Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
  • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
  • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06043—Leu-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06052—Val-amino acid

Definitions

• the present invention relates to a method for producing a lipid peptide.
• lipid peptide compound As a lipid peptide compound, it has been proposed to use a novel lipid peptide in which glycine or histidine is bound to palmitic acid or the like as a hydrogelling agent, and its supply method has become important.
• Patent Document 1 a method by solid-phase peptide synthesis has been generally shown as a method for producing a lipid peptide, it can be used only for a small amount of synthesis and mass production is difficult.
• Patent Document 2 The method described in Patent Document 2 is extremely excellent in that it can produce a practical lipid peptide compound that can be mass-produced at low cost without requiring more complicated operations as compared with the conventional production method. be. However, it is required to develop a method capable of producing a lipid peptide compound with high yield and high purity suitable for further industrial production.
• the present invention has been made in consideration of such circumstances, and an object thereof is a method capable of producing a lipid peptide compound with a higher yield and higher purity than a conventional production method. Is to provide.
• the present inventors paid attention to the method for removing the non-polar organic solvent after the reaction and before the neutralization and the raw material, and repeated diligent studies.
• a method for removing the non-polar organic solvent a method is adopted in which an organic acid is added to the solution after completion of the reaction to neutralize it, and then water and alcohol are added to separate the liquids to remove the non-polar organic solvent.
• a stable ethyl ester as a raw material, it has been found that the amount charged can be reduced, the reaction can be carried out in a uniform system, and the lipid peptide compound can be produced with higher yield and higher purity. Completed.
• the present invention has the equation (1) as a first aspect.
• R 1 represents an aliphatic group having 9 to 23 carbon atoms having a linear structure or a branched chain structure
• R 2 has a hydrogen atom or a branched chain having 1 or 2 carbon atoms.
• R3 is an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or carbon.
• an ester compound represented by the formula (2) represented by the formula (2).
• R 4 represents a- (CH 2 ) n -X group, n represents a number of 1 to 4, X represents an amino group, a guanidino group, -CONH 2 groups, or 1 to 3 nitrogen atoms. It represents a 5-membered ring or a 6-membered ring or a condensed heterocycle composed of a 5-membered ring and a 6-membered ring.
• the ⁇ -amino acid compound represented by the ring and the base are contained in a solvent containing a non-polar organic solvent.
• Equation (3) Reaction process to react with Equation (3) obtained in the reaction step
• An organic acid is added to a solution in which a salt of a lipid peptide represented by the above is dissolved to neutralize it, and then water and water are added.
• the formula (3) includes an extraction step of adding an alcohol and separating the liquids to remove a non-polar organic solvent, and a separation step of taking out the lipid peptide compound represented by the formula (3) from the solution after the extraction step.
• the second aspect is the production method according to the first aspect, wherein the solvent contains a non-polar organic solvent and an alcohol.
• n represents a number of 1 to 4 and X represents an amino group, a guanidino group or -CONH 2 group, or n represents 1 and X represents a pyrrole group and an imidazole.
• the production method according to the first aspect which represents a group, a pyrazole group or an imidazole group.
• R 1 represents a linear aliphatic group having 11 to 21 carbon atoms which can have 0 to 2 unsaturated bonds.
• R 2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which can have a branched chain having 1 carbon atom. ..
• R 2 represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group
• R 4 is an aminomethyl group, an aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, a 3-carbamoylbutyl group, a 2-guanidinoethyl group, a 3-guanidinopropyl group,
• the production method represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which can have a branched
• R 2 represents a hydrogen atom, a methyl group, an isopropyl group, an isobutyl group or a sec-butyl group
• R 4 is a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group
• the production method according to the sixth aspect which represents a 3-guanidinopropyl group, an imidazole methyl group or a 3-indole methyl group.
• the eighth aspect relates to the production method according to the first aspect, wherein the organic acid is acetic acid.
• the base is selected from an alkali metal, an alkali metal inorganic acid salt, an alkali metal hydroxide, an alkali metal alkoxide, an alicyclic amine, an alcohol solution thereof, or an alcohol dispersion thereof.
• the base is metallic sodium, metallic potassium, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, sodium methoxydo, sodium ethoxydo, potassium methoxyd, potassium.
• the production method according to the ninth aspect which is at least one selected from the alcohol dispersions of the above.
• the eleventh aspect is the production method according to the tenth aspect, wherein the base is sodium methoxide, a methanol solution thereof, or a methanol dispersion thereof.
• the non-polar organic solvent is at least selected from the group consisting of toluene, xylene, orthodichlorobenzene, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, and 1-hexene.
• the present invention relates to the manufacturing method according to the twelfth aspect, which is one type.
• the production method according to the second aspect wherein the solvent contains toluene and methanol or ethanol.
• the reaction between the ester compound represented by the formula (1) and the ⁇ -amino acid compound represented by the formula (2) is carried out at a reaction temperature of 65 ° C to 75 ° C.
• equation (1) (In the formula, R 1 represents an aliphatic group having 9 to 23 carbon atoms having a linear structure or a branched chain structure, and R 2 has a hydrogen atom or a branched chain having 1 or 2 carbon atoms. Represents an alkyl group having 1 to 4 carbon atoms to be obtained, and R3 is an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or carbon. Represents an aryl group that may be substituted with an alkyl group having 1 to 6 atoms.) And an ester compound represented by the formula (2).
• R 4 represents a- (CH 2 ) n -X group, n represents a number of 1 to 4, X represents an amino group, a guanidino group, -CONH 2 groups, or 1 to 3 nitrogen atoms. It represents a 5-membered ring or a 6-membered ring or a condensed heterocycle composed of a 5-membered ring and a 6-membered ring.
• the ⁇ -amino acid compound represented by the ring and the base are contained in a solvent containing a non-polar organic solvent.
• Equation (3) obtained in the reaction step
• R 1 , R 2 and R 4 represent those defined above.
• An organic acid is added to a solution in which a salt of a lipid peptide represented by the above is dissolved to neutralize it, and then water and water are added.
• Extraction step in which alcohol is added and the solution is separated to remove the non-polar organic solvent.
• the present invention relates to a method for producing a lipid peptide compound represented by the formula (3).
• Equation (4) (In the formula, X represents a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and -OC (O) R 1 group, and R 1 has a linear structure or a branched chain structure having 9 to 23 carbon atoms.
• R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms
• R 3 is an alkyl group having 1 to 6 carbon atoms.
• R 1 , R 2 and R 3 represent those defined above.
• R 4 is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms which can have a branched chain having 1 to 3 carbon atoms, a phenylmethyl group, a phenylethyl group,-(CH 2 ) n- .
• Equation (3) obtained in the reaction step (In the formula, R 1 , R 2 and R 4 represent those defined above.)
• An organic acid is added to a solution in which a salt of a lipid peptide represented by the above is dissolved to neutralize it, and then water and water are added.
• the formula (3) includes an extraction step of adding an alcohol and separating the liquids to remove a non-polar organic solvent, and a separation step of taking out the lipid peptide compound represented by the formula (3) from the solution after the extraction step.
• the lipid peptide compound represented by) or a method for producing a pharmaceutically usable salt thereof is carried out in a uniform phase at a reaction temperature of 35 ° C to 45 ° C.
• the manufacturing method described in the viewpoint is carried out in a uniform phase at a reaction temperature of 35 ° C to 45 ° C.
• the production method of the present invention can obtain a desired lipid peptide compound and a salt thereof with high purity and high yield, and has the effect of being suitable for an industrial production method.
• n is normal, "i” is iso, “s” or “sec” is secondary, “t” or “tert” is tertiary, and “c” is cyclo.
• O means ortho, "m” means meta, “p” means para, "Me” means methyl group, “Bu” means butyl group, and “tBu” means tertiary butyl group.
• R 1 represents an aliphatic group having 9 to 23 carbon atoms, and preferably R 1 is a linear aliphatic group or an unsaturated bond having 11 to 21 carbon atoms. It is desirable that it is a linear aliphatic group having two carbon atoms having 11 to 21 carbon atoms.
• a nonyl group a decyl group, an undecyl group, a dodecyl group (lauryl group), a tridecyl group, a tetradecyl group (myristyl group), a pentadecyl group and a hexadecyl group are given.
• Examples thereof include a group (palmityl group), a heptadecyl group (margaryl group), an octadecyl group (stearyl group), a nonadecyl group, an icosyl group, and a henicosyl group.
• R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms.
• the alkyl group having 1 to 4 carbon atoms which can have a branched chain having 1 or 2 carbon atoms in R2 has 1 to 4 carbon atoms in the main chain and 1 or 2 carbon atoms. It means an alkyl group that can have a branched chain, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group or a tert. -Butyl group and the like can be mentioned.
• R2 is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which can have a branched chain having 1 carbon atom, and more preferably a hydrogen atom.
• An alkyl group having 1 to 3 carbon atoms capable of having a branched chain having 1 carbon atom is an alkyl group having 1 to 3 carbon atoms in the main chain and capable of having a branched chain having 1 carbon atom. Specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an i-butyl group or a sec-butyl group, and a methyl group, an i-propyl group, etc. are preferable. It is an i-butyl group or a sec-butyl group.
• R 3 has an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. It represents an aryl group that may be substituted with an alkyl group, preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an ethyl group.
• R 4 represents a ⁇ (CH 2 ) n ⁇ X group.
• n represents a number of 1 to 4
• X is a 5-membered ring or a 5-membered ring which may have 1 to 3 amino groups, guanidino groups, -CONH 2 groups, or nitrogen atoms.
• X preferably represents an amino group, a guanidino group, a —CONH2 group, a pyrrole group, an imidazole group, a pyrazole group or an indole group, and more preferably an imidazole group.
• n is preferably 1 or 2, and more preferably 1.
• the- (CH 2 ) n -X group is preferably an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, a carbamoylmethyl group, a 2-carbamoylethyl group, 3-.
• lipid peptide compounds represented by the above formula (3) specific examples include the following compounds formed from the lipid part and the dipeptide part.
• amino acids histidine (His), glycine (Gly), valine (Val), isoleucine (Ile), alanine (Ala), arginine (Arg), asparagine (Asn), glutamine (Gln), leucine (Leu) , Lys, tryptophan (Trp) are used.
• N-lauroyl-Gly-His N-lauroyl-Gly-Trp, N-lauroyl-Gly-Gln, N-lauroyl-Gly-Asn, N-lauroyl-Gly-Arg, N-lauroyl-Gly-Lys, N -Lauroyl-Ala-His, N-Lauroyl-Ala-Trp, N-Lauroyl-Ala-Gln, N-Lauroyl-Ala-Asn, N-Lauroyl-Ala-Arg, N-Lauroyl-Ala-Lys, N-Lauroyl -Val-His, N-Lauroyl-Val-Trp, N-Lauroyl-Val-Gln, N-Lauroyl-Val-Asn, N-Lauroyl-Val-Arg, N-Lauroyl-Val-Lys, N-Lauroyl-Leu -His,
• lipid peptide compounds include N-lauroyl-Gly-His, N-lauroyl-Gly-Trp, N-lauroyl-Gly-Gln, N-lauroyl-Gly-Asn, and N-lauroyl-.
• the most suitable compounds are N-lauroyl-Gly-His, N-lauroyl-Gly-Gln, N-lauroyl-Gly-Asn, N-lauroyl-Gly-Lys, N-myristoyl-Gly-His, N-myristoyl.
• N-Gly-Gln N-Millitoyl-Gly-Asn, N-Millitoyl-Gly-Lys, N-Palmitoil-Gly-His, N-Palmitoil-Gly-Trp, N-Palmitoil-Gly-Gln, N-Palmitoil-Gly -Asn, N-palmitoyle-Gly-Lys, N-palmitoyle-Ala-His, N-palmitoyle-Ala-Trp, N-palmitoyle-Ala-Gln, N-palmitoyle-Ala-Asn, N-palmitoyle-Ala-Lys , N-palmitoyle-Val-His, N-palmitoyle-Val-Trp, N-palmitoyle-Val-Gln, N-palmitoyle-Val-Asn, N-palmitoyle-Val
• Examples of the lipid peptide having a branched chain structure include N-2- (4,4-dimethylpentane-2-yl) -5,7,7-trimethyloctanoyl-Gly-His and N-2-heptylundeca. Noil-Gly-His can be mentioned.
• the base used for the reaction between the ester compound represented by the above formula (1) and the ⁇ -amino acid compound represented by the above formula (2) is not particularly limited, but for example, metallic sodium.
• Alkali metals such as metallic potassium; alkali metal inorganic salts such as sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methoxydo, t-butoxy Alkali metal alkoxides such as potassium; aliphatic amines such as triethylamine and tri-n-butylamine; 1,8-diazabicyclo [5.4.0] -7-undecene (hereinafter, also referred to as DBU), 1,5-diazabicyclo [ 4.3.0] -Alicyclic amines such as 5-nonen (hereinafter also referred to as DBN); aromatic amines such as pyridine and 2-methyl-5-ethylpyridine, and alcohol
• sodium methoxide, sodium methoxide, potassium methoxide, potassium ethoxide, t-butoxypotassium, DBU or DBN are selected in consideration of increasing the conversion rate and further improving the yield of the target product.
• sodium methoxide, an alcohol solution of these metal alkoxides, or an alcohol dispersion is preferable.
• Sodium methoxide may be a solid, a methanol solution thereof, or a methanol dispersion thereof, and may be prepared and used in advance using metallic sodium and methanol or in a reaction system. Considering operability and yield, it is preferable to use a commercially available methanol solution of about 28% sodium methoxide.
• the amount of the base used is not particularly limited, and is usually about 1 to 10 equivalents with respect to the compound of the formula (1), preferably 1 equivalent to 5 equivalents, and 1.3 equivalents to 2 equivalents. Is more preferable.
• the non-polar organic solvent contained in the solvent used in the above reaction is not particularly limited, and a solvent that does not affect the reaction is appropriately selected and used from various solvents used in general organic synthesis. be able to. Specific examples thereof include saturated aliphatic compounds such as pentane, c-pentane, hexane, c-hexane, methyl c-hexane, heptane, c-heptane, octane, decane and decalin; 1-hexene, 1-octyne and the like. Unsaturated aliphatic compounds; aromatic compounds such as benzene, toluene, xylene, o-dichlorobenzene and the like can be mentioned. These solvents may be used alone or in combination of two or more.
• toluene, xylene, and orthodi are considered to prevent hydrolysis of the ester compound represented by the formula (1), increase the conversion rate, and further improve the yield of the target product.
• At least one selected from the group consisting of chlorobenzene, pentane, hexane, heptane, octane, c-pentane, c-hexane, methyl c-hexane, c-heptane and 1-hexene is preferable, and toluene is particularly preferable. ..
• the solvent used in the reaction preferably contains alcohol in addition to the non-polar solvent.
• the alcohol used here is not particularly limited, and an alcohol solvent that does not affect the reaction can be appropriately selected and used from various alcohol solvents used for general organic synthesis. Specific examples thereof include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol, s-pentanol, t.
• -Pentanol n-hexanol, i-hexanol, s-hexanol, t-hexanol, octanol, decanol, ethylene glycol, 1,3-butanol, glycerin and the like can be mentioned.
• solvents may be used alone or in combination of two or more.
• the reaction temperature of the ester compound represented by the above formula (1) and the ⁇ -amino acid compound represented by the above formula (2) can be any temperature as long as it is equal to or lower than the boiling point of the solvent used. Considering that the desired product can be obtained in a short time with good yield, 20 ° C to 150 ° C is preferable, 40 ° C to 80 ° C is more preferable, and 65 ° C to 75 ° C is even more preferable.
• the reaction time varies depending on the reaction temperature, the base used and the type of organic solvent, and therefore cannot be unconditionally specified, but is usually about 1 hour to 48 hours.
• the type of reaction it is possible to mix all the reagents at room temperature and then heat them to the reaction temperature, and it is also possible to control the reaction by dropping the necessary reagents.
• it can be carried out in any of a batch type, a continuous type, a reduced pressure type, a normal pressure type, and a pressurized type.
• a form in which a base is dropped at normal pressure is more preferable.
• an organic acid is added to neutralize, then water and alcohol are added and the non-polar organic solvent is removed by a liquid separation operation.
• the organic acid acetic acid is preferable.
• an alkali metal salt is preferable as the salt of the lipid peptide compound.
• hydrogen halide is added to the obtained product, preferably in a solvent containing water and alcohol, until the pH reaches the isoelectric point, which has been calculated in advance.
• the non-polar organic solvent is removed, and an aqueous solution containing the alcohol of the salt of the remaining lipid peptide compound.
• a solution of hydrogen halide is added to the mixture.
• the isoelectric point is also referred to as an isoelectric point, and is a pH value at which the formal charge becomes zero in the acid-base dissociation state of the molecule.
• the isoelectric point value can be calculated from the acid dissociation constant (pKa) of the molecule, and can be calculated from the structure of the molecule using, for example, the calculation software Calculator Plugins manufactured by ChemAxon. It is also possible to calculate the isoelectric point from the actually measured zeta potential value.
• pKa acid dissociation constant
• the hydrogen halide used in the above pH adjusting operation is usually used in the form of an aqueous solution because the operation is easy, and examples thereof include hydrochloric acid, hydrobromic acid and the like, preferably hydrochloric acid.
• hydrochloric acid hydrochloric acid
• hydrobromic acid preferably hydrochloric acid.
• the crude product of the lipid peptide compound (free form) is recovered by filtration or the like, and this is subjected to post-treatment such as washing and recrystallization as necessary. And get the purified product.
• the ester compound represented by the above formula (1) used in the present invention can be obtained by reacting the compound represented by the following formula (4) with the compound represented by the following formula (5). .. (In the equation, X, R 1 , R 2 and R 3 represent those defined above.)
• an organic acid is added to the solution after completion of the reaction for neutralization, and then water and alcohol are added to remove the non-polar organic solvent by a liquid separation operation, so that the non-polar organic solvent is removed. Easy recovery and disposal of organic solvent.
• the polar solvent such as DMF used so far in the production of the lipid peptide tends to gel due to the action of the lipid peptide after cooling, but a non-polar organic solvent is used. As a result, gelation can be prevented, which is very useful in manufacturing.
• the solution becomes alkaline after the reaction, but by using the amount of hydrogen chloride aqueous solution required for neutralization, neutralization is completed without gelation, and the free form can be recovered.
• the precipitated free crude crystals can be purified by a known method such as recrystallization to obtain a pure target product.
• the salt of the lipid peptide compound can be reprecipitated as a solid and recovered by dropping a layer (lower layer) of the alcohol solution of the salt of the lipid peptide compound into the organic solvent.
• Example 1 Synthesis of N-palmitoyle-Gly-ethyl 15.2 g (0.11 mol) of glycine ethyl ester hydrochloride and 50 g of water were added to a 500 mL four-necked flask, and 10.6 g of sodium carbonate (base) was added. 0.10 mol), 75 g of water, and 100 g of toluene as an organic solvent were added and stirred. Then, 25.0 g (0.090 mol) of palmitic acid chloride was added dropwise thereto at a reaction temperature of 40 to 45 ° C.
• Example 2 Example was added to a 1 L four-necked flask with 14.1 g (0.090 mol) of histidine and 62.1 g of toluene, and 16.7 g (0.086 mol) of a sodium methoxide 28% methanol solution as a base was added dropwise.
• the toluene solution of N-palmitoyl-Gly-ethyl obtained in 1 was azeotropically dehydrated, and then added together with 12.4 g of methanol to raise the temperature to 70 ° C. Then, 13.2 g (0.068 mol) of a 28% sodium methoxide solution as a base was started to be added dropwise, and stirring was continued at about 70 ° C.
• Example 1 After the reaction of Example 2 was completed, the pH was changed from 11 to pH 7 by adding 12.7 g of an ion exchange resin (Amberlite FPC3500) to the place cooled to 60 ° C. The solution obtained by filtering the ion exchange resin was reprecipitated in 135.0 g of acetonitrile to obtain an N-palmitoyl-Gly-His-free form. Analysis by HPLC revealed that a methylated compound of N-palmitoyl-Gly-His was produced at an area percentage of 0.2%.
• an ion exchange resin Amberlite FPC3500
• Example 3 The same method was used except that the ion exchange resin used in Example 3 was changed to a clay mineral (Galleon Earth V2 10.0 g), but neutralization was not completed only when the pH changed from 11 to 10. ..
• Example 4 The same method was used except that the ion exchange resin used in Example 3 was changed to magnesium silicate (Kyoward 600 10.0 g), but neutralization was not completed only when the pH changed from 11 to 10. rice field.
• Example 4 In Example 3, 5.08 kg (32.7 mol) of histidine and 22.4 kg of toluene were added to a 200 L reaction vessel, and 6.00 kg (31.1 mol) of a sodium methoxide 28% methanol solution as a base was added dropwise. The obtained toluene solution of N-palmitoyl-Gly-ethyl was added together with 4.47 kg of methanol and the temperature was raised to 70 ° C. Then, 4.74 kg (24.6 mol) of a 28% sodium methoxide solution as a base was started to be added dropwise, and stirring was continued at about 70 ° C. for 4 hours.

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