JPH10101688A - Organic bismuth derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new triaryl bismuth derivative useful as a raw material for various functional materials, drug delivery agents capable of being traced with X-rays, dendrimers containing bismuth as a central atom, etc. SOLUTION: A new organic bismuth derivative of formula I X is a group of the formula: SO2 NR<1> R<2> (R<1> , R<2> are each a 1-6C alkyl which may be substituted by one or two hydroxyl groups protective or not protected); Y is H, a 1-6C alkyl, a group of the formula: SO2 NR<1> R<2> ; Z<1> -Z<3> are H, a group of formula II [X' is H, a group of the formula: SO2 NR<1> 'R<2> ' (R<1> ', R<2> ' are each the same as R<1> ); Y' is H, a 1-6C alkyl, a group of the formula: SO2 NR<1> 'R<2> '}. The derivative of formula I is useful as a functional material for nano-scale catalysts, reaction vessels, MRI contrast media, chemical sensors, information- having materials, adhesives, coatings, separating media, light energy-absorbing materials, radiation-shielding materials, X-ray contrast media, drug delivery agents, etc., and further as an intermediate for synthesizing organic bismuth polymers, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an organic bismuth derivative having a bismuth as a central atom to give a dendrimer having excellent functionality.

[0002]

2. Description of the Related Art Dendrimers (also called dendrons) are macromolecules close to perfect spheres and exhibit a uniform molecular weight. (Po
lymer Journal vol. 17, p. 117, 198
5 years).

[0003] Dendrimers are expected as functional materials such as nanoscale catalysts or reaction vessels, MRI contrast agents, chemical sensors, information possessing materials, adhesive or coating materials, separation media, and light energy absorbing materials. It is also used as a synthetic intermediate for synthesizing a molecule having a higher molecular weight. Bismuth, on the other hand,
It is an element located at atomic number 83 belonging to Group V of the Periodic Table of the Elements, sixth period, and is the heaviest element as a stably existing element and has radiation shielding ability.

Organic bismuth compounds are generally chemically unstable as represented by trialkylbismuths, but triphenylbismuths have been reported to be more stable compounds.

A) Vestn. Leenigrad. U
niv. , Fiz. , Khim. , No. 4, 113-11
6, 1971; Chemical Abstract
ts, Vol. 76 (No. 20), 1119603 describes a tris (p-substituted phenyl) bismuth compound having a sulfoamide group or a methoxy group at the para position of the benzene ring.

B) Phosphorus Sulfu
r. , Vol. 14, No. 2, pp. 253-260, 1983 describes a tris (2,6-dialkoxyphenyl) compound having a methoxy group or an ethoxy group at the 2,6-position of the benzene ring, respectively.

C) J. Coord. Chem. , 12
Vol. 53-57, 1982, describes a tris (o-substituted phenyl) bismuth compound having a methoxy, methylthio or dimethylamino group at the ortho position of the benzene ring.

[0008] However, none of these documents describes a dendrimer-like bismuth compound.

[0009]

Means for Solving the Problems As a result of diligent studies, the present inventor has found that a completely new organic bismuth derivative (WO96 / 19487), which has been previously invented by us, having a central atom of bismuth can be obtained. The present invention has led to the invention of an organic bismuth derivative which provides a dendrimer having a simple structure and excellent functionality. This compound group has a new functionality because it has a bismuth atom at the center in addition to the functionality expected of conventional dendrimers.

In particular, they have found that they can be used as radiation shielding materials, and that they can be used as X-ray contrast agents or X-ray traceable drug delivery agents if added with water solubility, and completed the present invention.

That is, the present invention provides a compound of the formula (I)

[0012]

Embedded image[Where X is SO_TwoNR¹R^Two(R¹And R^TwoIs independently C
_1-6Represents an alkyl group and may be protected 1 or 2
May be substituted with a single hydroxyl group). Y is hydrogen
Atom, C_1-6Alkyl group or SO_TwoNR¹R^Two(R¹And R^Two
Is independently C _1-6Represents an alkyl group, even if protected
(May be substituted with one or two good hydroxyl groups)
You.

Z ¹ , Z ² and Z ³ represent a hydrogen atom or a compound of the formula (I
I)

[0014]

Embedded image[Wherein X ′ is a hydrogen atom or SO_TwoNR¹'R^Two’(R¹’
And R^Two’Is C_1-6Represents an alkyl group, even if protected
(May be substituted with one or two good hydroxyl groups)
You. Y 'is a hydrogen atom, C_1-6Alkyl group or SO_TwoNR¹’
R^Two’(R¹’, R ^Two’Is C_1-6Represents an alkyl group and is protected
May be substituted with one or two hydroxyl groups
Good)), at least one of which has the formula (II)
The organic bismuth derivative represented by the following formula:

Hereinafter, substituents of the compound of the present invention will be described.

The C _1-6 alkyl group may be linear, branched or cyclic, and may be methyl, ethyl, n-propyl, i-
-Propyl, c-propyl, n-butyl, i-butyl,
s-butyl, t-butyl, c-butyl, n-pentyl,
i-pentyl, s-pentyl, neopentyl, c-pentyl, 1-methylbutyl, 1,2-dimethylpropyl,
n-hexyl, c-hexyl, 1-methylpentyl, 2-ethylbutyl and the like.

The alkyl group may be substituted at any position with one or two hydroxyl groups. The hydroxyl group may be protected. Examples of the hydroxyl-protecting group include a trimethylsilyl group, a triethylsilyl group and a tert-silyl group. Silyl groups such as butyldimethylsilyl group and t-butyldiphenylsilyl group,
Substituted methyl group represented by methoxymethyl group, substituted ethyl group represented by 1-ethoxyethyl group and allyl group,
And substituted benzyl groups represented by benzyl group, p-methoxybenzyl group and p-phenylbenzyl group.
Further, as a protecting group, a protecting group capable of simultaneously protecting two hydroxyl groups may be contained, and examples thereof include methylene acetal, ethylene acetal, 1-t-butylethylidene ketal, isopropylidene ketal, benzylidene acetal, and the like. Methoxymethylene acetal, ethoxyethylene acetal, di-t-butylsilylene,
Tetra-t-butoxy-disiloxane, 1,3 diylidene, ethyl boronate and phenyl boronate.

In the present specification, n represents normal, i represents iso, s represents secondary, t represents tertiary, Me represents a methyl group, and Et represents an ethyl group.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The organic bismuth derivative represented by the formula (I) of the compound of the present invention, which explains the method for producing the compound of the present invention, can be prepared by the method represented by the following reaction formula.

[0020]

Embedded image [Wherein, X, Y, Z, X ′ and Y ′ represent the same meaning as described above. M represents an alkali metal, and Q represents a halogen atom. That is, n-butyllithium, s-butyllithium, and t-butyllithium represented by the formula (III)
After reacting an alkali metal base such as butyllithium, phenyllithium, or sodium amide to replace the hydrogen atom at the ortho position of the substituent X with an alkali metal atom to generate a substituted phenylalkali metal derivative (IV), The compound (I) of the present invention can be produced by reacting the bismuth derivative (V).

The trialkylbismuth (III) can be obtained from WO9
It can be produced by the method described in JP-A-6 / 19487. For example, when Q = iodine, the diphenylhalobismuth derivative (V) is synthesized as follows.

[0022]

Embedded image

[In the formula, p-Tol represents p-toluyl]
The alkali metal base is used in an amount of 1 to 10 equivalents, preferably 1 to 4 equivalents. The reaction temperature can be in the range of -78 ° C to 40 ° C. Compound (V) is used in an amount of 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (III).

Examples of the reaction solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and diisopropyl ether, and mixed solvents thereof, and amides such as N, N-dimethylformamide and N-methylpyrrolidone. A mixed solvent system with a system solvent and an ether solvent can be employed.

As a method for deprotecting a compound having a hydroxyl group, a commonly used method is used. In the case of a silyl group, a fluoride ion type compound and an acid catalyst are used. Examples of the fluoride ion type compound include tetraalkylammonium fluorides such as tetrabutylammonium fluoride, alkali metal fluoride salts such as lithium fluoride, sodium fluoride, potassium fluoride and cesium fluoride, and pyridine hydrofluoride. With Examples of the acid catalyst include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and citric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, and acidic ion exchange resins.

When the protecting group is a substituted methyl group, a substituted ethyl group,
In the case of a substituted benzyl group, acetal or ketal, the above-mentioned acidic catalyst is often used, but other methods can also be used.For example, in the case of a substituted benzyl group or benzyl ketal, hydrogenation conditions or birch reduction Conditions may be used. In the case of boronate, acetone-water or water-ethanol is used.

As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction.

[0028] The reaction temperature can be usually set between -20 ° C and the boiling point of the solvent.

The method of isolating and purifying the compound (I) of the present invention includes recrystallization, various types of chromatography using silica gel, liquid chromatography and the like. ,
A method such as affinity chromatography may be effective.

[0030]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention will be described in detail below with reference to Examples (Reference Examples and Synthesis Examples). The present invention is not limited to these embodiments. In addition, each symbol of "NMR" and "MS" in Reference Examples and Synthesis Examples is "nuclear magnetic resonance spectrum" and "mass spectrum", respectively.
Represents Unless otherwise specified, nuclear magnetic resonance spectra are measured in deuterated chloroform.

Embodiment 1

[0032]

Embedded image A solution of 423 mg (0.5 mmol) of triarylbismuth (VI) in 7 ml of THF was added at −78 ° C. with 1 equivalent of tB.
uLi was added dropwise. The clear, colorless solution turned into a yellow solution. After stirring at −78 ° C. for 30 minutes, 380 mg (0.5 mg
mmol) of diarylbismuth iodide (VII)
Was added dropwise in a THF (3 ml) solution. The dark yellow solution once turned orange and then turned pale yellow. After 75 minutes, the mixture was quenched with 10 ml of saturated saline and extracted twice with 10 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by filtration to obtain 740 mg of a white solid. This was purified by silica gel column chromatography (elution hexane: ethyl acetate = 6: 1) to find that the starting material triarylbismuth (VI) was 25% and the dibismuth compound (VIII) was 3%.
7%, tribismuth (IX) 18% and tetrabismuth (X) 7% were obtained.

Analytical data Dibismuth compound (VIII) ¹ H-NMR (200 MHz), δ ppm; 1.13
(30H, t, J = 7.2 Hz), 3.26 (16H,
q, J = 7.2 Hz), 3.37 (4H, q, J = 7.
3 Hz), 7.14 (1H, t, J = 7.3 Hz),
7.35 (4H, td, J = 7.4Hz, 1.5H
z), 7.48 (4H, td, J = 7.5 Hz, 1.3)
Hz), 7.73 (4H, dd, J = 7.3 Hz, 0.
8 Hz), 7.82 (2H, d, J = 7.3 Hz),
7.98 (4H, dd, J = 7.7 Hz, 1.1 Hz) MS; M ⁺ -C ₆ H ₄ SO ₂ NEt ₂ = 1265 IR; ν _max / cm ^-1 ; 3048-2874,146
8, 1320, 1148, 1015, 932, 737,
677,583. Elemental analysis; Found C: 40.58%, H: 4.61%, N: 4.56% Calculated C: 40.62%, H: 4.70%, N: 4.74% Melting point: 143 ° C

Tribismuth (IX) ¹ H-NMR (200 MHz), δ ppm; 1.07
-1.20 (42H, m), 3.18-3.32 (28
H, m), 7.15 (2H, t, J = 7.3 Hz),
7.36 (5H, t, J = 7.3 Hz), 7.47 (5
H, t, J = 7.3 Hz), 7.70 (4H, d, J =
7.3 Hz), 7.74 (1H, d, J = 7.6H)
z), 7.81 (2H, d, J = 7.2 Hz), 7.8
6 (2H, d, J = 7.1 Hz), 7.96 (1H,
d, J = 7.6 Hz), 7.97 (4H, d, J = 7.
6 Hz) MS; M ⁺ = 2109 IR; νV _max / cm ^-1 ; 3048-2874,146
6,1320,1148,1013,930,737,
677,583. Elemental analysis; Found C: 39.64%, H: 4.66%, N: 4.53% Calculated C: 39.83%, H: 4.58%, N: 4.64% Melting point: 132 ° C

Tetrabismuth compound (X) ¹ H-NMR (200 MHz); δ ppm; 1.13
(54H, t, J = 7.0 Hz), 3.27 (36H,
q, J = 7.0 Hz), 7.16 (3H, t, J = 7.
3 Hz), 7.30 (6H, t, J = 6.7 Hz),
7.45 (6H, t, J = 6.7 Hz), 7.67 (6
H, d, J = 7.2 Hz), 7.80 (3H, d, J =
7.0Hz), 7.89 (3H, d, J = 7.0H)
z), 7.97 (6H, d, J = 7.7 Hz) IR; ν _max / cm ^-1 ; 2975-2874,147
0,1320,1148,1013,928,735,
675,581. Elemental analysis; Found C: 39.63%, H: 4.61%, N: 4.50% Calculated C: 39.40%, H: 4.52%, N: 4.59% Melting point: 162 ~ 164 ° C

Example 2 A solution of 170 mg (0.2 mmol) of triarylbismuth (VI) in 3 ml of THF at -78.degree.
-BuLi was added dropwise. After stirring at −78 ° C. for several minutes,
C. and the mixture was stirred for 1 hour. After cooling again to -78 ° C,
A solution of 460 mg (0.6 mmol) of diarylbismuth iodide (VII) in 3 ml of THF was added dropwise. The solution was warmed to room temperature overnight. Quenched with 10 ml of water and extracted three times with 10 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated by filtration.
mg of a white solid were obtained. This was subjected to silica gel column chromatography (elution hexane: ethyl acetate = 6:
Purification according to 1) yielded 9% of the starting material triarylbismuth (VI), 2% of dibismuth (VIII), 10% of tribismuth (IX) and 31% of tetrabismuth (X).

The analytical data of each compound obtained is shown in Example 1.
Of each of the matches.

Embodiment 3

[0039]

Embedded image 340 mg (0.4 mmol) of triarylbismuth; a solution of compound (VI) in 3 ml of THF at -78 ° C.
Five equivalents of t-BuLi were added dropwise. After stirring at -78 ° C for several minutes, the temperature was raised to 0 ° C and the mixture was stirred for 1 hour. Meanwhile, tri
0.39 g of s (p-tolyl) bismuthane
(0.81 mmol) was dissolved in 5 mL of THF.
130 ° C (0.4 mmol) of trichlorobismuth at ℃
After a few minutes, the mixed solution was heated to room temperature and stirred for 2 hours to prepare a compound (XI), which was added to the previous solution.
It was added dropwise at 78 ° C. The solution was warmed to room temperature overnight. Quench with water 10ml and dichloromethane 10ml
Extracted three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated by filtration to obtain 740 mg of a white solid. This was purified by silica gel column chromatography (elution hexane: ethyl acetate = 6: 1) to find that the starting material triarylbismuth was 2%, dibismuth compound; compound (XII) 2%, tribismuth compound; compound (XIII) 6% and Tetrabismuth compound; 11% of compound (XIV) was obtained.

Analysis data Dibismuth compound (XII) ¹ H-NMR (200 MHz); δ ppm; 1.05
(6H, t, J = 7.1 Hz), 1.14 (12H,
t, J = 7.1 Hz), 2.31 (6H, s), 3.2
7 (12H, m), 7.15 (1H, t, J = 7.2H
z), 7.21 (4H, d, J = 7.8 Hz), 7.3
4 (2H, td, J = 7.3 Hz, 1.1 Hz);
48 (2H, td, J = 7.4 Hz, J = 1.3H
z), 7.59 (4H, d, J = 7.7 Hz), 7.7
2 (2H, dd, J = 7.4 Hz, 1.3 Hz);
76 (1H, dd, J = 7.3 Hz, J = 1.2H
z), 7.98 (2H, dd, J = 7.8 Hz, J =
1.3 Hz), 8.11 (1H, dd, J = 7.2H)
z, 1.3 Hz) IR; ν _max / cm ^-1 ; 2973-2872,132
0,1148,1011,926,791,735,6
75, 581, 478. Elemental analysis; Found C: 42.82%, H: 4.49%, N: 3.28% Calculated C: 42.75%, H: 4.48%, N: 3.40% Melting point: 95 ~ 100 ° C

Tribismuth compound (XIII) ¹ H-NMR (200 MHz); δ ppm; 1.03
(12H, t, J = 7.2 Hz), 1.12 (6H,
t, J = 7.1 Hz), 2.31 (12H, s), 3.
23 (8H, q, J = 7.3 Hz), 3.27 (4H,
q, J = 7.1 Hz), 7.16 (2H, t, J = 7.
3 Hz), 7.20 (8H, d, J = 7.0 Hz),
7.34 (1H, td, J = 7.1, J = 1.6H
z), 7.47 (1H, td, J = 7.6 Hz, J =
1.3Hz), 7.59 (8H, d, J = 7.1H)
z), 7.76 (1H, dd, J = 7.6 Hz, J =
1.2Hz), 7.80 (2H, d, J = 7.4H)
z), 7.96 (1H, dd, J = 7.9 Hz, J =
1.1 Hz), 8.11 (2H, d, J = 7.3 Hz) IR; ν _max / cm ⁻¹ ; 2961 to 2932, 129
1,1146,1073,791,739,673,5
83,480. Elemental analysis; Found C: 42.97%, H: 4.22%, N: 2.52% Calculated C: 42.83%, H: 4.21%, N: 2.58% Melting point: 102 ~ 108 ° C

Tetrabismuth form (XIV) ¹ H-NMR (200 MHz), δ ppm, 1.01
(18H, t, J = 7.0 Hz), 2.30 (18H, t, J = 7.0 Hz)
s), 3.22 (12H, q, J = 7.0 Hz), 7.
17 (3H, t, J = 7.3 Hz), 7.19 (12
H, d, J = 7.8 Hz), 7.58 (12, d, J =
7.8 Hz), 7.85 (3H, dd, J = 7.3H)
z, J = 1.4 Hz), 8.11 (3H, dd, J =
7.3 Hz, J = 1.3 Hz) IR; ν _max / cm ^-1 ; 2969-2870,129
3,1146,1011,907,791,741,6
73,602,480. Elemental analysis; Found C: 43.03%, H: 4.00%, N: 2.03% Calculated C: 42.88%, H: 4.05%, N: 2.08% Melting point: 111 ° C

Embodiment 4

[0044]

Embedded image A solution of 810 mg (0.5 mmol) of triarylbismuth (XV) in 7 ml of THF was added at −78 ° C. with 1 equivalent of t-B.
uLi was added dropwise. The clear, colorless solution turned into a yellow solution. After stirring at -78 ° C for 30 minutes, 640 mg (0.5
mmol) of diarylbismuth iodide (XVI)
Was added dropwise in a THF (3 mL) solution. The dark yellow solution once turned orange and then turned pale yellow. 75 minutes later, saturated saline
Quenched with 10 mL and extracted twice with 10 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated by filtration to obtain 740 mg of a white solid. This was purified by silica gel column chromatography (elution hexane: ethyl acetate = 6: 1) to find that the raw material triarylbismuth (XV) was 29% and the dibismuth compound (XVII)
30% was obtained.

Analytical data Dibismuth compound (XVII) ¹ H-NMR (200 MHz); δ ppm; 0.01
(60H, s), 0.87 (90H), 3.45 (20
H, brt), 3.71 (20H, brt), 7.11.
(1H, t, J = 7.7 Hz), 7.33 (4H, t,
J = 7.2 Hz), 7.47 (4H, t, J = 7.2H)
z), 7.66 (4H, d, J = 7.3 Hz), 8.0
1 (4H, d, J = 8.1 Hz)

Embodiment 5

[0047]

Embedded image 377 mg of the dibismuth compound (XVII) obtained in Example 4
(−36 ° C. in an 8 mL THF solution of 0.136 mmol)
Then, a 1.5 mL solution of 1.0 MTBAF (tetrabutylammonium fluoride) / THF solution was slowly added dropwise. The pale yellow solution turned into a colorless solution. After 20 minutes, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. A saturated ammonium chloride solution was added, and THF was distilled off. Extract four times with chloroform,
After concentration, 2 g of an oil was obtained. This was purified by silica gel chromatography to obtain 100 g of compound (XVIII) as an oil. (Yield 45
%) Analysis data ¹ H-NMR (200 MHz); δ ppm; 2.69
(20H, broad), 3.66 (20H, broad)
d), 5.11 (10H, broad), 7.03 (1
H, t), 7.24 (4H, t), 7.42 (4H,
t, J = 7.4 Hz), 7.58 (4H, d, J = 7.
4 Hz), 7.67 (2H, d, J = 7.3 Hz),
7.88 (4H, d, J = 7.4 Hz)

[0048]

The compound of the present invention can be used as a nanoscale catalyst or reaction vessel, MRI contrast agent, chemical sensor, information possessing material, adhesive or coating material, separation medium,
It can be used as a functional material such as a light energy absorbing material. It is also used as a synthetic intermediate for synthesizing an organic bismuth molecule having a higher molecular weight. The compound of the present invention can be used particularly as a radiation shielding material, and can also be used as an X-ray contrast agent or an X-ray traceable drug delivery agent.

Claims (12)

[Claims] 1. A compound of the formula (I)[Where X is SO_TwoNR¹R^Two(R¹And R^TwoIs independently C
_1-6Represents an alkyl group and may be protected 1 or 2
May be substituted with a single hydroxyl group). Y is hydrogen
Atom, C_1-6Alkyl group or SO_TwoNR¹R^Two(R¹And R^Two
Is independently C _1-6Represents an alkyl group, even if protected
(May be substituted with one or two good hydroxyl groups)
You. Z¹, Z^TwoAnd Z^ThreeIs a hydrogen atom or a compound of formula (II)[Wherein X ′ is a hydrogen atom or SO_TwoNR¹'R^Two’(R¹’
And R^Two’Is C_1-6Represents an alkyl group, even if protected
(May be substituted with one or two good hydroxyl groups)
You. Y 'is a hydrogen atom, C_1-6Alkyl group or SO_TwoNR¹’
R^Two’(R¹’, R ^Two’Is C_1-6Represents an alkyl group and is protected
May be substituted with one or two hydroxyl groups
Good)), at least one of which has the formula (II)
Organic bismuth derivative represented by the following formula: 2. The organic bismuth derivative according to claim 1, wherein Y ′ is a hydrogen atom or a C _1-6 alkyl group. 3. The organic bismuth derivative according to claim 1, wherein Y is a hydrogen atom or a C _1-6 alkyl group. 4. The organic bismuth derivative according to claim 2, wherein Y is a hydrogen atom or a C _1-6 alkyl group. 5. The organic bismuth derivative according to claim 2, wherein X ′ is a hydrogen atom. 6. The organic bismuth derivative according to claim 4, wherein X ′ is a hydrogen atom. 7. The organic bismuth derivative according to claim ^1, wherein R ¹ and R ² are independently a C _1-6 alkyl group. 8. The organic bismuth derivative according to claim 2, wherein R ¹ and R ² are independently a C _1-6 alkyl group. 9. The organic bismuth derivative according to claim 3, wherein R ¹ and R ² are independently a C _1-6 alkyl group. 10. The organic bismuth derivative according to claim 4, wherein R ¹ and R ² are independently a C _1-6 alkyl group. 11. The organic bismuth derivative according to claim 5, wherein R ¹ and R ² are independently a C _1-6 alkyl group. 12. The organic bismuth derivative according to claim 6, wherein R ¹ and R ² are independently a C _1-6 alkyl group.