JPH083172A - Phenylboronic acid derivative and its production - Google Patents

Abstract

PURPOSE:To obtain the subject derivative capable of being efficiently reacted with a polymer or a medicine, useful for introducing boronic acid group or a fluoroalkyl group, simply and effectively by reacting a prescribed fluorinated aminophenylboronic acid with an amino acid and deprotecting the reaction product. CONSTITUTION:This derivative is expressed by formula I {(a) is 1 or 2; Rf is F or CbF2bX [X is F, H or Cl; (b) is 1-10] or CF(CF3) [OCF2CF(CF3)]cOC3F7[(c) is 0 or 1-8]; R<1> is H or a 1-10C hydrocarbon; (n) is 0-6] such as 3- aminoacetylamino-2-trifluoromethylphenylboronic acid. For example, the derivative is obtained by reacting (A) a fluorinated aminophenylboronic acid of formula II with (B) an amino acid containing a protected amino group and deprotecting. 3-Amino-2-trifluoromethylphenylboronic acid is preferably used as the component A and alpha-aminobutyric acid as the component B.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel and useful phenylboronic acid derivative having a boronic acid group, an aminoalkyl group and a fluoroalkyl group, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Polymers containing phenylboronic acid groups utilize the property that phenylboronic acid groups form a reversible complex with the hydroxyl groups of polyvalent hydroxyl compounds, and in the field of affinity chromatography the separation of sugars is considered. Used for purification. Polymers that can be used for the separation and purification of such sugars include, for example, phenylboronic acid-
The crosslinked agarose gel is Matrex (registered trademark) PBA-30 manufactured by Amicon.

Further, JP-A-4-124144 and JP-A-4-124144.
-124145 and Japanese Unexamined Patent Publication No. 5-93019, phenylboronic acid derivatives such as acryloylaminobenzeneboronic acid, methacryloylaminobenzeneboronic acid, and 4-vinylbenzeneboronic acid are used as a boronic acid group-containing monomer, and other monomers are used. Polymers containing boronic acid groups copolymerized with are described. Then, these boronic acid group-containing polymers are used as sugar-responsive polymers and used in diabetes treatment systems and the like. Further, JP-A-5-26277
No. 9 also describes a boronic acid group-containing monomer having a vinyl group, and a polymer composed of this monomer is used as a sugar-responsive polymer.

However, the phenylboronic acid derivatives described in these publications are useful as a monomer for obtaining a boronic acid group-containing polymer because the functional group is a vinyl group, but other than vinyl groups. Since there is no functional group, it is impossible to modify the polymer afterwards to introduce a boronic acid group into the polymer. Further, a boronic acid group cannot be introduced into a compound other than a polymer, such as a drug.

On the other hand, as the fluorinated phenylboronic acid, m-fluorophenylboronic acid (US Pat.
55175), p-fluorophenylboronic acid (US Pat. No. 360701, Bull. Chem. Soc. Jpn., 61, 30.
08-3010 (1988)), 2,3-difluorophenylboronic acid (WO 8905792, WO 9802425).
Issue, J. Chem. Soc. Trans. II., 12, 2041-53 (198
9)), p-trifluorophenylboronic acid (J. Chem. S
oc. Trans. I., 3, 715-720 (1990)), 4-Vorono-2
-Fluoro-D, L-phenylalanine (Appl. Radia
t. Isot., 42, 325-328 (1991)) and the like are known. However, since these fluorinated phenylboronic acids only have a fluoro group or a trifluoromethyl group as a substituent other than the boronic acid group and do not have a highly reactive functional group, they are the same as above. It is not possible to introduce a boronic acid group into these compounds by later modifying the polymer or drug.

By the way, JP-A-5-301880 describes a fluorinated aminophenylboronic acid having an amino group directly bonded to a benzene ring. However, this fluorinated aminophenylboronic acid has a low reactivity to polymers and drugs because the amino group is directly bonded to the benzene ring. Therefore, these compounds are modified later to introduce a boronic acid group. Has a problem of low reaction rate.

[0007]

The object of the present invention is to provide an aminoalkyl group capable of efficiently reacting with a polymer or drug, a boronic acid group capable of forming a reversible complex with a hydroxyl group such as a saccharide, and an electron. A novel and useful phenylboronic acid derivative having an inhalable fluoroalkyl group, and a method for producing the same.

[0008]

The present invention provides the following phenylboronic acid derivative and a method for producing the same. (1) A phenylboronic acid derivative represented by the general formula [1].

[Chemical 4][In the Formula, a is 1 or 2, R_fIs -F, -C_bF_2bX (was
However, X is F, H or Cl, b is an integer of 1-10),
Or -CF (CF₃) [OCF₂CF (CF₃)]_cOC ₃F
₇(However, c is 0 or an integer of 1 to 8). R¹Is
H or a hydrocarbon group having 1 to 10 carbon atoms, n is an integer of 0 to 6
Indicates a number. ] (2) General formula [2]

[Chemical 5][In the Formula, a is 1 or 2, R_fIs -F, -C_bF_2bX (was
However, X is F, H or Cl, b is an integer of 1-10),
Or -CF (CF₃) [OCF₂CF (CF₃)]_cOC ₃F
₇(However, c is 0 or an integer of 1 to 8). 〕so
Fluorinated aminophenylboronic acid shown and amino group
After reacting with the protected amino acid, remove the protecting group.
Pheny represented by the general formula [1]
Method for producing ruboronic acid derivative.

In the general formula [1], H ₂ N- (CH ₂ ) _n
The —CH (R ¹ ) —CONH— group, the boronic acid group and the R _f group may be bonded to any position of the benzene ring, and any 2
The positional relationship between the two groups may be any of an ortho, meta, or para positional relationship.

The fluoroalkyl group represented by R _f in the general formula [1] or [2] is specifically a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a perfluorobutyl group, a perfluoropentyl group. , Perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, 1,1-difluoromethyl group, 1,1,2,2-tetrafluoroethyl group,
1,1,2,2,3,3-hexafluoropropyl group,
ω-hydroperfluorobutyl group, ω-hydroperfluoropentyl group, ω-hydroperfluorohexyl group,
ω-hydroperfluoroheptyl group, ω-hydroperfluorooctyl group, ω-hydroperfluorononyl group,
ω-hydroperfluorodecyl group, 1-chloro-1,1
-Difluoromethyl group, 2-chloro-1,1,2,2-
Tetrafluoroethyl group, 3-chloro-1,1,2,
2,3,3-hexafluoropropyl group, ω-chloroperfluorobutyl group, ω-chloroperfluoropentyl group, ω-chloroperfluorohexyl group, ω-chloroperfluoroheptyl group, ω-chloroperfluorooctyl group, ω-chloroperfluoro group Nonyl group, ω-chloroperfluorodecyl group, perfluoro-1-methyl-2-
Oxapentyl group, perfluoro-1,4-dimethyl-
2,5-dioxaoctyl group, perfluoro-1,4
7-trimethyl-2,5,8-trioxaundecyl group, perfluoro-1,4,7,10-tetramethyl-
2,5,8,11-tetraoxatetradecyl group, perfluoro-1,4,7,10,13-pentamethyl-
2,5,8,11,14-pentaoxaheptadecyl group, perfluoro-1,4,7,10,13,16-hexamethyl-2,5,8,11,14,17-hexaoxaeicosyl group, Perfluoro-1,4,7,10,
13,16,19-heptamethyl-2,5,8,11,
14,17,20-heptaoxatricosyl group, perfluoro-1,4,7,10,13,16,19,22-
Octamethyl-2,5,8,11,14,17,20,
23-octaoxahexacosyl group, perfluoro-
1,4,7,10,13,16,19,22,25-nonamethyl-2,5,8,11,14,17,20,2
Examples include 3,26-nonaoxanonacosyl group and the like.

Examples of the hydrocarbon group having 1 to 10 carbon atoms represented by R ¹ in the general formula [1] include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Examples thereof include alkyl groups such as isobutyl group, sec-butyl group and tert-butyl group; substituted alkyl groups such as benzyl group.

In the general formula [1], H ₂ N- (CH ₂ ) _n
Specific examples of the group represented by —CH (R ¹ ) —CO— include aminoacyl groups derived from the following amino acids.

[Chemical 6]

In addition to the above, H ₂ N-(CH ₂ ) _n --CH (R
¹ ) Specific examples of the group represented by -CO- include 4-aminobutyryl group, 5-aminovaleryl group, 6-aminohexanoyl group, 7-aminoheptanoyl group, 8-aminooctanoyl group and the like amino acids. The aminoacyl group derived from can be mentioned.

Specific examples of the phenylboronic acid derivative represented by the general formula [1] include 3-aminoacetylamino-2-trifluoromethylphenylboronic acid and 3-aminoacetylamino-4-trifluoromethyl. Phenylboronic acid, 3-aminoacetylamino-5-
Trifluoromethylphenylboronic acid, 3-aminoacetylamino-6-trifluoromethylphenylboronic acid, 3-aminoacetylamino-2,4-bis (trifluoromethyl) phenylboronic acid, 3-aminoacetylamino-2- Pentafluoroethylphenylboronic acid,
3-aminoacetylamino-4-pentafluoroethylphenylboronic acid, 3-aminoacetylamino-5-pentafluoroethylphenylboronic acid, 3-aminoacetylamino-6-pentafluoroethylphenylboronic acid, 3-aminoacetylamino -2,5-bis (pentafluoroethyl) phenylboronic acid, 3-aminoacetylamino-2-heptafluoropropylphenylboronic acid, 3-aminoacetylamino-4-heptafluoropropylphenylboronic acid, 3-aminoacetylamino −
5-heptafluoropropylphenylboronic acid, 3-aminoacetylamino-6-heptafluoropropylphenylboronic acid, 3-aminoacetylamino-2,6-bis (heptafluoropropyl) phenylboronic acid, 3-
Aminoacetylamino-6-perfluorobutylphenylboronic acid, 3-aminoacetylamino-4,5-bis (perfluorobutyl) phenylboronic acid, 3-aminoacetylamino-2-perfluoropentylphenylboronic acid, 3-aminoacetylamino -4,6-bis (perfluoropentyl) phenylboronic acid, 3-aminoacetylamino-4-perfluorohexylphenylboronic acid, 3-aminoacetylamino-5,6-bis (perfluorohexyl) phenylboronic acid,

3-aminopropionylamino-2-trifluoromethylphenylboronic acid, 3-aminopropionylamino-4-trifluoromethylphenylboronic acid, 3-aminopropionylamino-5-trifluoromethylphenylboronic acid, 3- Aminopropionylamino-6-trifluoromethylphenylboronic acid, 3-aminopropionylamino-2,4-bis (trifluoromethyl) phenylboronic acid, 3-aminopropionylamino-2-pentafluoroethylphenylboronic acid, 3
-Aminopropionylamino-4-pentafluoroethylphenylboronic acid, 3-aminopropionylamino-
5-pentafluoroethylphenylboronic acid, 3-aminopropionylamino-6-pentafluoroethylphenylboronic acid, 3-aminopropionylamino-2,5
-Bis (pentafluoroethyl) phenylboronic acid, 3
-Aminopropionylamino-2-heptafluoropropylphenylboronic acid, 3-aminopropionylamino-4-heptafluoropropylphenylboronic acid, 3-
Aminopropionylamino-5-heptafluoropropylphenylboronic acid, 3-aminopropionylamino-
6-heptafluoropropylphenylboronic acid, 3-aminopropionylamino-2,6-bis (heptafluoropropyl) phenylboronic acid, 3-aminopropionylamino-6-perfluorobutylphenylboronic acid,
3-aminopropionylamino-4,5-bis (perfluorobutyl) phenylboronic acid, 3-aminopropionylamino-2-perfluoropentylphenylboronic acid, 3-aminopropionylamino-4,6-bis (perfluoropentyl) phenylboron Acid, 3-aminopropionylamino-4-perfluorohexylphenylboronic acid, 3-aminopropionylamino-5,6-bis (perfluorohexyl) phenylboronic acid and the like.

The phenylboronic acid derivative represented by the general formula [1] is obtained by reacting the fluorinated aminophenylboronic acid represented by the general formula [2] with an amino group-protected amino acid. Then, it can be produced by removing the amino-protecting group from this intermediate.

Specific examples of the fluorinated aminophenylboronic acid represented by the general formula [2] include 3-amino-2-trifluoromethylphenylboronic acid and 3-amino-2-trifluoromethylphenylboronic acid.
Amino-4-trifluoromethylphenylboronic acid, 3
-Amino-5-trifluoromethylphenylboronic acid,
3-amino-6-trifluoromethylphenylboronic acid, 3-amino-2,4-bis (trifluoromethyl)
Phenylboronic acid, 3-amino-2-pentafluoroethylphenylboronic acid, 3-amino-4-pentafluoroethylphenylboronic acid, 3-amino-5-pentafluoroethylphenylboronic acid, 3-amino-6-penta Fluoroethylphenylboronic acid, 3-amino-2,
5-bis (pentafluoroethyl) phenylboronic acid,
3-amino-2-heptafluoropropylphenylboronic acid, 3-amino-4-heptafluoropropylphenylboronic acid, 3-amino-5-heptafluoropropylphenylboronic acid, 3-amino-6-heptafluoropropylphenylboron Acid, 3-amino-2,6-bis (heptafluoropropyl) phenylboronic acid,

3-amino-6-perfluorobutylphenylboronic acid, 3-amino-4,5-bis (perfluorobutyl) phenylboronic acid, 3-amino-2-perfluoropentylphenylboronic acid, 3-amino-4, 6
-Bis (perfluoropentyl) phenylboronic acid, 3
-Amino-4-perfluorohexylphenylboronic acid, 3-amino-5,6-bis (perfluorohexyl) phenylboronic acid, 3-amino-5-perfluoroheptylphenylboronic acid, 3-amino-2,4-bis ( Perfluoroheptyl) phenylboronic acid, 3-amino-6-perfluorooctylphenylboronic acid, 3-
Amino-2,5-bis (perfluorooctyl) phenylboronic acid, 3-amino-2-perfluorononylphenylboronic acid, 3-amino-2,6-bis (perfluorononyl) phenylboronic acid, 3-amino-4- Perfluorodecylphenylboronic acid, 3-amino-4,5-
Bis (perfluorodecyl) phenylboronic acid, 3-amino-5- (1,1-difluoromethyl) phenylboronic acid, 3-amino-4,6-bis (1,1-difluoromethyl) phenylboronic acid, 3- Amino-6- (1,
1,2,2-Tetrafluoroethyl) phenylboronic acid, 3-amino-5,6-bis (1,1,2,2-tetrafluoroethyl) phenylboronic acid, 3-amino-2
-(1,1,2,2,3,3-hexafluoropropyl) phenylboronic acid, 3-amino-2,4-bis (1,1,2,2,3,3-hexafluoropropyl)
Phenylboronic acid,

3-amino-4- (ω-hydroperfluorobutyl) phenylboronic acid, 3-amino-2,5-bis (ω-hydroperfluorobutyl) phenylboronic acid, 3-amino-5- (ω-hydro) Perfluoropentyl) phenylboronic acid, 3-amino-2,6-bis (ω
-Hydroperfluoropentyl) phenylboronic acid, 3
-Amino-6- (ω-hydroperfluorohexyl) phenylboronic acid, 3-amino-4,5-bis (ω-hydroperfluorohexyl) phenylboronic acid, 3-amino-2- (ω-hydroperfluoroheptyl) phenyl Boronic acid, 3-amino-4,6-bis (ω-hydroperfluoroheptyl) phenylboronic acid, 3-amino-4
-(Ω-hydroperfluorooctyl) phenylboronic acid, 3-amino-5,6-bis (ω-hydroperfluorooctyl) phenylboronic acid, 3-amino-5- (ω
-Hydroperfluorononyl) phenylboronic acid, 3-
Amino-2,4-bis (ω-hydroperfluorononyl) phenylboronic acid, 3-amino-6- (ω-hydroperfluorodecyl) phenylboronic acid, 3-amino-
2,5-bis (ω-hydroperfluorodecyl) phenylboronic acid,

3-amino-2- (1-chloro-1,1-
Difluoromethyl) phenylboronic acid, 3-amino-
2,5-bis (1-chloro-1,1-difluoromethyl) phenylboronic acid, 3-amino-4- (2-chloro-1,1,2,2-tetrafluoroethyl) phenylboronic acid, 3- Amino-2,6-bis (2-chloro-1,
1,2,2-tetrafluoroethyl) phenylboronic acid, 3-amino-4- (3-chloro-1,1,2,2,2
3,3-hexafluoropropyl) phenylboronic acid,
3-amino-2,6-bis (3-chloro-1,1,2,
2,3,3-hexafluoropropyl) phenylboronic acid,

3-amino-5- (ω-chloroperfluorobutyl) phenylboronic acid, 3-amino-4,5-bis (ω-chloroperfluorobutyl) phenylboronic acid, 3-amino-6- (ω-chloro Perfluoropentyl) phenylboronic acid, 3-amino-4,6-bis (ω
-Chloroperfluoropentyl) phenylboronic acid, 3
-Amino-2- (ω-chloroperfluorohexyl) phenylboronic acid, 3-amino-5,6-bis (ω-chloroperfluorohexyl) phenylboronic acid, 3-amino-4- (ω-chloroperfluoroheptyl) phenyl Boronic acid, 3-amino-2,4-bis (ω-chloroperfluoroheptyl) phenylboronic acid, 3-amino-5
-(Ω-chloroperfluorooctyl) phenylboronic acid, 3-amino-2,5-bis (ω-chloroperfluorooctyl) phenylboronic acid, 3-amino-6- (ω
-Chloroperfluorononyl) phenylboronic acid, 3-
Amino-2,6-bis (ω-chloroperfluorononyl) phenylboronic acid, 3-amino-2- (ω-chloroperfluorodecyl) phenylboronic acid, 3-amino-
4,5-bis (ω-chloroperfluorodecyl) phenylboronic acid,

3-amino-4- (perfluoro-1-methyl-2-oxapentyl) phenylboronic acid, 3-amino-4,6-bis (perfluoro-1-methyl-2-)
Oxapentyl) phenylboronic acid, 3-amino-5-
(Perfluoro-1,4-dimethyl-2,5-dioxaoctyl) phenylboronic acid, 3-amino-5,6-bis (perfluoro-1,4-dimethyl-2,5-dioxaoctyl) phenylboronic acid , 3-amino-6- (perfluoro-1,4,7-trimethyl-2,5,8-trioxaundecyl) phenylboronic acid, 3-amino-
2,4-bis (perfluoro-1,4,7-trimethyl-2,5,8-trioxaundecyl) phenylboronic acid, 3-amino-2- (perfluoro-1,4,7,1)
0-tetramethyl-2,5,8,11-tetraoxatetradecyl) phenylboronic acid, 3-amino-2,5-
Bis (perfluoro-1,4,7,10-tetramethyl-2,5,8,11-tetraoxatetradecyl) phenylboronic acid, 3-amino-4- (perfluoro-1,
4,7,10,13-pentamethyl-2,5,8,1
1,14-pentaoxaheptadecyl) phenylboronic acid, 3-amino-2,6-bis (perfluoro-1,
4,7,10,13-pentamethyl-2,5,8,1
1,14-pentaoxaheptadecyl) phenylboronic acid, 3-amino-5- (perfluoro-1,4,7,1)
0,13,16-hexamethyl-2,5,8,11,1
4,17-hexaoxaeicosyl) phenylboronic acid, 3-amino-4,5-bis (perfluoro-1,
4,7,10,13,16-hexamethyl-2,5
8,11,14,17-hexaoxaeicosyl) phenylboronic acid,

3-amino-6- (perfluoro-1,
4,7,10,13,16,19-heptamethyl-2,
5,8,11,14,17,20-heptaoxatricosyl) phenylboronic acid, 3-amino-4,6-bis (perfluoro-1,4,7,10,13,16,19)
-Heptamethyl-2,5,8,11,14,17,20
-Heptaoxatricosyl) phenylboronic acid, 3-amino-2- (perfluoro-1,4,7,10,13,
16,19,22-octamethyl-2,5,8,11,
14,17,20,23-octaoxahexacosyl)
Phenylboronic acid, 3-amino-5,6-bis (perfluoro-1,4,7,10,13,16,19,22-
Octamethyl-2,5,8,11,14,17,20,
23-octaoxahexacosyl) phenylboronic acid,
3-amino-4- (perfluoro-1,4,7,10,
13,16,19,22,25-nonamethyl-2,5
8,11,14,17,20,23,26-nonaoxanononacosyl) phenylboronic acid, 3-amino-2,4-
Bis (perfluoro-1,4,7,10,13,16,
19,22,25-Nonamethyl-2,5,8,11,1
4,17,20,23,26-nonaoxanononacosyl)
Examples include phenylboronic acid.

As the amino acid protected with the amino acid to be reacted with the fluorinated aminophenylboronic acid represented by the general formula [2], the amino group of the amino acid represented by the following general formula [3] is a benzyloxycarbonyl group (hereinafter , Z group), t-butoxycarbonyl group (hereinafter referred to as B group).
oc group) and 9-fluorenylmethoxycarbonyl group (hereinafter sometimes referred to as Fmoc group), and other amino acids protected by a protecting group.

[Chemical 7] (In the formula, R ¹ and n have the same meanings as described above.)

Specific examples of the amino acid represented by the general formula [3] include α-aminobutyric acid, alanine, β-alanine, alloisoleucine, isoleucine, glycine, norvaline, norleucine, valine, phenylalanine,
4-aminobutanoic acid, 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid and the like can be mentioned. These can be used in any of L-form, D-form and DL-form.

Examples of amino acids with protected amino groups include Z
A group-protected amino acid (hereinafter sometimes referred to as Z-amino acid) has good crystallinity and is excellent in that it can be stored for a long period of time, and therefore it is preferably used.

The Z-amino acid can be obtained by reacting an amino acid with benzyloxycarbonyl chloride (hereinafter sometimes referred to as Z-Cl) by the Schotten-Baumann method. Alternatively, a commercially available Z-amino acid can be used. When obtaining a Z-amino acid, it is preferable to add an equivalent amount of Z-Cl to the amino acid if it is an anhydrous system, since by-products will be reduced, but it is 0.1 to 10 moles per mol of the amino acid. It can be used in the range of.
Examples of the solvent used at that time include acetonitrile, tetrahydrofuran (THF), dioxane, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), dimethylacetamide (DMAc) and the like.

An amino acid protected with a Boc group or an Fmoc group (hereinafter sometimes referred to as Boc-amino acid or Fmoc-amino acid) can be prepared by using t-butoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl chloride. It can be obtained in the same manner as above.

The reaction between the fluorinated aminophenylboronic acid represented by the general formula [2] and the Z-amino acid is carried out by carbonyldiimidazole (hereinafter sometimes referred to as CDI), dicyclohexylcarbodiimide, N-cyclohexyl-
It can be carried out in the presence of a coupling reagent such as N '-(2-morpholinoethyl) carbodiimide-meso-p-toluenesulfonate. First, CD for Z-amino acid
After adding I to generate an N-acyl derivative, the N-acyl derivative
The acyl derivative is reacted with the amino group of the fluorinated aminophenylboronic acid to give the protecting group-attached intermediate. The charged molar ratio of fluorinated aminophenylboronic acid to Z-amino acid is 1: 0.01 to 100, preferably 1: 0.
It is desirable that it is 1-10. The solvent used at that time is acetonitrile, THF, dioxane, ethyl acetate, diethyl ether, DMSO, DMF, DMAc.
And so on. The reaction temperature is -20 ° C to + 100 ° C,
It is desirable that the temperature is preferably -10 ° C to + 60 ° C. Further, the reaction time can be 30 minutes to 120 hours, but it is desirable to set other conditions so as to be practically 1 to 60 hours.

The reaction between the fluorinated aminophenylboronic acid represented by the general formula [2] and the Boc-amino acid or Fmoc-amino acid can be carried out in the same manner as above.

Next, the amino-protecting group is removed from the intermediate to obtain the phenylboronic acid derivative of the present invention. To remove the protecting group, 1) palladium black or 5
-10% catalytic reduction method using palladium on carbon; 2)
An acid treatment method using an acid such as trifluoroacetic acid, anhydrous hydrogen fluoride or trifluoromethanesulfonic acid; 3) CTH in which hydrogen is directly transferred to an intermediate having a protecting group in the presence of a hydrogen compound and a catalyst to remove the hydrogen. (Catalytic T
ransfer Hydrogenation) method can be adopted.

In the catalytic reduction method of the above 1), the protective group-bonded intermediate is dissolved in a solvent such as DMF and the like in the presence of the above catalyst under H ₂ atmosphere for 0.5 to 120 hours, preferably 1 The protecting groups can be easily removed by stirring for ~ 24 hours. In the acid treatment method of the above 2), the protecting group can be easily removed by stirring the intermediate to which the protecting group is bound in an aqueous solution containing the above acid. The CTH method of 3) above is a method of directly transferring hydrogen to an intermediate having a protective group bonded to remove the protective group in the presence of a hydrogen compound and a catalyst, and the hydrogen compound is, for example, ammonium formate, In addition, palladium carbon or the like can be used as the catalyst.

Using 3-amino-6-heptafluoropropylphenylboronic acid as the fluorinated aminophenylboronic acid of the general formula [2] and Z-glycine as the amino acid with the amino group protected, the protecting group is removed by catalytic reduction. The synthetic scheme for producing 3-aminoacetylamino-6-heptafluoropropylphenylboronic acid is
It is shown by the following reaction formula [4].

Embedded image

Since the phenylboronic acid derivative of the present invention thus obtained has a highly reactive aminoalkyl group, it can be efficiently reacted with a functional group such as a carboxylic acid group in a polymer to be bonded. it can. Therefore, since the boronic acid group and the fluoroalkyl group can be efficiently introduced into the existing polymer later, it is not necessary to polymerize the polymer containing these groups from the monomer. Further, the amount of boronic acid group introduced can be easily adjusted. Furthermore, the range of compounds that can introduce a boronic acid group is expanded, and a boronic acid group can be introduced into a compound other than a polymer (copolymer) such as a drug.

In the phenylboronic acid derivative of the present invention, since the fluoroalkyl group which is an electron-withdrawing group is bonded to the benzene ring, the boronic acid group is a polyvalent compound such as a saccharide even under alkaline conditions as well as near neutrality. A reversible complex can be formed with the hydroxyl group of the hydroxyl compound. Such a polymer having a boronic acid group and a fluoroalkyl group introduced by using the phenylboronic acid derivative of the present invention has the same sugar structure as a conventional polymer having a boronic acid group or a boronic acid group and a fluoroalkyl group. It can be used as a responsive polymer.

[0036]

INDUSTRIAL APPLICABILITY The phenylboronic acid derivative of the present invention is a novel compound and has an aminoalkyl group capable of efficiently reacting with a polymer or drug. It is useful when introducing a fluoroalkyl group. According to the manufacturing method of the present invention,
The phenylboronic acid derivative can be easily and efficiently produced.

[0037]

EXAMPLES Next, the present invention will be described in more detail by way of examples, which should not be construed as limiting the invention thereto. Example 1 0.638 g (3.050 mmol) of Z-glycine T
0.495 g (3.053 m) of carbonyldiimidazole was added to an HF (5 ml) solution while stirring in ice water (0 ° C).
mol) was added and the mixture was stirred for 90 minutes, and then a solution of 0.254 g (0.763 mmol) of 3-amino-6-heptafluoropropylphenylboronic acid (having ethanol bound) in THF (5 ml) was added. After reacting at room temperature for 50 hours with stirring, concentrate under reduced pressure, dissolve the residue in diethyl ether (300 ml), and wash with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water (100 ml each). did. After dehydration with sodium sulfate, the filtrate was concentrated under reduced pressure and dried under reduced pressure overnight to obtain 0.531 g of a yellow syrup. 5 ml of ethyl acetate with this syrup
15 ml of ligroin was added dropwise thereto, and the solution was allowed to stand in a cold room to precipitate white crystals. After collecting the white crystals by filtration, IR, ¹ H-NM
Structural analysis by R confirmed that Z-glycine was introduced into 3-amino-6-heptafluoropropylphenylboronic acid. The yield is 0.
The yield was 272 mg and the yield was 72%. The analysis results are as follows.

IR (KBr): (in cm ^-1 ) 1680, 1540 (-CONHR), 1340 (CF
₃ ), 1230 (CF ₂ ), 880, 830 (aromatic
CH, 1,2,4-trisubstituted) ¹ H-NMR (DMSO-d ₆ / TMS): δ (in p
pm) 3.84 (2H, CH ₂ (glycyl)), 5.06 (2H,
CH ₂ (benzyl)), 7.2-7.4 (5H, phenyl (benz
yl)), 7.51, 7.66, 7.80 (3H, phenyl
(phenyl boronic acid)), 7.60 (1H, -OCO
NH-), 8.23 (2H, OH), 10.3 (1H,
-CONH-)

Next, the Z group of the above reaction product was removed by catalytic reduction as follows. That is, the above reaction product 250
mg (0.504 mmol) was dissolved in 20 ml of DMF, 50 mg of 10% palladium carbon was added as a catalyst, and the mixture was stirred at room temperature for 12 hours under H ₂ atmosphere. After the palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in diethyl ether (400 ml), distilled water (50 ml) was added, and the mixture was vigorously stirred. Next, a sodium hydroxide solution was added to the distilled water side to adjust the pH to about 9. The white precipitate formed by this was collected, and IR, ¹ H
-It was confirmed by NMR and MS that pure 3-aminoacetylamino-6-heptafluoropropylphenylboronic acid was obtained. The yield was 46 mg. The analysis results are as follows.

IR (KBr): (in cm ^-1 ) 1680, 1540 (-CONHR), 1340 (CF
₃ ), 1230 (CF ₂ ), 880, 830 (aromatic
CH, 1,2,4-trisubstituted) ¹ H-NMR (DMSO-d ₆ / TMS): δ (in p
pm) 3.30 (2H, CH ₂ ), 7.49, 7.71, 7.
85 (3H, phenyl), 8.24 (2H, OH) FAB-MS ( glycerol, Positive): m / z 418 ([M + glycerol -2H ₂ O ⁺ H] +)

Example 2 The Z-amino acid in Example 1 was replaced with Z-β-alanine 0.
3-Aminopropionylamino-4-heptafluoro was prepared in the same manner as in Example 1 except that 681 g (3.050 mmol) was replaced with 3-amino-4-heptafluoropropylphenylboronic acid as the fluorinated aminophenylboronic acid. Propylphenylboronic acid was obtained. The analysis results are as follows.

IR (KBr): (in cm ^-1 ) 1680, 1540 (-CONHR), 1340 (CF
₃ ), 1225 (CF ₂ ), 875, 830 (aromatic
CH, 1,2,4-trisubstituted) ¹ H-NMR (DMSO-d ₆ / TMS): δ (in p
pm) 2.80, 3.18 (4H, 2CH ₂ ), 7.60,
7.81, 7.84 (3H, phenyl), 8.26 (2
H, OH) FAB-MS (glycerol, Positive): m / z 432 ([M + glycerol -2H ₂ O ⁺ H] +)

Example 3 The Z-amino acid in Example 1 was replaced with Boc-glycine 0.
To 613 g (3.050 mmol), the fluorinated aminophenylboronic acid was changed to 0.382 g (0.763 mmol) of 3-amino-4,6-bis (heptafluoropropyl) phenylboronic acid (with ethanol bound), 3-Aminoacetylamino-4,6-bis (heptafluoropropyl) phenylboronic acid was obtained in the same manner as in Example 1 except that the Boc group was removed using trifluoroacetic acid. The analysis results are as follows.

IR (KBr): (in cm ^-1 ) 1680, 1540 (-CONHR), 1345 (CF
₃ ), 1235 (CF ₂ ), 840 (aromatic CH, 1,4
-Disubstituted) ¹ H-NMR (DMSO-d ₆ / TMS): δ (in p
pm) 3.30 (2H, CH ₂ ), 7.40, 7.64 (2
H, phenyl), 8.23 (2H , OH) FAB-MS ( glycerol, Positive): m / z 586 ([M + glycerol -2H ₂ O ⁺ H] +)

Example 4 The Z-amino acid in Example 1 was added to Boc-β-alanine (0.577 g, 3.050 mmol), and the fluorinated aminophenylboronic acid was added to 3-amino-6-perfluorohexylphenylboronic acid (ethanol was Combined)
3-Aminopropionylamino-6-perfluorohexylphenylboronic acid was obtained in the same manner as in Example 1 except that 0.369 g (0.763 mmol) was used and the Boc group was removed using trifluoroacetic acid. The analysis results are as follows.

IR (KBr): (in cm ^-1 ) 1680, 1540 (-CONHR), 1340 (CF
₃ ), 1230 (CF ₂ ), 880, 830 (aromatic
CH, 1,2,4-trisubstituted) ¹ H-NMR (DMSO-d ₆ / TMS): δ (in p
pm) 2.75, 3.18 (4H, 2CH ₂ ), 7.48,
7.71, 7.85 (3H, phenyl), 8.24 (2
H, OH) FAB-MS (glycerol, Positive): m / z 582 ([M + glycerol -2H ₂ O ⁺ H] +)

Reference Example 1 The reactivity of 3-aminoacetylamino-6-heptafluoropropylphenylboronic acid obtained in Example 1 was measured by
It was investigated by the reaction rate with a vinylpyrrolidone-maleic anhydride copolymer. That is, DMF solvent (2.5 m
3-aminocetylamino-6-heptafluoropropylphenylboronic acid 40 mg (0.110 mmo in 1).
1) and 0.123 ml of triethylamine (0.88
2 mmol) was added and dissolved. To this, 92.5 mg of N-vinylpyrrolidone-maleic anhydride copolymer (containing maleic anhydride residue 0.442 mmol) was added, and the mixture was added at 40 ° C.
And the phenylboronic acid derivative was introduced into the copolymer. Then, the reaction solution was dropped into diethyl ether for reprecipitation purification, and a light brown powder 101.3 was obtained.
mg was obtained. This polymer was dissolved in 10 ml of a 0.1 M sodium bicarbonate aqueous solution, and the unreacted anhydrous ring was opened by stirring at 60 ° C. for 3 hours. After purification by dialysis (MWCO: 1,000) for 2 days and ion exchange (carboxylic acid type cation exchange resin), it was freeze-dried to obtain a polymer having a phenylboronic acid derivative introduced therein. The phenylboronic acid derivative contained in the obtained polymer was quantified by atomic absorption spectrometry, and the reaction rate was determined from the result. The results are shown in Table 1.

Reference Examples 2 to 4 Using the phenylboronic acid derivatives obtained in Examples 2 to 4, the reaction rate was determined in the same manner as in Reference Example 1. The results are shown in Table 1.
Shown in

Comparative Reference Examples 1 and 2 3-amino- having an amino group directly bonded to a benzene ring
6-heptafluoropropylphenylboronic acid or 3
The reaction rate of -amino-4,6-bis (heptafluoropropyl) phenylboronic acid to the N-vinylpyrrolidone-maleic anhydride copolymer was examined in the same manner as in Reference Example 1. The results are shown in Table 1.

[0050]

[Table 1]

As can be seen from the results in Table 1, Examples 1 to 1
It can be seen that the phenylboronic acid derivative of 4 has higher reactivity than phenylboronic acid in which the amino group is directly bonded to the benzene ring.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazunori Kataoka 1083-4 Omuro, Kashiwa City, Chiba Prefecture (72) Inventor Yoshiyuki Koyama 1-18-11-403 Saginuma, Miyamae-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Ishihara Shoji 3-7-25 Nishifune, Funabashi City, Chiba Prefecture

Claims (2)

[Claims] 1. Phenylboron represented by the general formula [1]
Acid derivative. [Chemical 1][In the Formula, a is 1 or 2, R_fIs -F, -C_bF_2bX (was
However, X is F, H or Cl, b is an integer of 1-10),
Or -CF (CF₃) [OCF₂CF (CF₃)]_cOC ₃F
₇(However, c is 0 or an integer of 1 to 8). R¹Is
H or a hydrocarbon group having 1 to 10 carbon atoms, n is an integer of 0 to 6
Indicates a number. ] 2. A general formula [2]:[In the Formula, a is 1 or 2, R_fIs -F, -C_bF_2bX (was
However, X is F, H or Cl, b is an integer of 1-10),
Or -CF (CF₃) [OCF₂CF (CF₃)]_cOC ₃F
₇(However, c is 0 or an integer of 1 to 8). 〕so
Fluorinated aminophenylboronic acid shown and amino group
After reacting with the protected amino acid, remove the protecting group.
The general formula [1] is characterized in that[In the Formula, a is 1 or 2, R_fIs -F, -C_bF_2bX (was
However, X is F, H or Cl, b is an integer of 1-10),
Or -CF (CF₃) [OCF₂CF (CF₃)]_cOC ₃F
₇(However, c is 0 or an integer of 1 to 8). R¹Is
H or a hydrocarbon group having 1 to 10 carbon atoms, n is an integer of 0 to 6
Indicates a number. ] The manufacture of the phenylboronic acid derivative represented by
Method.