WO2022014413A1 - Method for producing optically active 1,1,3-trimethyl-4-aminoindane - Google Patents

Abstract

The purpose of the present invention is to provide a novel method for producing optically active 1,1,3-trimethyl-4-aminoindane by means of a preferential crystallization method using an achiral acid and without using an optically active acid.　The present invention provides a method for producing optically active 1,1,3-trimethyl-4-aminoindane, the method including: a first step for mixing optically active 1,1,3-trimethyl-4-aminoindane and an achiral acid in the presence of a solvent so as to precipitate an acid salt of these; and a second step for mixing the acid salt obtained in the first step with a base so as to obtain optically active 1,1,3-trimethyl-4-aminoindane.

Description

Method for Producing Optically Active 1,1,3-trimethyl-4-Aminoindane

The present invention relates to a method for producing optically active 1,1,3-trimethyl-4-aminoindane.

Patent Document 1 describes that optically active 1,1,3-trimethyl-4-aminoindane is useful as a synthetic intermediate for a compound having a plant disease preventive effect. Further, in Patent Document 1, D-tartaric acid is used to optically resolve the racemic 1,1,3-trimethyl-4-aminoindane to obtain (R) -1,1,3-trimethyl-4-. It is also stated that aminoindane can be obtained.

International Publication No. 2011/162397

An object of the present invention is to provide a new method for producing optically active 1,1,3-trimethyl-4-aminoindane by a preferential crystallization method with an achiral acid without using an optically active acid. Is.

Under such circumstances, the present inventor has reached the present invention as a result of diligent studies. That is, the present invention includes the following inventions.
[1] Obtained in the first step and the first step of mixing optically active 1,1,3-trimethyl-4-aminoindan and an achiral acid to precipitate their acid salts in the presence of a solvent. The optically active 1,1,3-trimethyl-4-aminoindan comprises a second step of mixing the acid salt and the base to obtain an optically active 1,1,3-trimethyl-4-aminoindan. Manufacturing method.
[2] The optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step is more than the optical purity of the optically active 1,1,3-trimethyl-4-aminoindane used in the first step. [1] The production method according to [1], which is characterized by high optical purity.
[3] The optical purity of the optically active 1,1,3-trimethyl-4-aminoindane used in the first step is 40% e. e. The optical purity of the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step is 89% e. e. The manufacturing method according to [2] described above.
[4] The production method according to any one of [1] to [3], wherein the optically active 1,1,3-trimethyl-4-aminoindane contains a large amount of R-form.
[5] The production method according to any one of [1] to [4], wherein the pKa of the acid is less than 2.8.
[6] One or more acids selected from the group consisting of sulfuric acid, hydrogen sulfate, sulfamic acid, organic sulfonic acid, hydrohalogen acid, phosphoric acid, organic phosphoric acids, nitrate, tetrafluoroboric acid, and carboxylic acid. The production method according to any one of [1] to [4], which is an acid.
[7] Acids are sulfuric acid, sodium hydrogensulfate, potassium hydrogensulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphate, diphosphate. One or more acids selected from the group consisting of hydrogenphenyl, nitrate, tetrafluoroboric acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, 2-nitrobenzoic acid, chloroacetic acid, and bromoacetic acid, [1]-[ 4] The manufacturing method according to any one of the above items.
[8] The optically active 1,1,3-trimethyl-4-aminoindane obtained by the production method according to any one of [1] to [7] and the formula (1):

(In the formula, R ¹ and R ² each independently represent a C1-C6 alkyl group or hydrogen atom which may be substituted with one or more halogen atoms, and R ³ is a halogen atom, hydroxy. Represents a C1-C6 alkoxy group that may be substituted with a group or one or more halogen atoms.)
By reacting with the compound represented by, the formula (2):

(In the formula, R ¹ and R ² have the same meanings as above. The carbon atom marked with * represents an asymmetric carbon atom.)
A production method further comprising the step of obtaining the optically active compound represented by.

According to the present invention, the optical purity of 1,1,3-trimethyl-4-aminoindane can be efficiently improved.

Hereinafter, the present invention will be described in detail.
The present invention is a method for producing optically active 1,1,3-trimethyl-4-aminoindan, wherein the production method is described in the following steps, that is, optically active 1,1,3 in the presence of a solvent. -Mixing trimethyl-4-aminoindane and an achiral acid to precipitate their acid salts (first step), and mixing the acid salts obtained in the first step with a base to obtain optical light. The step (second step) for obtaining an active 1,1,3-trimethyl-4-aminoindan is included.

First, the first step of mixing an acid with a solution containing optically active 1,1,3-trimethyl-4-aminoindane to precipitate their acid salts will be described.

First, when the term "optically active 1,1,3-trimethyl-4-aminoindane" is described in the present specification, unless otherwise specified, the racemic mixture of the R-form, which will be described later, is contained in enantiorich. It means the form of the body or its R body itself.
The optically active 1,1,3-trimethyl-4-aminoindane used in the first step has an optical purity of 40% e. e. When it is the above (for example, 66% e.e. or more), the optical purity of the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step tends to be high (usually 89% e.e.). e. Or more, for example, 91% e.e. or more, 92% e.e. or more, 96% e.e. or more, 97% e.e. or more, 99% e.e. or more) preferable. The optically active 1,1,3-trimethyl-4-aminoindane preferably contains a large amount of R-form in that it is useful as a synthetic intermediate of the compound having a plant disease preventive effect described in Patent Document 1. When the optically active 1,1,3-trimethyl-4-aminoindane used in the first step contains a large amount of R-form, usually, the optically active 1,1,3-trimethyl-4-amino obtained in the second step is obtained. Indan contains a lot of R-forms.
The structural formulas of the R-form and the S-form of 1,1,3-trimethyl-4-aminoindane are shown below.

As a method for producing optically active 1,1,3-trimethyl-4-aminoindan, 2,2,4-trimethyl-1-quinoline is acylated with an optically active acylating agent and then hydrogenated to be optically active. Examples thereof include a production method in which a 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline derivative is obtained, further isomerized with sulfuric acid, and then hydrolyzed (for example, JP-A-7-215921). See publication). Further, by asymmetric hydrogenating the 2,2,4-trimethyl-1-quinoline derivative, the above-mentioned optically active 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline derivative can be obtained. It is also known (see, eg, International Publication No. 2015/141564), which is then isomerized with sulfuric acid and then hydrolyzed to give optically active 1,1,3-trimethyl-4-aminoindan. You can also get it. In the first step of the present invention, optically active 1,1,3-trimethyl-4-aminoindane obtained by these methods can be provided.

The acid may be an achiral acid, and among the optically active 1,1,3-trimethyl-4-aminoindane, a large amount of the optically active salt of the optically active substance can be preferentially precipitated. It may be an acid.
In order to form such a salt, an acid having an acid dissociation constant (pKa) of less than 2.8 is usually used.
Here, the acid dissociation constant is determined by the equilibrium constant (Ka) of the ionization equilibrium of the acid when the acid dissociation reaction in which hydrogen ions are released from the acid, or the dissociation constant (pKa) which is a negative common logarithm thereof. It is an index showing the strength of acid expressed. The larger the equilibrium constant Ka value or the smaller the dissociation constant pKa value, the stronger the acid.
As the acid dissociation constant (pKa) in the present invention, calculated values (values calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02) are recorded in SciFinder, which is a database provided by Chemical Abstracts Service. If so, use that value. Such a value can be searched from, for example, the homepage of the Japan Association for International Chemical Information (https://www.jaici.or.jp/SCIFINDER/). For acids whose calculated values are not recorded in SciFinder, the data posted on the Chemical Book homepage (https://www.chemicalbook.com/) is adopted, and for acids not listed in such homepage, Applied. Catalysis A: Calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02 if the values listed in General 492 (2015) 252-261 are used and are not published in such magazines. Adopt the value.

Acids with an acid dissociation constant (pKa) of less than 2.8 include sulfuric acid, hydrogen sulfate, sulfamic acid, organic sulfonic acid, hydrohalogenate, phosphoric acid, organic phosphoric acids, nitrate, tetrafluoroboric acid and carboxylic acid. Acids are mentioned, and it is preferable to use one or more acids selected from the group consisting of these acids.
Examples of the hydrogen sulfate include hydrogen sulfate alkali metal salts such as sodium hydrogen sulfate, lithium hydrogen sulfate, and potassium hydrogen sulfate.
Examples of the organic sulfonic acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, taurine and the like.
Examples of the hydrogen halide include hydrochloric acid, hydrobromic acid, and hydrogen iodide.
Examples of organic phosphoric acids include phenyl dihydrogen phosphate, ethyl dihydrogen phosphate, phenylphosphonic acid, and methylphosphonic acid.
Examples of the carboxylic acid include oxalic acid, trichloroacetic acid, trifluoroacetic acid, dichloroacetic acid, monochloroacetic acid, monobromoacetic acid, 2-nitrobenzoic acid, pentafluorophenylcarboxylic acid and the like.
Among these, one or more acids selected from the group consisting of sulfuric acid, hydrogen sulfate, sulfamic acid, organic sulfonic acid, hydrohalic acid, phosphoric acid, organic phosphoric acids, nitric acid, tetrafluoroboric acid, and carboxylic acid. It is more preferable to use it. Sulfuric acid, sodium hydrogensulfate, potassium hydrogensulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphate, dihydrogenphobic phenyl, nitrate, tetra It is further preferred to use one or more acids selected from the group consisting of fluoroboric acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, 2-nitrobenzoic acid, chloroacetic acid, and bromoacetic acid. Sulfate, sodium hydrogensulfate, potassium hydrogensulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphate, dihydrogenphobic phenyl, nitrate, tetra It is even more preferred to use one or more acids selected from the group consisting of fluoroboric acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, and 2-nitrobenzoic acid.
The amount of the acid used is usually 0.7 mol to 1.5 mol, preferably 0 in the case of an acid other than sulfuric acid, with respect to 1 mol of optically active 1,1,3-trimethyl-4-aminoindan. The range is from 7.7 mol to 1.0 mol, and in the case of sulfuric acid, it is usually in the range of 0.35 mol to 0.5 mol, preferably 0.35 mol to 0.45 mol.

Examples of the solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; water; ether solvents such as tetrahydrofuran; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; aromatic hydrocarbons such as toluene, xylene, and ethylbenzene. Solvents; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; aliphatic hydrocarbon solvents such as heptane and hexane; and alicyclic hydrocarbon solvents such as cyclopentane and cyclohexane, alcohol solvents and aromatics. A hydrocarbon solvent and water are preferable. Two or more of these solvents may be mixed and used.
The amount of the solvent used is usually 0.5 parts by weight to 20 parts by weight, preferably 1.0 part by weight to 10 parts by weight, based on 1 part by weight of 1,1,3-trimethyl-4-aminoindane. It is a range.

The mixing temperature is usually in the range of 20 ° C to 100 ° C.
The mixing order may be that 1,1,3-trimethyl-4-aminoindane, an acid and a solvent may be mixed at one time, or after mixing the acid and the solvent, the resulting mixture may be mixed with 1,1,1. 3-trimethyl-4-aminoindane may be added. A mixture of an acid and a solvent may be added to 1,1,3-trimethyl-4-aminoindane. Further, after mixing 1,1,3-trimethyl-4-aminoindane with a solvent, an acid or a mixture of an acid and a solvent may be added to the obtained mixture. A method of mixing 1,1,3-trimethyl-4-aminoindane with a solvent and then adding an acid or a mixture of the acid and the solvent to the obtained mixture is preferable. If the crystals do not precipitate even after mixing and cooling, the crystals may be precipitated by partially distilling off the solvent.

Mixing may be performed collectively, continuously, or divided (for example, dropped). When an acid is added to a mixture of 1,1,3-trimethyl-4-aminoindane and a solvent, the acid may be added all at once or continuously, but may be added in portions. Is preferable.

A salt of optically active 1,1,3-trimethyl-4-aminoindane may be precipitated only by mixing an acid with a solution of optically active 1,1,3-trimethyl-4-aminoindane. Usually, by cooling the resulting mixture, the optically active acid salt of 1,1,3-trimethyl-4-aminoindane can be precipitated. By separating the acid salt precipitated from the mixture by a solid-liquid separation treatment such as filtration, the optically active acid salt of 1,1,3-trimethyl-4-aminoindan and the remaining 1,1,3- It can be separated into a solution containing trimethyl-4-aminoindan and its acid salt. If the optically active acid salt of 1,1,3-trimethyl-4-aminoindane does not precipitate even after cooling, the acid salt may be precipitated by distilling off a part of the solvent.

The temperature after cooling is lower than the above-mentioned mixing temperature, preferably in the range of −20 ° C. to 30 ° C., and more preferably in the range of −10 ° C. to 20 ° C.
The cooling rate is not particularly limited, but is usually in the range of about 1 ° C./hour to 100 ° C./hour.

The optically active acid salt of 1,1,3-trimethyl-4-aminoindane extracted in the first step may be used as it is in the next second step, but at least one selected from the above solvents. It may be served after washing with the solvent of. Further, it may be dried and then subjected to the second step if necessary.

Next, the second step of mixing the acid salt and the base obtained in the first step to obtain optically active 1,1,3-trimethyl-4-aminoindane will be described.

As the base, any base having a base strength capable of decomposing the optically active acid salt of 1,1,3-trimethyl-4-aminoindane can be used without particular limitation.
Examples of the base include an inorganic base and an organic base.
Examples of the inorganic base include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metals carbonate, and alkali metals phosphate.
Examples of the alkali metal hydroxide include sodium hydroxide and potassium hydroxide.
Examples of the alkaline earth metal hydroxide include calcium hydroxide and magnesium hydroxide.
Examples of the alkali metal carbonate include potassium carbonate and sodium carbonate.
Alkaline carbonate earth metals include calcium carbonate and magnesium carbonate.
Examples of the alkali metal phosphate include trisodium phosphate and tripotassium phosphate.
Alkali metal hydroxides are preferred.
Examples of organic bases include tertiary amines, secondary amines, and primary amines.
Examples of the tertiary amine include triethylamine, tripropylamine, tributylamine and the like.
Examples of the secondary amine include diethylamine, dipropylamine, dibutylamine and the like.
Examples of the primary amine include butylamine and benzylamine.
It is preferably a tertiary amine.
The amount of the base is usually in the range of 0.5 mol to 3 mol in terms of base with respect to 1 mol of the acid used in the first step. The mixing temperature is usually in the range of 10 ° C to 80 ° C.

The mixing of the acid salt and the base obtained in the first step may be carried out in the presence of an organic solvent and / or water. Examples of the organic solvent include aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; aliphatic hydrocarbon solvents such as heptane and hexane; alicyclic type such as cyclopentane and cyclohexane. Examples include, but are not limited to, hydrocarbon solvents; ether solvents such as diethyl ether and tert-butyl methyl ether; and ester solvents such as ethyl acetate; and mixed solvents thereof.
The total amount of the organic solvent and / or water used is usually 10 parts by weight or less with respect to 1 part by weight of the acid salt.

The mixing order may be such that the optically active acid salt of 1,1,3-trimethyl-4-aminoindan, the base in an aqueous solution if necessary, and the organic solvent if necessary may be mixed at once. , The acid salt and, if necessary, a mixture with an organic solvent, and if necessary, an aqueous solution of the base may be mixed. Further, the acid salt may be added to a mixture of an aqueous solution of a base and an organic solvent, if necessary. In particular, it is preferable to add the acid salt to a mixture of an organic solvent and, if necessary, an aqueous solution of the base.

After completion of mixing, the mixture is usually separated into an organic layer and an aqueous layer, which are separated to obtain an organic layer, and if necessary, an organic solvent is distilled off to obtain an optically active 1, 1,3-trimethyl-4-aminoindane can be taken out. As described above, the optical purity of the optically active 1,1,3-trimethyl-4-aminoindane thus obtained is usually the optically active 1,1,3-trimethyl-4-aminoindane used in the first step. Higher than the optical purity of.
When the optically active 1,1,3-trimethyl-4-aminoindan is used for the amidation reaction D described later, the acid salt is subjected to the reaction with the compound represented by the formula (1-3) as it is. First, the acid salt is neutralized by the base in the reaction system to give optically active 1,1,3-trimethyl-4-aminoindan, which reacts with the compound represented by the formula (1-3). Therefore, the second step of the present invention and the amidation reaction D can be continuously performed.

Next, the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step and the formula (1):

(In the formula, R ¹ and R ² each independently represent a C1-C6 alkyl group or a hydrogen atom which may be substituted with one or more halogen atoms, and R ³ is a halogen atom or a hydroxy group. , Or a C1-C6 alkoxy group that may be substituted with one or more halogen atoms.)
By reacting with the compound represented by, the formula (2):

(In the formula, R ¹ and R ² have the same meanings as above. The carbon atom marked with * represents an asymmetric carbon atom.)
The process of obtaining the compound represented by the above will be described. Hereinafter, the reaction between the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step and the compound represented by the formula (1) is referred to as "amidation reaction" in the present specification. May be described.

The notation "CX-CY" in the present specification means that the number of carbon atoms is X to Y. That is, the notation "C1-C6" means that the number of carbon atoms is 1 to 6.
^{Examples of the C1-C6 alkyl group represented by R 1} and R ² in the formulas (1) and (2) and which may be substituted with one or more halogen atoms include a methyl group, an ethyl group and an n-propyl group. Group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, perfluoroethyl group, perfluoro n -Propyl group, perfluoroisopropyl group, perfluoron-butyl group, perfluorosec-butyl group, perfluorotert-butyl group, perfluoron-pentyl group, perfluoron-hexyl group, trichloromethyl group, tribromomethyl group, and triiode Examples include a methyl group.
As R ¹ , a hydrogen atom or a methyl group is preferable, and a hydrogen atom is more preferable.
The R ^2, a methyl group, monofluoromethyl group, preferably a difluoromethyl group or a trifluoromethyl group, difluoromethyl group is more preferable.
The halogen atom represented by R ³ in formula (1), a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the C1-C6 alkoxy group represented by R ³ which may be substituted with one or more halogen atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group and sec-. Butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, trifluoromethoxy group, difluoromethoxy group, perfluoroethoxy group, perfluoron-propoxy group, perfluoroisopropoxy group, perfluoron-butoxy group, Examples thereof include perfluorosec-butoxy group, perfluorotert-butoxy group, perfluoron-pentyloxy group, perfluoron-hexyloxy group, trichloromethoxy group, tribromomethoxy group, triiodomethoxy group and the like.
As R ^3, a chlorine atom, an ethoxy group or a hydroxyl group are preferred, and a chlorine atom is more preferable.
Examples of the compound represented by the formula (1) (hereinafter, may be referred to as “compound (1)” in the present specification) include 1-methyl-3-difluoromethylpyrazole-4-carboxylate ethyl, 1. -Methyl-3-difluoromethylpyrazole-4-carboxylic acid, 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride and the like can be mentioned.
Examples of the optically active compound represented by the formula (2) (hereinafter, may be referred to as “optically active compound (2)” in the present specification) are (R)-(-)-N- (1). , 1,3-trimethylindan-4-yl) -1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide and the like.

The amidation reaction may be carried out under the condition that the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step reacts with the compound (1). , B, C or D is preferred.

<Amidation reaction A>
Amidation reaction A is an optically active 1,1,3-trimethyl-4-aminoindan obtained in the second step, R ³ is a hydroxy group in the formula (1) (herein, Hereinafter, it may be referred to as “compound (1-1)”) in the presence of a dehydration condensing agent to obtain an optically active compound (2).

(In the formula, R ¹ and R ² have the same meanings as described above.)

Examples of the dehydration condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbodiimide compounds such as 1,3-dicyclohexylcarbodiimide, and (benzotriazole-1-yloxy) tris (dimethylamino). Phosphonium hexafluorophosphate may be mentioned.
The amount of the dehydration condensing agent used is usually in the range of 1 mol to 5 mol per 1 mol of the compound (1-1).
The amount of optically active 1,1,3-trimethyl-4-aminoindane used is usually in the range of 0.5 mol to 3 mol per 1 mol of compound (1-1).

The reaction between the optically active 1,1,3-trimethyl-4-aminoindane and compound (1-1) is usually carried out in the presence of a solvent inert to the reaction. Such solvents include ether solvents such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, and tert-butyl methyl ether; aliphatic hydrocarbon solvents such as hexane, heptane, and octane; aromatic carbides such as toluene, xylene, and ethylbenzene. Hydrogen solvent; Halogened hydrocarbon solvent such as chlorobenzene; Ester solvent such as butyl acetate and ethyl acetate; Nitrile solvent such as acetonitrile; Acid amide solvent such as N, N-dimethylformamide; Sulfoxide solvent such as dimethyl sulfoxide, and Examples thereof include a nitrogen-containing aromatic compound solvent such as pyridine, and a mixed solution of two or more of these. The amount of the solvent used is usually in the range of 1 part by weight to 20 parts by weight with respect to 1 part by weight of the compound (1-1). The reaction temperature is usually in the range of −20 ° C. to 150 ° C., and the reaction time is usually in the range of 1 hour to 24 hours.

After completion of the reaction, the obtained reaction mixture and water; an aqueous solution of a base such as an aqueous solution of sodium hydrogen carbonate, an aqueous solution of sodium carbonate, an aqueous solution of ammonium chloride, an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide; or an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid or The optically active compound (2) can be taken out by mixing it with an aqueous solution of an acid such as acetic acid to precipitate a solid, and filtering the obtained mixture. When the solid does not precipitate, the optically active compound (2) can be taken out by extracting the obtained mixture with an organic solvent and performing post-treatment operations such as separating, drying and concentrating the organic layer. The organic layer is water: aqueous solution of alkali metal hydrogen carbonate such as sodium hydrogen carbonate aqueous solution: aqueous solution of alkali metal carbonate such as sodium carbonate aqueous solution: ammonium chloride aqueous solution: alkali metal water such as sodium hydroxide aqueous solution and potassium hydroxide aqueous solution. Aqueous solution of oxide: Alternatively, it may be washed with an aqueous solution of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid. Cleaning of the organic layer is usually carried out in the range of 0 ° C to 70 ° C, preferably 20 ° C to 60 ° C. The extracted optically active compound (7) can be further purified by column chromatography, recrystallization and the like.

<Amidation reaction B>
In the amidation reaction B, the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step and the compound (1-1) are reacted in the presence of Lewis acid to cause an optically active compound. This is the step of obtaining (2).

As Lewis acid, metal chlorides such as titanium tetrachloride, zirconium tetrachloride, and aluminum chloride: titanium ethoxydo, titanium propoxide, zirconium ethoxydo, zirconium propoxide, aluminum ethoxydo, aluminum propoxide, antimonate, And metal alkoxide compounds such as antimonpropoxide: tetrakis (dimethylamino) titanium, dichlorobis (dimethylamino) titanium, and metal amide compounds such as tetrakis (diethylamino) titanium: boric acid, 3,5-bis (trifluoromethyl) phenyl. Boron compounds such as boronic acid, 2,4-bis (trifluoromethyl) phenylboronic acid, and pentafluorophenylboronic acid: triphenylmethyltetrakis (pentafluorophenyl) borate, triphenylmethyltetrakis (3,5-bistrifluoro) Examples thereof include borate compounds such as methylphenyl) borate and N, N-dimethylanilinium tetrakis (pentafluorophenyl) borate.
The amount of Lewis acid used is usually in the range of 0.001 mol to 3 mol per 1 mol of compound (1-1).
The amount of optically active 1,1,3-trimethyl-4-aminoindane used is usually in the range of 0.5 mol to 3 mol per 1 mol of compound (1-1).

The reaction of the optically active 1,1,3-trimethyl-4-aminoindane with compound (1-1) is usually carried out in the presence of a solvent inert to the reaction. Examples of such a solvent include the above-mentioned solvents as the solvents that can be used for the amidation reaction A. The amount of the solvent used is usually in the range of 1 part by weight to 20 parts by weight with respect to 1 part by weight of the compound (1-1). The reaction temperature is usually in the range of −20 ° C. to 150 ° C., and the reaction time is usually in the range of 1 hour to 120 hours, and it is preferable to carry out the reaction while removing the by-product water.
After completion of the reaction, the optically active compound (2) can be taken out by performing the same treatment as in the amidation reaction A.

<Amidation reaction C>
Amidation reaction C is an optically active 1,1,3-trimethyl-4-aminoindan obtained in the second step, R ³ in the formula (1) is optionally substituted with one or more halogen atoms A compound which is also a good C1-C10 alkoxy group (hereinafter, may be referred to as “compound (1-2)” in the present specification) is reacted in the presence of a Lewis acid or a Lewis base for optical activity. This is a step of obtaining compound (2).

(In the formula, R ¹ and R ² are as defined above, and R ^{3 'represents} one or more halogen atoms which may be substituted C1-C6 alkoxy group.)

Lewis acids include metal chlorides such as titanium tetrachloride, zirconium tetrachloride, and aluminum chloride, and titanium ethoxydo, titanium propoxide, zirconium ethoxydo, zirconium propoxide, aluminum ethoxydo, aluminum propoxide, and antimonate. , And metal alkoxide compounds such as antimonopropoxide.
The amount of Lewis acid used is usually in the range of 0.01 mol to 3 mol per 1 mol of compound (1-2).
The amount of optically active 1,1,3-trimethyl-4-aminoindane used is usually in the range of 0.5 mol to 3 mol per 1 mol of compound (1-2).

Lewis bases include metal alkoxide compounds such as sodium methoxyd, sodium ethoxydo, sodium tert-butoxide, potassium methoxyd, potassium ethoxydo and potassium tert-butoxide: metal hydrides such as sodium hydride: lithium diisopropylamide and tert. -Lithium compounds such as butyl lithium: silicon compounds such as sodium hexamethyldisilazane and potassium hexamethyldisilazane: aluminum compounds such as trimethylaluminum, triethylaluminum and triisobutylaluminum.
The amount of Lewis base used is usually in the range of 0.01 mol to 3 mol per 1 mol of compound (1-2).
The amount of optically active 1,1,3-trimethyl-4-aminoindane used is usually in the range of 0.5 mol to 3 mol per 1 mol of compound (1-2).

The reaction of the optically active 1,1,3-trimethyl-4-aminoindane with compound (1-2) is usually carried out in the presence of a solvent inert to the reaction. Examples of such a solvent include the above-mentioned solvents as the solvents that can be used for the amidation reaction A. The amount of the solvent used is usually in the range of 1 part by weight to 20 parts by weight with respect to 1 part by weight of the compound (1-2). The reaction temperature is usually in the range of −20 ° C. to 150 ° C., and the reaction time is usually in the range of 1 hour to 110 hours, and it is preferable to carry out the reaction while removing the by-product alcohol.
After completion of the reaction, the optically active compound (2) can be taken out by performing the same treatment as in the amidation reaction A.

<Amidation reaction D>
Amidation reaction D is an optically active 1,1,3-trimethyl-4-aminoindan obtained in the second step, and R ³ is a halogen atom in the above formula (1) (herein, Hereinafter, it may be referred to as “compound (1-3)”) in the presence of a base to obtain an optically active compound (2).

(In the equation, R ¹ and R ² have the same meanings as described above, and R ^{3 ″} represents a halogen atom.)

Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary amines such as triethylamine and diisopropylethylamine; and nitrogen-containing aromatic compounds such as pyridine and 4-dimethylaminopyridine.
The amount of the base used is usually in the range of 5 mol, preferably 1 mol to 3 mol, from the catalytic amount, relative to 1 mol of the optically active 1,1,3-trimethyl-4-aminoindane.
As described above, when the optically active 1,1,3-trimethyl-4-aminoindane is used as it is in the amidation reaction D without decomposing the acid salt obtained in the first step, it is necessary for its neutralization. The amount of the base to be used may be determined in consideration of the amount of the base.
The amount of the compound (1-3) to be used is usually 0.5 mol to 1.5 mol, preferably 0.8 mol, based on 1 mol of the optically active 1,1,3-trimethyl-4-aminoindan. From 1.3 mol, more preferably in the range of 1.0 mol to 1.2 mol.

The reaction between the optically active 1,1,3-trimethyl-4-aminoindane and compound (1-3) is usually carried out in the presence of a solvent. The solvent may be any one inert to the reaction, for example, an aliphatic hydrocarbon solvent such as pentane, hexane, heptane, octane and cyclohexane; an aromatic hydrocarbon solvent such as toluene, xylene and ethylbenzene; dichloromethane, chloroform. , 1,2-Dichloroethane and halogenated aliphatic hydrocarbon solvents such as carbon tetrachloride; halogenated aromatic hydrocarbon solvents such as chlorobenzene, dichlorobenzene and trichlorobenzene; diethyl ether, diisopropyl ether, tert-butylmethyl ether, cyclohexyl Ether solvents such as methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile; and mixed solutions of two or more of these include aromatic hydrocarbon solvents. Halogenized aromatic hydrocarbon solvents and ether solvents are preferred, with toluene, xylene, ethylbenzene, chlorobenzene and tetrahydrofuran more preferred. The amount of the solvent used is preferably 1 part by weight to 20 parts by weight, more preferably 2 parts by weight to 10 parts by weight, based on 1 part by weight of the optically active 1,1,3-trimethyl-4-aminoindane. It is a range.

The reaction temperature is usually in the range of −20 ° C. to 80 ° C., preferably 0 ° C. to 70 ° C., more preferably 20 ° C. to 60 ° C., and the reaction time is usually in the range of 0.1 hour to 24 hours.
After completion of the reaction, the optically active compound (2) can be taken out by performing the same treatment as in the amidation reaction A.
The extracted optically active compound (2) can be further purified by column chromatography, recrystallization and the like, and is preferably purified.
As a purification method, a method in which the optically active compound (2) is dissolved in a solvent to prepare a solution and recrystallization is performed using the solution is preferable. Seed crystals may be used for recrystallization.
Such solvents include aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane and cyclohexane; aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene; dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride and the like. Halogenated aliphatic hydrocarbon solvent; Halogenized aromatic hydrocarbon solvent such as chlorobenzene, dichlorobenzene and trichlorobenzene; diethyl ether, diisopropyl ether, tert-butylmethyl ether, cyclohexylmethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane and the like. Ether solvents; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile; alcohol solvents such as methanol, ethanol and 2-propanol; and mixed solutions of two or more of these include aliphatic hydrocarbon solvents, Aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents and ester solvents are preferred, with toluene, xylene, ethylbenzene, hexane, heptane and ethyl acetate more preferred.

Hereinafter, the present invention will be described in more detail by way of examples.
In the examples, the R-form / S-form ratio was analyzed using high performance liquid chromatography (area percentage method) using a chiral column. 1,1,3-trimethyl-4-aminoindane and (R)-(-)-N- (1,1,3-trimethylindane-4-yl) -1-methyl-3-difluoromethylpyrazole-4-yl The respective contents of the carboxylic acid amide were analyzed using liquid chromatography (internal standard method). The pKa values shown in each of the following examples are values quoted from the following.
(1) Calculated values recorded in SciFinder (https://www.jaici.or.jp/SCIFINDER/) (searched on May 22, 2020),
(2) Data posted on the Chemical Book homepage (https://www.chemicalbook.com/) (searched on May 22, 2020),
(3) Applied Catalysis A: General 492 (2015) 252-261.

Example 1
<First step using sulfuric acid ((1) pKa = -3.2)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 60 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 2.9 g of sulfuric acid in 24 g of water was added dropwise thereto at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction mixture was kept warm at 60 ° C. for 3 hours, cooled to room temperature for 3 hours, and further cooled to 10 ° C. for 1 hour. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 15 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 13 g of a salt of 2 molecules of (R) -1,1,3-trimethyl-4-aminoindane and 1 molecule of sulfuric acid. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 99.5: 0.5, yield = 58%

Example 2
<First step using p-toluenesulfonic acid ((1) pKa = -0.43)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 60 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 19 g of p-toluenesulfonic acid in 15 g of methanol was added dropwise thereto at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction mixture was kept warm at 60 ° C. for 3 hours, cooled to room temperature for 3 hours, and further cooled to 10 ° C. for 1 hour. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 15 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 25.6 g of (R) -1,1,3-trimethyl-4-aminoindane p-toluenesulfonate. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 94.7: 5.3, yield = 74%

Example 3
<First step using sodium hydrogensulfate ((3) pKa = 1.99)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 60 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 9.6 g of sodium hydrogensulfate monohydrate in 15 g of water was added dropwise thereto at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction mixture was kept warm at 60 ° C. for 3 hours, allowed to cool to room temperature for 3 hours, and further cooled to 10 ° C. for 1 hour. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 15 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 19.3 g of (R) -1,1,3-trimethyl-4-aminoindane-sodium hydrogensulfate salt. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 96.4: 3.6, yield = 66%

Example 4
<First step using hydrobromic acid ((2) pKa = -9)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of toluene were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by adding 11.5 g of a 49% aqueous hydrobromic acid solution to the solution was added dropwise at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction solution was heated to 80 ° C., kept warm for 1 hour, and then cooled to 25 ° C. for 4 hours. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 16.2 g of (R) -1,1,3-trimethyl-4-aminoindane hydrobromide. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 99.6: 0.4, yield = 63%

Example 5
<First step using oxalic acid ((1) pKa = 1.38)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 7.2 g of oxalic acid in 80 g of water was added dropwise thereto at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction solution was heated to 80 ° C., kept warm for 1 hour, and then cooled to 25 ° C. for 5 hours. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 16.7 g of (R) -1,1,3-trimethyl-4-aminoindane oxalate. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 98.8: 1.2, yield = 63%

Example 6
<First step using trichloroacetic acid ((1) pKa = 0.09)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of toluene were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 12 g of trichloroacetic acid in 6 g of methanol was added dropwise at 60 ° C. over 30 minutes, and crystals were precipitated. The reaction solution was heated to 80 ° C., kept warm for 1 hour, and then cooled to 25 ° C. for 5 hours. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 16.2 g of (R) -1,1,3-trimethyl-4-aminoindane trichloroacetate. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 99.9: 0.1, yield = 48%

Example 7
<First step using chloroacetic acid ((1) pKa = 2.65)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of toluene were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 9.5 g of chloroacetic acid in 10 g of methanol was added dropwise at 60 ° C. over 30 minutes, and the reaction solution was cooled to room temperature, but no crystals were precipitated. Methanol was distilled off at a bath temperature of 40 ° C. using an evaporator, and then the reaction mixture was cooled to 15 ° C. for 1 hour to precipitate crystals. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 5.5 g of (R) -1,1,3-trimethyl-4-aminoindane chloroacetic acid salt. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 95.9: 4.1, yield = 20%

Example 8
<First step using phenyl dihydrogen phosphate ((1) pKa = 1.2)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 60 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. The solution obtained by dissolving 17.4 g of phenyl dihydrogen phosphate in 15 g of methanol was added dropwise at 60 ° C. over 30 minutes, and the reaction solution was cooled to 30 ° C. in 5 hours. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 14.6 g of (R) -1,1,3-trimethyl-4-aminoindan phosphate dihydrogen phenyl salt. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 99.9: 0.1, yield = 42%

Example 9
<First step using 2-nitrobenzoic acid ((1) pKa = 2.19)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of toluene were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 16.7 g of 2-nitrobenzoic acid in 10 g of methanol and 10 g of tetrahydrofuran was added dropwise at 60 ° C. over 30 minutes and cooled to room temperature, but no crystals were precipitated. After distilling off methanol and tetrahydrofuran at a bath temperature of 40 ° C. using an evaporator, the reaction mixture was cooled to 25 ° C., and crystals were precipitated. Cooled. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 16.8 g of (R) -1,1,3-trimethyl-4-aminoindane 2-nitrobenzoate. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 99.6: 0.4, yield = 49%

Example 10
<First step using sulfamic acid ((1) pKa = -8.5)>
17.5 g of 1,1,3-trimethyl-4-aminoindane (R-form / S-form = 83/17) and 50 g of methanol were placed in a nitrogen-substituted 300 mL flask, and the temperature of the mixture was raised to 60 ° C. A solution obtained by dissolving 6.8 g of sulfamic acid in 40 g of water was added dropwise at 60 ° C. over 30 minutes and cooled to room temperature, but no crystals were precipitated. After distilling off methanol at a bath temperature of 40 ° C. using an evaporator, crystals were precipitated when cooled to 10 ° C., so the temperature was raised again to 40 ° C., and the reaction mixture was cooled to 10 ° C. in 2 hours. .. The reaction solution was filtered under reduced pressure with Nuche, and the crystals were washed twice with 10 g of toluene under reduced pressure on Nuche and deliquesed. The crystals were dried to obtain 9.5 g of (R) -1,1,3-trimethyl-4-aminoindanesulfamate. Optical purity analysis was performed by liquid chromatography to determine the optical purity.
Optical isomer ratio R: S = 98.1: 1.9, yield = 35%

Example 11
<Second step>
A nitrogen-substituted 100 mL flask was charged with 19 g of (R) -1,1,3-trimethyl-4-aminoindan / sodium hydrogensulfate salt obtained in Example 3, 14.2 g of a 27% sodium hydroxide aqueous solution, and 40 g of toluene. , The mixture was stirred at room temperature for 30 minutes. The toluene layer was washed once with 5 g of water, and then the toluene was distilled off to obtain 11.2 g of (R) -1,1,3-trimethyl-4-aminoindane. Internal standard substance method by liquid chromatography Content analysis method and optical purity analysis were performed to determine the content and optical purity.
Optical isomer ratio R: S = 96.4: 3.6, content 98%, yield = 98%

Example 12
<Amidation reaction D>
14.0 parts of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid and 35.1 parts of xylene were mixed under a nitrogen atmosphere at room temperature. The resulting mixture was heated to 100 ° C. 11.2 parts of thionyl chloride was added dropwise to the obtained mixture over 5 hours. The resulting mixture was stirred at 100 ° C. for 15 hours and then cooled to 40 ° C. Thionyl chloride and xylene were distilled off from the obtained reaction mixture under reduced pressure to obtain brown 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride.
(R) -1,1,3-trimethyl-4-aminoindane 14.6 parts, triethylamine 9.2 parts and xylene 38.1 parts were mixed to prepare a solution. A solution prepared by dissolving the above-mentioned 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid chloride in 13.2 parts of xylene in the obtained solution was added at 45 ° C to 50 ° C over 2 hours. Dropped. The resulting mixture was stirred at 45 ° C-50 ° C for 15 hours. After mixing the obtained reaction mixture with a 20% aqueous sodium hydroxide solution, the organic layer was separated. The obtained organic layer was washed successively with water, 18% hydrochloric acid, water, 1% aqueous sodium hydroxide solution and water, and then concentrated under reduced pressure conditions to (R)-(-)-N- (1, 1,3-trimethylindan-4-yl) -1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide was obtained in an amount of 27.5 parts.

According to the present invention, optically active (R) -1,1,3-trimethyl-4-aminoindane can be efficiently produced. Such a compound prepares (R)-(-)-(1,1,3-trimethylindan-4-yl) -1-methyl-3-difluoromethylpyrazole-4-carboxylic acid amide having a plant disease preventive effect. Useful as an intermediate.

Claims (8)

1. The first step of mixing optically active 1,1,3-trimethyl-4-aminoindan and an achiral acid to precipitate their acid salts in the presence of a solvent, and the obtained in the first step. A method for producing optically active 1,1,3-trimethyl-4-aminoindane, which comprises a second step of mixing an acid salt and a base to obtain optically active 1,1,3-trimethyl-4-aminoindan. ..
2. The optical purity of the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step is higher than the optical purity of the optically active 1,1,3-trimethyl-4-aminoindane used in the first step. The manufacturing method according to claim 1, wherein the product is characterized by a high value.
3. The optical purity of the optically active 1,1,3-trimethyl-4-aminoindane used in the first step is 40% e. e. The optical purity of the optically active 1,1,3-trimethyl-4-aminoindane obtained in the second step is 89% e. e. The manufacturing method according to claim 2, which is the above.
4. The production method according to any one of claims 1 to 3, wherein the optically active 1,1,3-trimethyl-4-aminoindane contains a large amount of R-form.
5. The production method according to any one of claims 1 to 4, wherein the pKa of the acid is less than 2.8.
6. The acid is one or more acids selected from the group consisting of sulfuric acid, hydrogen sulfate, sulfamic acid, organic sulfonic acid, hydrohalogenated acid, phosphoric acid, organic phosphoric acids, nitric acid, tetrafluoroboric acid, and carboxylic acid. , The manufacturing method according to any one of claims 1 to 4.
7. Acids are sulfuric acid, sodium hydrogensulfate, potassium hydrogensulfate, sulfamic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phenylphosphate, phenyldihydrogen phosphate, Any of claims 1 to 4, which is one or more acids selected from the group consisting of nitric acid, tetrafluoroboic acid, oxalic acid, trifluoroacetic acid, trichloroacetic acid, 2-nitrobenzoic acid, chloroacetic acid, and bromoacetic acid. The manufacturing method according to paragraph 1.
8. The optically active 1,1,3-trimethyl-4-aminoindane obtained by the production method according to any one of claims 1 to 7 and the formula (1):
   
   

   

   (In the formula, R ¹ and R ² each independently represent a C1-C6 alkyl group or hydrogen atom which may be substituted with one or more halogen atoms, and R ³ is a halogen atom, hydroxy. Represents a C1-C6 alkoxy group that may be substituted with a group or one or more halogen atoms.)
   By reacting with the compound represented by, the formula (2):
   

   

   (In the formula, R ¹ and R ² have the same meanings as above. The carbon atom marked with * represents an asymmetric carbon atom.)
   A production method further comprising the step of obtaining the optically active compound represented by.