JPH02215793A - Alkylation of nucleoside - Google Patents

Abstract

PURPOSE:To effect alkylation of the title compound simply in high yield by allowing a specific halogenonucleoside to react with a trialkylaluminum reagent in the presence of a palladium catalyst. CONSTITUTION:In nucleoside, the positions to introduce alkyls is halogenated, preferably brominated or iodinated to prepare halogenonucleoside such as halogeno-purine-nucleoside. The halogenonucleoside is preferably protected its hydroxyl groups with a silyl and allowed to react with 1 to 5 equivalents, per mole of the nucleoside, of a trialkylaluminum reagent such as trimethylaluminum in the presence of palladium catalyst in a solvent such as THF at 30 deg.C to the solvent-refluxing temperature for 1 to 100 hours. Then, the product is isolated, purified and deprotected, when needed, to give the subject compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for alkylating nucleosides.

[Conventional technology]

Chemically modifying naturally occurring nucleosides.

It is an essential means to obtain new biologically active compounds.

Conventionally, as a method for alkylating a desired site of a purine nucleoside,
Method using valent iron ions (Tatrahadron,
30.2677 (1974)), ■Method using Grignard reagent (Tetrahedron Lett,
, 3 Sat., 3159 (1979)), ■ A method of subjecting ethoxycarbonylmethylpurine nureoside to a decarboxylation reaction ((:he*, Phara, Bull, ).

33.3263 (1985)), ■ A method in which nucleosides are lithiated using lithium diisopropylamide (LDA) and then methylated (ChaIl.

Pharm, Bull, 35.72 (1987)
) etc. are known.

On the other hand, as a method for alkylating a desired site of a pyrimidine nucleoside, Method for obtaining ethyl uridine or propyl uridine by decomposition or hydrogenation (J, Am,
Chew+, Soc.

100, 8106 (1978), J.O.
rg, Ches,.

43.2870 (1978)), ■Method for reducing p-tolylthiomethyluridine using Raney nickel (J, Cham, Soc, Chem, Commun.
,, 877 (1983), 5ynthssis,
259 (1982)), ■2', 3', 5'-
A method in which tris-0-(tetrabutyldimethylsilyl)uridine is lithiated using secondary butyllithium and tetramethylethylenediamine and then reacted with an electrophilic reagent (Terahadron Lett, 28.87
(1987) ) have been reported.

[Problem to be solved by the invention]

Conventional methods are unsatisfactory because the reaction steps are long and a satisfactory yield cannot be obtained, or side reaction products are produced in which sites other than those to which the alkyl group is intended to be introduced are alkylated. For example, among the above-mentioned conventional methods, the Sumo wrestler method using a Grignard reagent only progresses into mail formation, and the yield of the target product is low, so it cannot be said to be a practical method.

[Means to solve the problem]

As a result of repeated research on a novel alkylation method for nucleosides, the present inventors have discovered that using a raw material compound and a halogenonucleoside in which the site into which an alkyl group is to be introduced is halogenated, the raw material compound and a trialkylaluminum reagent are combined. The present invention has been completed based on the discovery that the target compound can be prepared in good yield by an extremely simple method of reacting in the presence of a palladium catalyst.

Specifically, the present invention provides a method for alkylating nucleosides, which comprises reacting a halogenonucleoside whose site for introducing an alkyl group is halogenated with a trialkylaluminium reagent in the presence of a palladium catalyst. This method provides a method for

The present invention will be explained in detail below.

It is a halogenonucleoside. Examples of halogens in the raw material compound include chlorine, bromine, and iodine, but those containing highly reactive bromine or iodine are particularly preferred as raw material compounds. Examples include pyrimidine nucleosides. Among such halogenonucleosides, those having a ribofuranosyl residue in the sugar moiety are specifically exemplified.

Examples of the halogenopurine ribonucleosides include 8-halogenopurine ribonucleosides (e.g., 8-halogenoadenosine, 8-halogenoguanosine, 8-halogenoinosine, 8-halogenoxanthosine, etc.), 2-halogenopurine ribonucleosides (e.g., 2-halogenopurine ribonucleosides), halogenoinosine, 2-halogenoinsine, etc.), 6-halogenopurine ribonucleoside (e.g., 2-amino-6-halogenopurine ribonucleoside, 2-hydroxy-6-
halogenoprine ribonucleosides, etc.).

Examples of the halogenopyrimidine ribonucleosides include 5-halogenopyrimidine ribonucleosides (eg, 5-halogenocytidine, 5-halogenouridine, etc.) 7.

The raw material compounds are not limited to bofuranosides such as the above-mentioned exemplified compounds, but include deoxyribofuranosides halogenated at the position corresponding to the above-mentioned ribonureoside (for example, 2'
-Deoxyribofuranoside.

3'-deoxyribofuranoside, etc.), arabinofuranoside, xylofuranoside, and glucofuranoside.

Although the raw material compound may be an unprotected compound in which the hydroxyl group of the sugar moiety is not protected, it is preferable to use a protected compound in which the hydroxyl group is appropriately protected.

As such a protecting group, any group that is commonly used as a protecting group for the hydroxyl group of a nucleoside and does not affect the reaction of the method of the present invention may be used. Specifically, acetyl, propionyl, Acyl groups such as butyryl, benzoyl, naphthoyl, acetal or ketal type protecting groups such as ethylidene, propylidene, isopropylidene, benzylidene, cyclohexylidene, cyclopentylidene, methoxymethylidene, ethoxymethylidene, dimethoxymethylidene, benzyl, p -Aralkyl groups such as methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, α- or β-naphthylmethyl, α-naphthyldiphenylmethyl, trimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, triisopropyl Cyril,
Examples include silyl groups such as tetraisoprobyl disiloxyl (TIPDS), and silyl groups are particularly preferred.

The method of the present invention is a method in which such a raw material compound and a trialkylaluminium reagent are reacted in the presence of a palladium catalyst.

The trialkylaluminum reagent used has an alkyl group corresponding to the alkyl group to be introduced. Specific examples of such trialkylaluminum reagents include trimethylaluminum, triethylaluminum, tri-n-probylyaluminum, tri-propylaluminum, tri-n-butylaluminum, tri-i-butylaluminum, tri-t-butylaluminum. , tricyclopropyl aluminum, and the like. Many of the trialkylaluminum reagents are commercially available, and these commercially available products may be used.

Palladium catalysts include bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)
Palladium dichloride, bis(benzonitrile)palladium dichloride, tetrakis(triphenylphosphine)palladium, a combination of palladium dichloride and triphenylphosphine, and the like can be used.

As the reaction solvent, basic solvents such as triethylamine, tributylamine, dimethylaniline, diethylaniline, and pyridine, ether solvents such as tetrahydrofuran and dioxane, and single or mixed solvents such as acetonitrile, dimethylformamide, and dimethylsulfoxide can be used. can.

The reaction is carried out using a trialkylaluminum reagent in an amount of 1 to 5 times equivalent, preferably 2 to 4 times equivalent, per mole of halogenonucleoside, and a catalyst amount (about 1% to 11Qmmol).
1 reaction temperature in the reaction solvent using a palladium catalyst of 30
It can be carried out by reacting for 1 to 100 hours at a temperature of .degree. C. to solvent reflux. Furthermore, if one reaction is carried out under a stream of inert gas such as argon, the reaction will proceed with better yield.

After the reaction, the desired compound is obtained by isolation and purification and, if necessary, removal of protecting groups.

Isolation and purification may be carried out by appropriately selecting a method commonly used for nucleosides (eg, adsorption chromatography, recrystallization method, etc.).

Furthermore, for the removal of the protecting group, a method commonly used for the protecting group used can be employed, for example.

In the case of a silyl group, ammonium fluoride treatment, alkaline hydrolysis, etc. may be used.

〔Effect of the invention〕

The method of the present invention uses an easily available halogenonucleoside as a raw material compound, and uses an extremely simple method of cross-coupling the halogenonucleoside with a trialkylaluminium in the presence of a palladium catalyst to achieve high yields.
The desired compound can be obtained. Therefore, it is an extremely versatile method for alkylating nucleosides.

〔Example〕

Example 1 [In the formula, R represents an alkyl group, the same applies hereinafter] 8-bromoadenosine derivative (X=OH or H) (L mm
ola) and ammonium sulfate (5■) were mixed with hexamethyldisilazane (HMDS) (20aI2) and heated at 120°C under anhydrous conditions until the raw materials were dissolved in HMDS.

After the reaction, the reaction solution was filtered to remove ammonium sulfate, and the filtrate was distilled off under reduced pressure. 5 mmole% palladium catalyst [combination of palladium dichloride and triphenylphosphine (PdC1°+2PPh,)] was added to the residue (
A) or tetrakis(triphenylphosphine)palladium cpa (PPha)
IR, ) (2-4 eq.) was added through the septum with a syringe and heated to reflux. The completion of the reaction was determined by confirming the disappearance of the raw materials by thin layer chromatography (TLC) (developing solution: chloroform/methanol = 10:1.
(Confirmed with benzene/ethyl acetate = 3 = 7). The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (approximately 100 mg), and an aqueous ammonium chloride solution (6 mmole of ammonium chloride was added to 5 mmoles of water) in methanol (approximately 100 mg).
The reaction solution was heated under reflux for 3 hours, and the reaction solution was distilled off under reduced pressure, followed by column chromatography (developing solvent: chloroform/methanol = 5:1. Support: Wakogeno L5'C-so).

(Wako Pure Chemical Industries-I or Florigi/L@(Kishida Kagaku@11)) to isolate and purify the target product to obtain an 8-alkyladenosine derivative.

Table 1 Et: Ethyl 1-Bu: i-Butyl? 1) H-NMR (DMSO-d,) δ: 8.08 (IH,s, H-2 )7.32 (2
H, brs, NH,) 5.99 (IH, m, 0H) 5.78 (LH, d, J=7.32Hz, H1')
5.38 (IH, d, 0th generation 5.25 (IH, d, 0H) 4.96 (LH, m, H-2') 4.18 (LH, brs, H-3') 4.03 (
LH, brs, H-4') 3.75-3.42 (2
H, m, H-5')2,78 (2H= rn--C
$CH(CHJJ2, 19 (LH,m, -CH,C
Q((:)!,),)0,99 (6H,d, J=6
．． 35) Elemental analysis of 1z, -CM, CH(CH,)
C1,H,I□N, O,・115C,H,OH total 2,95 (2H,'! J=7.70Hz, -C
company, CH,)2.19 (LH,m,H-2') 1,33 (3H,t, J=7.70Hz, -CH
,C1,) Elemental analysis C□3Hyu? Example 2 as Ni o3 2) 2'-7'oxy-8-dithyadenosine 1H-N
MR (DMSO-d,) δ: 8.08 (LH, s, H-2) 7, 21 (2
H, brs, NH, )6.29 (IH, t, J=7
．． 26Hz, H-1')5.60 (LH,m,0H
) 5.32 (IH, d, 0H) 4.49 (IH, brs, H-3') 3,92 (
IH, brs, H-4') 3.71-3.50 (
2H,m,H-5')3.12 (IH,m,H-2
) 2-bromoadenosine (1 mmole) and ammonium sulfate (5 mm) were mixed in HMDS (20 mmole),
After 0 reactions in which the raw materials were heated at 120° C. under anhydrous conditions until they were dissolved in HMDS, the 1 reaction solution was filtered to remove ammonium sulfate, and the filtrate was distilled off under reduced pressure. 5 servings of ale on the residue
% palladium catalyst [combination of palladium cyclolide and triphenylphosphine (PdC1□+2PPh3
) (A) or tetrakis(triphenylphosphine)palladium (Pd(PPb3), )(B) ) and 40 mM of tetrahydrofuran were added and heated to reflux under an argon atmosphere. After a few minutes, trialkylaluminum reagent (AI
R,) (2-4 eq.) was added through the septum with a syringe and heated to reflux.

The completion of the reaction was determined by confirming the disappearance of the raw materials by TLC (developing solution: chloroform/methanol = 10
:l, confirmed with benzene/ethyl acetate = 3nia). The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (about 100 d), and an aqueous ammonium chloride solution (6 mmole of ammonium chloride dissolved in 5 mm of water) was added dropwise thereto, and the mixture was heated under reflux for 3 hours.

The reaction solution was distilled off under reduced pressure, and the target product was isolated and purified using column chromatography (developing solvent: chloroform/methanol = 5:1, carrier: Wakogel C-300 or Florisil) to obtain a 2-alkyladenosine derivative. Ta.

Compounds 1), 2), and 3) have M instead of melting point.
Measured values of S and 1H-NMR (DMSO-d,) are shown.

1) 2-Ethyladenosine MS: 295 (M”) 'H-NMR δ: 8.27 (IH, s, H-8) 7.27 (2
H,brs,Ndan2) 5.87 (IH,d,J=6.83Hz,H-1'
) 5.68 (LH, m, 0H) 5.43 (IH, m0H) 5.21 (LH, m, 0H) 4.69 (LH, dd, J=11.72, 6.831
(z, H-2')4.18 (IH, brs, H-3
' ) 4.00 (IH, brs, H-4' ) 3.7
4-3.42 (2H,m,H-5')2,67 (
2H,C1,J=++7.81Hz, -CH,CH,
)1, 25 (3H, t, J=7.81Hz, -C
H, CMJ) 2) 2-n-propyladenosine MS: 309 (M”) 'H-NMR δ: 8.26 (LH, s, H-8) 7.27 (2
H,brs=NHJ 5゜86 (IH,d,J=6.844!z,H-1'
) 5.73 (1H, m, Odan) 5.43 (LH, d, 0H) 5.20 (IH, d, O!lri 4.69 (LH, dd, J=11.72, 6. 84)
tz, H-2') 4, 16 (LH, brs, H-
3')4,00 (LH,brs,H-4')3
．． 74-3.53 (2H,m,H-5')2,83
<2H-t-J=7.32)tz2%CHzCHs)
1,74 (2H,m, -CH,CH,CH,)0,
93 (3) f,' t, J=7.32H1,-CH
, CH, C33) 3) 2-i-butyladenosine MS: 323 (M+) "H-NMR δ: 8.26 (IH, s, H-8) 7, 27 (2H, brs, N!12) 5 .86 (
LH, d, J = 6.84Hz, H-1') 5.80
(IH, m, Odan) 5.43 (LH, d, 0H) 5.21 (IH, d, ○W 4.69 (IH, dd, J=11.72, 6.84H
z, H-2')4゜1.6 (IH, brs, H-
3')4,00 (LH,hrs, H-4')3
．． 72-3.50 (2H,m,H-5')2,52
(2H,m, -C!!,CH(C1,),)2,1
7 (IH,m, -CH,CH(CI,),)0,9
0 (6H, d, J = 6.35Hz, -(H,C
H(Ciii)2) Example 3 8-bromoguanosine (1 mole) and ammonium sulfate (5!1 g) were mixed in HMDS (20d),
After one reaction in which the raw materials were heated at 120° C. under anhydrous conditions until they were dissolved in HMDS, the reaction solution was filtered to remove ammonium sulfate, and the filtrate was distilled off under reduced pressure.

5 mmols% palladium catalyst [a combination of palladium dichloride and triphenylphosphine (P
dC1□+2PPhi) (A) or tetrakis(triphenylphosphine)palladium (Pd(PP
h, ), )(B)] and tetrahydrofuran 40- were added and heated to reflux under an argon atmosphere. After a few minutes, trimethylaluminum (2 to 4 equivalents) was added through the septum with a syringe and heated to reflux for 24 hours. The completion of the reaction was determined by confirming the disappearance of the raw materials using TLC (developing solution: chloroform/methanol = 10:1; benzene/ethyl acetate = 3N).

The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (ioo-), and an aqueous ammonium chloride solution (6 mmole of ammonium chloride) was added thereto.
(dissolved in water) was added dropwise, and the mixture was heated under reflux for 3 hours. The reaction solution was distilled off under reduced pressure and subjected to column chromatography (developing solvent: chloroform/methanol = 5:1.
The target product was isolated and purified using a carrier (Wakogel C-300 or Florisil) to obtain 8-methylguanosine.

The results are shown in Table 3.

Table 3 Example 4 2-amino-6-chloropurine-9-riboside (1 ga
ole) and ammonium sulfate (5) in HMDS (2
0ail), and the raw materials were heated to 120°C under anhydrous conditions.
After one reaction in which the mixture was heated until dissolved in MDS, the reaction solution was filtered to remove ammonium sulfate, and the filtrate was distilled off under reduced pressure. The residue contains 5+ueole% palladium catalyst [a combination of palladium dichloride and triphenylphosphine (PdC1,+2PPh,) (A) or tetrakis(triphenylphosphine)palladium (Pd(PPh)
i) 4) (B) ) and tetrahydrofuran 40al
After a few minutes, trimethylaluminum (2 to 4 equivalents) was added through the septum with a syringe and heated to reflux. 8 The completion of the reaction was determined by checking the disappearance of the raw materials by TLC. (Developing solution: chloroform/methanol = 10:1. Benzene/ethyl acetate =
The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the mixture was distilled off under reduced pressure. The residue was dissolved in methanol (100 atff), and an aqueous ammonium chloride solution (6 mmole of ammonium chloride dissolved in 511 I2 of water) was added dropwise thereto, and the mixture was heated under reflux for 3 hours.

The reaction solution was distilled off under reduced pressure, and the target product was isolated and purified by column chromatography (developing solvent: chloroform/methanol = 5 = 1, carrier: Wakogel C-300 or Florisil), and 2-amino-6 -Methylpurine-9-riboside was obtained.

The results are shown in Table 4.

Table 4 Example 5 5-bromouridine derivative (X=OH, Y=H1X=Y
=H or X=H, Y=OH) (liuiole)
and ammonium sulfate (5■) were mixed with HMDS (20d) and heated at 120°C under anhydrous conditions until the raw materials were dissolved in HMDS. After the reaction, the reaction solution was filtered to remove ammonium sulfate and the filtrate was distilled off under reduced pressure. did. The residue was 50% O1a% palladium catalyst [a combination of palladium dichloride and triphenylphosphine (PdC1i +
2PPhi) (A) or tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (B
)) and tetrahydrofuran 40- were added and heated to reflux under an argon atmosphere, after several minutes.

Trimethylaluminum (2 to 4 equivalents) was added through the septum with a syringe and heated to reflux. The completion of the reaction was determined by confirming the disappearance of the raw material by TLC (Developing solution:
Chloroform/methanol = 10:1. (Confirmed with benzene/ethyl acetate = 3 = 7).

The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (100ml), tetrabutylammonium fluoride was added dropwise to this solution, and the mixture was heated at room temperature for 1 hour.
Allowed to react for ~2 hours.

The reaction solution was distilled off under reduced pressure, and the target product was isolated and purified using column chromatography (developing solvent: chloroform/methanol = 5 = 1, carrier: Wakogel C-300 or Florisil) to obtain a 5-alkyluridine derivative. Ta.

The results are shown in Table 5.

Example 6 5-iodouridine derivative (X=OH, Y=H.

X=Y=H or X=H, Y=OH) (1ti+ole
) and ammonium sulfate (5■) in HMDS (20-)
After the reaction was heated at 120° C. under anhydrous conditions until the raw materials were dissolved in HMDS, the reaction solution was filtered to remove ammonium sulfate, and the filtrate was distilled off under reduced pressure. 5 for residue
+amols% palladium catalyst [combination of palladium dichloride and triphenylphosphine (pdcl
, +zpph, ) (A) or tetrakis(triphenylphosphine)palladium (Pd(PPhi)4)(
B)) and tetrahydrofuran 40- were added and heated to reflux under an argon atmosphere, after several minutes.

Trialkylaluminium reagent (AIR,) (2-4
equivalent amount) was added through the septum with a syringe and heated to reflux.
The completion of the reaction was determined by confirming the disappearance of the raw materials by TLC (Developing solution: chloroform/methanol = 10
:1. The reaction solution was thoroughly shaken with chloroform/water, the chloroform layer was treated with Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (100-), and an aqueous ammonium chloride solution (5 ml of ammonium chloride was added to 5 ml of water) was dissolved in methanol (100-).
-) was added dropwise, and the mixture was heated under reflux for 3 hours.

The reaction solution was distilled off under reduced pressure, and the target product was isolated and purified using column chromatography (developing solvent: chloroform/methanol = 5:1, carrier: Wakogel C-300 or Florisil) to obtain a 5-alkyluridine derivative. Ta.

The results are shown in Table 6.

Table 6 1) 5-ethyluridine IH-NMR (DMSO-d,) δ: 7.76 (IH,s, H-6) 5.82 (I
H, d, J = 5.38 Hz, H1') 5.36 (I
H, d, ○H) 5.17-5.08 (2H, m, 2XOH) 06-4
．． 00 (2H,m,H-2'r-H-3'86 (L
H, brs, H-4')

Claims (1)

[Claims] 1) A method for alkylating nucleosides, the method comprising reacting a halogenonucleoside whose site for introducing an alkyl group is halogenated with a trialkylaluminum reagent in the presence of a palladium catalyst.