KR20160026720A - Method for producing ether compound - Google Patents

Abstract

Provided is a method of producing an ether compound which is useful for production of a phosphoramidite of a nucleotide and represented by chemical formula (3). In chemical formula (3), R represents an alkyl group having 1-6 carbon atoms. The method of the present invention comprises a step A in which a compound represented by chemical formula (1) reacts with metal alkane thiolate having 1-6 carbon atoms in 2-methoxyethanol, wherein n is an integral of 0-5, X is a halogen atom, an alkyl group, a cyano group, a nitro group, or a trifluoromethyl group having 1-3 carbon atoms; a step B in which an organic layer is separated by adding a hydrocarbon solvent having 5-8 carbon atoms and water to a resultant mixture obtained in the step A; a step C in which bis(alkylthio)ether is generated by distilling the solvent from the organic layer obtained in the step B; and a step D in which the bis(alkylthio)ether obtained in the step C reacts with a halogenating agent and 2-cyanoethanol in an ether solvent.

Description

[0001] METHOD FOR PRODUCING ETHER COMPOUND [0002]

The present invention relates to a process for producing an ether compound represented by the following formula (3).

The ether compound of formula (3) is useful for preparing phosphoramidites of nucleotides:

Wherein R represents an alkyl group having from 1 to 6 carbon atoms.

The ether compound of formula (3) can be prepared from bis (chloromethyl) ether (cf. WO 2013/027843). However, bis (chloromethyl) ether is a highly reactive compound, which is not easy to be used industrially.

It is proposed to use bis (aryloxymethyl) ether instead of bis (chloromethyl) ether to prepare the alpha, alpha '-substituted dimethyl ether (cf. USP-3,954,878, JP Hei 04-036269A).

The present invention provides a process for preparing an ether compound of formula (3) comprising:

Step A: Reaction of the compound of formula (1) with a metal alkanethiolate having 1 to 6 carbon atoms in 2-methoxyethanol

Wherein n is an integer of 0 to 5, X is a halogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, a nitro group or a trifluoromethyl group,

Step B: To a reaction mixture obtained in Step A, a hydrocarbon solvent having 5 to 8 carbon atoms and water is added and the organic layer is separated,

Step C: Distillation of the solvent from the organic layer obtained in Step B to produce bis (alkylthiomethyl) ether, and

Step D: The bis (alkylthiomethyl) ether obtained in Step C is reacted with a halogenating agent in an ether solvent and 2-cyanoethanol.

First, step A will be described in detail.

Examples of compounds of formula (1) include: bis (phenoxymethyl) ether, bis (4-chlorophenoxymethyl) ether, bis Bis (2,4,6-trichlorophenoxymethyl) ether, bis (2,4,6-trichlorophenoxymethyl) ether, bis , Bis (2,3,5,6-tetrachlorophenoxymethyl) ether, bis (2,3,4,6-tetrachlorophenoxymethyl) ether, bis (2,3,4,5,6-penta (2,6-dichloro-4-cyanophenoxymethyl) ether, bis (2,4,6-dichlorophenoxymethyl) Bis (2,6-dibromo-4-nitrophenoxymethyl) ether, bis (2,3,4,5,6-pentabromophenoxymethyl) (2,6-dibromo-4-cyanophenoxymethyl) ether and bis (2,3,4,5,6-pentafluorophenoxymethyl) Le.

In the present invention, bis (2,4,6-trichlorophenoxymethyl) ether is preferably used.

Examples of metal alkanethiolates having 1 to 6 carbon atoms include metal alkanethiolates such as sodium methanethiolate, sodium ethanethiolate, lithium methanethiolate and potassium methanethiolate. Metal alkanethiolates are commercially available, and mixtures of aqueous alkanethiolate solutions, such as sodium methanethiolate and water (e.g., 50% aqueous sodium methanethiolate), may be used. The reaction of an alkane thiol having 1 to 6 carbon atoms with a metal (e.g., Na or K), a reaction of an alkane thiol having 1 to 6 carbon atoms with a metal hydride (e.g., NaH or KH) To 6 carbon atoms and a metal hydroxide (for example, NaOH or KOH).

In the present invention, sodium methanethiolate (NaSCH ₃ ) is preferably used.

In step A, 2-methoxyethanol is used as the solvent.

The metal alkanethiolate is used usually in an amount of 2 to 4 equivalents, preferably 3 equivalents to the compound of the formula (1).

The amount of 2-methoxyethanol is usually 1 to 20 times by weight, preferably 5 to 10 times by weight, based on the compound of the formula (1).

The reaction temperature of Step A is in the range of 90 to 120 캜, preferably 100 to 105 캜. The reaction time ranges from 1 to 24 hours, preferably from 4 to 6 hours.

The termination of the reaction can be confirmed by, for example, sampling a part of the reaction mixture and analyzing it by gas chromatography (GC), thin layer chromatography (TLC) or liquid chromatography (LC).

Next, step B will be described in detail.

Examples of saturated hydrocarbon solvents having 5 to 8 carbon atoms include saturated hydrocarbon solvents such as pentane, hexane, heptane, octane and saturated cyclic hydrocarbon solvents such as cyclohexane and cyclooctane. In the present invention, a saturated hydrocarbon solvent having 5 to 8 carbon atoms is preferably used, but hexane or heptane is more preferably used.

In step B, a saturated hydrocarbon solvent and water are added to the reaction mixture obtained in step A, usually under stirring, and stirred sufficiently. The mixture is left to separate into water phase and organic phase after standing.

The amount of water added to the reaction mixture is usually 0.5 to 10 times by weight, preferably 1 to 4 times by weight, based on 2-methoxyethanol used in Step A. Water may also include alkali or inorganic salts, for example, 10% sodium hydroxide solution or sodium chloride solution may be used.

The amount of the hydrocarbon solvent to be added is usually 1 to 20 times by weight, preferably 4 to 12 times by weight, based on the 2-methoxyethanol used in the step A.

The hydrocarbon solvent and water are usually added to the reaction mixture at 10 to 80 占 폚, and then stirred at 10 to 80 占 폚. The hydrocarbon solvent and water may be added in any order or poured simultaneously.

The mixture is separated into an aqueous layer and an organic layer. For separation into these layers, the pH of the aqueous layer is adjusted to 9-12 with an inorganic base (for example, an aqueous sodium hydroxide solution) or an inorganic acid (for example, dilute hydrochloric acid).

After separation, the aqueous layer can be reextracted with a hydrocarbon solvent.

In step B, the obtained organic layer is washable with water, brine or an alkaline solution of pH 8-11. The water used for washing is usually 1 to 4 times by weight with respect to the organic layer. The organic layer can be dried or discolored by adding a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate or, if necessary, adding an adsorbent such as activated carbon.

Next, Step C is described in detail.

In step C, the solvent is distilled from the organic layer obtained in step B to give bis (alkylthiomethyl) ether of high purity.

When the solvent is distilled, distillation is usually carried out under atmospheric pressure to 2 kPa (= 15 mmHg) pressure, and the liquid temperature at the time of concentration is preferably in the range of room temperature to 100 deg.

The solvent distilled in step C is reusable as the extraction solvent in step B.

Next, Step D will be described in detail.

Examples of the halogenating agent include N-halogenated succinimides such as N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide; N-halogenated hydantoin such as 1,3-diiodo-5,5-dimethylhydantoin; And halogens such as chlorine, fluorine, and iodine. In step D, N-halogenated succinimide is preferably used, and N-iodosuccinimide is more preferably used.

Examples of the ether solvent include tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether and dioxane. In step D, tetrahydrofuran is preferably used.

The bis (alkylthiomethyl) ether obtained in Step C can be used without special purification steps such as distillation or column chromatography.

In step D, it is preferred that an acid or salt is present in the reaction system. The acid or salt is not particularly limited, and for example, an acid selected from the group consisting of perfluoroalkanoic acid and its salt, perfluoroalkanesulfonic acid and its salt, alkanesulfonic acid and salts thereof is used. Examples of salts include copper salts and silver salts. Trifluoromethanesulfonic acid is particularly preferably used.

The reaction temperature in Step D is in the range of -80 ° C to 0 ° C, preferably -50 ° C to -30 ° C.

The amount of 2-cyanoethanol is usually 0.5 to 2.0 equivalents, preferably 0.8 to 1.5 equivalents based on the amount of bis (methylthiomethyl) ether. The amount of the halogenating agent is usually 0.5 to 2.0 equivalents, preferably 0.8 to 1.5 equivalents based on the amount of bis (methylthiomethyl) ether.

The reaction time ranges from 1 to 24 hours, preferably from 2 to 6 hours.

The termination of the reaction can be confirmed, for example, by sampling a portion of the reaction mixture and analyzing it by GC, TLC or LC.

After completion of the reaction, the reaction can be stopped by adding a base such as triethylamine to the reaction mixture. The ether compound-containing residue can be obtained by pouring the reaction mixture into water and performing ordinary post-treatment such as organic solvent extraction, washing and concentration. The residue can be subjected to a purification operation such as distillation or column chromatography to obtain a high-purity ether compound.

The compound of formula (1) can be prepared, for example, by the process disclosed in USP-4,021,475 or JP Hei04-290840A.

The preparation of compounds of formula (1) is described below.

The compound of formula (1) can be prepared by reacting bis (acetoxymethyl) ether with a compound of formula (2)

(Wherein n and X have the same definitions as above).

The reaction is usually carried out in the presence of a metal catalyst in an organic solvent.

Examples of compounds of formula (2) are phenol, 4-chlorophenol, 4-nitrophenol, 4-cyanophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol, 2,3,6 - trichlorophenol, 2,3,5,6-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, 2,3,4,5,6-pentachlorophenol, 2,6-dichloro- -Nitrophenol, 2,6-dichloro-4-cyanophenol, 2,4,6-tribromophenol, 2,3,4,5,6-pentabromophenol, 2,6-dibromo- 4-cyanophenol and 2,3,4,5,6-pentafluorophenol.

Examples of the organic solvent include toluene, xylene, mesitylene, dichlorobenzene, and orthodichlorobenzene. Orthodichlorobenzene is preferably used.

Examples of metal catalysts include aluminum oxide, aluminum sulphate and zinc oxide.

The amount of the compound of the formula (2) is usually 2 to 6 equivalents relative to the bis (acetoxymethyl) ether.

The order of mixing the compound of formula (2), bis (acetoxymethyl) ether, metal catalyst and organic solvent is non-limiting, preferably bis (acetoxymethyl) ether is added to the other mixture.

The reaction can be carried out under reduced pressure.

After completion of the reaction, the compound of formula (1) is obtained in a metal catalyst-containing state, and the mixture can be used in step A as it is.

Further, the compound of formula (1) through hot filtration or dissolution in a solvent, followed by filtration and removal of the metal catalyst, is available in step A.

Bis (acetoxymethyl) ether can be obtained by carrying out purification by reaction with acetic anhydride and 1,3,5-trioxane and distillation. As raw materials for preparing the compound of formula (1), crude bis (acetoxymethyl) ether without purification by distillation can also be used.

Bis (acetoxymethyl) ether can be obtained by reaction of acetic anhydride and 1,3,5-trioxane in aqueous perchloric acid solution.

Example

Hereinafter, the present invention will be described in detail by examples and the like.

First, a production example of an ether compound will be described.

Production Example 1-1 (Steps A to C)

To 800 ml of 2-methoxyethanol was added 100 g (pure content 95.0 g) of bis (2,4,6-trichlorophenoxymethyl) ether containing 5% by weight of alumina and 50 mg of sodium methane 91.4 g of thiolate (pure content 45.7 g, 3.0 eq.) Was added thereto, and the mixture was stirred at 100 to 105 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. Then, hexane and 10% aqueous NaOH solution were added and stirred. The mixture was allowed to stand and then separated. The obtained organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was subsequently distilled under ordinary pressure to obtain 32.2 g of bis (methylthiomethyl) ether (referred to as compound Y) as a residue.

Production example 1-2 (step D)

To 170 ml of tetrahydrofuran were added 11.3 g of compound Y, 7.0 g of 2-cyanoethanol (1.2 equivalents to the amount of compound Y) and 11.3 g of molecular sieve 4A, and the mixture was stirred at -50 ≪ 0 > C. Trifluoromethanesulfonic acid (0.03 equivalent based on the amount of the compound Y) and N-iodosuccinimide (1.2 equivalent based on the amount of the compound Y) were added, and the mixture was stirred at an isothermal temperature for 3 hours. The reaction mixture was poured into a pre-cooled aqueous solution containing 10% sodium thiosulfate and 5% sodium hydrogencarbonate and extracted with ethyl acetate. The organic solvent was distilled off from the resulting organic solvent layer under reduced pressure, and the obtained residue was applied to silica gel chromatography (eluent: hexane-ethyl acetate) to obtain 6.7 g of an ether compound.

The yield based on bis (2,4,6-trichlorophenoxymethyl) ether is 55%.

Production Example 2-1

To 800 ml of 2-methoxyethanol was added 62.1 g of sodium methanethiolate (pure content 31.0 g, 3.0 eq.) Containing 64.5 g of bis (2,4,6-trichlorophenoxymethyl) ether and 50% ), And the mixture was stirred at 100 to 105 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and hexane and 10% aqueous NaOH solution were added and stirred. The mixture was allowed to stand and then separated. The obtained organic solvent layer was dried over anhydrous sodium sulfate, and the solvent was subsequently distilled under ordinary pressure to obtain 16.2 g of bis (methylthiomethyl) ether as a residue.

Production example 2-2 (step D)

The bis (methylthiomethyl) ether obtained in Production Example 2-1, 2-cyanoethanol and molecular sieve 4A were added to tetrahydrofuran, and the mixture was cooled to -50 ° C to -45 ° C under a nitrogen atmosphere. Trifluoromethanesulfonic acid and N-iodosuccinimide were added thereto and stirred at an isothermal temperature. The reaction mixture was poured into a pre-cooled aqueous solution containing 10% sodium thiosulfate and 5% sodium hydrogencarbonate and extracted with ethyl acetate. The organic solvent was distilled off from the resulting organic solvent layer under reduced pressure, and the obtained residue was applied to silica gel chromatography (eluent: hexane-ethyl acetate) to obtain an ether compound.

Next, a process for producing bis (2,4,6-trichlorophenoxymethyl) ether used as a raw material is described.

Reference Example 1

A mixture of 1715 g of acetic anhydride and 80 mg of 70% aqueous perchloric acid solution was heated to 65 DEG C in a nitrogen atmosphere. 721 g of 1,3,5-trioxane was added in small portions while keeping the internal temperature at 110 占 폚 or lower. Heating at 110 占 폚 was continued until the entire 1,3,5-trioxane was consumed (over 2 hours) and fractional distillation under reduced pressure (87 to 90 占 폚, 5-6 mmHg) yielded 1228 g of bis Ethoxymethyl) ether. The yield is 99.7%.

Reference Example 2

592 g of 2,4,6-trichlorophenol and 20 g of alumina (neutral, 200 to 300 mesh) were added to 972 ml of orthodichlorobenzene and heated to 185 to 190 占 폚. 162.0 g of bis (acetoxymethyl) ether was added dropwise over 3 hours while the internal temperature was maintained at 185-190 ° C, and the reaction mixture was stirred for a further 9 hours. The reaction mixture was cooled to 100 to 120 캜, and orthodichlorobenzene was distilled off under reduced pressure. After completion of the distillation, the mixture was cooled to room temperature, methanol was added, and the mixture was stirred for 2 hours. The solid was filtered, washed with methanol and dried to give 377 g of bis (2,4,6-trichlorophenoxymethyl) ether containing 5% by weight of alumina. The yield is 81.9% (calculated by excluding the alumina fraction).

According to the preparation, ether compounds of formula (3) useful for the preparation of phosphoramidites of the nucleotides can be prepared.

Claims (9)

A process for preparing an ether compound of formula (3) comprising:

(Wherein R represents an alkyl group having 1 to 6 carbon atoms)
Step A: Reaction of the compound of formula (1) with a metal alkanethiolate having 1 to 6 carbon atoms in 2-methoxyethanol

(Wherein n is an integer of 0 to 5, X is a halogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, a nitro group or a trifluoromethyl group)
Step B: To a reaction mixture obtained in Step A, a hydrocarbon solvent having 5 to 8 carbon atoms and water is added and the organic layer is separated,
Step C: Distillation of the solvent from the organic layer obtained in Step B to produce bis (alkylthiomethyl) ether, and
Step D: The bis (alkylthiomethyl) ether obtained in Step C is reacted with a halogenating agent in an ether solvent and 2-cyanoethanol. The process according to claim 1, wherein the compound of formula (1) is bis (2,4,6-trichlorophenoxymethyl) ether. 3. The process according to claim 1 or 2, wherein in step B, the hydrocarbon solvent having from 5 to 8 carbon atoms is hexane or heptane. 3. The process according to claim 1 or 2, wherein the metal alkanethiolate is sodium methanethiolate. 4. The process of claim 3, wherein the metal alkanethiolate is sodium methanethiolate. 3. The process according to claim 1 or 2, wherein the ether solvent in step D is tetrahydrofuran. 4. The process of claim 3, wherein the ether solvent in step D is tetrahydrofuran. 5. The process of claim 4, wherein the ether solvent in step D is tetrahydrofuran. 6. The method of claim 5, wherein the ether solvent in step D is tetrahydrofuran.