) * | 2000-06-29 | 2003-05-07 | 成都三高生化有限公司 | 一种α,ω,δ-三苄氧羰基精氨酸的制备工艺 |
-
2015
- 2015-03-23 JP JP2016510323A patent/JP6484220B2/ja active Active
- 2015-03-23 US US15/129,927 patent/US10202337B2/en active Active
- 2015-03-23 CN CN201580017051.8A patent/CN106132926B/zh active Active
- 2015-03-23 SG SG11201608114QA patent/SG11201608114QA/en unknown
- 2015-03-23 WO PCT/JP2015/058672 patent/WO2015146882A1/ja active Application Filing
- 2015-03-23 EP EP15769421.7A patent/EP3124470B1/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH1171335A (ja) * | 1997-08-27 | 1999-03-16 | Fuji Photo Film Co Ltd | 芳香族カルボンアミド類の製造方法 |
JP2001199943A (ja) * | 2000-01-21 | 2001-07-24 | Kemikurea:Kk | 2,6−ジブロモ−4−トリフルオロメトキシアニリンの製造方法 |
JP2002173457A (ja) * | 2000-12-05 | 2002-06-21 | Daicel Chem Ind Ltd | ケトン化合物の製造方法 |
WO2003066563A1 (fr) * | 2002-02-04 | 2003-08-14 | Kaneka Corporation | Procede d'obtention d'acides 2-halogeno-carboxyliques optiquement actifs |
JP2003300926A (ja) * | 2002-04-08 | 2003-10-21 | Nippon Shokubai Co Ltd | α−ヒドロキシカルボン酸又はα−オキソカルボン酸の製造方法 |
JP2011526910A (ja) * | 2008-06-30 | 2011-10-20 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 置換ピリミジン誘導体の製造方法 |
Non-Patent Citations (2)
Title |
---|
JETTEN M. ET AL.: "A one-pot N-protection of L- arginine", TETRAHEDRON LETTERS, vol. 32, no. 42, 1991, pages 6025 - 8, XP055227329, ISSN: 0040-4039 * |
ZERVAS L. ET AL.: "Studies on Arginine peptides. I. Intermediates in the synthesis of N-terminal and C-terminal arginine peptides", J. ORG. CHEM., vol. 22, no. 11, 1957, pages 1515 - 21, XP001074255 * |
Also Published As
Publication number | Publication date |
---|---|
CN106132926A (zh) | 2016-11-16 |
US10202337B2 (en) | 2019-02-12 |
SG11201608114QA (en) | 2016-11-29 |
EP3124470B1 (en) | 2020-01-08 |
EP3124470A4 (en) | 2017-11-01 |
US20170174622A1 (en) | 2017-06-22 |
CN106132926B (zh) | 2019-05-21 |
JPWO2015146882A1 (ja) | 2017-04-13 |
JP6484220B2 (ja) | 2019-03-13 |
EP3124470A1 (en) | 2017-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20150353577A1 (en) | Method for producing (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one | |
EP3313841A1 (en) | Process for the preparation of a xanthine-based compound | |
US10538507B2 (en) | Preparation process for high-purity dabigatran etexilate | |
WO2014191426A1 (en) | Process for the purification of melphalan | |
WO2016088031A1 (en) | A process for purification of carfilzomib | |
JP6484220B2 (ja) | トリ−カルボベンゾキシ−アルギニンの製造方法 | |
US11427530B2 (en) | Synthesis of 4-chlorokynurenines and intermediates | |
CN112694445A (zh) | 一种噁拉戈利钠中间体的纯化方法 | |
WO2010122682A1 (ja) | N-アルコキシカルボニル-tert-ロイシンの製造法 | |
JP6781030B2 (ja) | L−カルノシン誘導体またはその塩、及びl−カルノシンまたはその塩の製造方法 | |
KR101427221B1 (ko) | 플루복사민 자유 염기의 정제방법 및 이를 이용한 고순도 플루복사민 말레이트의 제조방법 | |
CN105418477B (zh) | 降低雷迪帕韦中间体中非对映异构体杂质含量的方法 | |
HU228593B1 (en) | Process for the purification of a salt of clavulanic acid | |
JP5166747B2 (ja) | アルキルアミノピリジン類の精製方法 | |
RU2741389C1 (ru) | Способ получения промежуточного соединения для синтеза лекарственного средства | |
JP5397706B2 (ja) | 高純度1−ベンジル−3−アミノピロリジンの製造方法 | |
AU2017378044B2 (en) | Method of preparing benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate | |
JP5704763B2 (ja) | トランス−4−アミノシクロペンタ−2−エン−1−カルボン酸誘導体の製造 | |
CN108707086B (zh) | 一种(1s,4s)-n-(4-羟基四氢萘-1-基)叔丁氧基碳酰胺的纯化工艺 | |
JP2007131589A (ja) | N−アルコキシカルボニルアミノ酸の製造方法 | |
JP2004238322A (ja) | (r)−3−アミノペンタンニトリルメタンスルホン酸塩の製造方法 | |
JP5503930B2 (ja) | 3−アミノ−1−tert−ブトキシカルボニルピペリジンの精製方法およびそのクエン酸塩 | |
JP5836851B2 (ja) | ブリンゾラミドの製造方法 | |
JP2019131532A (ja) | 酸無水物、および該酸無水物を用いたl−カルノシンの製造方法 | |
WO2018159028A1 (ja) | N-ベンジル-2-ブロモ-3-メトキシプロピオン酸アミド及びその中間体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15769421 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2016510323 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15129927 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2015769421 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015769421 Country of ref document: EP |