JPS5862195A - Production of 1-beta-d-arabinofuranosyl-(e)-5-(2- halogenovinyl)uracil - Google Patents

Abstract

PURPOSE:Novel 1-beta-D-aravinofuranosyl-5-(2-carboxyvinyl)uracil is subjected to halogenation and decarboxylation to give the titled compound used as a medicine such as an antiviral. CONSTITUTION:Novel 1-beta-D-arabinofuranosyl-5-(2-carboxyvinyl)uracil (abbreviated to 5-carboxyvinylaraU) of formulaI(R<1>, R<2>, R<3> are H, protecting group; A is H, cation) or its salt is subjected to halogenation and decarboxylation, preferably with N-halogenosuccinimide as a halogenating reagent, to give 5- halogenovinylaraU. The starting compound, 5-carboxyvinylaraU of formulaI, is prepared by making a compound of formula III react with an acrylic alkyl ester in the presence of a tertiary amine, phosphine and a palladium catalyst, preferably in a polar solvent to give a compound of formula IV (R<4> is alkyl and hydrolyzing the compound of formula IV and by hydrolyzing the compound IV.

Description

[Detailed description of the invention] □ The present invention relates to 1-β-D-arabinofurano/rufE)
-5--(2-halogenovinyl)uranol (J[F5-
It is abbreviated as Halogeno Vinylara U. ).

5-halogenovinylara U has remarkable antiviral activity and is a compound useful as a medicine such as an antiviral agent (see Japanese Patent Application Laid-open No. 87599/1983).

The present invention relates to general formula (1) [wherein R1, R2, R8j↓ are the same or different, hydrogen or an acyl group such as acetyl, imbutyryl, benzoyl, benzyl, a pyranyl group, or a protecting group such as a phosphoric acid residue; 1-'β-D-'Terapinoplano represented by A indicates a cation which forms a salt that is soluble in the reaction solvent of the present invention, such as potassium or sodium. Silu(El-5-C2'-carboquinvinyl)uracil (hereinafter abbreviated as 5-carboquinvinylaraU) or a salt thereof is reacted with a halogenating agent to form a compound of the general formula (If) [wherein R1 , R2, and R3 have the same meanings as above, and X represents a halogen such as bromine, chlorine, or iodine. ] Provides a method for producing 5-halogenovinylara U represented by the following.

Hereinafter, the reaction of the present invention will be specifically explained.

It is preferable that the raw material 5-carboxyvinylara U is subjected to the reaction in a form soluble in the reaction solvent. for example,
When water is used as a reaction solvent, it is preferably used as a potassium salt or sodium salt. Note that this compound is a new compound or can be easily synthesized by the method shown in the reference examples.

As the halogenating agent, N-promuco-11 phosphate imide, N
- N-710 Genocono X phosphate imide such as iodosuccinimide, N-chloroco/monophosphate imide, other 6-organic halogenating agents, atomic halogen or hydrogen bromide with bromine, chlorine, iodine f, J, Hydrogen halides such as hydrogen iodide can be used; among these, N-710 genoconolimide is particularly preferred.

The reaction solvent should be selected appropriately depending on the solubility and stability of the halogenating agent and the solubility of the raw material compound1.
Although not generally specified, water, dimethylformamide, dimethyl sulfoxide, etc. are usually used. In particular, an aqueous solvent such as water is preferred when using N-bromoconolyphosphate imide, and anhydrous dimethylformamide is preferred when using N-iodoconolypholymide or atomic bromine, iodine, etc. .

Although the reaction conditions are not particularly limited, the reaction is usually completed within several hours at room temperature to 80°C.

The +1i separation and purification of the target compound from the reaction solution can be carried out by conventional methods, such as adsorption chromatography using glue gel, adsorption resin, etc. as a carrier, ion exchange chromatography, recrystallization, etc. Known purification means may be appropriately selected and used in combination.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, and a method for synthesizing the raw material compounds will be shown as a reference example.

Example 6 Add 70 grams of potassium acetate to water 5e heated to 50°C.
After adding and dissolving 09.7 g of carboquinvinylara U], 74.29 g of N-bromosuccinimide was added over 15 minutes, and the mixture was further heated at 60°C for 1 hour. After the reaction is complete,
It was adsorbed on a 5e column of adsorption resin Diaion HP-20 (trade name; manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with 20% ethanol. The eluted fraction of the target compound was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from water to obtain 51.79 crystals of 5-bromovinylara U (yield: 42.4%).

Melting point: 195°C (decomposition) Elemental analysis value: Calculated value as C,1HI8N206Br: C,87,84;H,8,75;N,8.02
% actual value: C, 87,94iH, 8,56; N, 8.
01% Reference Example 1-β-D-arabinofuranosyl-5-iodo-2:8
: 4.219 ml of 5'-triacetyluracil, methyl acrylate BOOwl, 150 ml of triethylamine, 22.59 ml of triphenylphosphine and 19.19 ml of palladium arsenate were added to 1.36 e of tetrahydrofuran, and the mixture was heated under reflux for 3 hours with stirring. After cooling the reaction solution, chloroform 1.57? was added and stirred, the insoluble matter was filtered off and reduced, and the mixture was concentrated to dryness under pressure. Add ethanol to the obtained residue and
1, cooled, precipitated crystals were collected by filtration, and recrystallized from ethanol to obtain 1-β-D-arabinofuranone-5-methoxycarbonylvinyl-2:8:5'-)lyacetyluracil crystals 213Q. I got it.

0.0 g of the above compound. IN sodium hydroxide solution 2
After dissolving in 5e, it was left at room temperature for 4 hours, and the reaction solution was adjusted to pH 7,
The precipitated crystals were collected by filtration and recrystallized from water to obtain 5.99q of crystals of 5-carboquinvinyla-U.

Melting point, 272-273°C Ultraviolet absorption spectrum: 0,1+5 N-HCl λ □a x 801.2' 67 nm (
Shoulder) Elemental analysis value' Calculated value as Cl2HI4N208: C, 45,87; H, 4,49; N, 8. 919
6 Actual value: C, 45,87; H, 4,87; N, 8.7
8% Patent Applicant (677) Yamasa Soy Co., Ltd. 71 IJ Co., Ltd. Procedural Amendment (Method) % Formula % 1 Display of Case 1982 Patent Application No. 161153 2 Title of Invention 1-β-D-Arabinofuranone fEl − 5-/2
-Production method of (halogenovinyl) uracil 3, Relationship with the case of the person making the amendment Patent applicant address Postal code 288 2-10-14 Shinsei-cho, Chof-shi, Chiba Prefecture Amendment order dated February 7, 1982 (Sent on April 428, 1982) 5 Written amendment to the procedure subject to amendment (spontaneous) July 1980/r Kazuo Wakasugi, Commissioner of the Japan Patent Office 1, Indication of the case Patent Application No. 161153 of 1988 2 Title of the invention 1-β-D-RapinouranonrootE) -5-(2
-Production method of (halogenovinyl) uranol 8, Relationship with the review case to be amended Patent applicant address Postal code 288 Copied specification according to the method; the same applies hereinafter) " A is” and “potassium 1” and “
Add "hydrogen or".

2) In the 9th to 7th lines from the bottom of page 5 of the specification, [1] is replaced with ``water, N, N-dimethylformamide, N, N-dimethylacetamide, formamide, etc.'' 9, mixed solvent or water-containing solvent of amide solvent with

3) When r N-bromosuccinimide is used, an aqueous solvent such as water is preferable, and the description 1 is deleted.

4) “Iodine-1 and 1” in the fourth line from the bottom of page 5 of the specification
Add 1 and chlorine-1 between the

5) In lines 4 to 8 from the bottom of page 5 of the specification, "dimethylformamide" is corrected to "rN,N-dimethylformamide or N,N-dimethylacetamide."

6) In the 10th line from the top of page 6 of the specification, 1 Example 1 is corrected to ``Example II.''

7) The following [Example 21, "Implementation Add descriptions of Example 31 and Example 41.

(Example 2) After dissolving 5-carboxine and Nilara U50'7 in 500 ml of 'N,N-tumethylformamide, N-bromosuccinimide 349 was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. The resulting residue was recrystallized from water to obtain 34 g of crystals of 5-bromovinylara U (yield: 6
1.3%).

Example 3 5-carboquinobinylara U5oq N,N-.

Dissolved in 500 liters of dimethylacetamide at 1000C
After heating, 25.59 g of N-chlorosuccinimide was added in portions, and the mixture was further heated for 30 minutes. Dilute the reaction solution with water to 2.4
After diluting to
It was adsorbed to t) and eluted with 10% ethanol. One elution fraction of the target compound was collected and concentrated to dryness under reduced pressure.
The residue was recrystallized from water to obtain 12.59 crystals of 5-chlorovinyla-U (yield: 258%).

Melting point: 223-224°C (decomposition) Elemental analysis value: c, calculated value as 1H18N206cl: C, 11,86; old 4.8. O; N-, 9,19%
Actual value: C, 4129; H, 4,17; N, 9.4
496 Example 4 5 Carboxyvinifleara U25Q with N,N dimethylacetamide 250g+I! After dissolving, heat to 70°C.
The mixture was heated to JI1, 21.59 g of N-iodoconolyl phosphate imide was added, and the mixture was further heated for 5 hours. After diluting the reaction solution to 1.5e with water, apply it to a Diaion HP-20 column (500 gen/)
20% ethanol 5e, 80% ethanol 8
The eluted fractions of the target compound eluted with 2e were collected and concentrated to dryness under reduced pressure. The obtained residue was recrystallized from water to give 5
-Yotovinylara U crystals of 8.8'/cm were obtained.

Melting point: 170-175°C (decomposed), H2O ultraviolet absorption spectrum, Max 298.253 nm
Elemental analysis value 'C11H18N2061 Calculated value C,,8B, 85;H,8,81;N,,7
．． 07% actual value: C, 88, 83; H, 8, 18; N
, 6.96% procedural amendment (voluntary) August 50, 1982 Kazuo Wakasugi, Commissioner of the Japan Patent Office ■, Indication of the case 1982 Patent Application No. 161153 2, Title of the invention 1-β-D -Arabinofuranoneru(E), -5-(2
- Halogenovinyl) Uranium 4 Production Process 3, Relationship with the case of the person making the amendment Patent applicant address Postal code 288 2-10-14, Shinsei-cho, Choshi-shi, Chiba Prefecture Complete specification subject to amendment Details H 1 , Title of the Invention 1 β-D-Arabinofuranosyl-(El-5-(2
-Halogenovinyl) uracil fJJ construction? h2, Claims 1) General formula [11 [In the formula, R1, R2, and R3 are the same or different and represent hydrogen or a protecting group, and A represents hydrogen or a cation.

] 1-β-D-arabinofuranone, Ru 5
-(2carboxyvinyl)uracil or a salt thereof is subjected to a halogenated deabonic acid reaction to form a compound of the general formula [1] [In the formula, R1, R2, and R3 have the same meanings as above, and X represents a halogen. 1-β-D-arabinofuranon-fEl-5-(2- ) 10 Genovinyl) Method for producing uracil.

2) The halogenation decarboxylation reaction is carried out using N- as a halogenating agent.
1-β-D-arabinofuranotrue (El-5-
(2-halogenovinyl) uracilno production method.

3. Detailed Description of the Invention The present invention 111-β-D-arabinofura8-cycyl-l
The present invention relates to a method for producing -5-(2-halogenovinyl)uranol (hereinafter abbreviated as 5-halogenovinylara-U).

5-halogenovinylara U has remarkable antiviral activity and is a compound useful as a medicine such as an antiviral agent (see Japanese Patent Application Laid-open No. 87599/1983).

The present invention is based on the general formula [1] [wherein R1, R2, and R3 are the same or different and represent hydrogen or a protective group, and A represents hydrogen or a cation.

] l -β-D-arabinofuranosyl
-5-(2-carboxyvinyl)uracil (hereinafter abbreviated as 5-carboxyvinylaraU) or a salt thereof is subjected to a halogen decarboxylation reaction to obtain the general formula [L] [wherein R1, R2, and R8 are as described above] It has the same meaning as , and X represents 7% rogens such as bromine, chlorine, and iodine. ] Provides a method for producing 5-halogenovinylara U represented by the following.

Hereinafter, the reaction of the present invention will be specifically explained.

The raw material 5-carboxyvinylaraTI is represented by the general formula [1]. In the formula, when R1, R2, and R8 are protecting groups, the protecting groups are those commonly used in nucleotide chemistry and are not particularly limited. Specific examples include acyl groups such as acetyl, butyryl, imbutyryl, and benzoyl, as well as benzyl groups, trityl groups, and pyranyl groups. Also, in the formula, A
Examples include cations that form salts soluble in the reaction solvent, such as hydrogen, potassium, silver, and lead. It is preferable that the raw material compound is subjected to the reaction in a form soluble in the reaction solvent.

For example, when water is used as a reaction solvent, it is preferable to use it as a potassium salt or a sodium salt.

Although this compound is a new compound, it can be easily synthesized, for example, by the method shown in Reference Examples. That is, general formula (1) [wherein R1', R'', , R'a'fi 1 [group].

[In the formula, R1', R2' is obtained by reacting wasalel 1 rasyl and an acrylic acid alkyl ester in the presence of a tertiary organic amine phosphine and a palladium catalyst, preferably in a polar solvent. ,R'''has the same meaning as above.
), R4 represents an alkyl group derived from an acrylic acid alkyl ester. This is a method of obtaining a 5-alkoxycarbonylvinyl compound represented by the following formula and further subjecting it to a hydrolysis reaction.

The type of protecting group of the compound [seal] in this first reaction is
The types of protecting groups for R1, R2, and R3 are the same as those described above. In addition, the alkyl groups of acrylic acid alkyl esters include methyl, ethyl, propyl, isopropyl, butyl, t-
Lower alkyl groups such as butyl are preferred. Examples of tertiary amines include trimethylamine, triethylamine, tri-n-butyfuramine, N,N-dimethylpropylamine, and tetramethylenediamine. Examples of phosphines include trimethylphosphine, triethylphosphine, tri-butylphosphine, tribenzylphosphine, and triphenylphosphine. , t1J-1)-7, tertiary phosphine such as tri-0-tolylphosphine, methylphenylphosphine, and diethyltolylphosphine, and palladium acetate, palladium chloride, etc. as the palladium catalyst. Although this reaction is carried out without a solvent, it is preferable to use tetrahydrofuran, dioxane,
Perform in a polar solvent such as acetic acid or acetonitrile. The reaction conditions are usually room temperature to reflux temperature, and the reaction is completed in several hours to several tens of hours.

Further, the hydrolysis reaction of the 5-alkoxycarbonylvinyl compound may be carried out by a conventional method, and a method using either a base catalyst or an acid catalyst may be used.

Base catalysts include sodium hydroxide, potassium hydroxide,
Ammonia, sodium carbonate, potassium carbonate or sodium bicarbonate can be used. As the acid catalyst, hydrochloric acid, sulfuric acid, acetic acid or formic acid can be used.

The halogenation and decarboxylation of the method of the present invention is carried out by a method in which a halogenating agent acts on a conventional carboxylic acid or its salt.

As the halogenating agent, those capable of liberating atomic halogen in the reaction system can be used. Examples of such a halogenating agent include N-bromoconomonolipolymide, N-iodosuccinimide, N-chlorosuccinimide, and the like.
N - /
0genophthalic acid imide, N-halogenosuccinimide such as N-')chlorophenylsulfonamide, N-no\logenosulfonamide such as N-dichlorophenylsulfonamide, t-butylhypohalide, t-butylhypobromide, etc. Atomic halogens such as t-butyl hypohalide, bromine, chlorine, and iodine can be used. This is suitable.

The reaction solvent should be selected appropriately depending on the solubility and stability of the halogenating agent and the solubility of the raw material compound, and cannot be specified in general, but it is usually water, N,N-dimethylformamide, N,N-dimethylacetamide, A single amide solvent such as formamide, a mixed solvent, or a water-containing solvent is used. Particularly preferred is anhydrous N,N-dimethylformamide or N,N-dimethylacetamide when, for example, N-halogenosuccinimide or atomic bromine, iodine, chlorine, etc. are used. ' Although the reaction conditions are not particularly limited, the reaction is usually completed within several hours at room temperature to 80°C.

Isolation and purification of the target compound from the reaction solution may be carried out by conventional methods, such as adsorption chromatography using solica gel or adsorption resin as a carrier, ion exchange chromatography, recrystallization method, etc. The purification means may be appropriately selected and used in combination.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, and a method for synthesizing the raw material compounds will be shown as a reference example.

Example 1 Potassium acetate 70 LJ and 5 liters of water heated to 608 C
After adding and dissolving 109.7 g of -carboxyvinylara U, 74.2 Li of N-bromocono monopolyimide was added over 15 minutes, and the mixture was further heated at 60°C for 1 hour. After the reaction was completed, it was adsorbed on a 51 column of adsorption resin Diaion HP120 (trade name; manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with 20% ethanol. The eluted fraction of the target compound was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from water to obtain 51.7 g of crystals of 5-bromovinylara U (yield: 42.7 g).
4%).

Melting point = 195°C (decomposition) Elemental analysis value: Calculated value as C1IHHN206Br:
C,87,84;I(,s,75;N,8.02%Actual value:C,87,94;H,l56;N,8.01
% Example 2 After dissolving 5-carboxyvinylara U5(]' in 500 mt of N,N dimethylformamide, 84 fl of N-promuccinimide was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was recrystallized from water to obtain crystals 84'/ of 5-bromovinylara U (yield: 613%).

Example 3 5-Carboquinvinylara U309 was dissolved in 500 ml of N,N-dimethylacetamide, heated to 100°C, and then 25.5 ml of N-chlorosuccinimide was added little by little and heated for further 30 minutes. The reaction solution was diluted to 2.41% with water, adsorbed onto a Diaion HPI120 column (800i/), and eluted with 10% ethanol 5e. The eluted fractions of the target compound were collected, concentrated under reduced pressure to dryness, and the residue was recrystallized from water to obtain 125 g of crystals of 5-chlorovinylara-U.
was obtained (yield 25.896).

, Melting point: 223-224°C (decomposition) Elemental analysis 1 Analysis value: Calculated value as C1tHtaN206C': C, 48,86, H, 4,80; N, 9.19% Actual value: C, 48,29; H ,4,17;N,9.44%
Example 4 After dissolving 5-carboxyvinylara U259 in 250 ml of N,N-dimethylacetamide, the mixture was heated to 70°C, 21.5 g of N-iodosuccinimide was added, and the mixture was further heated for 1 hour for 5 hours. After diluting the reaction solution with water to 55a 1
．． It was adsorbed onto a Diaion HPII-20 column (500 ml) at a concentration of 20%.

Elution was performed with 80% ethanol 3.2e. The eluted fractions of the target compound were collected and concentrated to dryness under reduced pressure. The obtained residue was recrystallized from water to obtain crystal 88 of 5-iodovinylara U.
8g was obtained.

Melting point: 170-175°C (decomposition) Ultraviolet absorption spectrum: λH20298, 253nma
x Elemental analysis value 'C11H18N206■ Calculated value: C, 88, 85;) 1. 3.81;N, 7.
0796 actual value: C, 88,88; H, 8,13; N,
6.96% Reference Example 1-β-D~arabinofura. Nonru 5-iodine-2'
, 421 g of 8', 5'-triacetyluracil,
300 ml of methyl acrylate, 1 ethylamine
50 wt, triphenylphosphine 722.59 and palladium arsenate 1919 in tetrahydrofuran 1,8-
61 and heated for 3 hours with stirring. After cooling the reaction solution, 1.5e of chloroform was added and stirred, the insoluble materials were filtered off, and the mixture was concentrated to dryness under reduced pressure.Ethanol was added to the resulting residue to make 2e, and the precipitated crystals were separated by cooling. After filtering, recrystallize from ethanol 17l β-D-arabinofuranone-5-methquinecarbonylvinyl-2', 8'
, 213 g of crystals of 5'-triacetyluracil were obtained.

The above compound log is 0. After dissolving in IJ solution 2.5e, the reaction solution was left at room temperature for 4 hours, the pH of the reaction solution was adjusted to 7.0, and the solution was concentrated under reduced pressure to 250 tel.
- It was cold at night. The precipitated crystals were collected by filtration and recrystallized from water to obtain 599q of crystals of 5-carboxyvinylara-U.

Melting point: 272-2736C1 Ultraviolet absorption spectrum: λ"05"IC' 801, 2671m (F
F) ax

Claims (1)

[Claims] 1) General formula [1] [In the formula, R1, R2, and R3 are the same or different and represent hydrogen or a protective group, and A represents hydrogen or a cation. ] 1-β-D-arabinofuranone (E
l-5-(2-carboxyvinyl)uracil or a salt thereof is reacted with a chlorogenating agent to form a compound of the general formula [1] [wherein R1, R2, and R3 are the same as above and have the same meaning as C, and
does not represent halogeno, 1-β-D arabinofurano true fE+ -5-(2-halogenovinyl) represented by ]
A method for producing 1-β-D-arabinofurano/ru(El-5-(2-halogenovinyl)uranol) characterized by obtaining uranol. 2) The halogenating agent is N-halogenosuccinimide. A method for producing 1-β-D-arabinofuranone-1El-5-(2-halogenovinyl)uracil according to Scope 1.