JPH03215484A - Production of 2',3'-dideoxy-beta-ribonucleoside - Google Patents

Abstract

PURPOSE:To readily obtain the subject compound having an anti-AIDS virus effect and useful as a raw material of related compounds by carrying out a condensation reaction between a substituted pyrimidine derivative and a halogenodideoxy-pentofuranose derivative in the presence of a tertiary amine. CONSTITUTION:A condensation reaction is carried out between a 5-substituted pyrimidine derivative of formula I [R<1>-R<3> are (substituted)alkyl or phenyl; X is O or N having atoms or atomic groups; Y is H, (halogen-substituted)alkyl or alkenyl] and a 1-halogeno-2,3-dideoxy-pentofuranose derivative of formula II (R<4> is OH-protecting group; Z is halogen) in the presence of a tertiary amine (e.g. triethylamine or pyridine) to obtain the objective 1-(2,3-deoxy-beta-D- pentofuranosyl)-pyrimidine derivative of formula III.

Description

[Detailed Description of the Invention] [Field of Industrial Application] This invention itself has an anti-AIDS virus effect,
and 2',3'-, which is a raw material for related compounds for pharmaceutical use a.
The present invention relates to a method useful for the production of dideoxy β-ribonucleosides.

[Conventional technology]

Conventionally, as a method for producing 2',3°-dideoquine-β-ribonucleoside, (i) the corresponding ribonucleondo derivative or 2'-deoquine ribonucleondo derivative is selectively prepared at the 2° and 3° positions; Two methods are known: (i) a method in which the hydroxyl group of is eliminated, and (ii) a method in which a condensation reaction between a 2,3-dideoxyribose derivative and a nucleic acid base is used.

An example of (i) is a method in which the hydroxyl group at the 3° position of a 2°-deoxyribonucleoside is converted into a thiocarbonate ester and then decarboxylated [Insetech Communication (Syn
tl+. Commun. ),! 985 Volume 15 No. 40
Page 1] and by thermally decomposing the 2゛, 3゜ circular orthoester of uridine! - (2,3'-dideoxy-β101 bentofuranosyl)1 uracil in 11 Na, a method of replacing the nucleobase with another using a special strain of Escherichia coli [Journal of Organic Chemistry] (J.Org.CI+eIl.), 1
988, Volume 53, Page 5170].

An example of (I1) is the method of Forina et al. [Tetrahedron l.c.
tt. ), 1988 Vol. 29, No. 1239], Okabe et al. [Journal of Organic Chemistry (J
．． Org,+Jcs. ) 1988 Vol. 53 No. 4780
page] etc.

[Problem to be solved by the invention]

However, in the above method (i), it is necessary to use a harmful a-grade tin compound or to use a bacterial flavor that is generally difficult to handle. In addition, in method (11), a mixture of the target β-form and the by-product α-form is obtained,
The ratio is at most β:α-6:4, generally resulting in an equal mixture.

In view of the above circumstances, it is an object of the present invention to provide a method capable of producing 2',3'-dideoxy-β-ribonucleoside more selectively and in high yield.

[Means to solve the problem]

In order to solve the above problems, the present inventor efficiently condensed a 5-substituted pyrimidine derivative and a 1-halogeno-2,3'-dideoxy-bentofuranose derivative in the presence of tertiary amines. and a high β of 7096
The reaction proceeds with high body selectivity, and after purification, l-(2.3
It has been found that '-dideoxy-β-D-bentofuranoneru)-pyrimidine derivatives can be obtained.

That is, the 2゛,3゜'-dideoxy-β of this invention
A method for producing a monoribonucleoside is a monosubstituted pyrimidine derivative (old) represented by the general formula: Represents a phenyl group. ), and a l-halogeno-2,3-dideoquine-bentofuranose derivative (II) represented by the following general formula (in the formula, R4 represents a general hydroxyl group retention 3u, and Z represents a halogen atom). is condensed in the presence of a tertiary amine to obtain a 1-(2,3'-dideoxy-β-D-benfuranosyl)-pyrimidine derivative represented by the following general formula: It is.

(In the formula, R = I represents 0 taste as shown in the general formula (2), and X and Y represent 0 taste as shown in the general formula (2).) Hereinafter, the manufacturing method of the present invention will be explained in detail.

The 5-monosubstituted pyrimidine derivative (III) is obtained by silylating the carbonyl group at the 2-position and the X group at the 4-position of a pyrimidine base and introducing a triorganosilyl group. for example,
11. Triorganosilyl chloride was added to a pyrimidine base suspended in hexamethyldisilane/vJ solution, and the mixture was heated to reflux under an argon gas atmosphere. However, the method is not particularly limited to this method.

As the pyrimidine base, thymine, uracil, and cytosine obtained by decomposition from a nucleic acid, and other pyrimidine bases synthesized from these bases by a conventional method can be used.

Those used include, for example, trimethylsilyl group, [-butyldimethylsilyl group, phenyldimethylsilyl group, etc., but are not particularly limited.

X in General 2 represents an oxygen atom, a hydrogen atom, or a nitrogen atom that converts an atom or atomic group such as an alkyl group or an acyl group into H. In addition, Y is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or an alkyl group or an alkenyl group which may be substituted with a halogen atom. .

On the other hand, 1-halogeno 2,3'-dideoxy-pen゜
Furanose derivative (II) is disclosed in Japanese Patent Application Laid-open No. 64-H (
It can be obtained by the method disclosed in Bristol-Myers 11 Application).

The reason for protecting the hydroxyl group at the 5-position of the derivative (II) is to prevent the derivatives from causing condensation at the 5-position hydroxyl group and from converting into a villanose form. Also,
5 In the case of monosubstituted pyrimidine derivative (I[I), if the hydroxyl group at the 5-position of derivative (II) is not protected, 2.
3'-dideoxy-bentofuranose is a derivative (III
) is removed from the silyl protecting group and replaced with a pyjmidine base. This base itself, unless silylated, is insoluble in solvents and has no reactivity with the derivative (1).

For this purpose, the silyl protecting group of di-9-isomer゜(■) was removed,
The hydroxyl group at the 5-position of the derivative J9 form (II) is protected to prevent it from being converted to a non-reactive pyrimidine base.

Those used to protect the hydroxyl group at the 5-position of the 1-halokeno 2.3'-dideoxy-pentofuranose derivative (b) (the same applies to R4 in the general formula (i)) include, for example, a benzyl group,
Aralkyl groups such as trityl groups, or acetinole groups,
probiotinole group, bivaloinole group, anlu group such as henzoyl group, aryloxycarbonyl group such as ethoxycarbonyl group, phenoxycarbonyl group, etc., or when these protecting groups whiten the phenyl group, alkyl as a substituent. Examples include those containing (-i), a halogen atom, a nitro group, an alkoxy group, etc., but are not particularly limited.

In the condensation reaction between the 1-halogeno 2,3'-dideoxy-bentofuranose derivative (II) and the 5-substituted pyrimidine derivative (m), the amount of (III) to (II) is equal to or more, preferably 2 equivalents. of tertiary amines (i(1
- It is done in the code. Examples of the tertiary amines include triethylamine, pyridine, α-picoline, β-vicoline, γ-picoline, 2,6-lutidine, and sym-collidine. For example, the condensation reaction is carried out at ambient temperature in a suitable solvent, preferably chloroform, using tertiary amines acting as a catalyst, e.g. 50 mol%, and is usually completed within 15 hours. do.

By separating the reaction mixture obtained by the above condensation using crystallization or chromatography, it is possible to obtain the target pure 2',3''-dideoxy-β-ribonucleoside (1). can.

〔Example〕

Examples of the present invention will be described below.

Thionyl chloride was added to a solution of 0.89 g (4.0 mol) of 2,3-dideoxy-510-penzoyl-1)-bentofuranose in 25 ml of chloroform prepared according to the method described in Japanese Patent Application No. 1-246455. 48
ml ((i.6an+ol)) was added and stirred at room temperature for 5 hours under an argon gas atmosphere. .3-dideoxy-5-〇1penzoyl-1)-pentofuranose4. On the other hand, 0.2 ml of l-lymethylsilyl chloride was added to a suspension of 0.87 g (7.8 mmol) of uracil in 15 nul of hexamethyldisilazane, and 30 mmol was added under an argon gas atmosphere.
The mixture was heated to reflux for a minute. When the suspended crystals were completely dissolved, the mixture was cooled to room temperature. After cooling, low-boiling compounds are distilled off under reduced pressure with a vacuum pump to leave an oily residue. 1;

After dissolving the obtained residue in 20 ml of anhydrous chloroform, the previously prepared 1-chloro-2,3-dideoxy-5
10-penzoyl 10-bentofuranose 3.9+ua
ol and 100 μI of pyridine (2.0 ssol
) in chloroform IOm+ was added, and the mixture was stirred overnight at room temperature under an argon gas atmosphere. After the reaction was completed, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. This H layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue.

The obtained residue was purified by silica gel column chromatography (chloroform:methanol-9G:4). After that, high performance liquid chromatograph (fixed layer = YMCA-31
33, ODS. Diameter 30+nX length 250mw+;
Mobile phase: acetonitrile:water - 35:65, flow rate 7.5
ml/min; detection: ultraviolet absorption, λ-254 ns) to separate isomers and obtain 1 column 1f white 1-(2,3-dideoxy-5-0-penzoyl-β-D-benfuranosyl) 0.65 g (2.1 smol) of uracil (yield 52%) was obtained. This product was further recrystallized from ethyl acetate.

The physical data of the product are as follows.

Melting point: 14G. 0-149.0°C' Ito NMR (CDCI3):
δ(1)pm)9.81(br..llI.NII)
,8.03(d,J=7.2Hz ,211,aros
atIc-1f), 7.88 (d.J=8.1Hz.
l11, ll-6). 7. GI (L.J-7.4Hz
．． III, aromatle-11), 7.47 (
L. J”7.5 11z, 211, aromatic
-11), (i.lO(dd.J=6.B&3.2H
z, ill, II-1'), 5. 56(d
, J-8. lHz, Ill. II-5),
4.65 (dd, J=12.4 & 2.9 Hz,
I11, II-5°). 4.57 (dd.J-12.3
&4.3 11z, 111.11-5'), 4.49
-4.40 (+g, 111.11-4°), 2.58-
2.44 (s, I11, It-2'), 2.20-2
．． 05 (m, 211, If-2°.11-3°). 2.
05-1.87 (m, +11.113°) Thymine 1.0
A suspension of 1 g (8.0+u+ol) in 40 ml of 1,2-dichloroethane and 4 m of hexamethylsidylazane
3.5 ml of }limethylsilyl chloride was added, and the mixture was heated under reflux for 3 hours under an argon gas atmosphere. When the suspended crystals were completely dissolved, the mixture was cooled to room temperature. After cooling, the low boiling point substances are distilled off under reduced pressure with a vacuum pump, and the porridge-like residue is evaporated.

After dissolving the blued residue in 20 ml of anhydrous chloroform, 4. Ossol and Viridin 160 p l (2
．． Add 0 smol ) of chloroform lOm+ solution,
Stirred overnight at room temperature under an argon gas atmosphere. After the reaction was completed, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. This organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue.

The obtained residue was purified by silica gel column chromatography (chloroform:methanol-97:3). After that, high performance liquid chromatograph (fixed layer: YMCA-30
3. ODS. Diameter 30×Length 250W; Moving layer:
Acetonitrile:water-38:82. The isomers were separated using a flow rate of 7.5 ml/min; detection: ultraviolet absorption, λ-254 ns), and l-(2,3-dideoxy-5
0.09 g (2.1 msol) (yield 52%) of 10-penzoyl-β-D-benfuranosyl)thymine was obtained. This product was further recrystallized from ethyl acetate.

The physical data of the product are as follows.

Melting point: 106.0-109.0°C 'II NMR (CDCI3): δ(p
ps) 10.05 (br., lIl.NII), 8.0
5 (di-7.1 Hz, 21l.arosatlc
-11), 7. (i0(t, J-7.411z, I
! I, aroIlat lc-11), 7. 46
(t.J-7.5Hz.211.aro
sat lc-II), 7.30 (s, III,
II-6). 6. 12(dd, J=6.5&4.
3Hz. III, 111'). 4.65 (dd, J
-12. I & 2.8Hz, III, II-5°).
4.53 (dd, J-12.2 & 4.6Hz,
111.11-5゛), 4.48-4.42 (s.11
1.11-4°), 2.55-2.38(s.IIl,
II-2°), 2.25-1.92 (l1.31I, I
I-2', II-3'). 1.70 (S, 311.MO
) 0.89 g (8.0 svol) of hexamethyldisilazane l[iml i(k) was heated to reflux under an argon gas atmosphere for 30 minutes.The suspended crystals were completely dissolved. At this point, the mixture was cooled to room temperature.Then, low-boiling substances were distilled off under reduced pressure with a vacuum pump to obtain a ridge-shaped residue.

After dissolving the obtained residue in 150 ml of anhydrous chloroform, l-chloro2.3-
Dideoxy-5 101 Penzoyl 101 Bentofuranose 4. (Ig + aol and pyridine l (fO μl
(2.0 mmol) in IO ml of chloroform was added, and the mixture was stirred overnight at room temperature under an argon gas atmosphere. After the reaction was completed, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. This organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue.

The obtained residue was purified by silica gel force column chromatography (methylene chloride:methanol-85:15) and then purified by high performance liquid chromatography (fixed bed: YMC A3G3.
ODS. Diameter 30mm x length 250am; moving layer:
Acetonitrile:water-28:72. Flow rate 10ml/min;
Detection: I-(2,3-dideoxy-5-
0.69 g (2,1■■01) of 0-penzoyl-β-D-benfuranosyl)cytosine (yield 51%) was obtained.

This product was further recrystallized from ethyl acetate.

The physical data of the product are as follows.

Melting point: 141.5-143.0°C Ito NMR (CDCI 1 ): δ (pp
s+) 8.02 (d.J-7.1 Hz, 211,
aro+gaLIc-11). 7.69 (d, J-7.
4 11z, ltl. lI-G) 7.57 (t.J
-7.4Hz, Ill, aro*atie-1f)
．． 7. 44 (L, J-7.5Hz, 211, a
rol1atic-It). 6.06 (dd.J-6.
6&3. IHz. IIl. lI-1'). 5.77
(d.J-7.4Hz, 111.11-5), 4.
58 (dd.J-12.3&3.511z, I
If. If-5°). 4.54 (dd.J-12
．． 2 & 4.6 fiz, llI. Ii5゜). 4.
45-4.37 (w.Il1, If-4°). 2.53
-2.38 (s.111.11-2'). 2.13-1
．． 99 (1,211.11-2°.1 to 3°). lJ7
-1.73 (m, III, if3゛) Production of uracil l. 0.5 ml of trimethylsilyl chloride was added to a suspension of 12 g (+0.0+ mol) of hexamethyldisilazane in 20 ml, and the mixture was heated under reflux for 30 minutes under an argon atmosphere. When the suspended crystals were completely dissolved, the mixture was cooled to room temperature, and the pressure was reduced using a vacuum pump to distill off low-boiling substances. The obtained porridge was dissolved in anhydrous chloroform 5
5.0 m*ol of l-chloro-2,3-dideoxy-5-0-(p-chloropenzoinole)-D-pentopyranose prepared in the same manner as in Example 1 and 200 m*ol of pyridine. u R (2.5 smol)
A 1 oml solution of Cooporum was added thereto, and the mixture was stirred overnight at room temperature under an argon gas atmosphere. After the reaction was completed, the reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with chloroform,
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography (chloroform:methanol 97:3) and then recrystallized from ethyl acetate to obtain the desired l-[2
．． 3-dideoxy-5-0-(p-chlorobenzoyl)
-β-D-benfuranosyl]uracil 0.68 g (1
．． 9 saol) (yield 39%) was obtained.

Melting point: lG5.0-167°C If-NMR (CDC I3): δ(p
ps) 9.19 (br., ltl. NII). 7.97
(d, J-8.711z .211, arosaL
ie-I1). 7.82 (d.J-8.211z,
111.11-(i). 7.45 (t.J-8.7Hz
．． 211. aromatlc-lt). 6.08
(dd.J-6.6&3.5 11z.l1l.ll
-1'). 5.82 (d, J-8.2Hz.llI.I
I-5), 4.62 (dd.J-13.B & 3.6H
z, 111. 5°), 4.55 (dd, J=13.
6 & 5.3 Hz. l11. Il-5'). 4.49
-4.40 (s.III, Ito4'). 2.58-2.
44(s, ll1.H-2'). 2.20-2.0
6 (s.211.11-2°.11-3'). 1.98
-1.83 (s,lIl.Ih3゜) [Effect of the invention] According to this invention, it itself has an anti-AIDS virus effect.
2',3'-dideoxy-β-ribonucleoside, which is a compound that not only serves as a raw material for other pharmaceutically related substances, but also can be synthesized easily and with selectivity for the β-isomer,
In addition, it can be easily separated in a thousand steps of recrystallization. This makes it possible to stably supply the substance in large quantities.

Claims (1)

[Scope of Claims] A method for producing 2',3'-dideoxy-β-ribonucleoside, comprising a 5-substituted pyrimidine derivative (III
), ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^1, R^2 and R^3 are the same or different and represent an optionally substituted alkyl group or phenyl group, X represents an oxygen atom or a nitrogen atom having an atom or atomic group. Y represents a hydrogen atom, a halogen atom,
Or represents an alkyl group or alkenyl group which may be substituted with a halogen atom. ) and 1-halogeno-2,3-dideoxy-pentofuranose derivative (II) shown by the general formula below, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^4 is the protection of the hydroxyl group (Z represents a halogen atom) in the presence of tertiary amines to form 1-(2,3-dideoxy-β-D-pentofuranosyl)-pyrimidine represented by the following general formula. Process for producing 2',3'-dideoxy-β-ribonucleoside characterized by obtaining derivative (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (I) (In the formula, R^4, X and Y (as above)