JP4534024B2 - Compound separation carrier and compound separation method - Google Patents

Description

  The present invention relates to a method for separating a compound and a separation carrier used therefor. More specifically, the present invention relates to a method for separating a compound using a specific carrier and a solvent system and a separation carrier.

  Various solvents are used in the organic synthesis reaction, and a combination of a solvent, a reagent, a reaction temperature, and the like that are suitable for each reaction is an important factor that determines the success or yield of the reaction. Therefore, usually, the product is separated from the reaction solvent at each stage of the reaction, and the operation of proceeding to the next step is repeated.

  However, since this separation operation is very complicated and time-consuming, the importance of a method in which the product is bound to a solid (such as beads) and only the product is taken out from the solution system is recognized. Since these solid-phase methods perform chemical reactions on solid surfaces, they are generally less reactive than when they are reacted in a homogeneous solution system, and there are problems such as beads swelling and dissolving in certain solvents. is there.

  Thus, a fluorous synthesis method (see Non-Patent Documents 1 and 2), a compatible-multiphase organic solvent system, etc. that have the advantages of the homogeneous liquid phase method and the solid phase method have been proposed (Patent Document 1 and 2).

  However, these methods have limited organic solvents that can be used. For example, the method described in Patent Document 1 or 2 is a new concept for quickly and easily reacting and separating substances using a solvent system that performs two-phase separation or homogenization in accordance with temperature changes. A cycloalkane or an alkane solvent is used. However, the lower layer solvent is limited to highly polar organic solvents, and these methods can be used for solvents that are always miscible with cycloalkane or alkane regardless of temperature change, such as dichloromethane, chloroform, diethyl ether, tetrahydrofuran, etc. Could not be applied.

However, since these highly miscible solvents have a very wide range of uses in synthetic chemistry, the prior art has a great limitation in terms of applicability. Therefore, it has been difficult to continuously proceed the reaction while sequentially converting a versatile solvent such as alkyl halide, ether, alcohol, nitrile, nitro, amide, sulfoxide.
JP 2003-62448 A JP 2003-183298 A I. T. T. Horvath, J. et al. Rabai, Science, 1994, 266, 72 J. et al. A. Gladysz, Science, 1994, 266, 55

  The object of the present invention is not only to quickly and easily separate and purify unnecessary reagents and by-products from the target product after completion of the reaction, but also to perform a multi-step synthesis reaction under various organic solvent conditions. It is an object of the present invention to provide a method that can be repeatedly performed and a separation carrier used therefor.

  The present inventors have found that an excellent separation carrier can be obtained by adding a specific hydrophobic moiety (hydrophobic unit) to a saccharide (sugar chain unit), and completed the present invention.

  That is, in the present invention, the hydrocarbon chain having 6 to 40 carbon atoms which may have a substituent is ester-bonded or ether-bonded to at least one hydroxyl group of the saccharide, and has at least one hydroxyl group. This is a carrier for separating compounds.

  The present invention also relates to a polyalcohol obtained by reducing pentose, hexose, pentose or hexose, a polyhydroxyketone obtained by oxidizing pentose or hexose, a polyhydroxyaldehyde obtained by oxidizing pentose or hexose. And at least one selected from the group consisting of a polyhydroxycarboxylic acid obtained by oxidizing pentose or hexose.

  Moreover, this invention is a support | carrier for isolation | separation of a compound shown by following General formula (1)-(6).

（式中、Ｌ₁〜Ｌ₆は、それぞれ独立に、置換基を有してもよい炭素原子数６〜４０の炭化水素基、置換基を有してもよい炭素原子数６〜４０のアシル基またはＨを、Ｘは、Ｓ、Ｎ、Ｏ、ＣまたはＨを、示す。ただし、Ｌ₁〜Ｌ₆の少なくとも１つは、Ｈである。）

(In the formula, L _{1 to} L ₆ are each independently a hydrocarbon group having 6 to 40 carbon atoms which may have a substituent, or an acyl having 6 to 40 carbon atoms which may have a substituent. A group or H, X represents S, N, O, C or H, provided that at least one of L _{1 to} L ₆ is H.)

  The present invention is also a compound separation carrier represented by the following general formula (7) or (8).

  The present invention also provides a compound separation carrier in which at least two of the above separation carriers are bonded to each other.

The present invention also provides:
(1) a step of binding a first substance to the separation carrier,
(2) A step of preparing a carrier solution by dissolving the separation carrier combined with the first substance in a soluble solvent,
(3) adding an additive solvent that facilitates the reaction between the first substance and the second substance to the carrier solution to form one liquid phase;
(4) adding the second substance to the carrier solution to which the additive solvent has been added, reacting with the first substance, and obtaining the separation carrier to which the produced compound is bound;
(6) separating the carrier solution and the additive solvent;
(7) recovering the carrier solution;
A method for separating a compound, comprising:

  In addition, the present invention is the separation method described above, wherein in the step (1), the first substance is bonded to the hydroxyl group of the separation carrier.

  In addition, the present invention is the separation method described above, wherein in the step (1), the first substance is bound via a linker unit.

  Moreover, this invention is said separation method characterized by the soluble solvent being a C4-C40 cyclic hydrocarbon or chain | strand-shaped hydrocarbon in a process (2).

  The present invention is also the above separation method, wherein in step (2), the soluble solvent is at least one selected from the group consisting of cyclohexane, methylcyclohexane and decalin.

  In the step (3), the present invention is characterized in that the additive solvent is at least one selected from the group consisting of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, nitromethane, and methanol. , The separation method described above.

  Further, the present invention is the separation method described above, wherein in step (6), the carrier solution and the added solvent are separated by adding a solvent having a high affinity for the added solvent.

  Further, the present invention is the separation method described above, wherein in step (6), the carrier solution and the added solvent are separated by changing the temperature.

The present invention also includes (5) a step of distilling off part or all of the added solvent,
The separation method as described above, further comprising:

The present invention also includes (8) a step of desorbing the compound produced from the carrier in the recovered carrier solution,
The separation method as described above, further comprising:

  The present invention is also the above separation method, wherein the reaction is a peptide synthesis reaction, an oligosaccharide synthesis reaction, an oligosaccharide peptide synthesis reaction or an oligosaccharide lipid synthesis reaction.

  The present invention also provides a method for producing a peptide, oligosaccharide, oligosaccharide peptide or oligoglycolipid, characterized by using the separation method described above.

The present invention also provides:
(1) A step of preparing a carrier solution by dissolving the above-mentioned separation carrier in a soluble solvent,
(2) adding an additional solvent that facilitates the reaction between the separation carrier and the second saccharide to the carrier solution to form one liquid phase;
(3) adding the second saccharide to the carrier solution to which the additive solvent has been added, performing a reaction with the separation carrier, and obtaining the separation carrier to which the second saccharide is bound;
(4) separating the carrier solution and the additive solvent;
(5) recovering the carrier solution;
It is a manufacturing method of the polysaccharide characterized by including this.

  According to the present invention, unnecessary reagents and by-products can be separated from the target product with the target product quickly and easily after completion of the reaction, and the multi-step synthesis reaction can be performed under various organic solvent conditions. It is possible to provide a method that can be repeatedly performed and a separation carrier used therefor.

  First, the carrier for separating the compound of the present invention will be described.

  In the separation carrier of the present invention, a hydrocarbon chain having 6 to 40 carbon atoms which may have a substituent is ester-bonded or ether-bonded to at least one hydroxyl group of a saccharide, and at least one hydroxyl group It is what has.

  The saccharide used in the separation carrier of the present invention is not particularly limited, but is a polyalcohol obtained by reducing pentose, hexose, pentose or hexose, polyhydroxyketone obtained by oxidizing pentose or hexose, pentose or Preferable examples include polyhydroxyaldehyde obtained by oxidizing hexose and polyhydroxycarboxylic acid obtained by oxidizing pentose or hexose.

  In addition, examples of the separation carrier of the present invention include those represented by the following formulas (1) to (8).

（式中、Ｌ₁〜Ｌ₆は、それぞれ独立に、置換基を有してもよい炭素原子数６〜４０の炭化水素基、置換基を有してもよい炭素原子数６〜４０のアシル基またはＨを、Ｘは、Ｓ、Ｎ、Ｏ、ＣまたはＨを、示す。ただし、Ｌ₁〜Ｌ₆の少なくとも１つは、Ｈである。）

(In the formula, L _{1 to} L ₆ are each independently a hydrocarbon group having 6 to 40 carbon atoms which may have a substituent, or an acyl having 6 to 40 carbon atoms which may have a substituent. A group or H, X represents S, N, O, C or H, provided that at least one of L _{1 to} L ₆ is H.)

  The number of carbon atoms in the hydrocarbon chain in the separation carrier of the present invention is usually 6 to 40, preferably 10 to 30, more preferably 14 to 24, and still more preferably 16 to 20. .

  Further, the separation carrier of the present invention may be one in which at least two of the above separation carriers are bonded to each other. The binding mode is not particularly limited, and examples thereof include those linked in a sugar skeleton (sugar chain unit) so as to form a disaccharide or a polysaccharide.

  Next, the separation method of the present invention will be described.

The separation method of the present invention includes the following steps.
(1) A step of binding the first substance to the separation carrier of the present invention,
(2) A step of preparing a carrier solution by dissolving the separation carrier combined with the first substance in a soluble solvent,
(3) adding an additive solvent that facilitates the reaction between the first substance and the second substance to the carrier solution to form one liquid phase;
(4) A step of adding the second substance to the carrier solution to which the additive solvent is added and reacting with the first substance to obtain the separation carrier to which the produced compound is bound (6) the carrier Separating the solution and the additive solvent;
(7) A step of recovering the carrier solution.

  In the step (1), the method for bonding the separation carrier of the present invention and the first substance is not particularly limited, and examples thereof include bonding the first substance to the hydroxyl group of the separation carrier. Moreover, there is no restriction | limiting in particular as a mode of a coupling | bonding at this time, For example, using an ester bond and an ether bond is mentioned.

  In addition, when the separation carrier of the present invention and the first substance are bonded, they may be bonded via an appropriate linker unit. The linker unit is not particularly limited as long as it can bind the separation carrier of the present invention and the first substance, and examples thereof include 4-hydroxy-diphenyl-methyl-benzoic acid. .

  The soluble solvent used in the present invention is not particularly limited as long as it can dissolve the separation carrier of the present invention, and examples thereof include cyclic hydrocarbons or chain hydrocarbons having 4 to 40 carbon atoms. . More specifically, for example, cyclohexane, methylcyclohexane, decalin and the like can be mentioned. These solvents may be used alone or in combination of two or more.

  The concentration at which the separation carrier of the present invention is dissolved in the soluble solvent is appropriately determined depending on the properties of the solvent, the separation carrier, the first substance and the second substance used in the reaction, etc. ~ 0.1 g / ml.

  The additive solvent used in the present invention is not particularly limited as long as it facilitates the reaction between the first substance and the second substance. The solvent, the carrier for separation, the first substance used in the reaction, and the second substance are used. It is determined appropriately depending on the properties of the substance, soluble solvent and the like. Specific examples include dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, nitromethane, methanol, and the like. These solvents may be used alone or in combination of two or more.

  The amount of added solvent is not particularly limited as long as it facilitates the reaction between the first substance and the second substance. The solvent, the carrier for separation, the first substance and the second substance used in the reaction are not limited. It is determined appropriately according to the properties of the soluble solvent and the like.

  In the present invention, the method for separating the carrier solution and the additive solvent is not particularly limited, and examples thereof include changing the temperature. That is, acetonitrile, dimethylformamide, nitromethane, methanol, etc. are known to either form a completely homogeneous solution with the above-mentioned soluble solvent at a certain temperature or to separate into two phases. Yes. Therefore, when acetonitrile, dimethylformamide, nitromethane, methanol, or the like is used as an additive solvent, the reaction between the first substance and the second substance is performed in a temperature range where a complete homogeneous phase is obtained, and then the system is used. By changing the temperature from a temperature at which a completely uniform solution is obtained to a temperature at which the solution is separated into two phases, the solution can be easily separated into two phases.

  In this case, the soluble solvent containing the separation carrier in the upper layer is separated from the additive solvent in the lower layer. And since unnecessary reagents dissolve in the lower layer, the compound produced by the reaction between the first substance and the second substance can be easily separated into the upper layer.

  Another method for separating the carrier solution and the added solvent is to add a third solvent having a high affinity for the added solvent. For example, when dichloromethane, chloroform, diethyl ether, tetrahydrofuran, or the like is used as the additive solvent, acetonitrile, dimethylformamide, nitromethane, methanol, or the like can be used as the third solvent. While these third solvents have a high affinity for the above-mentioned added solvent, they have a relatively low affinity for the above-mentioned soluble solvent. Therefore, by adding the third solvent, as described above, It becomes possible to separate into two phases in a certain temperature range.

  In this case, the soluble solvent containing the separation carrier in the upper layer is separated from the mixed phase of the third solvent and the added solvent in the lower layer. And since unnecessary reagents dissolve in the lower layer, the compound produced by the reaction between the first substance and the second substance can be easily separated into the upper layer.

  In this case, after completion of the reaction between the first substance and the second substance, two or more phases can be efficiently separated by distilling off all or a part of the added solvent. In addition, since a reagent, a by-product, etc. which exist in reaction container may precipitate by completely distilling off, it is preferable to add a 3rd solvent before distilling off completely.

  In the present invention, by collecting the separated carrier solution, it is possible to easily obtain a separation carrier to which the produced compound is bound.

  For example, when performing sequential multi-step reactions such as peptide synthesis, the recovered carrier solution can be returned to step (3), and the reaction can be repeated, separated, and recovered to efficiently perform the synthesis reaction. It will be possible.

  Further, by removing the generated compound from the recovered separation carrier, it becomes possible to separate and produce the target compound.

  There is no restriction | limiting in particular as reaction of the 1st substance in this invention, and a 2nd substance, For example, using preferably for peptide synthesis reaction, oligosaccharide synthesis reaction, oligopeptide synthesis reaction, oligoglycolipid synthesis reaction, etc. it can. Accordingly, the first substance and the second substance may be any substance as long as they are materials used for these reactions.

  In the present invention, as shown in FIG. 1, it is also possible to use a plurality of separation carriers bonded to each other at one part or two or more parts of a hydrophobic unit, a sugar chain unit, a linker unit and a peptide unit. Is possible.

  In the present invention, a polysaccharide can be easily produced by using a separation carrier itself as a starting material for oligosaccharide synthesis and binding a second saccharide thereto.

The process in this case is as follows.
(1) a step of preparing a carrier solution by dissolving the separation carrier of the present invention in a soluble solvent;
(2) adding an additional solvent that facilitates the reaction between the separation carrier and the second saccharide to the carrier solution to form one liquid phase;
(3) adding the second saccharide to the carrier solution to which the additive solvent has been added, performing a reaction with the separation carrier, and obtaining the separation carrier to which the second saccharide is bound;
(4) separating the carrier solution and the additive solvent;
(5) A step of collecting the carrier solution.

  In this case, the soluble solvent, the added solvent, or the separation method of these solvents can be the same as the separation method of the present invention described above.

  EXAMPLES Hereinafter, the present invention will be described with reference to examples. However, the present invention is not limited to the description of the following examples.

<Example 1: Synthesis of carrier for separation>
α-methylglucoside (1) (8.064 g, 0.0412 mol) and imidazole (5.6625 g, 0.0824 mol) are dissolved in 200 ml of DMF, and TBDPSCl (t-butyldiphenylsilyl chloride, 16.9983 g, 0.0618 mol) is dissolved. Was added and stirred at room temperature for 24 hours. Ether was added, washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The obtained product (2) was dissolved in 80 ml of THF, and DMAP (dimethylaminopyridine 0.4334 g, 3.547 mmol) triethylamine (42.6019 g, 0.418 mol) and stearyl chloride (63.3 g, 0.209 mol) were added. The product (3) was obtained at 31% by sequentially adding at room temperature, reacting at 50 ° C. for 18 hours, and recrystallization. Next, TBDPS protected sugar carrier (0.874 g, 0.710 mmol) was dissolved in 30 ml of tetrahydrofuran. After the solution was cooled to 0 ° C., 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (2.17 ml) and acetic acid (0.2985 g, 4.97 mmol) were added. After stirring at room temperature for 18 hours, ether was added, washed with water, dried over magnesium sulfate and the solvent was distilled off to obtain the separation carrier (4) of the present invention in a yield of 72%.

<Reference Example 1: Synthesis of a carrier for separation in which a linker unit and an amino acid derivative are bonded>
The separation carrier (4) obtained in Example 1 (0.619 g, 0.5 mmol) and trityl alcohol (0.456 g, 1.5 mmol [3 eq]) were dissolved in 30 ml of dichloromethane, and DMAP (0.01 mmol [0.01 mmol [ 0.2 eq]) and DIPCI (diisopropylcarbodiimide 0.567 g, 4.5 mmol [9 eq]) were added and reacted for 4 hours to distill off the solvent. Thereafter, liquid separation was performed with hexane-acetonitrile, and the hexane layer was concentrated and dried to obtain a separation carrier (5) in which 4- (hydroxy-diphenyl-methyl) -benzoic acid was subjected to a condensation reaction as a linker unit.

  Thereafter, the product was dissolved in toluene, thionyl chloride was added and refluxed for 20 minutes, and the solution was distilled off. A dichloromethane solution in which diisopropylethylamine (0.387 g, 3.0 mmol) and Fmoc phenylalanine (0.387 g, 1.0 mmol) were dissolved was added to the chlorinated carrier. The product (6) was obtained with a yield of 36%.

<Example 2: Synthesis of disaccharide>
The following shows an example in which the separation carrier is used as a starting material for disaccharide synthesis.

  Hydrophobic separation carrier A (octadecanoic acid 2-hydroxymethyl-6-methoxy-4,5-bis-octadecanoyl-tetrahydropyran-3-yl ester) (1.087 g, 1. 094 mmol), thioglycoside (1.80 g, 2.19 mmol [2 eq]) and activated molecular sieves 4Å (4.52 g) are dissolved in 30 ml of a mixed solution of dichloromethane and methylcyclohexane 1: 1 (v / v). Stir for minutes. After cooling the solution to 0 ° C., N-iodosuccinimide (0.5829 g, 2.61 mmol [2.2 eq]) and trimethylsilyl trifluoromethanesulfonate (0.1317 g, 0.593 mmol [0.5 eq]) were sequentially added. Added. After confirming disappearance of the sugar receptor by TLC (hexane: ethyl acetate = 4: 1, reaction time 5 hours), 30 ml of dimethylformamide was added, and then dichloromethane was distilled off under reduced pressure. This solution separated into two phases at 20 ° C. After discarding the lower layer, the upper layer solution was washed twice with 30 ml of dimethylformamide. Product B was obtained from the upper layer (methylcyclohexane layer) in a yield of 93%.

  Subsequently, 15 ml of tetrahydrofuran was added to 15 ml of methylcyclohexane solution of product B (1.212 g, containing 0.710 mmol of disaccharide) to obtain a homogeneous solution. The solution was cooled to 0 ° C., and 1.0 M tetrabutylammonium fluoride / tetrahydrofuran solution (2.17 ml [3 eq]) and acetic acid (0.2985 g, 4.97 mmol [7 eq]) were added. After stirring at room temperature for 18 hours, 30 ml of dimethylformamide was added, and then tetrahydrofuran was distilled off using a rotary evaporator. The solution was cooled to 20 ° C. and separated into two phases. After the lower layer solution was discarded, it was further washed twice with 30 ml of dimethylformamide. The deprotected product from the upper layer methylcyclohexane solution was obtained in 72% yield.

Carrier A for separation (octadecanoic acid 2-hydroxymethyl-6-methoxy 4,5-bis-octadecanoyl-tetrahydropyran-3-yl ester)
(Octadecanic acid 2-hydroxymethyl-6-methoxy-4,5-bis-octadecanoyloxy-tetrahydro-pyran-3-yl ester)
¹ H-NMR (300 MHz; CDCl ₃ )) d5.58 (1H, t, J = 9.90 Hz), 5.01 (1H, t, J = 9.90 Hz), 4.97 (1H, d, J = 3.67 Hz), 4.87 (1H, dd, J = 9.90, 3.67 Hz), 3.76 (1H, m), 3.68 (1H, m), 3.57 (1H, m ), 3.40 (3H, s), 2.41-2.17 (6H, m), 1.64-1.43 (6H, m), 1.34-1.14 (84H, m), 1.01 (9H, s) and 0.88 (9H, t, J = 6.60 Hz); HRMScaldcd. for C ₆₁ H ₁₁₆ O ₉ Nam / z 1015.8517, found 1015.85170

Product B (6- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxymethyl) -tetrahydro-pyran-2,3,4,5-tetraol derivative)
(6- (3,4,5-Trihydroxy-6-hydroxymethyl-tetra-hydroxy-2-ylmethyl) -tetrahydro-pyran-2,3,4,5-tetravalent)
¹ H-NMR (300 MHz; CDCl ₃ )) d7.94 (2H, dd, J = 8.46, 1.46 Hz), 7.85 (2H, dd, J = 8.46, 1.46 Hz), 7 .83 (2H, dd, J = 8.46, 1.46 Hz), 7.67 (1H, dd, J = 7.88, 1.65 Hz), 7.57 (1H, dd, J = 7.88) , 1.46 Hz), 7.52-7.47 (2H, m), 5.83 (1H, t, J = 9.72 Hz), 5.63 (1H, t, J = 9.72 Hz), 5 .50 (1H, dd, J = 9.72, 7.88 Hz), 5.42 (1H, dd, J = 9.90, 9.35 Hz), 4.66 (1H, d, J = 7.88 Hz) ), 4.81 (1H, dd, J = 10.27, 9.35 Hz), 4.69 (1H, dd, J = 9.90, 3.49 Hz), 4 64 (1H, d, J = 3.49 Hz), 3.98-3.90 (2H, m), 3.87-3.78 (3H, m), 3.60 (1H, dd, J = 11) .5, 8.07 Hz), 2.97 (3H, s), 2.54-2.11 (6H, m), 1.58-1.41 (6H, m), 1.32-1.17. (84H, m), 1.02 (9H, s) and 0.87 (9H, t, J = 7.15); HRMScalcdd. forC ₁₀₄ H ₁₅₆ O ₁₇ SiNam / z 1728.1009, found 1728.10094

<Reference Example 2: Confirmation of product separability by solvent separation>
When 30 ml of acetonitrile was added to a mixed solution consisting of 30 ml of dichloromethane and 30 ml of methylcyclohexane, a uniform solution was formed at 25 ° C. Using this homogeneous solution consisting of dichloromethane, methylcyclohexane, acetonitrile 1: 1: 1 (v / v / v), the volatile solvent was distilled off at a constant temperature under reduced pressure, and the remaining liquid was kept at the same temperature. Two-phase separation was performed. 100 ml of the above solution was decompressed at 0.05 Pa and 40 ° C. using a rotary evaporator. After 15 minutes, dichloromethane in the solution decreased to 31%, but methylcyclohexane and acetonitrile each remained above 98%. The solution was cooled to 20 ° C. and separated into two phases. Next, the lower layer solution of the solution separated into two phases was discarded, 30 ml of acetonitrile was added, stirred, and the lower layer solution was discarded three times. By this operation, the amount of dichloromethane contained in the upper layer (layer containing methylcyclohexane as a main component) was reduced to 0.004% or less. From this result, the carrier for separation was dissolved in a mixed solution of methylcyclohexane: dichloromethane, and after carrying out a certain reaction, a certain amount of dichloromethane was distilled off and washed with a third solvent, so that it was dissolved in methylcyclohexane. It has been shown that a series of processes for separating the separation carrier can be realized.

<Reference Example 3: Synthesis of separation carrier with linker unit attached>
Carrier for separation (4) obtained in Example 1 (0.619 g, 0.5 mmol), 4- {4-formylphenoxy} butyric acid (0.210 g, 1.0 mmol), DIPCI (3 eq), DMAP (0.1 eq) was dissolved in anhydrous dichloromethane and reacted at room temperature for 1 hour. After the reaction, the solvent was distilled off, 40 mL of hexane was added, and the mixture was washed twice with 20 mL of acetonitrile.

  Then 20 mL of methanol and sodium borohydride (0.076 g, 2 mmol) were added. After the reaction, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated by filtration. Octadecanoic acid 6- [4- (4-hydroxymethyl-phenoxy) -butyryloxymethyl] -2-methoxy-4, 5-Bis-octadecanoyloxy-tetrahydro-pyran-3-yl ester (7) was obtained with a yield of 78%.

Product (7) Octadecanoic acid 6- [4- (4-Hydroxymethyl-phenoxy) -butyryloxymethyl] -2-methoxy-4,5-bis-octadecanoyloxy-tetrahydro-pyran-3 -Yl ester Octadecanoic acid 6- (4- {4-hydroxymethyl-phenoxy} -butyryloxymethyl) -2-methyoxy-4.5-bis-octadecanoyloxy-tetrahydro-pyran-3-ylester

¹ H-NMR (600 MHz; CDCl ₃ ) δ 7.29 (2H, d, J = 8.54 Hz), 6.883 (2H, d, J = 8.54 Hz), 5.49 (1H, t, J = 9.77), 5.07 (1H, t, J = 9.77), 4.932 (1H, dd, J = 10.3, 3.66 Hz) 4.84 ((1H, dd, J = 10 .3, 3.66 Hz), 4.62 (2H, d, J = 5.86), 4.24 (1H, dd, J = 12.2, 4.88 Hz), 4.15-4.10 ( 1H, m), 4.02 (2H, t, J = 6.11 Hz), 3.99-3.94 (1H, m), 3.37 (3H, s), 2.58 (2H, t, J = 7.08 Hz), 2.32-2.09 (8H, m), 1.64-1.58 (6H, m), 1.26 (84H, s), 0.89 (9H, t, J = 7.08Hz)

¹³ C-NMR (150 MHz; CDCl ₃ ) δ 172.9, 172.69, 172.53, 172.22, 158.37, 133.16, 128.53, 114.5, 96.73, 70.67, 69.54, 68.12, 67.19, 66.56, 64.97, 61.89, 55.32, 51.32, 42.15, 34.10, 34.02, 33.98, 33. 94, 31.83, 30.47, 29.61, 29.58, 29.49, 29.43, 29.40, 29.38, 29.27, 29.23, 29.17, 29.1, 29.0, 28.9, 24.8, 24.7, 24.6, 24.5, 23.4, 22.6, 14.0

<Reference Example 4: Synthesis of separation carrier to which linker unit and amino acid derivative are bonded>
Octadecanoic acid 6- [4- (4-hydroxymethyl-phenoxy) -butyryloxymethyl] -2-methoxy-4,5-bis-octadecanoyloxy-tetrahydro-pyran obtained in Reference Example 3 -3-yl ester (0.174 g, 0.3 mmol) was dissolved in 20 mL of dichloromethane and Fmoc phenylalanine (0.387 g, 0.45 mmol), DIPCI (diisopropylcarbodiimide, 0.114 g, 0.9 mmol), DMAP (dimethyl) Aminopyridine, 0.1 eq) was added and stirred at room temperature for 1 hour. After concentrating and partially distilling off the solvent, 30 mL of methylcyclohexane and 30 mL of acetonitrile were added to separate into two phases. After removing the lower layer, the upper layer was washed with acetonitrile three times, and the solvent was distilled off. As a result, octadecanoic acid 6- (4- {4- [2- (9H-fluoren-9-ylmethoxycarbonylamino)- 3-phenyl-propionyloxymethyl] -phenoxy} -butyryloxymethyl) -2-methoxy-4,5-bis-octadecanoyloxy-tetrahydro-pyran-3-yl ester (8) in 98% yield. Obtained at a rate.

  Product (8) Octadecanoic acid 6- (4- {4- [2- (9H-fluoren-9-ylmethoxycarbonylamino) -3-phenyl-propionyloxymethyl] -phenoxy} -butyryloxy Methyl) -2-methoxy-4,5-bis-octadecanoyloxy-tetrahydro-pyran-3-yl ester

  Octadecanoic acid 6- (4- {4- [2- (9H-fluoren-9-ylmethoxycarbonylamino) -3-phenyl-propionyloxymethyl] -phenoxy} -butyryloxymethyl) -2-methoxy-4.5-bis-octadecanoyloxy-tetrahydro- pyran-3-yl ester

¹ H-NMR (400 MHz; CDCl ₃ ) δ 7.77 (2H, d, J = 7.3 Hz), 7.55 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.3 Hz), 7.33-7.27 (3H, m), 7.24-7.20 (4H, m), 7.02-6.98 (2H, m), 6.85 (2H) , D, J = 8.5 Hz), 5.51 (1H, dd, J = 10.0, 9.5 Hz), 5.27-5.10 (2H, m), 5.08 (1H, dd, J = 10.0, 9.5 Hz), 4.93 (1H, d, J = 3.7 Hz), 4.88 (1H, dd, J = 10.0, 3.7 Hz), 4.71-4 .65 (1H, m), 4.4-4.3 (2H, m), 4.25 (1H, dd, J = 12.2, 2.7 Hz), 4.21-4.17 (1H, m), 4.13 (1H , Dd, J = 12.2, 2.7 Hz), 4.00 (2H, t, J = 5.6 Hz), 3.97-3.95 (1H, m), 3.38 (3H, s) 3.10 (2H, dd, J = 6.8, 6.3 Hz), 2.58 (2H, t, J = 6.8 Hz) 2.34-2.19 (6H, m), 2.12 (2H, qui, J = 6.8 Hz), 1.25 (90H.brs), 0.88 (9H, t, J = 7.08 Hz)

¹³ C-NMR (150 MHz; CDCl ₃ ) δ 172.9, 172.7, 172.6, 159.1, 155.5, 143.8, 143.5, 141.3, 135.6, 130.5 , 129.4, 128.5, 127.7, 127.2, 127.0, 125.1, 119.9, 114.5, 96.9, 70.7, 69.6, 68.1, 67 3,67.1,66.966.6,61.9,55.4,54.8,47.1,38.134.1,34.0,340.3,31.9,30.5 29.7, 29.6, 29.61, 29.5, 29.4, 29.3, 29.28, 29.23, 29.14, 29.1, 29.0, 24.9, 24. .522.7, 14.1

FIG. 1 is a diagram showing an example of the present invention using a plurality of separation carriers.

Claims (18)

The hydrocarbon chain having 6 to 40 carbon atoms, which may have a substituent, is ester-bonded or ether-bonded to at least one hydroxyl group of the saccharide, and has at least one hydroxyl group, Compound carrier for separation. Polysaccharide obtained by reducing pentose, hexose, pentose or hexose, polyhydroxy ketone obtained by oxidizing pentose or hexose, polyhydroxy aldehyde obtained by oxidizing pentose or hexose, and pentose or hexose The carrier for separation according to claim 1, wherein the carrier is at least one selected from the group consisting of polyhydroxycarboxylic acids obtained by oxidation. A carrier for separating compounds represented by the following general formulas (1) to (6).

(In the formula, L _{1 to} L ₆ are each independently a hydrocarbon group having 6 to 40 carbon atoms which may have a substituent, or an acyl having 6 to 40 carbon atoms which may have a substituent. A group or H, X represents S, N, O, C or H, provided that at least one of L _{1 to} L ₆ is H.) A carrier for separating a compound represented by the following general formula (7) or (8).

A carrier for separating a compound, wherein at least two of the carrier for separation according to claim 1 are bonded to each other. (1) a step of binding the first substance to the separation carrier according to any one of claims 1 to 5;
(2) A step of preparing a carrier solution by dissolving the separation carrier combined with the first substance in a soluble solvent,
(3) adding an additive solvent that facilitates the reaction between the first substance and the second substance to the carrier solution to form one liquid phase;
(4) adding the second substance to the carrier solution to which the additive solvent has been added, reacting with the first substance, and obtaining the separation carrier to which the produced compound is bound;
(6) separating the carrier solution and the additive solvent;
(7) recovering the carrier solution;
A method for separating a compound, comprising: The separation method according to claim 6, wherein in the step (1), the first substance is bonded to the hydroxyl group of the separation carrier. The separation method according to claim 6 or 7, wherein in the step (1), the first substance is bound via a linker unit. The separation method according to any one of claims 6 to 8, wherein in the step (2), the soluble solvent is a cyclic hydrocarbon or a chain hydrocarbon having 4 to 40 carbon atoms. The separation method according to any one of claims 6 to 9, wherein in step (2), the soluble solvent is at least one selected from the group consisting of cyclohexane, methylcyclohexane and decalin. In the step (3), the additive solvent is at least one selected from the group consisting of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, nitromethane and methanol. The separation method according to any one of the above. The separation method according to any one of claims 6 to 11, wherein in the step (6), the carrier solution and the added solvent are separated by adding a solvent having a high affinity for the added solvent. The separation method according to any one of claims 6 to 12, wherein in step (6), the carrier solution and the added solvent are separated by changing the temperature. (5) a step of distilling off part or all of the added solvent;
The separation method according to claim 6, further comprising: (8) a step of desorbing the compound produced from the carrier in the recovered carrier solution;
The separation method according to claim 6, further comprising: The separation method according to any one of claims 6 to 15, wherein the reaction is a peptide synthesis reaction, an oligosaccharide synthesis reaction, an oligosaccharide peptide synthesis reaction or an oligoglycolipid synthesis reaction. A method for producing a peptide, oligosaccharide, oligosaccharide peptide or oligoglycolipid, characterized by using the separation method of claims 6 to 16. (1) A step of preparing a carrier solution by dissolving the separation carrier according to any one of claims 1 to 5 in a soluble solvent,
(2) adding an additional solvent that facilitates the reaction between the separation carrier and the second saccharide to the carrier solution to form one liquid phase;
(3) adding the second saccharide to the carrier solution to which the additive solvent has been added, performing a reaction with the separation carrier, and obtaining the separation carrier to which the second saccharide is bound;
(4) separating the carrier solution and the additive solvent;
(5) recovering the carrier solution;
A method for producing a polysaccharide, comprising:

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