KR20220025790A - Method for producing ether compound - Google Patents

Abstract

The present invention relates to a method for preparing an ether compound represented by chemical formula (3). In chemical formula (3), R represents a C1-C6 alkyl group. The method includes the steps of: (A) allowing a compound represented by chemical formula (1) to react with a C1-C6 metal alkane thiolate in 2-methoxyethanol, wherein in chemical formula (1), n represents an integer of 0-5, and X represents a halogen atom, C1-C3 alkyl, cyano, nitro or trifluoromethyl group; (B) adding a C5-C8 hydrocarbon solvent and water to the reaction mixture obtained from step (A) and isolating an organic layer; (C) carrying out distillation of the solvent from the organic layer obtained from step (B) to provide bis(alkylthiomethyl)ether; and (D) allowing the bis(alkylthiomethyl)ether obtained from step (C) to react with a halogenating agent and 2-cyanoethanol in an ether solvent.

Description

Method for producing an ether compound {METHOD FOR PRODUCING ETHER COMPOUND}

This invention relates to the manufacturing method of the ether compound of following formula (3).

Ether compounds of formula (3) are useful for the preparation of phosphoramidite of nucleotides:

wherein R represents an alkyl group having 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 very reactive compound, and industrial use is not easy.

For the preparation of α,α′-disubstituted dimethyl ethers, it is proposed to use bis(aryloxymethyl) ethers instead of bis(chloromethyl) ethers (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: reacting the compound of formula (1) with a metal alkanethiolate having 1 to 6 carbon atoms in 2-methoxyethanol

wherein n is an integer from 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 the reaction mixture obtained in step A are added a hydrocarbon solvent having 5 to 8 carbon atoms and water, and the organic layer is separated;

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

Step D: Reacting the bis(alkylthiomethyl) ether obtained in step C with a halogenating agent and 2-cyanoethanol in an etheric solvent.

First, step A will be described in detail.

Examples of the compound of formula (1) include: bis(phenoxymethyl) ether, bis(4-chlorophenoxymethyl) ether, bis(4-nitrophenoxymethyl) ether, bis(4-cyano Phenoxymethyl) ether, bis(2,4-dichlorophenoxymethyl) ether, bis(2,4,6-trichlorophenoxymethyl) ether, bis(2,3,6-trichlorophenoxymethyl) ether , bis (2,3,5,6-tetrachlorophenoxymethyl) ether, bis (2,3,4,6-tetrachlorophenoxymethyl) ether, bis (2,3,4,5,6-penta Chlorophenoxymethyl) ether, bis (2,6-dichloro-4-nitrophenoxymethyl) ether, bis (2,6-dichloro-4-cyanophenoxymethyl) ether, bis (2,4,6- Tribromophenoxymethyl) ether, bis(2,3,4,5,6-pentabromophenoxymethyl) ether, bis(2,6-dibromo-4-nitrophenoxymethyl) ether, bis (2,6-dibromo-4-cyanophenoxymethyl) ether and bis(2,3,4,5,6-pentafluorophenoxymethyl) ether.

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

Examples of the metal alkanethiolate 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 it is possible to use an aqueous solution of the metal alkanethiolate, such as a mixture of sodium methanethiolate and water (eg 50% aqueous sodium methanethiolate). Also, reaction of an alkanethiol having 1 to 6 carbon atoms with a metal (eg Na or K), reaction of an alkanethiol having 1 to 6 carbon atoms with a metal hydride (eg NaH or KH), or 1 It can be prepared according to the reaction of an alkanethiol having to 6 carbon atoms with a metal hydroxide (eg, NaOH or KOH).

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

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

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

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

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

The completion of the reaction can be confirmed, for example, by sampling a portion 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 the saturated hydrocarbon solvent having 5 to 8 carbon atoms include saturated chain hydrocarbon solvents such as pentane, hexane, heptane, and 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 allowed to separate into an aqueous phase and an 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 relative to the 2-methoxyethanol used in step A. In addition, water may contain an alkali or an inorganic salt, for example, a 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 relative to the 2-methoxyethanol used in step A.

A hydrocarbon solvent and water are added to the reaction mixture, usually at 10 to 80°C, and then also stirred at usually 10 to 80°C. The hydrocarbon solvent and water may be added in any order or may be poured in 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 to 12 with an inorganic base (eg aqueous sodium hydroxide solution) or an inorganic acid (eg dilute hydrochloric acid).

After separation, the aqueous layer can be re-extracted with a hydrocarbon solvent.

In step B, the obtained organic layer is washable with water, brine, or an alkaline solution having a pH of 8 to 11. Water used for washing is usually 1 to 4 times by weight relative to the organic layer. The organic layer may be dried or decolorized 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 will be described in detail.

In step C, bis(alkylthiomethyl) ether of high purity is obtained by distilling off the solvent from the organic layer obtained in step B.

When the solvent is distilled off, the distillation is usually carried out under a pressure condition of atmospheric pressure to 2 kPa (= 15 mmHg), and the liquid temperature during concentration is preferably in the range of room temperature to 100°C.

The solvent distilled in step C can be reused as a solvent for extraction 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 hydantoins 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, cyclopentylmethyl ether and dioxane. In step D, tetrahydrofuran is preferably used.

The bis(alkylthiomethyl) ether obtained in step C can be used without special purification procedures 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 salts, perfluoroalkanesulfonic acid and its salts, and alkanesulfonic acid and its salts is used. Examples of the salt include a copper salt and a silver salt. Trifluoromethanesulfonic acid is particularly preferably used.

The reaction temperature of step D is within 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 completion of the reaction can be confirmed by, for example, sampling a portion of the reaction mixture and analyzing it by GC, TLC, or LC.

After completion of the reaction, the reaction may be stopped by adding a base such as triethylamine to the reaction mixture. The reaction mixture is poured into water, and a residue containing an ether compound can be obtained by ordinary post-treatment operations 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 an ether compound of high purity.

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

The preparation of the compound of formula (1) is described below.

A 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 the compound of formula (2) include 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-4 -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 the metal catalyst include aluminum oxide, aluminum sulfate, and zinc oxide.

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

The mixing order of the compound of formula (2), the bis(acetoxymethyl) ether, the metal catalyst and the organic solvent is not limited, and the bis(acetoxymethyl) ether is preferably 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 state containing a metal catalyst, and the mixture can be used as it is in step A.

Additionally, the compound of formula (1) via hot filtration or dissolution in a solvent followed by filtration and removal of the metal catalyst can be used in step A.

Bis(acetoxymethyl) ether can be obtained by reaction with acetic anhydride and 1,3,5-trioxane, and purification by distillation. As a raw material for preparing the compound of formula (1), it is also possible to use crude bis(acetoxymethyl) ether that has not undergone purification by distillation.

Bis(acetoxymethyl) ethers are obtainable by reaction with acetic anhydride and 1,3,5-trioxane in aqueous perchloro acid solution.

Example

Hereinafter, the present invention will be specifically described by way of Examples and the like.

First, an example of the preparation of the ether compound will be described.

Preparation Example 1-1 (Steps A to C)

Sodium methane containing 100 g (95.0 g pure water content) of bis(2,4,6-trichlorophenoxymethyl) ether containing 5% by weight of alumina in 800 ml of 2-methoxyethanol, and 50% of water 91.4 g of thiolate (45.7 g of pure water, 3.0 equivalents) was added and stirred at 100 to 105° C. under a nitrogen atmosphere for 4 hours. 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 then the solvent was distilled off under normal pressure to obtain 32.2 g of bis(methylthiomethyl)ether (referred to as compound Y) as a residue.

Preparation 1-2 (Step D)

To 170 ml of tetrahydrofuran, 11.3 g of compound Y, 7.0 g of 2-cyanoethanol (1.2 equivalents relative to the amount of compound Y) and 11.3 g of molecular sieve 4A were added, and the mixture was stirred at -50°C to -50°C under a nitrogen atmosphere. It was cooled to -45°C. Trifluoromethanesulfonic acid (0.03 equivalents relative to the amount of compound Y) and N-iodosuccinimide (1.2 equivalents relative to the amount of compound Y) were added, and the mixture was stirred at isothermal temperature for 3 hours. The reaction mixture was poured into a pre-cooled aqueous solution containing 10% sodium thiosulfate and 5% sodium hydrogen carbonate and extracted with ethyl acetate. The organic solvent was distilled from the obtained organic solvent layer under reduced pressure, and the obtained residue was subjected 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%.

Preparation 2-1

In 800 ml of 2-methoxyethanol, 64.5 g of bis(2,4,6-trichlorophenoxymethyl) ether, and 62.1 g of sodium methanethiolate with 50% water (31.0 g of pure water, 3.0 equivalents) ) was added, and the mixture was stirred at 100 to 105° C. under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, 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 then the solvent was distilled off under normal pressure to obtain 16.2 g of bis(methylthiomethyl)ether as a residue.

Preparation Example 2-2 (Step D)

Bis(methylthiomethyl) ether obtained in Preparation 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 and stirred at isothermal temperature. The reaction mixture was poured into a pre-cooled aqueous solution containing 10% sodium thiosulfate and 5% sodium hydrogen carbonate and extracted with ethyl acetate. The organic solvent was distilled from the obtained organic solvent layer under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate) to obtain an ether compound.

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

Reference Preparation Example 1

A mixture of 1715 g of acetic anhydride and 80 mg of a 70% aqueous perchloro acid solution was heated to 65° C. in a nitrogen atmosphere. While maintaining the internal temperature at 110° C. or less, 721 g of 1,3,5-trioxane was added little by little. Heating at 110° C. is maintained until the entire 1,3,5-trioxane is consumed (at least 2 hours), followed by fractional distillation under reduced pressure (87 to 90° C., 5 to 6 mmHg) 1228 g of bis(acetonitrile) thoxymethyl) ether was obtained. The yield is 99.7%.

Reference Preparation Example 2

To 972 ml of orthodichlorobenzene, 592 g of 2,4,6-trichlorophenol and 20 g of alumina (neutral, 200-300 mesh) were added, and heated to 185-190°C. While maintaining the internal temperature at 185 to 190°C, 162.0 g of bis(acetoxymethyl) ether was added dropwise over 3 hours, and the reaction mixture was stirred for an additional 9 hours. The reaction mixture was cooled to 100-120° C., and orthodichlorobenzene was distilled off under reduced pressure. After completion of 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 obtain 377 g of bis(2,4,6-trichlorophenoxymethyl)ether containing 5% by weight of alumina. The yield is 81.9% (calculated excluding the alumina fraction).

According to the preparation, the ether compound of formula (3) useful for the preparation of phosphoramidite of 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: reacting the compound of formula (1) with a metal alkanethiolate having 1 to 6 carbon atoms in 2-methoxyethanol

(wherein n is an integer from 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 the reaction mixture obtained in step A are added a hydrocarbon solvent having 5 to 8 carbon atoms and water, and the organic layer is separated;
Step C: distilling the solvent from the organic layer obtained in step B to produce bis(alkylthiomethyl) ether, and
Step D: Reaction of the bis(alkylthiomethyl) ether obtained in step C with a halogenating agent and 2-cyanoethanol in an ether solvent. The process according to claim 1, wherein the compound of formula (1) is bis(2,4,6-trichlorophenoxymethyl) ether. 3. Process according to claim 1 or 2, wherein the hydrocarbon solvent having 5 to 8 carbon atoms in step B is hexane or heptane. 3. Process according to claim 1 or 2, wherein the metal alkanethiolate is sodium methanethiolate. 4. The method of claim 3 wherein the metal alkanethiolate is sodium methanethiolate. 3. Process according to claim 1 or 2, wherein the ether solvent in step D is tetrahydrofuran. 4. The process according to claim 3, wherein the ether solvent in step D is tetrahydrofuran. 5. The process according to claim 4, wherein the ether solvent in step D is tetrahydrofuran. 6. The process according to claim 5, wherein the ether solvent in step D is tetrahydrofuran.