JP2015020960A - Method for producing chroman compound and intermediate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing N-{(3R,4S)-3-hydroxy-6-methoxy-2,2-dimethyl-4-(phenetylamino)chroman-7-yl}methansulfonamide in an industrial scale.SOLUTION: There is provided a new method for producing N-{(3R,4S)-3-hydroxy-6-methoxy-2,2-dimethyl-4-(phenetylamino)chroman-7-yl}methanesulfonamide compound via N-(6-methoxy-2,2-dimethyl-2H-chromene-7-yl)-N-(methylsulfonyl)methanesulfonamide from N-(2,5-dimethoxyphenyl)methanesulfonamide.

Description

  The present invention relates to a method for producing a chroman compound expected to be used as a pharmaceutical product and an intermediate thereof.

（^＊は相対配置を表す） N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide represented by the following formula (1) Compound (1)) is known to have an antiarrhythmic action (see Patent Document 1).

( ^{* Indicates} relative arrangement)

As a method for producing compound (1), the following synthetic route is known (Patent Document 1).

  However, in the above route, there is a process using an expensive asymmetric oxidation catalyst at the beginning of the process, and there are some problems from the viewpoint of industrialization, such as the production of compound (3) requires a high temperature of 190 ° C. doing.

（^＊は相対配置を示す） On the other hand, although it is known that the compound (12) is synthesized by an asymmetric epoxidation reaction of the compound (11) (Patent Documents 2 and 3), a synthesis for inducing the compound (12) to the compound (1). The route is not known.

( ^{* Indicates} relative arrangement)

  From the above, a novel method for producing compound (1) suitable for production on an industrial scale has been demanded.

International Publication No. 2005/080368 International Publication No. 2007/105658 International Publication No. 2011/007877

  The objective of this invention is providing the manufacturing method of a compound (1) on an industrial scale.

に表される化合物をアセチル化して、式（１４）

に表される化合物とし、これを脱メチル化して式（１５）

に表される化合物とし、これをアセトンとの反応により環化して式（１６）

に表される化合物とし、これをＮ−メタンスルホニル化して式（１７）

に表される化合物とし、これを還元して式（１８）

に表される化合物とし、これを脱水オレフィン化することを特徴とする、式（１１）

で表される、Ｎ−（６−メトキシ−２，２−ジメチル−２Ｈ−クロメン−７−イル）−Ｎ−（メチルスルホニル）メタンスルホンアミドの製造方法。
（ＩＩ）
式（１２）

（^＊は相対配置を表す）
に表される化合物に、２−フェニルエチルアミンを反応させ、式（１９）

（^＊は相対配置を表す）
に表される化合物とし、脱メタンスルホニル化することを特徴とする、式（１）

（^＊は相対配置を表す）
で表されるＮ−｛（３Ｒ^＊，４Ｓ^＊）−３−ヒドロキシ−６−メトキシ−２，２−ジメチル−4−（フェネチルアミノ）クロマン−７−イル｝メタンスルホンアミドの製造方法。
（ＩＩＩ）
式（１４）

で表される化合物。
（ＩＶ）
式（１５）

で表される化合物。
（Ｖ）
式（１６）

で表される化合物。
（ＶＩ）
式（１７）

で表される化合物。
（ＶＩＩ）
式（１８）

で表される化合物。
（ＶＩＩＩ）
式（１９）

（^＊は相対配置を表す）
で表される化合物。 As a result of intensive studies, the present inventors have found a novel production method of compound (11) and a novel production method for deriving compound (12) to compound (1), thereby completing the present invention. That is, the present invention is characterized by the following.
(I)
Formula (13)

The compound represented by formula (14)

And is demethylated to obtain a compound represented by the formula (15)

And cyclized by reaction with acetone to give a compound represented by formula (16)

And N-methanesulfonylated to give a compound represented by formula (17)

This is reduced to a compound represented by formula (18)

The compound represented by formula (11) is characterized by dehydrating olefins:

A method for producing N- (6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide represented by the formula:
(II)
Formula (12)

( ^{* Indicates} relative arrangement)
2-phenylethylamine is reacted with the compound represented by formula (19)

( ^{* Indicates} relative arrangement)
A compound represented by formula (1), characterized in that it is demethanylated.

( ^{* Indicates} relative arrangement)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide represented by the formula:
(III)
Formula (14)

A compound represented by
(IV)
Formula (15)

A compound represented by
(V)
Formula (16)

A compound represented by
(VI)
Formula (17)

A compound represented by
(VII)
Formula (18)

A compound represented by
(VIII)
Formula (19)

( ^{* Indicates} relative arrangement)
A compound represented by

  According to the present invention, it was possible to provide a method for producing compound (1) on an industrial scale.

Hereinafter, the present invention will be described in more detail.
In this specification, "n-" is normal, "i-" is iso, "s-" and "sec-" are secondary, "t-" and "tert-" are tertiary, and "o-" is Ortho, “m-” means meta, “p-” means para.

In the present specification, the description of C _xy means a substituent or a compound having x to y carbon atoms.

The C _1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched. Examples thereof include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group and n-hexyl group. Etc.

The C _7-12 aralkyl group means a group in which one phenyl group is substituted on the C _1-6 alkyl group. The phenyl group may be substituted at any position on the C _1-6 alkyl group. Examples thereof include benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group and the like.

The C _6-10 aryl group means an aryl group having 6 to 10 carbon atoms. Examples thereof include a phenyl group or a naphthyl group.

The C _3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, and the like.

および／または、以下の反応スキーム

（^＊は相対配置を表す）
から構成される。 The present invention provides the following reaction scheme:

And / or the following reaction scheme:

( ^{* Indicates} relative arrangement)
Consists of

  In these reactions, each intermediate may be isolated and used in the next step, or may be used as it is in the next step without being isolated or after being subjected to post-treatment.

The solvent that can be used in the production method of the present invention is not particularly limited as long as the reaction is not hindered.
water,
C _1-6 alcohol solvent (eg, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol)
Halogen-containing hydrocarbon solvent (for example, methylene chloride, chloroform, dichloroethane, chlorobenzene, 1,2-dichlorobenzene)
Carboxylic acid solvent (eg acetic acid, trifluoroacetic acid)
Sulfonic acid solvent (eg methanesulfonic acid)
Phosphate solvent (eg phosphoric acid)
Aromatic hydrocarbon solvents (eg benzene, toluene, xylene)
Aliphatic hydrocarbon solvent (eg, hexane, heptane)
Amide solvent (for example, N, N-dimethylformamide, N, N-dimethylacetamide)
Nitrile solvents (eg acetonitrile, propionitrile)
Ester solvent (eg ethyl acetate, propyl acetate, isopropyl acetate)
Ether solvents (eg, tetrahydrofuran, 1,4-dioxane)
Sulfone solvent (eg, dimethyl sulfone)
Sulfoxide solvent (eg, dimethyl sulfoxide)
Can be used.

  These solvents may be used alone or in combination of two or more.

に表される化合物とアセチル化剤を反応させて、式（１４）

に表される化合物を製造する工程について説明する。 Hereinafter, each reaction will be described in detail.
First, in the presence of a Lewis acid, the formula (13)

And a compound represented by formula (14)

The process for producing the compound represented by the above will be described.

  Examples of the Lewis acid used in the reaction include aluminum halide, iron halide, tin halide, zinc halide, and boron halide (halogenation means chlorination, bromide, or iodide). Is an aluminum halide, more preferably aluminum chloride. The amount used is from 0.1 to 2.0 mol times, preferably from 0.2 to 1.8 mol times, more preferably from 0.5 mol times to the reaction substrate. 1.5 mole times.

  The acetylating agent used in the reaction is acetyl halide (acetyl chloride, acetyl bromide, acetyl iodide, etc.), acetate ester (methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, etc.), or acetic anhydride. Preferred are acetyl halides (acetyl chloride, acetyl bromide, acetyl iodide, etc.), and more preferred is acetyl chloride. The amount thereof is 1.0 mol times to 10.0 mol times, preferably 1.0 mol times to 5.0 mol times, more preferably 1.0 mol times to 3 mol times with respect to the reaction substrate. 0.0 mole times.

  A solvent can be used for the reaction. The solvent used is a halogen-containing hydrocarbon solvent, preferably methylene chloride, chloroform, dichloroethane, chlorobenzene, 1,2-dichlorobenzene, and more preferably methylene chloride. The amount thereof is 1 to 50 times by weight, preferably 3 to 20 times by weight, more preferably 5 to 15 times by weight with respect to the reaction substrate.

  The temperature of the reaction is -20 ° C to 120 ° C, preferably -20 ° C to 60 ° C, more preferably -10 ° C to 40 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 24 hours, and more preferably 1 hour to 6 hours.

に表される化合物を脱メチル化反応させて、式（１５）

に表される化合物を製造する工程について説明する。 Next, in the presence of a reaction reagent that forms an iodide salt with a Lewis acid, the compound of the formula (14)

The compound represented by formula (15) is subjected to a demethylation reaction.

The process for producing the compound represented by the above will be described.

  Examples of the Lewis acid used in the reaction include aluminum halide, iron halide, tin halide, zinc halide, and boron halide (halogenation means chlorination, bromide, or iodide). Is an aluminum halide, more preferably aluminum chloride. The amount used is from 0.1 to 2.0 mol times, preferably from 0.2 to 1.8 mol times, more preferably from 0.5 mol times to the reaction substrate. 1.5 mole times. By reacting continuously from the previous step, the Lewis acid used in the previous step can be used as it is.

  Examples of reaction reagents that form iodide salts used in the reaction include alkali metal iodide salts (lithium iodide, sodium iodide, potassium iodide, etc.), alkaline earth metal salts (magnesium iodide, calcium iodide). ), Earth iodide metal salts (such as aluminum iodide and gallium iodide), transition metal salts (such as copper iodide and iron iodide), or ammonium iodide salts (ammonium iodide, tetramethyl iodide) Ammonium). An alkali metal iodide salt is preferable, sodium iodide or potassium iodide is more preferable, and sodium iodide is still more preferable. There is also a method of forming an iodide salt by neutralizing hydroiodic acid in the reaction. The amount of the iodide salt used is 1.0 mol times to 5.0 mol times, preferably 1.0 mol times to 3.0 mol times with respect to the reaction substrate.

  A solvent can be used for the reaction. The solvent used is a nitrile solvent or a mixed solution of a nitrile solvent and a halogen-containing hydrocarbon solvent. The nitrile solvent is preferably acetonitrile or propionitrile, more preferably acetonitrile. On the other hand, the halogen-containing hydrocarbon solvent is preferably methylene chloride, chloroform, dichloroethane, chlorobenzene or 1,2-dichlorobenzene, more preferably methylene chloride. The total amount of the solvent used is 1 to 50 times by weight, preferably 2 to 40 times by weight with respect to the reaction substrate.

  The temperature of the reaction is -20 ° C to 120 ° C, preferably -20 ° C to 60 ° C, more preferably -10 ° C to 40 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 24 hours, and more preferably 1 hour to 20 hours.

に表される化合物とアセトンを反応させて、式（１６）

に表される化合物を製造する工程について説明する。 Next, equation (15)

A compound represented by the formula (16) is reacted with acetone.

The process for producing the compound represented by the above will be described.

  The acetone used for the reaction is 1.0 to 50.0 molar equivalents, preferably 3.0 to 30.0 molar equivalents, more preferably 5.0 molar equivalents with respect to the reaction substrate. Equivalent to 15.0 molar equivalents. Further, the whole amount of the acetone may be added at the initial stage of the reaction, or after the partial addition at the initial stage, the remainder may be added in portions during the reaction. Moreover, the said acetone can also be dripped continuously during reaction.

  The reaction is carried out in the presence of an amine. The amine used is a secondary amine, preferably a dialkylamine or a cyclic amine, more preferably pyrrolidine, piperidine or morpholine, and still more preferably pyrrolidine. The amount used is 0.1 to 10.0 molar equivalents, preferably 0.5 to 5.0 molar equivalents, more preferably 1.0 molar equivalents with respect to the reaction substrate. Equivalent to 3.0 molar equivalents.

  Further, an acid may be used together with an amine. Examples of acids that can be used include organic acids (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, chloroacetic acid, trifluoroacetic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid). Etc., preferably acetic acid, chloroacetic acid or trifluoroacetic acid, more preferably acetic acid. The amount used is 0.1 molar equivalent to 10.0 molar equivalents, preferably 0.5 molar equivalents to 5.0 molar equivalents, more preferably 1.0 molar equivalents to 3.0 molar equivalents relative to the reaction substrate. Molar equivalent.

A solvent can be used for the reaction. The solvent used is a C _1-6 alcohol solvent, preferably ethanol, 1-propanol, 2-propanol or 1-butanol, more preferably 1-propanol or 1-butanol. The amount used is 1 to 50 times by weight, preferably 2 to 20 times by weight, more preferably 5 to 15 times by weight with respect to the reaction substrate.

  The temperature of the reaction is −20 ° C. to 120 ° C., preferably 20 ° C. to 110 ° C., more preferably 60 ° C. to 100 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 48 hours, and more preferably 1 hour to 40 hours.

に表される化合物と、塩化メタンスルホニルを反応させて、式（１７）

に表される化合物を製造する工程について説明する。 Next, Formula (16)

Is reacted with methanesulfonyl chloride to give a compound of formula (17)

The process for producing the compound represented by the above will be described.

  Methanesulfonyl chloride used in the reaction is 1.0 to 5.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, more preferably 1. 0 to 2.0 molar equivalents.

The reaction can be carried out in the presence of an amine. The amine used is a tertiary amine (each independently substituted with a C _1-6 alkyl group, a C _7-12 aralkyl group, a C _6-10 aryl group or a C _3-6 cycloalkyl group), A tertiary amine having a C _1-6 alkyl group is preferable, and triethylamine or diisopropylethylamine is more preferable. Further, the amount used is 1.0 to 5.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, more preferably 1.0 molar equivalents relative to the reaction substrate. To 2.0 molar equivalents.

  A solvent can be used for the reaction. The solvent used is a halogen-containing hydrocarbon solvent, preferably methylene chloride, chloroform, chlorobenzene or 1,2-dichlorobenzene, more preferably methylene chloride. The amount used is 1 to 50 times by weight, preferably 2 to 20 times by weight, more preferably 3 to 10 times by weight with respect to the reaction substrate.

  The temperature of the reaction is −20 ° C. to 120 ° C., preferably −10 ° C. to 100 ° C., more preferably −10 ° C. to 40 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 24 hours, more preferably 1 hour to 12 hours.

に表される化合物と還元剤を反応させて、式（１８）

に表される化合物を製造する工程について説明する。 Next, Formula (17)

The compound represented by the formula (18) is reacted with a reducing agent.

The process for producing the compound represented by the above will be described.

  The reducing agent used in the reaction is preferably a borohydride compound or an aluminum hydride compound, more preferably a borohydride compound, still more preferably sodium borohydride, sodium cyanoborohydride, or triacetoxy. Sodium borohydride, particularly preferably sodium borohydride. The amount of the reducing agent to be used is preferably from 0.25 molar equivalent to 4.0 equivalent, more preferably from 0.5 molar equivalent to 3.0 equivalent, still more preferably from 0.1 molar equivalent to the reaction substrate. 7 molar equivalents to 2.2 molar equivalents.

A solvent can be used for the reaction. Examples of the solvent used include C _1-6 ether solvents and C _1-6 alcohol solvents. The C _1-6 ether solvent is preferably tetrahydrofuran or 1,4-dioxane, more preferably tetrahydrofuran. The C _1-6 alcohol solvent is preferably methanol, ethanol, 1-propanol or 2-propanol, and more preferably methanol.
These solvents may be used alone or in combination of two or more. The total amount of the solvent is 1 to 50 times, preferably 2 to 20 times, more preferably 3 to 10 times the reaction substrate.

  The reaction temperature is -20 ° C to 120 ° C, preferably -10 ° C to 60 ° C, and more preferably -10 ° C to 40 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 24 hours, more preferably 1 hour to 12 hours.

に表される化合物から、酸触媒存在下、脱水反応を行うことにより、式（１９）

に表される化合物を製造する工程について説明する。 Next, Formula (18)

The compound represented by formula (19) is subjected to a dehydration reaction in the presence of an acid catalyst.

The process for producing the compound represented by the above will be described.

  The acid catalyst used in the reaction is organic acid (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, chloroacetic acid, trifluoroacetic acid) or inorganic acid (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, etc.) Inorganic acids), preferably methanesulfonic acid, benzenesulfonic acid or 4-toluenesulfonic acid, more preferably methanesulfonic acid. The amount used is from 0.001 molar equivalent to 1 molar equivalent, preferably from 0.005 molar equivalent to 0.5 molar equivalent, more preferably from 0.01 molar equivalent to 0.2 molar equivalent to the reaction substrate. Molar equivalent.

A solvent can be used for the reaction. The solvent used is an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, an ester solvent, a C _1-6 alcohol solvent or a nitrile solvent, preferably an aromatic hydrocarbon solvent or an ester solvent, more preferably toluene or Ethyl acetate. The total amount of the solvent is 1 to 20 times the weight of the reaction substrate, preferably 2 to 20 times the weight, more preferably 3 to 15 times the weight.

  The temperature of this reaction is -20 ° C to 120 ° C, preferably 20 ° C to 120 ° C, more preferably 40 ° C to 120 ° C.

  Water produced as a by-product in the reaction may be removed by adding a dehydrating agent, or may be removed by azeotroping with a solvent. Dehydrating agents that can be used include inorganic salts that can form hydrates such as magnesium sulfate (anhydrous), sodium sulfate, calcium chloride, and potassium carbonate, and those that dehydrate by reactions such as diphosphorus pentoxide and calcium oxide. , Silica gel, synthetic zeolite and the like that are dehydrated by adsorption. In the case of azeotroping with a solvent, a Dean Stark apparatus or a solvent distillation apparatus can be used. Further, this operation can be performed under normal pressure conditions or under reduced pressure conditions.

  The time required for the reaction is the time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 1 hour to 48 hours, more preferably 2 hours to 40 hours.

（^＊は相対配置を表す）
に表される化合物と２−フェニルエチルアミンを反応させて、式（１９）

（^＊は相対配置を表す）
に表される化合物を製造する工程について説明する。 Next, Formula (12)

( ^{* Indicates} relative arrangement)
And the compound represented by formula (19) is reacted with 2-phenylethylamine.

( ^{* Indicates} relative arrangement)
The process for producing the compound represented by the above will be described.

  The 2-phenylethylamine used in the reaction is 1.0 to 3.0 molar equivalents, preferably 1.0 to 2.0 molar equivalents, more preferably 1. 0 to 1.5 molar equivalents.

  The reaction can also be carried out in the presence of a Lewis acid. The Lewis acid used is a lithium salt compound, preferably lithium perchlorate, lithium carbonate, lithium nitrate, lithium phosphate, or lithium tetraborate, and more preferably lithium perchlorate. The amount used is 0.1 to 2.0 molar equivalents, preferably 0.5 to 1.5 molar equivalents, more preferably 0.8 molar equivalents, based on the reaction substrate. 1.2 molar equivalents.

A solvent can be used for the reaction. The solvent used is a C _1-6 alcohol solvent, an aromatic hydrocarbon, an aliphatic hydrocarbon, a nitrile solvent or an ether solvent, preferably a C _1-6 alcohol solvent or an ether solvent, more preferably ethanol, 1-propanol or 2-propanol, 1,4-dioxane. Particularly preferred is 1-propanol or 1,4-dioxane. These can be mixed and used, and water can be further mixed and used as a hydrous solvent. The total amount of the solvent is 1 to 20 times by weight, more preferably 1.5 to 10 times the weight of the substrate.

  The temperature of the reaction is −20 ° C. to 120 ° C., preferably 20 ° C. to 120 ° C., more preferably 60 ° C. to 100 ° C.

  The time required for the reaction is the time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 0.5 to 24 hours, more preferably 1 to 12 hours.

（^＊は相対配置を表す）
に表される化合物を加水分解させて、式（１）

（^＊は相対配置を表す）
に表される化合物を製造する工程について説明する。 Next, Formula (19)

( ^{* Indicates} relative arrangement)
To hydrolyze the compound represented by formula (1)

( ^{* Indicates} relative arrangement)
The process for producing the compound represented by the above will be described.

  The reaction is carried out using a basic aqueous solution (basic compound: alkali metal hydroxide, alkaline earth metal hydroxide, ammonia). The basic aqueous solution is preferably an aqueous solution of an alkali metal hydroxide, and more preferably an aqueous solution of sodium hydroxide or potassium hydroxide. The amount used is 0.5 to 5.0 molar equivalents, preferably 0.8 to 4.0 molar equivalents, more preferably 1.0 molar equivalents to the reaction substrate. 3.0 molar equivalents.

A solvent can be used as the reaction solvent. The solvent used is a water-soluble organic solvent (C _1-6 alcohol solvent, amide solvent, nitrile solvent, sulfoxide solvent, etc.). The water-soluble organic solvent is preferably a C _1-6 alcohol solvent or an amide solvent, more preferably a C _1-6 alcohol solvent, and still more preferably ethanol, 1-propanol or 2-propanol. The total amount of the solvent is 1 to 20 times the weight, more preferably 2 to 10 times the weight of the substrate.

  The temperature of the reaction is −20 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C., more preferably −10 ° C. to 40 ° C.

  The time required for the reaction is a time required for the reaction substrate to disappear, and is not particularly limited, but is preferably 5 minutes to 24 hours, more preferably 1 hour to 12 hours.

EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited to these examples. In Examples, NMR means nuclear magnetic resonance, and HPLC means high performance liquid chromatography.
In the examples, ECP300 manufactured by JEOL Ltd. was used for NMR analysis, and B-545 manufactured by Shibata Kagaku was used for melting point measurement. The HPLC analysis was performed under the following conditions using LC20A manufactured by Shimadzu Corporation.
Column: L-Column ODS (Chemicals Evaluation and Research Institute, diameter 4.6 mm, length 250 mm, particle size 5 μm)
Eluent: Methanol-0.01 mol / L ammonium acetate aqueous solution (45:55, volume ratio)
Flow rate: 1.0 ml / min Column temperature: 40 ° C
UV-Vis spectrophotometer: 235nm

Reference synthesis example 1
Synthesis of N- (2,5-dimethoxyphenyl) methanesulfonamide 300.04 g (1.96 mol) of 2,5-dimethoxyaniline, 185.91 g (2.35 mol) of pyridine and 2100 g of methylene chloride were mixed together to prepare methanesulfonyl chloride. 246.77 g (2.15 mol) was added dropwise, and the mixture was stirred at 20 to 25 ° C. for 3 hours. The reaction solution was added dropwise to 900 g of 1.6% hydrochloric acid, and the mixture was separated after stirring. The obtained organic layer was separated and washed with 900 g of 3% aqueous sodium hydrogen carbonate solution and 900 g of water. The obtained organic layer was evaporated to a residual amount of 900 g, 900 g of 1-propanol was added, and the solvent was distilled off to a residual amount of 1200 g. This was cooled to -3 ° C, and the precipitated crystals were collected by filtration, washed with 300 g of 1-propanol, and dried under reduced pressure at 40 ° C to give N- (2,5-dimethoxyphenyl) methanesulfonamide as a gray solid. 399.30 g (yield 88.2%) was obtained.
Appearance: Gray solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 2.97 (3H, s), 3.78 (3H, s), 3.85 (3H, s), 6.65 (1H, dd, J = 3.1 Hz, J = 9. 2 Hz), 6.84 (1 H, d, J = 8.9 Hz), 7.16 (1 H, d, J = 3.1 Hz)
Melting point: 59.7-59.8 ° C

Example 1
Synthesis of N- (4-acetyl-2,5-dimethoxyphenyl) methanesulfonamide 3.22 g (13.9 mmol) of N- (2,5-dimethoxyphenyl) methanesulfonamide and 32.3 g of methylene chloride and anhydrous aluminum chloride 1.85 g (13.9 mmol) was added, 2.73 g (34.8 mmol) of acetyl chloride was added dropwise, and the mixture was stirred at 1 ° C. to 4 ° C. for 3 hours. To the reaction solution, 16.1 g of water, 9.67 g of 6 mol / L hydrochloric acid and 100 g of ethyl acetate were added, and the mixture was separated after stirring. The obtained organic layer was separated and washed with 16.1 g of water. The obtained aqueous layer was extracted with 16.0 g of ethyl acetate. The organic layers were combined, the solvent was distilled off, and the precipitated crystals were collected by filtration, washed twice with 3.2 g of ethyl acetate, dried under reduced pressure at 40 ° C., and N- (4-acetyl-2,5-dimethoxyphenyl). ) 3.06 g (yield 80.4%) of methanesulfonamide was obtained as a slightly red solid.
Appearance: Slight red solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 2.62 (3H, s), 3.03 (3H, s), 3.88 (3H, s), 3.91 (3H, s), 7.08 (1H, s), 7.27 (1H, s), 7.42 (1H, s)
Melting point: 140.0-140.2 ° C

Example 2
Synthesis of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide 0.201 g (0.735 mmol) of N- (4-acetyl-2,5-dimethoxyphenyl) methanesulfonamide, anhydrous aluminum chloride 0.140 g (1.05 mmol), 0.169 g (1.13 mmol) of sodium iodide and 4.02 g of acetonitrile were mixed and stirred at 30 ° C. for 2 hours. 2 g of 2 mol / L hydrochloric acid and 20 mL of ethyl acetate were added to the reaction solution, and the mixture was separated after stirring. The obtained organic layer was separated and washed with 2 g of water. The obtained organic layer was evaporated, 20 mL of ethanol was added, the solvent was distilled off to a residual amount of 1.5 g, cooled to 0 ° C., and the precipitated crystals were collected by filtration and washed twice with 0.5 mL of ethanol. Then, this was dried under reduced pressure at room temperature to obtain 0.134 g (yield 70.7%) of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide as a yellow solid.
Appearance: yellow solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 2.57 (3H, s), 3.10 (3H, s), 3.87 (3H, s), 7.05 (1H, s), 7.11 (1H, s), 7.28 (1H, s), 12.40 (1H, s)
Melting point: 201.8-201.9 ° C

Example 3
Synthesis of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide 200.00 g (0.865 mol) of N- (2,5-dimethoxyphenyl) methanesulfonamide, 1400 g of methylene chloride, anhydrous aluminum chloride 138.41 g (1.04 mol) was added, 74.67 g (0.951 mol) of acetyl chloride was added dropwise, and the mixture was stirred at 12 to 13 ° C. for 2 hours. Acetonitrile 200g was dripped at this, sodium iodide 168.56g (1.12 mol) was added, and it stirred at 25 degreeC to 31 degreeC for 15 hours. 200 g of methanol was added dropwise to the reaction solution, the reaction solution was added dropwise to 400 g of methanol, 822 g (173 mmol) of 3% aqueous sodium hydrogen sulfite solution, cooled to 3 ° C., and the precipitated crystals were collected by filtration and washed twice with 200 g of methanol. And dried under reduced pressure at 50 ° C. to obtain 208.41 g (yield 92.9%) of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide as a yellow solid.

Example 4
Synthesis of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide 2.00 g of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide (7 .71 mmol), 1.10 g (15.4 mmol) of pyrrolidine and 20.03 g of 1-propanol were mixed and heated and stirred at 86 ° C. to 94 ° C. for 28 hours. During the 28 hours, 3.59 g (61 .8 mol) was added. The yield of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide was calculated by HPLC quantitative analysis and found to be 86.8%.

Example 5
Synthesis of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide 2.00 g of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide (7 .71 mmol), 1.10 g (15.4 mmol) of pyrrolidine, 20.03 g of 1-propanol, and 0.92 g (15.3 mmol) of acetic acid, and the mixture is heated and stirred at 88 to 94 ° C. for 28 hours, for 28 hours. 3.59 g (61.8 mol) of acetone was added in total. The yield of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide was calculated by HPLC quantitative analysis and found to be 96.7%.

Example 6
Synthesis of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide 135 g (0.521 mol) of N- (4-acetyl-5-hydroxy-2-methoxyphenyl) methanesulfonamide ), 74.10 g (1.04 mol) of pyrrolidine and 1350 g of 1-butanol were mixed, heated and stirred at 100 to 102 ° C. for 22 hours, and a total of 226.80 g (3.90 mol) of acetone was added during 22 hours. did. After the reaction, the reaction solution was added dropwise to a mixed solution of 338 g of water and 136 g of 35% hydrochloric acid, cooled to 14 ° C., and the precipitated crystals were collected by filtration, washed twice with 270 g of methanol, and dried under reduced pressure at 50 ° C. 128.73 g (yield 82.6%) of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) methanesulfonamide was obtained as an ocherous solid.
Appearance: Ocher solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.45 (6H, s), 2.68 (2H, s), 3.10 (3H, s), 3.88 (3H, s), 7.10 (1H, s), 7.24 (1H, s), 7.30 (1H, s)
Melting point: 212.4-212.5 ° C

Example 7
Synthesis of N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) -N- (methylsulfonyl) methanesulfonamide N- (6-methoxy-2,2-dimethyl-4-oxochroman- 7-yl) 50.00 g (0.167 mol) of methanesulfonamide, 23.66 g (0.234 mol) of triethylamine and 250 g of methylene chloride were mixed, and 24.86 g (0.217 mol) of methanesulfonyl chloride was added. Stir at 24 ° C. for 3 hours. After the reaction, 150 g of 6% hydrochloric acid was added dropwise, followed by liquid separation after stirring. The obtained organic layer was separated and washed with 150 g of 3% aqueous sodium hydrogen carbonate solution and 150 g of water. Of the obtained organic layer, 166 g of the organic layer was distilled off to a residual amount of 49.0 g. To this, 25.1 g of ethyl acetate was added, 75.0 g of n-hexane was added dropwise, the mixture was stirred at 19 ° C. for 1 hour, and the precipitated crystals were collected by filtration. 10.0 g of ethyl acetate and 50.1 g of n-hexane The mixture was washed with a mixed solution, and N- (6-methoxy-2,2-dimethyl-4-oxochroman-7-yl) -N- (methylsulfonyl) methanesulfonamide was obtained as a pale yellow solid, 29.45 g (yield 93. 4%).
Appearance: pale yellow solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.47 (6H, s), 2.73 (2H, s), 3.45 (3H, s), 3.92 (3H, s), 6.94 (1H, s), 7.43 (1H, s)
Melting point: 183.9-185.9 ° C

Example 8
Synthesis of N- (4-hydroxy-6-methoxy-2,2-dimethylchroman-7-yl) -N- (methylsulfonyl) methanesulfonamide N- (6-methoxy-2,2-dimethyl-4-oxochroman -7-yl) -N- (methylsulfonyl) methanesulfonamide 2.52 g (6.68 mmol) and tetrahydrofuran 25.2 g were mixed, cooled to 1 ° C., and sodium borohydride 0.516 g (13.6 mmol). And stirred at 1 to 2 ° C. for 1 hour and at room temperature for 5 hours. After the reaction, 12.6 g of 6% hydrochloric acid was added dropwise, 12.6 g of ethyl acetate was added, and the mixture was separated after stirring. The obtained organic layer was separated and washed with 12.6 g of 5% aqueous sodium hydrogen carbonate solution and 12.6 g of water. The obtained organic layer was evaporated to a residual amount of 30.0 g, 25.2 g of ethanol was added, and the solvent was distilled off to a residual amount of 12.6 g. Further, 2.52 g of ethanol was added, heated to 53 ° C., cooled to 1 ° C., the precipitated crystals were collected by filtration, washed twice with 3 ml of ethanol, dried under reduced pressure at 40 ° C., and N- (4-hydroxy 2.40 g (yield 94.9%) of -6-methoxy-2,2-dimethylchroman-7-yl) -N- (methylsulfonyl) methanesulfonamide was obtained as a white solid.
Appearance: White solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.32 (3H, s), 1.44 (3H, s), 1.83 (1H, dd, J = 9.5 Hz, J = 13.3 Hz), 2.21 (1H, dd, J = 6.1 Hz, J = 13.3 Hz), 3.42 (3H, s), 3.43 (3H, s), 3.89 (3H, s), 4.80-4.87 ( 1H, s), 6.75 (1H, s), 7.35 (1H, s)
Melting point: 188.8-188.9 ° C

Example 9
Synthesis of N- (6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide N- (4-hydroxy-6-methoxy-2,2-dimethylchroman -7-yl) -N- (methylsulfonyl) methanesulfonamide 0.0999 g (0.263 mmol), toluene 1.0 g, p-toluenesulfonic acid monohydrate 1.1 mg (0.00578 mmol) were mixed, The mixture was stirred at 50 ° C for 1.5 hours and at 80 ° C for 3.5 hours. After the reaction, 0.5 mL of 5% aqueous sodium hydrogen carbonate solution was added and the mixture was stirred and separated. To the obtained organic layer, 0.5 mL of water and 0.5 mL of ethyl acetate were added for liquid separation, and the solvent was distilled off and dried. To this, 0.43 g of ethyl acetate was added and dissolved by heating at 50 ° C. 0.43 g of n-heptane was added dropwise, cooled to 0 ° C., and the precipitated crystals were collected by filtration, washed with 1.5 mL of an n-heptane / ethyl acetate = 2/1 solution, dried at room temperature under reduced pressure, and N 0.0624 g (yield 65.5%) of-(6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide was obtained as a white solid.
Appearance: White solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.42 (6H, s), 3.41 (6H, s), 3.86 (3H, s), 5.71 (1H, d, J = 9.9 Hz), 6.29 (1H, d, J = 9.9 Hz), 6.63 (1H, s), 6.71 (1H, s)
Melting point: 174.4-174.5 ° C

Example 10
Synthesis of N- (6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide N- (6-methoxy-2,2-dimethyl-4-oxochroman- 7-yl) methanesulfonamide 150.00 g (0.501 mol), triethylamine 65.92 g (0.651 mol), and methylene chloride 750 g were mixed, and methanesulfonyl chloride 68.89 g (0.601 mol) was added dropwise to the solution at 32 ° C. For 2 hours. After the reaction, 450 g of 6% hydrochloric acid was added dropwise, followed by liquid separation after stirring. The obtained organic layer was separated and washed with 450 g of 3% aqueous sodium hydrogen carbonate solution and 450 g of water. The obtained organic layer was evaporated to a residual amount of 450 g, 1050 g of tetrahydrofuran was added, and the solvent was evaporated to a residual amount of 450 g.
To this, 225 g of tetrahydrofuran and 75 g of methanol were added and cooled to 5 ° C., 18.97 g (0.501 mol) of sodium borohydride was added, and the mixture was stirred at 11 to 13 ° C. for 2 hours. The reaction solution was added dropwise to a mixed solution of 600 g of ethyl acetate and 750 g of 6% hydrochloric acid, washed with 150 g of ethyl acetate, and separated after stirring. The obtained organic layer was separated with 750 g of 3% sodium bicarbonate-5% sodium chloride aqueous solution and 750 g of 5% sodium chloride aqueous solution. The obtained organic layer was distilled off to a residual amount of 450 g, 1050 g of toluene was added, and the solvent was distilled off to a residual amount of 900 g.
To this, 2.41 g (25.1 mmol) of methanesulfonic acid was added, and azeotropic dehydration was performed at 103 to 112 ° C. using a Dean-Stark trap for 2 hours. After cooling to room temperature, 150 g of 1-propanol was added, heated to 68 ° C., cooled to 14 ° C., and the precipitated crystals were collected by filtration, washed with a mixed solution of 150 g of toluene, 15 g of 1-propanol and 150 g of n-heptane, After drying under reduced pressure at 50 ° C., 156.95 g of N- (6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide was obtained as a slightly gray solid. Rate 86.7%).

Example 11
Synthesis of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} -N- (methylsulfonyl) methanesulfonamide N -{(1aR ^* , 7bR ^* )-6-methoxy-2,2-dimethyl-2,7b-dihydro-1aH-oxyleno [2,3-c] chromen-5-yl} -N- (methylsulfonyl) methane 1.50 g (3.97 mmol) of sulfonamide, 3.01 g of 1-propanol, and 0.482 g (3.98 mmol) of 2-phenylethylamine were mixed and stirred at 96 to 98 ° C. for 6 hours. After standing to cool, 7.5 g of 6% hydrochloric acid and 10 g of ethyl acetate were added to separate the layers. Separating and washing with 7.5 g of 3% aqueous sodium hydrogen carbonate solution and 7.5 g of 10% brine, and the concentrate was gradually changed from column chromatography (hexane-ethyl acetate, 95: 5 to 10:90, N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} -N- (methyl) 1.91 g (96.5% yield) of sulfonyl) methanesulfonamide was obtained as a pale yellow solid. This was further purified and subjected to the following analysis.
Appearance: Light orange solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.18 (3H, s), 1.45 (3H, s), 2.83 (2H, t, J = 5.8 Hz), 2.87-3.07 (2H, m) , 3.40 (3H, s), 3.41 (3H, s), 3.53 (1H, d, J = 9.9 Hz), 3.64 (1H, d, J = 10.6 Hz), 3 .72 (3H, s), 6.71 (1H, s), 6.72 (1H, s), 7.21-7.35 (5H, m)
Melting point: 130.6-131.6 ° C

Example 12
Synthesis of N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} -N- (methylsulfonyl) methanesulfonamide N -{(1aR ^* , 7bR ^* )-6-methoxy-2,2-dimethyl-2,7b-dihydro-1aH-oxyleno [2,3-c] chromen-5-yl} -N- (methylsulfonyl) methane 2.00 g (5.30 mmol) of sulfonamide, 10 ml of 1,4-dioxane, 564 mg (5.30 mmol) of lithium perchlorate and 0.80 ml (6.4 mmol) of 2-phenylethylamine were mixed, and 1. Stir for 5 hours. After allowing to cool, ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrate was subjected to column chromatography (hexane-ethyl acetate, 1: 1, volume ratio) and purified by N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} -N- 2.62 g (yield 99.2%) of (methylsulfonyl) methanesulfonamide was obtained as a pale yellow amorphous substance.

Example 13
^{N - {(3R *, 4S} *) -3- hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} synthesis methanesulfonamide N - ^{(3R *, 4S ^* ) 0.555 g (1.11 mmol) of 3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} -N- (methylsulfonyl) methanesulfonamide Dissolved in 5.5 ml of propanol, 2.5 ml (2.5 mmol) of 1 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at 22 ° C. for 2.5 hours. The reaction mixture was evaporated, ethyl acetate and saturated aqueous ammonium chloride solution were added, the phases were separated, the aqueous layer was re-extracted with chloroform, and the resulting organic layer concentrate was subjected to column chromatography (chloroform-ethyl acetate, 1: 2, volume ratio) and purified by N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methane 445 mg (95.1% yield) of sulfonamide was obtained as a colorless solid.
Appearance: colorless solid
¹ H-NMR (CDCl ₃ , TMS)
δ (ppm): 1.07 (3H, s), 1.34 (3H, s), 2.50-2.59 (1H, m), 2.73 (2H, t, J = 6.5 Hz) 2.91-2.83 (1H, m), 2.94 (3H, s), 3.34-3.57 (2H, m), 3.62 (3H, s), 6.61 (1H , S), 6.98 (1H, s), 7.15-7.30 (5H, m)
Melting point: 126.6-128.5 ° C

A novel process for producing N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide according to the present invention is: This is useful in that it can be manufactured inexpensively and safely.

Claims (8)

Formula (13)

The compound represented by formula (14)

And is demethylated to obtain a compound represented by the formula (15)

And cyclized by reaction with acetone to give a compound represented by formula (16)

And N-methanesulfonylated to give a compound represented by formula (17)

This is reduced to a compound represented by formula (18)

The compound represented by formula (11) is characterized by dehydrating olefins:

A method for producing N- (6-methoxy-2,2-dimethyl-2H-chromen-7-yl) -N- (methylsulfonyl) methanesulfonamide represented by the formula: Formula (12)

( ^{* Indicates} relative arrangement)
2-phenylethylamine is reacted with the compound represented by formula (19)

( ^{* Indicates} relative arrangement)
A compound represented by formula (1), characterized in that it is demethanylated.

( ^{* Indicates} relative arrangement)
N-{(3R ^* , 4S ^* )-3-hydroxy-6-methoxy-2,2-dimethyl-4- (phenethylamino) chroman-7-yl} methanesulfonamide represented by the formula: Formula (14)

A compound represented by Formula (15)

A compound represented by Formula (16)

A compound represented by Formula (17)

A compound represented by Formula (18)

A compound represented by Formula (19)

( ^{* Indicates} relative arrangement)
A compound represented by