JP6260259B2 - Boronic acid-containing phosphorylcholine compound, method for producing the same, and iodo group-containing compound modifier - Google Patents

Description

  The present invention relates to a boronic acid-containing phosphorylcholine compound, a method for producing the same, and an iodo group-containing compound modifier.

  The phosphorylcholine group is a polar group of phospholipid that constitutes a biological membrane. The phosphorylcholine group is excellent in hydrophilicity, moisture retention and biocompatibility, and has an action of suppressing protein adsorption.

  As compounds having a phosphorylcholine group, for example, α-glycerophosphorylcholine and 2-methacryloyloxyethyl phosphorylcholine polymers described in Patent Documents 1 and 2 are known.

  α-glycerophosphorylcholine can be used as a raw material for emulsifiers and moisturizers, for example. The 2-methacryloyloxyethyl phosphorylcholine polymer can be used, for example, as a raw material for cosmetics, contact lenses, and medical materials.

  A compound having both a phosphorylcholine group and a boronic acid in the same molecule (boronic acid-containing phosphorylcholine compound) can be used as a modifying agent for modifying a compound having an iodo group with a phosphorylcholine group. Patent Documents 3 and 4 disclose a method for producing a boronic acid-containing phosphorylcholine compound.

  In the technique described in Patent Document 3, an alkylboronic acid-containing phosphorylcholine compound is obtained by subjecting an olefin-containing phosphoryl compound to hydroboration using diborane and then hydrolyzing it.

  In the technique described in Patent Document 4, a phenylboronic acid-containing phosphorylcholine compound is modified with a phosphorylcholine group by Suzuki-Miyaura cross coupling between a phenylboronic acid-containing phosphorylcholine compound containing a fluorescent substance and a phenylboronic acid-containing phosphorylcholine compound. A fluorescent phosphorylcholine compound is obtained. The fluorescent phosphorylcholine compound described in Patent Document 4 can be used to determine the presence of residual malignant tumor stem cells in cancer treatment.

JP 7-118123 A JP 2000-279512 A US Pat. No. 5,144,045 Special table 2012-526822 gazette

  However, the alkylboronic acid-containing phosphorylcholine compound obtained in Patent Document 3 has significantly lower reactivity in the Suzuki-Miyaura cross-coupling reaction with the iodo group-containing compound than the phenylboronic acid-containing phosphorylcholine compound. Therefore, there is a possibility that the alkylboronic acid-containing phosphorylcholine compound cannot sufficiently modify the iodo group-containing compound with the phosphorylcholine group.

  Moreover, the manufacturing method of the phenyl boronic acid containing phosphorylcholine compound used by patent document 4 includes the complicated manufacturing process over eight processes which used the paraiodo benzyl bromide as a raw material.

  Further, in the boronic acid-containing phosphorylcholine compounds described in Patent Document 3 and Patent Document 4, the boronic acid and the phosphorylcholine group are connected by an alkylene group or an ether bond. On the other hand, boronic acid-containing phosphorylcholine compounds containing a functional group other than an alkylene group or an ether bond are not generally known.

  In view of the above circumstances, an object of the present invention is to provide a novel boronic acid-containing phosphorylcholine compound, a method for producing the same, and an iodo group-containing compound modifier.

（式（１）中、ｊは、０〜１５の整数を示す。ｋは、１〜９の整数を示す。Ｗは、フェニル基又はビニレン基を示す。−Ｘ（Ａ_１）−は、−Ｘ−Ａ_１−と、−Ａ_１−Ｘ−と、−Ｘ−とのうちのいずれか１つを示す。Ｘは、エステル結合と、ウレタン結合と、アミド結合と、２級アミノ基を含むメチレン基とのうちのいずれか１つを示す。Ａ_１は、下記式（２ａ）で表される構造と、下記式（２ｂ）で表される構造と、下記式（２ｃ）で表される構造とのうちのいずれか１つである。）

In order to achieve the above object, a boronic acid-containing phosphorylcholine compound according to an embodiment of the present invention is represented by the following formula (1).

(In formula (1), j represents an integer of 0 to 15. k represents an integer of 1 to 9. W represents a phenyl group or a vinylene group. -X (A ₁ )-represents-. X-A _1- , -A ₁ -X-, or -X- represents any one of X-, including an ester bond, a urethane bond, an amide bond, and a secondary amino group. A ₁ represents one of a methylene group, A ₁ is represented by the following formula (2a), the following formula (2b), and the following formula (2c). Any one of the structures.)

  A novel boronic acid-containing phosphorylcholine compound, a method for producing the same, and an iodo group-containing compound modifier

（式（４）中、ｊは、０〜１５の整数を示す。ｋは、１〜９の整数を示す。Ｗは、フェニル基又はビニレン基を示す。−Ｘ（Ａ_１）−は、−Ｘ−Ａ_１−と、−Ａ_１−Ｘ−と、−Ｘ−とのうちのいずれか１つを示す。Ｘは、エステル結合と、ウレタン結合と、アミド結合と、２級アミノ基を含むメチレン基とのうちのいずれか１つを示す。Ａ_１は、下記式（５ａ）で表される構造と、下記式（５ｂ）で表される構造と、下記式（５ｃ）で表される構造とのうちのいずれか１つである。）

The boronic acid-containing phosphorylcholine compound according to one embodiment of the present invention is represented by the following formula (4).

(In formula (4), j represents an integer of 0 to 15. k represents an integer of 1 to 9. W represents a phenyl group or a vinylene group. -X (A ₁ )-represents-. X-A _1- , -A ₁ -X-, or -X- represents any one of X-, including an ester bond, a urethane bond, an amide bond, and a secondary amino group. A ₁ represents one of a methylene group, A ₁ is represented by the following formula (5a), the following formula (5b), and the following formula (5c). Any one of the structures.)

  According to this configuration, a boronic acid-containing phosphorylcholine compound including any one of an ester bond, a urethane bond, an amide bond, and a methylene group including a secondary amino group can be provided.

（式（７）中、Ｙは、カルボキシル基と、一級アミノ基と、エポキシ基と、ホルミル基と、シクロカーボネート基とのうちのいずれか１つを示す。ｊは、０〜１５の整数を示す。Ｗは、フェニル基又はビニレン基を示す。）

（式（８）中、Ｚ、カルボキシル基と、一級アミノ基と、エポキシ基と、ホルミル基と、シクロカーボネート基とのうちのいずれか１つを示す。ｋは、１〜９の整数を示す。） In the method for producing a boronic acid-containing phosphorylcholine compound according to an embodiment of the present invention, a boronic acid-containing compound represented by the following formula (7) and a phosphorylcholine group-containing compound represented by the following formula (8) are prepared. The boronic acid-containing compound and the phosphorylcholine group-containing compound are subjected to an addition reaction.

(In formula (7), Y represents any one of a carboxyl group, a primary amino group, an epoxy group, a formyl group, and a cyclocarbonate group. J represents an integer of 0 to 15. W represents a phenyl group or a vinylene group.)

(In Formula (8), Z, a carboxyl group, a primary amino group, an epoxy group, a formyl group, and a cyclocarbonate group are shown. K shows the integer of 1-9.) .)

  According to this configuration, a method for producing a boronic acid-containing phosphorylcholine compound containing any one of an ester bond, a urethane bond, an amide bond, and a methylene group containing a secondary amino group can be provided. .

The iodo group-containing compound modifier according to one embodiment of the present invention is composed of the boronic acid-containing phosphorylcholine compound, and modifies a compound having an iodo group with a phosphorylcholine group.
The compound having an iodo group may be an iodo group-containing protein, an iodo group-containing polyethylene glycol, or an iodo group-containing peptide.

  According to this configuration, an iodo group-containing compound modifier that can satisfactorily modify a compound having an iodo group with a phosphorylcholine group can be provided.

  Embodiments of the present invention will be described below.

<Boronic acid-containing phosphorylcholine compound>
The boronic acid-containing phosphorylcholine compound according to one embodiment of the present invention has a boronic acid and phosphorylcholine group. Specifically, the boronic acid-containing phosphorylcholine compound according to this embodiment is represented by the formula (9).

In formula (9), j represents an integer of 0 to 15. j is preferably 0 or 1 from the viewpoint of availability. W represents a phenyl group or a vinylene group. -X (A ₁ )-represents any one of -X-A _1- , -A ₁ -X-, and -X-. X represents any one of an ester bond, a urethane bond, an amide bond, and a methylene group containing a secondary amino group. A1 is any _one of the structure represented by Formula (10) and the structure represented by Formula (11).

It should be noted that the direction of _{A 1} is optional. For example, the structure represented by Formula (10) may be —CH ₂ —CH (OH) — or —CH (OH) —CH ₂ —. Furthermore, the direction of the functional group of X is arbitrary. For example, the ester bond may be —C (O) O— or —OC (O) —. The urethane bond may be —NHC (O) O— or —OC (O) NH—. The amide bond may be —NHC (O) — or —C (O) NH—. The methylene group containing a secondary amino group may be —NHCH ₂ — or —CH ₂ NH—.

In the formula (9), examples of the boronic acid-containing phosphorylcholine compound in which W is a phenyl group, X is —C (O) O—, and A ₁ is a structure represented by the formula (10) include 3 -(1-dihydroxyborylbenzene-4-carbonyloxy) -2-hydroxypropylphosphorylcholine, 4- (1-dihydroxyborylbenzene-4-carbonyloxy) -3-hydroxybutylphosphorylcholine, 5- (1-dihydroxyborylbenzene- 4-carbonyloxy) -4-hydroxypentylphosphorylcholine, 6- (1-dihydroxyborylbenzene-4-carbonyloxy) -5-hydroxyhexylphosphorylcholine, 7- (1-dihydroxyborylbenzene-4-carbonyloxy) -6 Hydroxyheptylphosphorylcholine, 8- (1-dihydroxyborylbenzene-4-carbonyloxy) -7-hydroxyoctylphosphorylcholine, 9- (1-dihydroxyborylbenzene-4-carbonyloxy) -8-hydroxynonylphosphorylcholine, 10- (1-dihydroxyborylbenzene-4) -Carbonyloxy) -9-hydroxydecylphosphorylcholine, 11- (1-dihydroxyborylbenzene-4-carbonyloxy) -10-hydroxyundecylphosphorylcholine, 3-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] 2-hydroxypropylphosphorylcholine, 5-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] -4-hydroxypentylphosphorylcholine, 7-[(1-dihydroxyborylben) 4-ethyl) carbonyloxy] -6-hydroxyheptylphosphorylcholine, 9-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] -8-hydroxynonylphosphorylcholine, 11-[(1-dihydroxyborylbenzene- 4-ethyl) carbonyloxy] -10-hydroxyundecylphosphorylcholine, 3-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -2-hydroxypropylphosphorylcholine, 5-[(1-dihydroxyborylbenzene-4) -Butyl) carbonyloxy] -4-hydroxypentylphosphorylcholine, 6-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -5-hydroxyhexylphosphorylcholine, 7-[(1-dihydroxy) Rylbenzene-4-butyl) carbonyloxy] -6-hydroxyheptylphosphorylcholine, 9-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -8-hydroxynonylphosphorylcholine, 11-[(1-dihydroxyborylbenzene- 4-butyl) carbonyloxy] -10-hydroxyundecylphosphorylcholine and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound described above includes 6- (1-dihydroxyborylbenzene-4-carbonyloxy) -5-hydroxyhexylphosphorylcholine represented by formula (12) and formula (13). 11- (1-dihydroxyborylbenzene-4-carbonyloxy) -10-hydroxyundecylphosphorylcholine represented by the formula:

In the formula (9), the boronic acid-containing phosphorylcholine compound in which W is a vinylene group, X is —C (O) O—, and A ₁ is a structure represented by the formula (2) includes, for example, 6 -(Dihydroxyborylvinylcarbonyloxy) -5-hydroxyhexylphosphorylcholine, 11-[(6-dihydroxyboryl-5-hexen-1-yl) carbonyloxy] -10-hydroxyundecylphosphorylcholine and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound is preferably 6- (dihydroxyborylethynylcarbonyloxy) -5-hydroxyhexylphosphorylcholine represented by the formula (14).

In the formula (9), examples of the boronic acid-containing phosphorylcholine compound in which W is a phenyl group, X is —C (O) O—, and A ₁ is a structure represented by the formula (11) include 2 -(1-dihydroxyborylbenzene-4-carbonyloxy) -3-hydroxypropylphosphorylcholine, 3- (1-dihydroxyborylbenzene-4-carbonyloxy) -4-hydroxybutylphosphorylcholine, 4- (1-dihydroxyborylbenzene- 4-carbonyloxy) -5-hydroxypentylphosphorylcholine, 5- (1-dihydroxyborylbenzene-4-carbonyloxy) -6-hydroxyhexylphosphorylcholine, 6- (1-dihydroxyborylbenzene-4-carbonyloxy) -7- Hydroxyheptylphosphorylcholine, 7- (1-dihydroxyborylbenzene-4-carbonyloxy) -8-hydroxyoctylphosphorylcholine, 8- (1-dihydroxyborylbenzene-4-carbonyloxy) -9-hydroxynonylphosphorylcholine, 9- (1-dihydroxyborylbenzene-4) -Carbonyloxy) -10-hydroxydecylphosphorylcholine, 10- (1-dihydroxyborylbenzene-4-carbonyloxy) -11-hydroxyundecylphosphorylcholine, 2-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] -3-hydroxypropylphosphorylcholine, 4-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] -5-hydroxypentylphosphorylcholine, 6-[(1-dihydroxyborylben) 4-ethyl) carbonyloxy] -7-hydroxyheptylphosphorylcholine, 8-[(1-dihydroxyborylbenzene-4-ethyl) carbonyloxy] -9-hydroxynonylphosphorylcholine, 10-[(1-dihydroxyborylbenzene- 4-ethyl) carbonyloxy] -11-hydroxyundecylphosphorylcholine, 2-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -3-hydroxypropylphosphorylcholine, 4-[(1-dihydroxyborylbenzene-4) -Butyl) carbonyloxy] -5-hydroxypentylphosphorylcholine, 5-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -6-hydroxyhexylphosphorylcholine, 6-[(1-dihydroxy) Rylbenzene-4-butyl) carbonyloxy] -7-hydroxyheptylphosphorylcholine, 8-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -9-hydroxynonylphosphorylcholine, 10-[(1-dihydroxyborylbenzene- 4-butyl) carbonyloxy] -11-hydroxyundecyl phosphorylcholine and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound includes 5- (1-dihydroxyborylbenzene-4-carbonyloxy) -6-hydroxyhexylphosphorylcholine represented by formula (15) and formula (16). 10- (1-dihydroxyborylbenzene-4-carbonyloxy) -11-hydroxyundecylphosphorylcholine represented by the formula:

In the formula (9), as the boronic acid-containing phosphorylcholine compound in which W is a vinylene group, X is —C (O) O—, and A ₁ is a structure represented by the formula (11), for example, 5 -(Dihydroxyborylethynylcarbonyloxy) -6-hydroxyhexylphosphorylcholine, 10-[(6-dihydroxyboryl-5-hexen-1-yl) carbonyloxy] -11-hydroxyundecylphosphorylcholine, and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound is preferably 5- (dihydroxyborylethynylcarbonyloxy) -6-hydroxyhexylphosphorylcholine represented by the formula (17).

In the formula (9), examples of the boronic acid-containing phosphorylcholine compound in which W is a phenyl group, X is —NHC (O) O—, and A ₁ is a structure represented by the formula (10) include 3 -[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine, 5-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -4-hydroxypentylphosphorylcholine, 7- [ (1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -6-hydroxyheptylphosphorylcholine, 9-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -8-hydroxynonylphosphorylcholine, 11-[(1 -Dihydroxyborylbenzene-4-methyl) Carbamoyloxy] -10-hydroxyundecylphosphorylcholine, 3-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine, 5-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyl Oxy] -4-hydroxypentylphosphorylcholine, 7-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -6-hydroxyheptylphosphorylcholine, 9-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] And -8-hydroxynonylphosphorylcholine, 11-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -10-hydroxyundecylphosphorylcholine, and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound described above includes 3-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine represented by the formula (18), 6-[(1-Dihydroxyborylbenzene-4-methyl) carbamoyloxy] -5-hydroxypropylphosphorylcholine represented by (13) is preferable.

In the formula (9), the boronic acid-containing phosphorylcholine compound in which W is a vinylene group, X is —NHC (O) O—, and A ₁ is a structure represented by the formula (10) includes, for example, 3 -[(3-dihydroxyboryl-2-propen-1-yl) carbamoyloxy] -2-hydroxypropylphosphorylcholine, 6-[(4-dihydroxyboryl-3-buten-1-yl) carbamoyloxy] -5-hydroxy And hexyl phosphorylcholine.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound is a 3-[(3-dihydroxyboryl-2-propen-1-yl) carbamoyloxy] -2-hydroxypropylphosphorylcholine represented by the formula (20). It is preferable that

In the formula (9), the boronic acid-containing phosphorylcholine compound in which W is a phenyl group, X is —NHC (O) O—, and A ₁ is a structure represented by the formula (11) includes, for example, 2 -[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine, 4-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -5-hydroxypentylphosphorylcholine, 6- [ (1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -7-hydroxyheptylphosphorylcholine, 8-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -9-hydroxynonylphosphorylcholine, 10-[(1 -Dihydroxyborylbenzene-4-methyl) Carbamoyloxy] -11-hydroxyundecylphosphorylcholine, 2-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine, 4-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyl Oxy] -5-hydroxypentylphosphorylcholine, 6-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -7-hydroxyheptylphosphorylcholine, 8-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -9-hydroxynonylphosphorylcholine, 10-[(1-dihydroxyborylbenzene-4-ethyl) carbamoyloxy] -11-hydroxyundecylphosphorylcholine, and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound described above includes 2-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine represented by the formula (21), 5-[(1-Dihydroxyborylbenzene-4-methyl) carbamoyloxy] -6-hydroxypropylphosphorylcholine represented by (22) is preferable.

In the formula (9), the boronic acid-containing phosphorylcholine compound in which W is a vinylene group, X is —NHC (O) O—, and A ₁ is a structure represented by the formula (3) includes, for example, 2 -[(3-dihydroxyboryl-2-propen-1-yl) carbamoyloxy] -3-hydroxypropylphosphorylcholine, 5-[(4-dihydroxyboryl-3-buten-1-yl) carbamoyloxy] -6-hydroxy And hexyl phosphorylcholine.

From the viewpoint of ease of synthesis, the above boronic acid-containing phosphorylcholine compound is 2-[(3-dihydroxyboryl-2-propen-1-yl) carbamoyloxy] -3-hydroxypropylphosphorylcholine represented by the formula (23). It is preferable that

In the formula (9), as the boronic acid-containing phosphorylcholine compound in which W is a phenyl group and X is a structure represented by —NHCH ₂ —, for example, 2-[(4-dihydroxyborylbenzene-1-yl) Amino] ethyl phosphorylcholine, 4-[(4-dihydroxyborylbenzene-1-yl) amino] butyl phosphorylcholine, 6-[(4-dihydroxyborylbenzene-1-yl) amino] hexyl phosphorylcholine, 8-[(4-dihydroxy Borylbenzene-1-yl) amino] octylphosphorylcholine, 10-[(4-dihydroxyborylbenzene-1-yl) amino] decylphosphorylcholine, 2-[(1-dihydroxyborylbenzene-4-ethyl) amino] ethylphosphorylcholine, 4-[(1-dihydroxyborylben 4-ethyl) amino] butylphosphorylcholine, 6-[(1-dihydroxyborylbenzene-4-ethyl) amino] hexylphosphorylcholine, 8-[(1-dihydroxyborylbenzene-4-ethyl) amino] octylphosphorylcholine, 10 -[(1-dihydroxyborylbenzene-4-ethyl) amino] decylphosphorylcholine and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound is preferably 2-[(4-dihydroxyborylbenzene-1-yl) amino] ethylphosphorylcholine represented by the formula (18).

In the formula (9), as the boronic acid-containing phosphorylcholine compound in which W is a vinylene group and X is a structure represented by —NHCH ₂ —, for example, 2-[(3-dihydroxyboryl-2-propene-1 -Yl) amino] ethyl phosphorylcholine, 10-[(4-dihydroxyboryl-3-buten-1-yl) amino] decylphosphorylcholine and the like.

From the viewpoint of ease of synthesis, the boronic acid-containing phosphorylcholine compound is preferably 2-[(3-dihydroxyboryl-2-propen-1-yl) amino] ethylphosphorylcholine represented by the formula (19). .

<Method for producing boronic acid-containing phosphorylcholine compound>
The boronic acid-containing phosphorylcholine compound represented by formula (9) can be obtained by an addition reaction between the boronic acid-containing compound represented by formula (26) and the phosphorylcholine group-containing compound represented by formula (27). .

  In formula (26), W represents a phenyl group or a vinylene group. Y represents any one of a carboxyl group, a primary amino group, an epoxy group, a formyl group, and a cyclocarbonate group. j shows the integer of 0-15. j is preferably 0 or 1 from the viewpoint of availability. When W is a phenyl group, from the viewpoint of availability, it is preferable that the boronic acid is in the meta position or the para position with respect to the substituent having Y as the position of the substituent on the benzene ring. When W is a vinylene group, the stereoisomer may be a cis isomer or a trans isomer.

  In Formula (27), any one of Z, a carboxyl group, a primary amino group, an epoxy group, a formyl group, and a cyclocarbonate group is shown. k shows the integer of 1-9. k is preferably 1, 4 or 9 from the viewpoint of availability.

  In the formula (9), a boronic acid-containing phosphorylcholine compound in which X is —C (O) O— includes a boronic acid-containing compound in which Y in the formula (26) is a carboxyl group, and Z in the formula (27) is an epoxy group And a phosphorylcholine group-containing compound as described above in an aprotic polar solvent in the presence of a base.

  Examples of the boronic acid-containing compound in which W in formula (26) is a phenyl group and Y is a carboxyl group include 3-dihydroxyborylbenzoic acid, 3-dihydroxyborylphenylethanoic acid, 3- (4-dihydroxyborylphenyl). ) Butanoic acid, 4-dihydroxyborylbenzoic acid, 4-dihydroxyborylphenylethanoic acid, 4- (4-dihydroxyborylphenyl) butanoic acid and the like.

  Examples of boronic acid-containing compounds in which W in formula (26) is a vinylene group and Y is a carboxyl group include 3-dihydroxyboryl-2-propenoic acid, 5-dihydroxyboryl-4-pentenoic acid, and 7-dihydroxy. Examples include boryl-6-heptenoic acid.

  Examples of the phosphorylcholine group-containing compound in which Z in the formula (27) is an epoxy group include 2,3-epoxypropylphosphorylcholine, 3,4-epoxybutylphosphorylcholine, 4,5-epoxypentylphosphorylcholine, and 5,6-epoxyhexyl. Examples include phosphorylcholine, 6,7-epoxyheptylphosphorylcholine, 7,8-epoxyoctylphosphorylcholine, 8,9-epoxynonylphosphorylcholine, 9,10-epoxydecylphosphorylcholine, and 10,11-epoxyundecylphosphorylcholine.

  In the formula (9), a boronic acid-containing phosphorylcholine compound in which X is —NHC (O) O— includes a boronic acid-containing compound in which Y in the formula (26) is an amino group, and Z in the formula (27) is a cyclocarbonate. It is obtained by reacting a phosphorylcholine group-containing compound as a group in a polar solvent.

  Examples of boronic acid-containing compounds in which W in formula (26) is a phenyl group and Y is an amino group include (3-aminophenyl) dihydroxyborane, [3- (2-aminomethyl) phenyl] dihydroxyborane, [(3-aminoethyl) phenyl] dihydroxyborane, (4-aminophenyl) dihydroxyborane, [4- (2-aminomethyl) phenyl] dihydroxyborane, [4- (3-aminoethyl) phenyl] dihydroxyborane, etc. Can be mentioned.

  Examples of boronic acid-containing compounds in which W in formula (26) is a vinylene group and Y is an amino group include (3-amino-1-propenyl) dihydroxyborane and (4-amino-1-butenyl) dihydroxyborane. Etc.

  Examples of the phosphorylcholine group-containing compound in which Z in the formula (27) is a cyclocarbonate group include (2-oxo-1,3-dioxolan-4-yl) methylphosphorylcholine, 2- (2-oxo-1,3- Dioxolan-4-yl) ethyl phosphorylcholine, 3- (2-oxo-1,3-dioxolan-4-yl) propyl phosphorylcholine, 4- (2-oxo-1,3-dioxolan-4-yl) butyl phosphorylcholine, 5 -(2-oxo-1,3-dioxolan-4-yl) pentylphosphorylcholine, 6- (2-oxo-1,3-dioxolan-4-yl) hexylphosphorylcholine, 7- (2-oxo-1,3- Dioxolan-4-yl) heptylphosphorylcholine, 8- (2-oxo-1,3-dioxolan-4-yl) octy Phosphorylcholine, 9- (2-oxo-1,3-dioxolan-4-yl) nonyl phosphorylcholine.

In formula (9), a boronic acid-containing phosphorylcholine compound in which X is —NHCH ₂ — includes a boronic acid-containing compound in which Y in formula (26) is an amino group, and a phosphorylcholine in which Z in formula (27) is a formyl group It is obtained by reacting a group-containing compound with a protic polar solvent and further reacting with a reducing agent.

  Examples of boronic acid-containing compounds in which W in formula (26) is a phenyl group and Y is an amino group include (4-aminophenyl) dihydroxyborane and [4- (3-aminoethyl) phenyl] dihydroxyborane. Can be mentioned.

  Examples of boronic acid-containing compounds in which W in the formula (26) is a vinylene group and Y is an amino group include (3-amino-1-propenyl) dihydroxyborane, (4-amino-1-butenyl) dihydroxyborane, and the like. Can be mentioned.

  Examples of the phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group include formylmethylphosphorylcholine, 2-formylethylphosphorylcholine, 3-formylpropylphosphorylcholine, 4-formylbutylphosphorylcholine, 5-formylpentylphosphorylcholine, and 6-formylhexyl. Examples include phosphorylcholine, 7-formylheptylphosphorylcholine, 8-formisoctylphosphorylcholine, and 9-formylnonylphosphorylcholine.

  The phosphorylcholine group-containing compound in which Z in the formula (27) is an epoxy group can be obtained, for example, by the production method described in US Pat. No. 5,144,045.

  The phosphorylcholine group-containing compound in which Z in the formula (27) is a cyclocarbonate group can be obtained by, for example, a production method described in JP2009-242289A.

  The phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group and k = 1 can be obtained, for example, by the production method described in JP-A-2005-187456.

  The phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group and k = 2 to 9 can be obtained, for example, by oxidative cleavage of a dihydroxyl group-containing phosphorylcholine compound. This dihydroxyl group-containing phosphorylcholine compound is obtained by, for example, opening an epoxy group-containing phosphorylcholine compound obtained by epoxidation of an alkenyl group-containing phosphorylcholine compound described in US Pat. No. 5,144,045 in the presence of an acid catalyst. Can be obtained.

  In the production method according to this embodiment, a boronic acid-containing compound in which Y in formula (26) is a carboxyl group is subjected to a ring-opening addition reaction with a phosphorylcholine group-containing compound in which Z in formula (27) is an epoxy group. A reaction product having an ester bond and a hydroxyl group as represented by (12) to (17) can be obtained. The obtained reaction product can be used as it is without purification, or can be used after isolation and purification by treatment such as drying under reduced pressure, reprecipitation, recrystallization, column, ion exchange, gel filtration and the like.

  In the production method according to the present embodiment, as a solvent used for the reaction between the boronic acid-containing compound in which Y in formula (26) is a carboxyl group and the phosphorylcholine group-containing compound in which Z in formula (27) is an epoxy group, A general aprotic solvent can be employed.

  Examples of aprotic solvents that can be used include tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, acetone, ethyl methyl ketone, methylene chloride, chloroform, cyclopentyl methyl ether, N, N-dimethylformamide, dimethyl sulfoxide, and N-methyl. -2-pyrrolidone. From the viewpoint of compound solubility and compound reactivity, the aprotic solvent is preferably chloroform.

  The amount of the aprotic solvent used in this embodiment is usually 1 to 20 times, preferably 2 to 15 times the mass of the boronic acid-containing compound in which Z in the formula (27) is an epoxy group. The amount is most preferably 4 to 10 times.

  In the production method according to the present embodiment, the amount of the boronic acid-containing compound in which Y in formula (26) is a carboxyl group is 0 in terms of molar ratio with respect to the phosphorylcholine group-containing compound in which Z in formula (27) is an epoxy group. .5 to 2.0 times, preferably 0.8 to 1.5 times, and most preferably 1.0 to 1.2 times.

  When the amount of the boronic acid-containing compound is less than 0.5 times the amount of the phosphorylcholine group-containing compound, a high reaction conversion rate may not be obtained. Further, when the amount of the boronic acid-containing compound is larger than 2.0 times the amount of the phosphorylcholine group-containing compound, a boronic acid-containing compound that is wasted without contributing to the improvement of the reaction conversion rate is generated.

  In the production method according to this embodiment, the base used for the reaction between the boronic acid-containing compound in which Y in formula (26) is a carboxyl group and the phosphorylcholine group-containing compound in which Z in formula (27) is an epoxy group Examples thereof include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, and potassium carbonate. Of these bases, triethylamine is particularly preferable.

  The amount of the base used in the present embodiment is 0.05 to 0.5 times the molar ratio with respect to the phosphorylcholine group-containing compound in which Z in the formula (27) is an epoxy group, preferably 0.1 to 0. .2 times the amount.

  In the production method according to this embodiment, a boronic acid-containing compound in which Y in formula (26) is an amino group is subjected to a ring-opening addition reaction with a phosphorylcholine group-containing compound in which Z in formula (27) is a cyclocarbonate group, A reaction product having a urethane bond and a hydroxyl group as represented by formulas (18) to (24) can be obtained. The obtained reaction product can be used as it is without purification, or can be used after isolation and purification by treatment such as drying under reduced pressure, reprecipitation, recrystallization, column, ion exchange, gel filtration and the like.

  In the production method according to this embodiment, the reaction temperature in the reaction between the boronic acid-containing compound in which Y in formula (26) is a carboxyl group and the phosphorylcholine group-containing compound in which Z in formula (27) is an epoxy group is usually It is in the range of 0-80 ° C, preferably 30-60 ° C, most preferably 40-50 ° C.

  When the reaction temperature is lower than 0 ° C., the reaction may take a long time. Further, at a reaction temperature exceeding 80 ° C., even if the reaction temperature is increased, the reaction rate is not improved. Therefore, the reaction temperature is preferably suppressed to 80 ° C. or less from the viewpoint of production cost. Although reaction time is suitably determined by conditions, such as reaction temperature and a density | concentration, it is preferable normally that it is about 1 to 10 hours.

  In the production method according to the present embodiment, as a solvent used for the reaction between a boronic acid-containing compound in which Y in formula (26) is an amino group and a phosphorylcholine group-containing compound in which Z in formula (27) is a cyclocarbonate group In general, a common polar solvent can be used.

  Examples of polar solvents that can be used include methanol, ethanol, 1-propanol, 2-propanol, dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. From the viewpoint of compound solubility and compound reactivity, the polar solvent is preferably methanol.

  The amount of the polar solvent used in the present embodiment is usually 1 to 20 times, preferably 2 to 15 times the mass of the phosphorylcholine group-containing compound in which Z in formula (27) is a cyclocarbonate group, The amount is most preferably 4 to 10 times.

  In the production method according to the present embodiment, the amount of the boronic acid-containing compound in which Y in formula (26) is an amino group is the molar ratio with respect to the phosphorylcholine group-containing compound in which Z in formula (27) is a cyclocarbonate group. The amount is 0.5 to 3.0 times, preferably 1.0 to 2.5 times, and most preferably 1.5 to 2.0 times.

  When the amount of the boronic acid-containing compound is less than 0.5 times the amount of the phosphorylcholine group-containing compound, a high reaction conversion rate may not be obtained. Further, when the amount of the boronic acid-containing compound is more than 3.0 times the amount of the phosphorylcholine group-containing compound, a boronic acid-containing compound that is wasted without contributing to the improvement of the reaction conversion rate is generated.

  In the production method according to this embodiment, the reaction temperature in the reaction between the boronic acid-containing compound in which Y in formula (26) is an amino group and the phosphorylcholine group-containing compound in which Z in formula (27) is a cyclocarbonate group is: Usually, it is in the range of 0-50 ° C, preferably 10-40 ° C, most preferably 20-30 ° C.

  When the reaction temperature is lower than 0 ° C., the reaction may take a long time. Further, at a reaction temperature exceeding 50 ° C., even if the reaction temperature is increased, the reaction rate is not improved. Therefore, the reaction temperature is preferably suppressed to 50 ° C. or less from the viewpoint of production cost. Although reaction time is suitably determined by conditions, such as reaction temperature and a density | concentration, it is usually preferable that it is about 5 to 24 hours.

  In the production method according to this embodiment, a boronic acid-containing compound in which Y in formula (26) is an amino group is subjected to an addition reaction with a phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group. ) To (25), reaction products having an amino bond can be obtained. The obtained reaction product can be used as it is without purification, or can be used after isolation and purification by treatment such as drying under reduced pressure, reprecipitation, recrystallization, column, ion exchange, gel filtration and the like.

  In the production method according to the present embodiment, the solvent used for the reaction between the boronic acid-containing compound in which Y in formula (26) is an amino group and the phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group A general protic solvent can be employed.

  Examples of protic solvents that can be employed include methanol, ethanol, 1-propanol, 2-propanol, t-butanol, and the like. In addition, from the viewpoint of compound solubility and compound reactivity, the protic solvent is preferably methanol or ethanol.

  The amount of the protic solvent used in the present embodiment is usually 1 to 60 times, preferably 10 to 50 times the mass of the phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group. Most preferably, the amount is 20 to 40 times.

  In the production method according to this embodiment, the amount of the boronic acid-containing compound in which Y in formula (26) is an amino group is 0 in terms of molar ratio with respect to the phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group. .5 to 2.0 times, preferably 0.8 to 1.5 times, and most preferably 1.0 to 1.2 times.

  When the amount of the boronic acid-containing compound is less than 0.5 times the amount of the phosphorylcholine group-containing compound, a high reaction conversion rate may not be obtained. Further, when the amount of the boronic acid-containing compound is more than 2.0 times the amount of the phosphorylcholine group-containing compound, a wasteful boronic acid-containing compound that does not contribute to the improvement of the reaction conversion rate is generated.

  In the production method according to the present embodiment, as a reducing agent used for the reaction between a boronic acid-containing compound in which Y in formula (26) is an amino group and a phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group Examples include 2-picoline borane and sodium cyanohydroborate. The reducing agent is preferably 2-picoline borane.

  The amount of the reducing agent used in the present embodiment is 1.0 to 2.5 times, preferably 1.5 to 1.5, in molar ratio with respect to the phosphorylcholine group-containing compound in which Z in formula (27) is a formyl group. 2.0 times the amount.

  In the production method according to this embodiment, the reaction temperature in the reaction of the compound in which Y in formula (26) is an amino group and the compound in which Z in formula (27) is a formyl group is usually 0 to 60 ° C., preferably Is in the range of 10-40 ° C, most preferably 20-30 ° C.

  When the reaction temperature is lower than 0 ° C., the reaction may take a long time. In addition, at a reaction temperature exceeding 60 ° C., even if the reaction temperature is increased, the reaction rate is not improved. Therefore, the reaction temperature is preferably suppressed to 60 ° C. or less from the viewpoint of production cost. Although reaction time is suitably determined by conditions, such as reaction temperature and a density | concentration, it is preferable that it is normally about 1 to 5 hours.

<Iodo group-containing compound modifier>
Examples of the compound having an iodo group that can be modified by the boronic acid-containing phosphorylcholine compound represented by the formula (9) according to this embodiment include iodinated polyethylene glycol, iodinated peptide, and iodinated protein.

  The molecular weight of said iodinated polyethylene glycol is 400-20000.

  The molecular weight of the peptide having an iodo group is 100 to 1000. The type of amino acid constituting the peptide is arbitrary.

  Examples of the iodinated protein include BSA having an iodo group (albumin from bovine serum), KLH having an iodo group (keyhole limpet hemocyanin), and ovalbumin having an iodo group.

  A compound having an iodo group can be modified with a phosphorylcholine group by Suzuki-Miyaura cross-coupling of a boronic acid-containing phosphorylcholine compound and a compound having an iodo group in the presence of a palladium catalyst. The obtained reaction product can be used as it is without purification, or can be used after isolation and purification by treatment such as drying under reduced pressure, reprecipitation, recrystallization, column, ion exchange, gel filtration and the like.

  In the reaction between the boronic acid-containing phosphorylcholine compound and the iodo group-containing compound, a catalyst is not essential, but a catalyst is preferably used from the viewpoint of shortening the reaction time.

  As the usable catalyst, zero-valent or divalent palladium can be adopted. Examples of zero-valent or divalent palladium include tetrakis (triphenylphosphine) palladium, palladium (II) acetate, [1,1′-bis (diphenylphosphino) -ferrocene] palladium (II), and chloride [bis]. (Triphenylphosphine)] palladium (II), [bis (tricyclohexylphosphine)] palladium (II) chloride and the like.

  The amount of the catalyst used in the present embodiment is 0.01 to 1 times, preferably 0.02 to 0.5 times, most preferably 0.05, in molar ratio to the boronic acid-containing phosphorylcholine compound. -0.1 times the amount.

  In the method for modifying an iodo group-containing compound according to the present embodiment, a solvent in which the compound represented by the boronic acid-containing phosphorylcholine compound dissolves is appropriately used as the solvent in the reaction between the boronic acid-containing phosphorylcholine compound and the iodo group-containing compound. Is possible.

  Examples of the catalyst that can be employed include water, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, N-N'-dimethylformamide, dimethyl sulfoxide, and the like. From the viewpoint of compound solubility and compound reactivity, the solvent is preferably water.

  The amount of the catalyst used in the present embodiment is usually 1 to 60 times, preferably 10 to 50 times, and most preferably 20 to 40 times the mass ratio of the boronic acid-containing phosphorylcholine compound.

  The reaction temperature in the reaction between the boronic acid-containing phosphorylcholine compound and the iodo group-containing compound is usually in the range of 0 to 80 ° C, preferably 20 to 70 ° C, and most preferably 40 to 60 ° C.

  When the reaction temperature is lower than 0 ° C., the reaction may take a long time. Further, at a reaction temperature exceeding 80 ° C., even if the reaction temperature is increased, the reaction rate is not improved. Therefore, the reaction temperature is preferably suppressed to 80 ° C. or less from the viewpoint of production cost. The reaction time is appropriately determined depending on conditions such as reaction temperature and concentration, but it is usually preferably about 1 to 24 hours. The reaction temperature is particularly preferably a temperature (30 to 40 ° C.) at which the peptide and protein are not denatured.

  As the condensing agent used in the method for modifying an iodo group-containing protein according to this embodiment, one that can condense an amino group and a carboxyl group can be employed.

  Examples of the condensing agent that can be used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dibenzylcyclooctyne-N-hydroxysuccinimide ester, N-carbobenzoxyoxysuccinimide, N- ( 2-chlorobenzyloxycarbonyloxy) succinimide, N-[(9H-fluoren-9-ylmethoxy) carbonyloxy] succinimide, N-succinimidyl acrylate, N-succinimidyl-6- (2,4-dinitroanilylo) hexanoate, N- (1,2,2,2-tetrachloroethoxycarbonyloxy) succinimide, N- [2- (trimethylsilyl) ethoxycarbonyloxy] succinimide and the like can be mentioned. From the viewpoint of reactivity, the condensing agent is preferably dibenzylcyclooctyne-N-hydroxysuccinimide ester.

<Effects obtained in this embodiment>
The boronic acid-containing phosphorylcholine compound according to the present embodiment has a phosphorylcholine group exhibiting excellent biocompatibility such as hydrophilicity, moisture retention and suppression of protein adsorption in the molecule, and Suzuki-Miyaura cross cup with iodo group. Has boronic acid capable of ringing. Therefore, in the modifier according to the present embodiment, a phosphorylcholine group can be introduced into a low molecular compound, polymer, biomolecule or the like having an iodo group under mild conditions.

  Further, the boronic acid-containing phosphorylcholine compound according to the present embodiment has a high water solubility since it has a hydrogen bondable functional group such as a urethane bond, a hydroxyl group, an ester bond, or an amino group in the chain. Therefore, the boronic acid-containing phosphorylcholine compound according to this embodiment can be easily bound to a biomolecule in water.

  Furthermore, the boronic acid-containing phosphorylcholine compound according to the present embodiment includes a boronic acid-containing compound having an amino group or a carboxyl group, and an epoxy group, formyl group, or cyclohexane that can easily react with these functional groups under mild conditions. By reacting with a phosphorylcholine group having a carbonate group, it can be easily synthesized in a high yield.

  Hereinafter, examples will be described, but the present invention is not limited to the examples.

[Synthesis Example 1] Synthesis of phosphorylcholine group-containing compound (5,6-epoxyhexylphosphorylcholine) represented by formula (29) 1.06 g (4.0 mmol) of 5-hexenylphosphorylcholine represented by formula (28) in a 100 mL flask , 1.73 g (10.0 mmol) of metachloroperbenzoic acid and 40 mL of chloroform were added and reacted at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and 20 mL of water was added to the residue. The precipitated white solid was removed by filtration (filter paper: No. 5C), the filtrate was washed 3 times with 20 mL of ethyl acetate, the aqueous layer was concentrated under reduced pressure, and the 5,6-epoxy represented by the formula (29). Hexyl phosphorylcholine was obtained. The yield was 920 mg (3.23 mmol), and the yield was 82%.

[Synthesis Example 2] Synthesis of phosphorylcholine group-containing compound (10,11-epoxyundecylphosphorylcholine) represented by formula (31) In a 50 mL flask, 335 mg of 10-undecenylphosphorylcholine represented by formula (30) ( 1.0 mmol), 431 mg (2.5 mmol) of metachloroperbenzoic acid, and 10 mL of chloroform were added and reacted at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. The filtrate obtained by removing the precipitated white solid by filtration (filter paper: No. 5C) was washed three times with 10 mL of ethyl acetate, the aqueous layer was concentrated under reduced pressure, and 10,11-epoxyun represented by the formula (31). Decyl phosphorylcholine was obtained. The yield was 273 mg (0.78 mmol), and the yield was 78%.

[Synthesis Example 3] Synthesis of phosphorylcholine group-containing compound (1,3-dioxolan-2-one-4-methylphosphorylcholine) represented by formula (32) In a 500 mL four-necked flask, glycerin carbonate (1,3- 20.0 g (169 mmol) of dioxolan-2-one-methanol), 17.1 g (169 mmol) of triethylamine, and 250 mL of tetrahydrofuran were added, and the mixture was cooled to 0 ° C. with stirring. 24.0 g (169 mmol) of 2-chloro-2-oxa-1,3,2-dioxaphosphorane (manufactured by Sigma-Aldrich) was dissolved in 50 mL of tetrahydrofuran, and the resulting solution was added to the above flask with a dropping funnel. Was added dropwise. After completion of the dropwise addition, the reaction mixture was heated and the reaction was continued at room temperature for 2 hours. Triethylamine hydrochloride precipitated as a by-product was filtered off, and it was confirmed by NMR that 1,3-dioxolan-2-one-4-methylethylene cyclic phosphate was present in the filtrate. The obtained filtrate and 300 mL of acetonitrile were transferred to a 1 L pressure-resistant bottle with a tight stopper, and 40.0 g (676 mmol) of trimethylamine was added to the pressure-resistant bottle, which was sealed and reacted at 70 ° C. for 20 hours. After the excess trimethylamine was distilled off, the reaction solution was allowed to stand at −20 ° C. for half a day to form crystals. The product was filtered, washed with 1 L of acetonitrile, and dried under reduced pressure at 50 ° C. overnight to obtain 1,3-dioxolan-2-one-4-methylphosphorylcholine represented by the formula (24). The yield was 21.5 g (76.1 mmol), and the yield was 45.0%.

Synthesis Example 4 Synthesis of Compound (4- (4-Hydroxybutyl) -1,3-dioxolan-2-one) Represented by Formula (33) In a 200 mL flask, 1,2,6-hexanetriol ( 26.8 g (200 mmol) (manufactured by Tokyo Chemical Industry), 19.8 g (220 mmol) of dimethyl carbonate, and 60.8 g (440 mmol) of potassium carbonate were added and reacted at 80 ° C. for 15 hours. A liquid obtained by diluting the reaction mixture in 100 mL of ethyl acetate was washed with 100 mL of water three times. The organic layer was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain 4- (4-hydroxybutyl) -1,3-dioxolan-2-one represented by the formula (33). The yield was 25.3 g (158 mmol), and the yield was 79%.

[Synthesis Example 5] Synthesis of phosphorylcholine group-containing compound represented by formula (34) (4- (2-oxo-1,3-dioxolan-4-yl) butylphosphorylcholine) In a 500 mL four-necked flask, a compound of formula ( 33) 4- (4-hydroxybutyl) -1,3-dioxolan-2-one (20.0 g, 125 mmol), triethylamine (12.6 g, 125 mmol), and tetrahydrofuran (250 mL) were added, and the mixture was stirred with 0. Cooled to ° C. 17.8 g (125 mmol) of 2-chloro-2-oxa-1,3,2-dioxaphosphorane (manufactured by Sigma-Aldrich) was dissolved in 50 mL of tetrahydrofuran, and the resulting solution was added to the flask with a dropping funnel. Was added dropwise. After completion of the dropwise addition, the reaction mixture was heated and the reaction was continued at room temperature for 2 hours. Triethylamine hydrochloride precipitated as a by-product was filtered off, and it was confirmed by NMR that 1,3-dioxolan-2-one-4-butylethylene cyclic phosphate was present in the filtrate. The obtained filtrate and 300 mL of acetonitrile were transferred to a 1 L pressure bottle with a tight stopper, 29.6 g (500 mmol) of trimethylamine was added to the pressure bottle, sealed, and reacted at 70 ° C. for 20 hours. After the excess trimethylamine was distilled off, the reaction solution was allowed to stand at −20 ° C. for half a day to form crystals. The product was filtered, washed with 1 L of acetonitrile, and dried under reduced pressure at 50 ° C. overnight to obtain 4- (2-oxo-1,3-dioxolan-4-yl) butylphosphorylcholine represented by the formula (34). . The yield was 17.6 g (53.8 mmol), and the yield was 43.0%.

[Synthesis Example 6] Synthesis of phosphorylcholine group-containing compound (formylmethylphosphorylcholine) represented by formula (36) In a 500 mL four-necked flask, it is described in JP2009-242289A represented by formula (35). Then, 2.14 g (20.0 mmol) of 2,3-dihydroxypropylphosphorylcholine and 170 mL of water were added and stirred. 6.41 g (30.0 mmol) of sodium periodate was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and methanol was added to the residue. The precipitated solid was removed by filtration (filter paper: No. 5C), and an ion exchange resin (DIAION WA21 manufactured by Mitsubishi Chemical Corporation) was added to the filtrate, followed by stirring for 3 hours. The solid was removed by filtration (PTFE filter: 0.45 μm), and the filtrate was concentrated under reduced pressure to obtain formylmethylphosphorylcholine represented by the formula (36). The yield was 3.90 g (17.3 mmol), and the yield was 87%.

[Synthesis Example 7] Synthesis of phosphorylcholine group-containing compound represented by formula (38) (10,11-dihydroxyundecylphosphorylcholine) US Patent No. 5,144,045 represented by formula (37) in a 200 mL flask No. 10-undecylphosphorylcholine described in the specification, 1.68 g (5.0 mmol), 2.16 g (12.5 mmol) of metachloroperbenzoic acid, 650 mg of Amberlyst, 15 mL of chloroform, and 30 mL of water were added at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. The precipitated white solid was removed by filtration (filter paper: No. 5C), the filtrate was washed 3 times with 10 mL of ethyl acetate, the aqueous layer was concentrated under reduced pressure, and 10,11-dihydroxy represented by the formula (30). Undecyl phosphorylcholine was obtained. The yield was 1.75 g (4.75 mmol), and the yield was 95%.

[Synthesis Example 8] Synthesis of phosphorylcholine group-containing compound (9-formylnonylphosphorylcholine) represented by formula (39) In a 50 mL flask, 369 mg (1, .1) of 10,11-dihydroxyundecylphosphorylcholine represented by formula (38). 0 mmol) and 10 mL of water were added and stirred. 321 mg (1.5 mmol) of sodium periodate was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and methanol was added to the residue. The precipitated solid was removed by filtration (filter paper: No. 5C), and an ion exchange resin (DIAION WA21 manufactured by Mitsubishi Chemical Corporation) was added to the filtrate, followed by stirring for 3 hours. The solid was removed by filtration (PTFE filter: 0.45 μm), and the filtrate was concentrated under reduced pressure to obtain 9-formylnonylphosphorylcholine represented by the formula (39). The yield was 297 mg (0.88 mmol), and the yield was 88%.

[Example 1-1] A boronic acid-containing phosphorylcholine compound represented by formula (41) (6- (1-dihydroxyborylbenzene-4-carbonyloxy) -5-hydroxyhexylphosphorylcholine) and a formula (42) Synthesis of a boronic acid-containing phosphorylcholine compound (5- (1-dihydroxyborylbenzene-4-carbonyloxy) -6-hydroxyhexylphosphorylcholine) represented by the formula (29) synthesized in Synthesis Example 1 in a 50 mL flask 282 mg (1.0 mmol) of 5,6-epoxyhexyl phosphorylcholine, 182 mg (1.1 mmol) of 4-carboxyphenylboronic acid represented by the formula (40), and 5 mL of chloroform were added and stirred at room temperature. Triethylamine 10.1 mg (0.1 mmol) was added and reacted at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. This aqueous solution was washed with 10 mL of ethyl acetate three times, the aqueous layer was concentrated under reduced pressure, and 6- (1-dihydroxyborylbenzene-4-carbonyloxy) -5-hydroxyhexylphosphorylcholine represented by the formula (41) and the formula 5- (1-dihydroxyborylbenzene-4-carbonyloxy) -6-hydroxyhexyl phosphorylcholine represented by (42) was obtained at a ratio of 7: 3. The yield was 277 mg (0.62 mmol), and the yield was 62%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
_{^{1 H-NMR (CD 3 OD}} ): 1.36-1.59 (m, 6H, -O-CH 2 - CH 2 -CH 2 -CH 2 -CH -), 3.24 (s, 9H, - _{^{N + (CH 3) 3)}} , 3.61-3.62 (m, 2H, -O-CH 2 - CH 2 -N + (CH 3) 3), 3.76-4.66 (m, 7H _{, - CH 2 -CH-CH 2} -, - O- CH 2 -CH 2 -CH 2 -CH 2 -CH -), 4.23-4.30 (m, 2H, -O- CH 2 -CH 2 _{^{-N + - (CH 3) 3}} ), 7.85 (d, 2H, -CHofPh), 8.35 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 1.05

[Example 1-2] A boronic acid-containing phosphorylcholine compound (11- (1-dihydroxyborylbenzene-4-carbonyloxy) -10-hydroxyundecylphosphorylcholine) represented by formula (43) and formula (44) ( Synthesis of boronic acid-containing phosphorylcholine compound represented by 10- (1-dihydroxyborylbenzene-4-carbonyloxy) -11-hydroxyundecylphosphorylcholine) In a 50 mL flask, represented by the formula (31) synthesized in Synthesis Example 2 Then, 351 mg (1.0 mmol) of 10,11-epoxyundecylphosphorylcholine, 182 mg (1.1 mmol) of 4-carboxyphenylboronic acid represented by the formula (40) and 5 mL of chloroform were added and stirred at room temperature. Triethylamine 10.1 mg (0.1 mmol) was added and reacted at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. This aqueous solution was washed with 10 mL of ethyl acetate three times, the aqueous layer was concentrated under reduced pressure, and 11- (1-dihydroxyborylbenzene-4-carbonyloxy) -10-hydroxyundecylphosphorylcholine represented by formula (43), and 10- (1-dihydroxyborylbenzene-4-carbonyloxy) -11-hydroxyundecylphosphorylcholine represented by the formula (44) was obtained at a ratio of 7: 3. The yield was 284 mg (0.55 mmol), and the yield was 55%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
_{^{1 H-NMR (CD 3 OD}} ): 1.36-1.72 (m, 16H, -O-CH 2 - CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH _{^{2 -CH -), 3.24 (s}} , 9H, -N + (CH 3) 3), 3.62-3.63 (m, 2H, -O-CH 2 - CH 2 -N + (CH 3 _{) 3), 3.76-4.66 (m,} 5H, - CH 2 -CH- CH 2 -, - O- CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - _{CH 2 -CH 2 -CH -),} 4.26-4.33 (m, 2H, -O- CH 2 -CH 2 -N + - (CH 3) 3), 7.82 (d, 2H, - CHofPh), 8.34 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 1.12

[Example 1-3] A boronic acid-containing phosphorylcholine compound represented by formula (46) (6-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -5-hydroxyhexylphosphorylcholine) and formula (47 ) Synthesis of a boronic acid-containing phosphorylcholine compound (5-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -6-hydroxyhexylphosphorylcholine) represented by the formula (1) synthesized in Synthesis Example 1 in a 50 mL flask 29) 5,6-epoxyhexyl phosphorylcholine 282 mg (1.0 mmol), 5- (4-dihydroxyborylphenyl) pentanoic acid 244 mg (1.1 mmol) represented by formula (45), and chloroform 5 mL In addition, it was stirred at room temperature. Triethylamine 10.1 mg (0.1 mmol) was added and reacted at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of water was added to the residue. This aqueous solution was washed with 10 mL of ethyl acetate three times, and the aqueous layer was concentrated under reduced pressure to give 6-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -5-hydroxyhexyl phosphorylcholine represented by the formula (46). And 5-[(1-dihydroxyborylbenzene-4-butyl) carbonyloxy] -6-hydroxyhexylphosphorylcholine represented by the formula (47) at a ratio of 7: 3. The yield was 343 mg (0.68 mmol), and the yield was 68%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
_{^{1 H-NMR (CD 3 OD}} ): 1.24-1.60 (m, 10H, -O-CH 2 - CH 2 -CH 2 -CH 2 -CH -, - OC (O) CH 2 - CH 2 _{-CH 2 -CH 2 -Ph), 2.17} (t, 2H, -OC (O) CH 2 -CH 2 -CH 2 - CH 2 -Ph), 2.33 (t, 2H, -OC (O _{) CH 2 -CH 2 -CH 2 -CH} 2 -Ph) 3.24 (s, 9H, -N + (CH 3) 3), 3.61-3.62 (m, 2H, -O-CH 2 _{^{- CH 2 -N + (CH 3}} ) 3), 3.76-4.66 (m, 7H, - CH 2 -CH-CH 2 -, - O- CH 2 -CH 2 -CH 2 -CH 2 - _{CH -), 4.23-4.30 (m,} 2H, -O- CH 2 -CH 2 -N + - (CH 3) 3), 7.85 (d, 2H, CHofPh), 8.35 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 1.03

[Example 1-4] A boronic acid-containing phosphorylcholine compound represented by formula (49) (3-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine) and formula (50 ) Synthesis of a boronic acid-containing phosphorylcholine compound (2-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine) represented by the formula (3) synthesized in Synthesis Example 3 in a 50 mL flask 32) (2-oxo-1,3-dioxolan-4-yl) methylphosphorylcholine 283 mg (1.0 mmol) and methanol 10 mL were added. 373 mg (2.0 mmol) of 4-aminomethylphenylborate represented by the formula (48) was added and reacted at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was added dropwise into ethyl acetate (50 mL). The supernatant was removed, the precipitate was dried under reduced pressure, and 3-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine represented by the formula (49) and the formula (50) The represented 2-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine was obtained in a ratio of 3: 2. The yield was 382 mg (0.88 mmol), and the yield was 88%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
¹ H-NMR (CD ₃ OD): 3.25 (s, 9H, —N ⁺ (CH ₃ ) ₃ ), 3.62 to 3.64 (m, 2H, —O—CH ₂ —CH ₂ —N) _{^{+ (CH 3) 3),}} 3.90-3.97 (m, 4H, -O- CH 2 -CH-CH 2 -, - Ph- CH 2 -NH -), 3.98-4.21 ( _{m, 5H, -O-CH 2} -CH 2 -CH 2 -CH 2 - CH -CH 2 -, - NH-C (O) O- CH 2 -CH -, - OC (O) NH- CH 2 - _{), 4.28-4.37 (m, 2H,} -O- CH 2 -CH 2 -N + - (CH 3) 3), 7.44 (d, 2H, -CHofPh), 8.05 (d , 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 0.93, 1.10.

[Example 1-5] A boronic acid-containing phosphorylcholine compound represented by formula (51) (6-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -5-hydroxypropylphosphorylcholine) and formula (52 ) Synthesis of a boronic acid-containing phosphorylcholine compound (5-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -6-hydroxypropylphosphorylcholine) represented by the formula (5) synthesized in Synthesis Example 5 in a 50 mL flask. 34) 4- (2-oxo-1,3-dioxolan-4-yl) butylphosphorylcholine 325 mg (1.0 mmol) and methanol 10 mL were added. 373 mg (2.0 mmol) of 4-aminomethylphenylborate represented by the formula (48) was added and reacted at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was added dropwise into ethyl acetate (200 mL). The supernatant was removed, the precipitate was dried under reduced pressure, and 6-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -5-hydroxypropylphosphorylcholine represented by formula (51) and formula (52) The represented 5-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -6-hydroxypropylphosphorylcholine was obtained in a ratio of 3: 2. The yield was 392 mg (0.85 mmol), and the yield was 85%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
_{^{1 H-NMR (CD 3 OD}} ): 1.40-1.68 (m, 6H, -O-CH 2 - CH 2 -CH 2 -CH 2 -CH-CH 2 -), 3.25 (s, _{^{9H, -N + (CH 3)}} 3), 3.62-3.64 (m, 2H, -O-CH 2 - CH 2 -N + (CH 3) 3), 3.88-3.97 ( m, 4H, —O— CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH—CH ₂ —, —Ph— CH ₂ —NH—), 4.05-4.20 (m, 3H, —O—) _{CH 2 -CH 2 -CH 2 -CH 2} - CH -CH 2 -, - NH-C (O) O- CH 2 -CH -), 4.28-4.37 (m, 2H, -O- CH _{^{2 -CH 2 -N + - (CH}} 3) 3), 7.44 (d, 2H, -CHofPh), 8.05 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 1.15

[Example 1-6] Synthesis of boronic acid-containing phosphorylcholine compound represented by formula (54) (2-[(4-dihydroxyborylbenzene-1-yl) amino] ethylphosphorylcholine) Synthesis Example 6 was carried out in a 50 mL flask. 225 mg (1.0 mmol) of formylmethyl phosphorylcholine represented by the formula (36) synthesized in (1) and 10 mL of methanol were added. 137 mg (1.0 mmol) of 4-aminophenylboronic acid represented by the formula (53) and 214 mg (2.0 mmol) of 2-picoline borane were added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10 mL of water. This aqueous solution was washed with 10 mL of ethyl acetate three times, and the aqueous layer was concentrated under reduced pressure to obtain 2-[(4-dihydroxyborylbenzene-1-yl) amino] ethyl phosphorylcholine represented by the formula (54). The yield was 228 mg (0.66 mmol), and the yield was 66%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
¹ H-NMR (CD ₃ OD): 2.94 (t, 2H, —O—CH ₂ —CH ₂ —NH—), 3.20 (s, 9H, —N ⁺ (CH ₃ ) ₃ ), 3 .66-3.69 (m, 2H, —O—CH ₂ —CH ₂ —N ⁺ — (CH ₃ ) ₃ ), 3.99-4.03 (m, 2H, —O— CH ₂ —CH _{2 ^{-NH -), 4.29-4.35 (m,}} 2H, -O- CH 2 -CH 2 -N + - (CH 3) 3, 7.40 (d, 2H, -CH of Ph), 8 .02 (d, 2H, -CH of Ph)
³¹ P-NMR (CD ₃ OD): 0.80

[Example 1-7] Synthesis of boronic acid-containing phosphorylcholine compound (2-[(1-dihydroxyborylbenzene-4-ethyl) amino] ethylphosphorylcholine) represented by formula (56) In a 50 mL flask, Synthesis Example 6 225 mg (1.0 mmol) of formylmethyl phosphorylcholine represented by the formula (36) synthesized in (1) and 10 mL of methanol were added. 165 mg (1.0 mmol) of [4- (2-aminoethyl) phenyl] dihydroxyborane represented by the formula (55) and 214 mg (2.0 mmol) of 2-picoline borane were added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10 mL of water. This aqueous solution was washed 3 times with 10 mL of ethyl acetate, and the aqueous layer was concentrated under reduced pressure to obtain 2-[(1-dihydroxyborylbenzene-4-ethyl) amino] ethylphosphorylcholine represented by the formula (56). The yield was 325 mg (0.87 mmol), and the yield was 87%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
¹ H-NMR (CD ₃ OD): 2.33 (t, 2H, —NH—CH ₂ —CH ₂ —Ph), 2.85-2.96 (m, 4H, —O—CH ₂ —CH _{2) ^{-NH- CH 2 -CH 2 -Ph),}} 3.20 (s, 9H, -N + (CH 3) 3), 3.66-3.69 (m, 2H, -O-CH 2 - CH 2 _{^{-N + - (CH 3) 3}} ), 3.99-4.03 (m, 2H, -O- CH 2 -CH 2 -NH -), 4.29-4.35 (m, 2H, -O ^{_{- CH 2 -CH 2 -N + -}} (CH 3) 3, 7.40 (d, 2H, -CHofPh), 8.01 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 0.80

[Example 1-8] Synthesis of boronic acid-containing phosphorylcholine compound represented by formula (58) (2-[(3-dihydroxyborylbenzene-1-yl) amino] ethylphosphorylcholine) Synthesis Example 6 was added to a 50 mL flask. 225 mg (1.0 mmol) of formylmethyl phosphorylcholine represented by the formula (36) synthesized in (1) and 10 mL of methanol were added. 137 mg (1.0 mmol) of 3-aminophenylboronic acid represented by the formula (57) and 214 mg (2.0 mmol) of 2-picoline borane were added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10 mL of water. This aqueous solution was washed three times with 10 mL of ethyl acetate, and the aqueous layer was concentrated under reduced pressure to obtain 2-[(3-dihydroxyborylbenzene-1-yl) amino] ethyl phosphorylcholine represented by the formula (58). The yield was 235 mg (0.68 mmol), and the yield was 68%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
¹ H-NMR (CD ₃ OD): 2.94 (t, 2H, —O—CH ₂ —CH ₂ —NH—), 3.20 (s, 9H, —N ⁺ (CH ₃ ) ₃ ), 3 .66-3.69 (m, 2H, —O—CH ₂ —CH ₂ —N ⁺ — (CH ₃ ) ₃ ), 3.99-4.03 (m, 2H, —O— CH ₂ —CH _{2 ^{-NH -), 4.29-4.35 (m,}} 2H, -O- CH 2 -CH 2 -N + - (CH 3) 3, 7.41 (d, 1H, -CHofPh), 7.78 (Dd, 1H, -CHofPh), 7.94 (d, 1H, -CHofPh), 8.18 (d, 1H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 0.77

[Example 1-9] Synthesis of boronic acid-containing phosphorylcholine compound represented by formula (59) (10-[(4-dihydroxyborylbenzene-1-yl) amino] decylphosphorylcholine) Synthesis Example 8 was carried out in a 50 mL flask. 337 mg (1.0 mmol) of 9-formylnonylphosphorylcholine represented by the formula (39) synthesized in the above and 10 mL of methanol were added. 137 mg (1.0 mmol) of 4-aminophenylboronic acid represented by the formula (53) and 214 mg (2.0 mmol) of 2-picoline borane were added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10 mL of water. This aqueous solution was washed 3 times with 10 mL of ethyl acetate, and the aqueous layer was concentrated under reduced pressure to obtain 10-[(4-dihydroxyborylbenzene-1-yl) amino] decylphosphorylcholine represented by the formula (59). The yield was 263 mg (0.70 mmol), and the yield was 70%. The measurement results of ¹ H-NMR and ³¹ P-NMR concerning the obtained product are shown below.
_{^{1 H-NMR (CD 3 OD}} ): 1.45-1.70 (m, 16H, -O-CH 2 - CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH _{2 -CH 2 -NH -), 2.98} (t, 2H, -O-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - CH 2 - _{^{NH -), 3.20 (s,}} 9H, -N + (CH 3) 3), 3.64-3.67 (m, 2H, -O-CH 2 - CH 2 -N + - (CH 3) _{3), 3.94-3.99 (m, 2H} , -O- CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -NH- _{), 4.29-4.35 (m, 2H,} -O- CH 2 -CH 2 -N + - (CH 3) 3), 7.01 (d, 2 H, -CHofPh), 7.95 (d, 2H, -CHofPh)
³¹ P-NMR (CD ₃ OD): 0.83

[Example 2-1] Synthesis of phosphorylcholine group-containing polyethylene glycol In a 50 mL flask, 5.0 g (1.0 mmol) of polyethylene glycol (weight average molecular weight = 5000, SUNBRIGHT ME-050CS, manufactured by NOF), dimethylformamide (20 mL). Was added. 328 mg (1.5 mmol) of 4-iodoaniline (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred at room temperature for 5 hours. The reaction mixture was reprecipitated twice with ethanol, dried under reduced pressure and then lyophilized to obtain iodinated polyethylene glycol.
The obtained iodinated polyethylene glycol, 3-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -2-hydroxypropylphosphorylcholine represented by the formula (49) synthesized in Example 1-4, Example 461 mg (1.1 mmol) of 2-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -3-hydroxypropylphosphorylcholine mixture represented by formula (50) synthesized in 1-4, and phosphate buffer 10 mL (pH 8.0) was added. 0.2 mL (0.1 mmol) of a solution containing palladium acetate represented by L ₂ Pd (OAc) ₂ (the structure of L is represented by formula (60)) was added, and the mixture was stirred at 50 ° C. for 24 hours. The reaction mixture was reprecipitated twice with acetone, freeze-dried after drying under reduced pressure, and phosphorylcholine group-containing polyethylene glycol was obtained.

[Example 2-2] Synthesis of phosphorylcholine group-containing peptide In a 50 mL flask, 1.01 g (1.0 mmol) of poly L lysine (weight average molecular weight = 1013, commissioned synthetic product, Sigma-Aldrich), 4-iodoaniline 328 mg (1.5 mmol) and dimethyl sulfoxide 10 mL were added. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 287 mg (1.5 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was reprecipitated twice with ethanol, dried under reduced pressure and then lyophilized to obtain an iodinated peptide.
968 mg (0.8 mmol) of the obtained iodinated peptide, 6-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -5-hydroxy represented by the formula (51) synthesized in Example 1-5 Propyl phosphorylcholine, 361 mg (1.0 mmol) of a mixture of 5-[(1-dihydroxyborylbenzene-4-methyl) carbamoyloxy] -6-hydroxypropylphosphorylcholine represented by the formula (52) synthesized in Example 1-5, And 10 mL of phosphate buffer (pH 8.0) was added. 0.2 mL (0.1 mmol) of a solution containing palladium acetate represented by L ₂ Pd (OAc) ₂ was added, and the mixture was stirred at 30 ° C. for 24 hours. The reaction mixture was reprecipitated twice with ethanol, dried under reduced pressure, and then lyophilized to obtain a phosphorylcholine group-containing peptide.

[Example 2-3] Synthesis of phosphorylcholine group-containing BSA 100 mg of BSA (albumin from bovine serum) (Sigma-Aldrich) was dissolved in 10 mL of phosphate buffer (pH 7-9) and equilibrated with phosphate buffer. It was applied to a PD-10 (gel filtration column GE Healthcare) column. To this eluate, 2 mL of a dimethyl sulfoxide solution of 10 mg of dibenzylcyclooctyne-N-hydroxysuccinimide ester was added and stirred at room temperature for 30 minutes. 1 mL of 1M Tris-HCl buffer (pH 8.0) was added and stirred at room temperature for 5 minutes. The reaction solution was applied to a PD-10 column equilibrated with phosphate buffer. To this eluate, 2.5 mL of a phosphate buffer solution containing 10 mg of the phosphorylcholine group-containing peptide synthesized in Example 2-3 was added and stirred at room temperature for 3 hours. The reaction mixture was applied to a PD-10 column equilibrated with a phosphate buffer and lyophilized to obtain phosphorylcholine group-containing BSA.

<Quantitative determination of phosphorus>
In order to confirm that the phosphorylcholine group was well modified for the compounds synthesized in Example 2-1, Example 2-2, and Example 2-3, phosphorus was quantified (molybdenum blue method). Phosphorus was quantified using a phosphate cell test manufactured by Merck and the content of element P was measured with a simple total phosphorus meter.

Specifically, phosphorylcholine according to Example 2-1, Example 2-2, Example 2-3, and Example 2-4 prepared in a reaction cell at a predetermined concentration (≈0.01 wt%). 5 mL of an aqueous solution of a group-containing compound (cellulose, polyethylene glycol, peptide, BSA) is added, the p-1k reagent is added once, stirred and mixed, and then reacted at 120 ° C. for 30 minutes in the reactor (CR3200). As a reference, p-1k was added to a reaction cell containing only ion-exchanged water containing no phosphorylcholine group-containing compound, and the reaction was similarly performed in the reactor. After the reaction, cool for 30 minutes at room temperature, add 5 drops of p-2k reagent to each reaction cell and stir and mix. Then, p-3k reagent is added to each reaction cell once and left for 5 minutes. Thereafter, the content of P element (mg / l) was measured from the absorbance at 612 nm by pHoFlex.

  Table 1 shows the PC group introduction rate for Example 2-1, Example 2-2, and Example 2-3. In any of Example 2-1, Example 2-2, and Example 2-3, the PC group introduction rate was sufficiently high, and the phosphorylcholine group was modified well.

  The embodiment of the present invention has been described above, but the present invention is not limited to the above-described embodiment, and it is needless to say that various modifications can be made without departing from the gist of the present invention.

Claims (4)

A boronic acid-containing phosphorylcholine compound represented by the following formula (1).

(In formula (1), j represents an integer of 0 to 15. k represents an integer of 1 to 9. W represents a phenyl group or a vinylene group. -X (A ₁ )-represents-. X-A _1- , -A ₁ -X-, or -X- is one of the following: X represents -C (O) O-, -OC (O)- , - NHC (O) O—, —OC (O) NH— , —NHC (O) —, —C (O) NH— , —NHCH ₂ —, —CH ₂ NH— A ₁ is any one of a structure represented by the following formula (2a), a structure represented by the following formula (2b), and a structure represented by the following formula (2c). One.)

A boronic acid-containing compound represented by the following formula (3) and a phosphorylcholine group-containing compound represented by the following formula (4) are prepared,
Addition reaction of the boronic acid-containing compound and the phosphorylcholine group-containing compound
The manufacturing method of the boronic acid containing phosphorylcholine compound of Claim 1 .

(In formula (3), Y represents any one of a carboxyl group, a primary amino group, an epoxy group, a formyl group, and a cyclocarbonate group. J represents an integer of 0 to 15. W represents a phenyl group or a vinylene group.)

(In formula (4), Z represents any one of a primary amino group and an epoxy group when Y is a carboxyl group, and when Y is a primary amino group, , Represents any one of a formyl group and a cyclocarbonate group, and when Y is an epoxy group, it represents a carboxyl group, and when Y is a formyl group, it represents a primary amino group, and Y represents When it is a cyclocarbonate group, it represents a primary amino group, and k represents an integer of 1 to 9.) The phosphoric acid choline compound containing boronic acid according to claim 1,
An iodo group-containing compound modifier for modifying a compound having an iodo group with a phosphorylcholine group. An iodo group-containing compound modifier according to claim 3,
The iodo group-containing compound modifier, wherein the compound having an iodo group is an iodo group-containing protein, an iodo group-containing polyethylene glycol, or an iodo group-containing peptide.