JPS5857395A - 2-amino-6-alkoxycarbonylmethylpurine nucleoside - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(R<1> is lower alkyl; R<2> is H or protective group; R<3> is ribose residue, 2-deoxyribose residue, arabinose residue, xylose residue or 3-deoxyribose residue which may have protective group). EXAMPLE:2-Acetamido-6-ethoxycarbonylmethyl-9-(2, 3, 5-tri-O-acetyl-B-D-ribofuranosyl)purine. USE:Synthetic intermediate of 6C-substituted guanine nucleoside derivative. Decarboxylation of the compound gives 2-amino-6-methyl-purine nucleoside, and the ammonia treatment of the compound affords the novel substance 2-amino-6-carbamoylmethyl derivative having adenyldeaminase-inhibiting activity. PROCESS:The objective compound can be prepared by reacting the 2-amino-6- alkyl or arenesulfonylpurine nucleoside of formula II with the alkyl acetoacetate of formula III in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound 2-amino-6-alkoxycarbonylmethylpurine nucleoside and a method for producing the same.

The object compound of the present invention, 2-amino-6-alkoxycarbonylmethylpurine nucleoside, has the following general formula [1
] This is a compound represented by

3 In the formula, R1 is a lower alkyl group (methyl, ethyl, propyl, butyl, etc.), R2 is hydrogen or a protecting group, R3 is a ribose residue, a 2-deoxyribose residue, an arabinose residue, which may have a protecting group, Indicates a xylose or 3-deoquinolibose residue. Examples of protective groups include anru groups such as acetyl, butyryl, and benzoyl;
Alkylidene groups such as impropylidene and ethylidene,
It can be used in the field of nucleoside chemistry, including aralkylidene groups such as benzylidene, aralkyl groups such as trityl and benzyl, alkoxyalkylidene groups such as methquinomethylene, ethquinmethylene, and ethoxyethylene, and tetrahydropyranyl groups. Those suitable for the synthetic reaction or applied reaction of the compound of the present invention are exemplified.

The compound of the present invention is a new compound that has not been described in any literature, and by removing the alcohol residue of R1 by hydrolysis of the ester bond and decarboxylating it, the known compound 2-amino-
In addition to being able to lead to a 6-methylbrin nucleond, a 2-amino-6-carbamoylmethyl compound, a new substance having adenyl deaminase inhibitory activity, can be obtained by treatment with ammonia. As described above, the compounds of the present invention are useful as synthetic intermediates for 6CC-substituted guasononucleoside derivatives that are expected to exhibit various physiological activities.

The compound of the present invention has the general formula [■] 3 [wherein R2 and R3 have the same meanings as in the above general formula [I], and R4 represents an alkyl group or an aryl group. ] and a 2-amino-6-alkyl or arenesulfonyl purine nucleoside of the general formula rllll) in the presence of a base CH3COCH2COORI CI! ) [wherein, R
1 has the same meaning as in general formula [1] above. It can be produced by reacting with acetoacetic acid alkyl ester represented by ].

The alkyl group or aryl group of R4 in the compound of general formula [I] which is a raw material compound includes methyl, ethyl, butyl, 4-methylphenyl, 4-bromophenyl, 2,
Specific examples include 4.6-)limethylphenyl.

The reaction with acetoacetate alkyl ester is carried out by extracting protons from acetoacetate alkyl ester with a base to generate a carbanion, and reacting this with the raw material compound.

As the base, sodium hydride, n-butylpotassium, phenylpotassium, n-butyllithium, phenylsodium, potassium amide, sodium amide, etc. can be applied.

The reaction is usually carried out in a solvent, and an aprotic polar solvent is used as the solvent. Specifically, for example, tetrahydrofuran, hexamethylphosphoramide, dimethylformoquinde, dimethylformamide, dimethylacetamide, dimethquinethane, dioxane, acetonitrile, etc. may be used. In addition, 18-
It is also effective to coexist as a reaction accelerator a substance that increases the reactivity of the nucleophilic reagent, such as macrocyclic polyethers such as crown-6.

Although the temperature conditions for the reaction are not particularly limited, the reaction is usually carried out under heating conditions ranging from room temperature to the solvent reflux temperature. The reaction time may vary depending on the type of reaction solvent and base, the reaction temperature, etc., or may be according to a conventional method used in the chemical field. For example, separation and purification means such as adsorption column chromatography, distribution, and recrystallization can be applied as appropriate.

The compound of the present invention can be led to 2-amino/-6-methylpurine nucleoside through ester hydrolysis treatment and further decarboxylation treatment. 2-Amino-6-methylpurine nucleoside can be further converted into 2-methylpurine nucleosides which have various physiological activities by substitution reaction of 2-amine group.
-It is an important synthetic intermediate for substituted derivatives. Ester hydrolysis treatment can be carried out using conventional methods such as heat treatment,
Alkali treatment or acid treatment may be used.1゜Also, decarboxylation treatment may be performed by acid treatment or catalyst treatment (for example, benzoic anhydride, N-bromsuccinimide (NBS-containing copper powder, quinoline, etc.) treatment). .

EXAMPLES Hereinafter, the present invention will be more specifically explained by giving examples showing production examples of the compounds of the present invention and reference examples showing application examples thereof.

Example 1 A mixed solution of 248q of acetoacetic acid ethyl ester and 15s+ of tetrahydrofuran was added dropwise to a solution of 608g of 50% sodium hydride in 70xtl@'118 of tetrahydrofuran to obtain a transparent solution. This solution was converted to 0(6)-p-toluenesulfonyl-N+21.0f2), Ofg+.

(5) Add 385 g of tetraacetylguanonone to 290 ml of tetrahydrofuran, add 25
The mixture was heated to reflux for an hour.

After cooling the reaction solution, it was neutralized with acetic acid and concentrated to dryness under reduced pressure.

After partitioning the residue between water and chloroform and drying the chloroform layer with magnesium sulfate, 1.5 kq
was adsorbed onto a column of chloroform-methanol (99%).
:1), and the eluate was concentrated to dryness to yield 2-acetamido-6-nitoxocarponylmethyl-9-(2,8,5
20 g of (yield: 60%) was obtained.

Ultraviolet absorption spectrum eOH λmax 325 nm, 239 nm Mass spectrometry spectrum mle 521 (M+) Nuclear magnetic resonance spectrum (CDCl8) δ, ppm8,
85 (I H, b, s , NH) 8.04 (I H, s
, 8-H) 6, 19 (lH, d, 1'-H) 5, 86 (I
H, m, 2'-H)5, 75 (I H, m,
3'-H) 4, 42 (3H, m, 4'-H, 5'
-H)4,12 (2H,s, 6-CH214,1
8 (2H, (1, -QC shame CH3) 1, 26 (8H,
t, -0C82C) Example 2 Of61-p-toluenesulfonyl-NF2+, O(
3'1゜0[5Cutriacetyl-2'-deokinganosine 2.4 g in tetrahydrofuran 20IIIf solution was mixed with 6 wl of a carbanion tetrahydrofuran solution prepared from acetoacetic acid ethyl ester 1719 and 50% sodium hydride 0.42 g. In addition, 1 hour plus 41 IV
The refluxed reaction solution was cooled, neutralized with acetic acid, and concentrated to dryness under reduced pressure.

The obtained residue was extracted with chloroporm, and the extract was adsorbed and separated on a column chromatograph using Nori-Gel]00& to obtain 2-acetamido-6-nitoki7carbonylmethyl-9-(3,
682 mg of 5-di0-acetyl-β-D-2-deoquinolibofuranone-purine was obtained.

Ultraviolet plate - convergence vector λ: H296nm nuclear magnetic resonance spectrum (DMSO-d6) δppm8,88
(I H, b, s, NH) 8.09 L IH
, s, H-B) 6.87 (1B, t, H-1'
) 5.2-5.5 (I H, m, H-8') 4, 37
(8H, m, H-4', H-5') 4, 12
(2H,s, 6-CH2)2.5~3.0 (2
8, m, H-2') Application example 1 2-acetamido-6-nitoxycarponylmethyl-9
-(2,8,5-tri0-acetyl-β-D-ribofuranosyl)purine 16.59 was dissolved in IN-sodium hydroxide (50% ethanol) and left at room temperature for 25 hours. Cation exchange resin (Diaion PK-
216. H type) 880 tel was added, and the mixture was stirred at room temperature for 2 hours. Filter the resin and add 0.15N-ammonia water 1
．． 57? The filtrate and washing liquid were combined and concentrated under reduced pressure. The residue was made into a 1.51 aqueous solution, adsorbed on an 800 ml column of cation exchange resin (Diaion PK-216.H type), and eluted with 0.15N aqueous ammonia. The eluate was concentrated under reduced pressure, and the residue was recrystallized from water to give 2-amino-6-
4.5 g of needle-like crystals of methyl-9-β-D-ribofuranosylpurine were obtained (yield 508%).

Melting point 159°C Elemental analysis C11HI5N504・1/2 Calculated value as H2O (g): C, 45,52, H, 5,56;
N, 24. L (experimental value: C, 45, 89; H, 5
,24;N, 24.52 mass spectrometry spectrum ml
e 2824M+) Ultraviolet absorption spectrum nm λ? 1.11a'x-H0' 809.243 (
sh), 229λ? rl>N-NaOH297,229
Nuclear magnetic resonance spectrum (DMSO-d6) δppm8.
14 (IH, s, 8-H) 6, 28 (2H, b, s, NH2) 5, 78 (
I H, d, 1'-H) 2.4'1 (8H, s, 6
-CHB) Application example 2 2-acetamido-6-nidoxycarbonylmethyl-9
-(2,8,5-tri〇-acetyl-β-D-ribofuranosyl)purine was dissolved in 1'00 #I of anhydrous saturated ammonia methanol and then allowed to stand at room temperature for 3 days. The reaction solution was concentrated to dryness, and the residue was recrystallized from water to obtain 607 ml of needle-like crystals of 2-amino-6-carpamoylmethyl-9-β-D-ribofuranosylpurine (yield: 77. 5%).

Melting point 139°C Elemental analysis C! 2H16N6o5・1/2H2o calculation value: C, 48, 24;) I, 5.14;
N, 26.40 Experimental value (g): C, 43, Ll;
H, 4,95iN, 25.85 ultraviolet absorption spectrum nm? 306.244.221 λo, tN-HCI 317.250 (sh),
226ax λ01N-NaoH305, 244fsh), 227
ax nuclear magnetic resonance spectrum (DMSO-d6) δppm8.
18 (IH, s, 8-H)

Claims (1)

[Claims] l) General formula [1] 3 [In the formula, R1 is a lower alkyl group, R2 is hydrogen or a protecting group, R3 is a ribose residue that may have a protecting group, 2-
Indicates a deoxyribose, arabinose, xylose or 3-deoxyribose residue. ] 2-amine-6-alkoxycarbonylmethylsilicon nucleoside. 2) General formula CM] 3 [wherein R2 is a protecting group, R3 is a ribose residue, 2-deoxyribose residue, arabinose residue, xylose residue or 3-deoxyribose residue, which may have a protecting group; R4 represents an alkyl group or an aryl group. 2-amino-6-alkyl or arenesulfonylpurine nucleoside represented by
lDCHaCOCH2COOR1 [1] [In the formula, R1 represents a lower alkyl group. ] is reacted with acetoacetic alkyl ester represented by the general formula [1
] [In the formula, R1, R2, and R8 have the same meanings as above. A method for producing 2-amino-6-alkoxycarbonylmethylpurine nucleoside, which comprises synthesizing 2-amino-6-alkoxycarbonylmethylpurine nucleoside represented by the following.