Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
  • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a method for producing a sugar oxazoline derivative.
• sugar oxazoline derivatives have attracted attention as substrates for sugar chain synthesis using sugar chain-related enzymes, and methods for obtaining sugar oxazoline derivatives are being studied.
• tetraethylammonium chloride was used as a nucleophile and sodium bicarbonate was used as an acid scavenger in an acetonitrile solution of N-acetyl-3,4,6-tri-0-acetyl-hydarcosaminyl chloride.
• JP-A-9-30888 a method of producing a bicyclic sugar oxazoline derivative by reacting is used (JP-A-9-30888).
• JP-A-9-30888 a method of producing a bicyclic sugar oxazoline derivative by reacting is used (JP-A-9-30888).
• JP-A-9-30888 a method of producing a bicyclic sugar oxazoline derivative by reacting is used (JP-A-9-30888).
• JP-A-9-30888
• the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, by using metal fluoride as a reaction reagent, the fluoride exhibits both nucleophilicity and acid-capturing action, and the sugar oxazoline derivative It was found that the synthesis of the compound progressed, and that the removal of the fluoride was easy, and the present invention was completed.
• the present invention provides a method for producing a sugar oxazoline derivative represented by the following general formula (2), which comprises reacting an acylamino sugar represented by the following general formula (1) with a metal fluoride.
• at least one of R 2 and R 3 and at least one of R 4 and R 5 are H.
• R 1 R 2 , RRR 5 and R 6 are the same as described above.
• the present invention comprises reacting an acylamino sugar represented by the following general formula (1) with a metal fluoride, and then removing at least a part of the protecting group of the obtained sugar oxazoline derivative.
• This is a method for producing the sugar oxazoline derivative represented by the formula (3).
• R 2 , R 3 , 4 15 and 16 are each independently H, N 3 , OH protected by a protecting group, NH 2 protected by a protecting group, and Y—R 7 (Y is 0 or NH or S, and R 7 is a residue of a monosaccharide or an oligosaccharide, and when OH, NH 2 or C ⁇ OH is present, a monosaccharide or a group in which those groups are protected by a protecting group. Which are the residues of oligosaccharides). However, at least one of R 2 and R 3 and at least one of R 4 and R 5 are H. )
• R 2, R ⁇ R 4, 11 5 and 1 6 are each independently, H, N 3, which may be protected by a protective group OH, and good NH 2, be protected by a protecting group, Y—R 7 (Y is 0 or NH or S, and R 7 is a residue of a monosaccharide or an oligosaccharide, and when ⁇ H, NH 2 or CO OH is present, those groups are protected by a protecting group. A monosaccharide or oligosaccharide residue which may be protected). However, at least one of R 2 and R 3 and at least one of R 4 and R 5 are H. )
• the metal fluoride is preferably an alkali metal fluoride.
• the method for producing the sugar oxazoline derivative represented by the general formula (2) of the present invention is characterized by reacting the acylamino sugar represented by the general formula (1) with a metal fluoride.
• the acylamino sugar represented by the general formula (1) is not particularly limited depending on the origin and origin of the substance, and is necessary for those obtained from nature, those synthesized by genetic engineering using animal cells, microorganisms, etc. And the introduction of protecting groups in the usual way Can be used.
• X can be selected from fluorine, chlorine, bromine and iodine classified as the same halogen, and chlorine is particularly preferable.
• R 2, R 3, R 4 , R 5 and R 6 are each defined above in H, N 3, OH was protected by a protective group, NH 2 protected by a protecting group, YR Y (Y is 0 or NH 7 or S, and R 7 is a residue of a monosaccharide or an oligosaccharide, and when OH, NH 2 or COOH is present, a group of the monosaccharide or the oligosaccharide whose group is protected by a protecting group. Residue). However, at least one of R 2 and R 3 and at least one of R 4 and R 5 are H.
• Residues of monosaccharide or oligosaccharide of R 7 are usually those that have a residue at the 1-position of the original end instead of 1-position or oligosaccharide monosaccharide.
• the constituent sugar of the monosaccharide and the oligosaccharide may be an amino sugar or a sugar acid or a derivative thereof.
• the monosaccharide D-glucosamine, D-galactosamine, D-mannosamine, D-galactose, D-darucose, D-mannose, D-glucuronic acid, L-iduronic acid and derivatives thereof are preferable.
• Glycosaminoglycans having a repeating structure of disaccharide units as a basic skeleton and derivatives thereof are preferred. That is, a disaccharide or glycosaminodalican in which the sugar residue at the reducing end has the structure of a monosaccharide described as the above general formula (1) can also be used in the production method of the present invention.
• the above-mentioned derivatives include those obtained by acetylating NH 2 of the constituent sugars of monosaccharides or oligosaccharides and those obtained by sulfating OH.
• an oligosaccharide is an oligosaccharide in the ordinary sense composed of two or more monosaccharides, and is usually 2 to 20 or more sugars or 2 to 20 sugars.
• Substituents selected for R 2 , R 3 , RR 5 and R 6 are actually involved in the oxazoline formation reaction of the present invention. If the functional groups are not qualitatively involved and are presumed to be highly reactive during the oxazoline formation reaction of the present invention as in the ordinary synthesis reaction, it is necessary to prevent these from reacting. For example, a method may be considered in which the target substance is obtained by protecting with a protecting group used in a usual manner before subjecting to the above reaction of the present invention, and removing the protecting group after completion of the reaction. Therefore, in the acylamino sugar represented by the general formula (1), the group presumed to have high reactivity needs to be protected.
• the protective group is not particularly limited as long as it does not hinder the reaction in the presence of the metal fluoride of the acylamino sugar represented by the general formula (1), but specific examples include an acetyl group, a benzoyl group, Methyl benzoyl group, bivaloyl group, levulinyl group, t-butyloxycarbonyl group, etc., lower alkyl group such as methyl group, ethyl group (usually about 1 to 5 carbon atoms), benzyl group, phenethyl group, etc.
• Alkylidene groups such as aralkyl groups and isopropylidene groups, and aralkylidene groups such as benzylidene groups, and aryl groups are preferably used.
• the protective group a lower alkyl group or an aralkyl group is preferably used.
• the protecting group is appropriately selected according to the type of the group to be protected.A plurality of types of groups may be protected by the same type of protecting group, or a plurality of the same type of group may be protected by a plurality of types. It may be protected by any kind of protecting group.
• acylamino sugar used in the present invention include the following Examples 1 to 9.
• Example 1 X: C 1, R 1: CH 3, R 2: 0 CO CH 3, R 3: H, R 4: H, R 5: ⁇ CO CH 3, R 6: 0 CO CH generally a 3
• An acylamino sugar represented by the formula (1) X: C 1, R 1: CH 3 R 2: OCOCHss R 3: H, R 4: 0 CO CH 3, R 5: H, R 6: ⁇ CO CH 3 a is general formula (1) Asilamino sugar indicated.
• Example 3) X: C 1, R 1: CH 3, R 2: 0C_ ⁇ _CH 3, R 3: H, R 4: H, R 5:? 0- / - D- galacto Ichisu (0H is Asechiru group ), An acylamino sugar represented by the general formula (1), wherein R 6 : 0 C ⁇ CH 3 .
• Example 4 X: C 1, R 1: CH 3, R 2: 0- D- glucuronic acid (OH is protected by Asechiru group, and those protected with C00H Gabe Njiru group), R 3: H , R 4 : H, R 5 : OCOCH 3 and R 6 : OCOCH3, an acylamino sugar represented by the general formula (1).
• Example 5 X: C 1, R 1: CH 3, R 2: ⁇ one D- glucuronic acid (0H are protected by Asechi group, and those protected with C00H Gabe Njiru group),: R 3 : H, R 4 : OCOCH 3 , R 5 : H, 6 : 0 COCH 3 , an acylamino sugar represented by the general formula (1).
• Example 6 X: C 1, R 1: CH 3, R 2: 0- Fei _L- Izuron acid (0H is protected by Asechiru group, and those protected with C00H Gabe Njiru group), R 3: H, R 4: 0C0CH 3, R 5: H, R 6: ⁇ sheet Ruamino sugar represented by 0C0CH 3 a is formula (1).
• Example 8 X: C 1, R 1: CH 3, R 2: OCOCH 3, R 3: H, R 4: H, R 5: 0- 5-N- Asechiru -D - Darukosamin (OH is at Asechiru group Protected), R 6 : ⁇ An acylamino sugar represented by the general formula (1), which is CO CH 3 .
• the acylamino sugar shown in Example 1 above protects 0H at positions 3, 4, and 6 of N-acetyl-D-glucosamine, which is a constituent sugar of chitin, with an acetyl group, and converts ⁇ H at position 1 to a chlorine atom. It has been replaced.
• the acylamino sugars shown in Example 4 above were synthesized from 0H (positions 4 and 6 of hexosamine, positions 2, 3 and 4 of peronic acid) in the disaccharide unit composed of hyaluronic acid peronic acid and hexosamine.
• the acylamino sugar shown in Example 5 above has the ⁇ H (positions 4 and 6 of hexosamine and the positions 2, 3 and 4 of hexonic acid) in the disaccharide unit composed of peronic acid and hexosamine of chondroitin. It is protected with a cetyl group, the carboxyl group of a peronic acid residue is protected with a benzyl group, and the OH at position 1 of the hexosamine residue is replaced with a chlorine atom.
• the acylaminosugar shown in Example 6 above is the OH in the disaccharide unit composed of peronic acid and hexosamine of dermatan sulfate (positions 4 and 6 of hexosamine, positions 2, 3, and 4 of peronic acid) Is protected with an acetyl group, the carboxyl group of the peronic acid residue is protected with a benzyl group, and the OH at the 1-position of the hexosamine residue is substituted with a chlorine atom.
• the metal fluoride used in the production method of the present invention is not particularly limited, but is preferably an alkali metal fluoride, more preferably sodium fluoride, lithium fluoride, rubidium fluoride, or cesium fluoride. And the like.
• sodium fluoride fluoride is particularly preferred in consideration of handling as a reagent and price.
• metal fluoride may be used by being held on an inorganic solid carrier.
• the inorganic solid carrier include alumina, silica gel, magnesium oxide, molecular sieves (for example, Linde 4A (trade name)), clay (for example, montmorillonite), and diatomaceous earth (for example, celite (trade name)).
• alumina is particularly preferred.
• the conditions for the reaction between the acylamino bran represented by the general formula (1) and the metal fluoride are as long as the acylamino sugar used in the present invention reacts with the metal fluoride to produce a bicyclic sugar oxazoline derivative.
• the metal fluoride There is no particular limitation, and those skilled in the art can appropriately set the parameters.
• the solvent for the reaction is not particularly limited as long as it does not react with the used acylamino sugar and metal fluoride and can dissolve the used amino amino sugar, but it is not limited to acetonitril (CH 3 CN), dimethyl sulfoxide (DMSO), dimethylform Amide (DMF), tetrahydrofuran, xylene and the like are preferred, CH 3 CN, DMSO, and DMF are more preferred, and CH 3 CN is particularly preferred.
• the reaction conditions such as the amount of the metal fluoride used, the reaction temperature and the reaction time are appropriately set depending on the amount of the acylamino sugar used and the like.
• the molar ratio of the acylamino sugar to the metal fluoride is preferably 1:
• the reaction temperature is preferably from room temperature to the boiling point of the solvent, more preferably from 30 to 60 ° C. When the reaction is carried out at the boiling point of the solvent used, a reflux condenser or the like can be used.
• the reaction time is preferably 0.5 hours to 3 days.
• a specific example of a method for confirming the completion of the reaction is thin-layer chromatography.
• the reaction between the acylamino sugar represented by the general formula (1) and the metal fluoride is preferably performed in an atmosphere such as argon or nitrogen in order to avoid a reaction with water.
• a soxazoline derivative As a method for purifying the target substance, a soxazoline derivative, from the reaction-terminated liquid, it is possible to appropriately select and use a conventional purification method.For example, insoluble substances are removed from the reaction-terminated liquid, and then After removing the water-soluble substance dissolved in the reaction-completed solution by a liquid separation operation, purification by silica gel chromatography, recrystallization or the like can be mentioned.
• the method of removing the insoluble matter from the reaction-terminated liquid may be any method as long as the insoluble matter (solid) and the solution (liquid) are separated, and a commonly used filtration method using a glass filter, ceramic, or the like can be used.
• the sugar oxazoline derivative represented by the general formula (2) is obtained by the above method, and at least a part of the protecting group of the obtained sugar oxazoline derivative is removed. It is characterized by being removed.
• a saccharide-containing oxazoline derivative represented by the general formula (3) can be obtained in which at least a part of the protecting group of the saccharide-containing oxazoline derivative is removed. Removal of the protecting group can be performed according to a conventional method.
• the sugar oxazoline derivative obtained by the production method of the present invention is considered to be used as a substrate for polymer synthesis utilizing ring-opening polymerization of an oxazoline ring.
• R 2 to R A sugar oxazoline derivative obtained by using a compound in which at least one of 6 is a monosaccharide or an oligosaccharide (a disaccharide or glycosaminoglycan having a specific structure at the reducing end) utilizes an enzyme-catalyzed polyaddition reaction It is thought that it can be used as a synthetic substrate for glycosaminoglycans.
• a bicyclic sugar oxazoline derivative having an oxazoline ring at the reducing end of a lactosamine chain containing at least one basic skeleton composed of lactosamine disaccharide is obtained by the production method of the present invention, and the obtained derivative is used as a substrate.
• Lactosamine chain can be extended by allowing keratanase to act.
• Hyaluronic acid chains can be extended by the action of the enzyme.
• chitin or chitosan is obtained by reacting chitinase with dalcosamine having an oxazoline ring obtained by the production method of the present invention or a disaccharide having N-acetylglucosamine or dalcosamine bound to its non-reducing terminal as a substrate. It seems that it is also possible.
• the filtrate was concentrated in an evaporator, diluted with an excess amount of black-mouthed form, and separated with a saturated solution of sodium hydrogencarbonate and then with cold water until the pH of the solution became neutral. After the collected organic layer was dried over anhydrous sodium sulfate, sodium sulfate was removed by filtration, and the filtrate was concentrated by evaporation.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Saccharide Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=19038309

Family Applications (1)

Country Status (4)

Families Citing this family (11)

Citations (3)

• 2001
  • 2001-07-02 JP JP2001201316A patent/JP4866515B2/ja not_active Expired - Fee Related
• 2002
  • 2002-06-28 US US10/482,678 patent/US20040176588A1/en not_active Abandoned
  • 2002-06-28 WO PCT/JP2002/006575 patent/WO2003004508A1/ja not_active Ceased
  • 2002-06-28 EP EP02738865.1A patent/EP1405857B1/en not_active Expired - Lifetime

Patent Citations (3)

Non-Patent Citations (5)

Also Published As

Similar Documents

Legal Events