JPH1072398A - Production of 1-indanone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 1-indanone by which the subject compound useful as a medicine intermediate is obtained from a compound through to be useless by a simple operation, by reaction an N-indanylamide under a basic condition and thereafter hydrating the reaction product. SOLUTION: The objective 1-indanone of formula III is produced by reacting N-indanylamides of formula I [R is a (substituted) phenyl or a 1-8C lower alkyl; X is a halogen or a group of the formula OSO2 R' (R' is same as the R); NHCOR is at cis-position of X] under a basic condition to provide an N-indenylamide derivative of formula II and thereafter hydrating the N-indenylamide derivative of formula II. For example, cis-1-acetamide-2-bromoindane is preferably used as the compound of formula I. By using this method, a useful compound is obtained from the compound of formula I obtained as a reaction byproduct.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrially useful
The present invention relates to a method for producing 1-indanone.

[0002]

BACKGROUND OF THE INVENTION 1-Indanone is important as a pharmaceutical intermediate. For example, J. Org. Chem. , 55 , 4
237 (1990) discloses that this compound is a useful intermediate for the production of serotonin absorption inhibitors. Several methods for producing 1-indanone have been disclosed so far. For example, Lutz
z) etc. [J. Am. Chem. Soc. , 60 , 136
0 (1938)] is obtained by heating cis- (±) -2-chloroindan-1-ol or trans- (±) -2-chloroindan-1-ol in a dilute aqueous sodium hydroxide solution or dilute sulfuric acid aqueous solution. After acidifying the reaction solution,
Add an alcohol solution of dinitrophenylhydrazine,
1-Indanone, which is the target product, is obtained as a hydrazone derivative. (The following formula)

[0003]

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However, Lutz et al.'S method requires complicated operations such as removal of the produced 1-indanone as a hydrazine derivative, and produces a large amount of wastewater and wastewater as a by-product, resulting in poor volumetric efficiency and a low yield of the hydrazine derivative. Has problems.

[0005] Kriege [Justus
Liebigs Ann. Chem. , 481 , 26
3 (1930)] treats indene with lead tetraacetate to give 1-acetoxyindene, which is hydrolyzed to obtain the desired 1-indanone.
(The following formula)

[0006]

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[0007] Although the Kreig method is a relatively effective method, lead compounds are highly toxic and are intermediates 1-.
The method for synthesizing acetoxyindene is difficult and is not considered industrial.

[0008] Piva et al. [Tetrahed
ron Lett. , 33 , 2459 (1992)].
Dissolves trans-2-bromoindan-1-ol in benzene or toluene and irradiates with UV (λ = 254 nm) in the presence of p-toluenesulfonic acid to obtain the desired 1-indanone. . (The following formula)

[0009]

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[0010] However, this method requires the use of special equipment such as a photoreactor, and has the problems of poor volumetric efficiency and low yield.

As described above, a satisfactory method for producing 1-indanone has not been known, and it has been difficult to produce 1-indanone industrially and at low cost.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide an efficient method for producing 1-indanone.

[0013]

In the process for producing cis-1-amino-2-benzocycloalkanols filed earlier (Japanese Patent Application No. 8-115119), the inventors of the present invention have proposed a method for producing cis-1-amino-2-benzocycloalkanols as a by-product of the litter reaction. General formula (I) (wherein, R is a methyl group, X is a bromine atom, NHC
OR and X have a cis configuration and may be a racemic form or an optically active form), and have been found to produce N-indanylacetamide. Further, by reacting the compound under appropriate conditions, the 2-position halogen atom by halogen exchange by S _N 2 reaction, to produce a reaction active trans-2-bromo-1-acetamide indane, this Is a useful compound by treating the compound of formula (IV)

[0014]

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(Where the NH ₂ group and the OH group are in a cis configuration and may be a racemic form or an optically active form), and a method for producing 1-aminoindan-2-ol is proposed. I have.

The present inventors have found that the general formula (I) (wherein R is a methyl group, X is a bromine atom, and NHC
OR and X have a cis configuration, and may be a racemic form or an optically active form).
The reaction conditions for generating an unsaturated bond by 1,2-elimination without inverting the substituent X at the position (where X is a bromine atom) were studied in detail, and the present invention was completed. . That is, the present invention provides a compound represented by the general formula (I):

[0017]

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(Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms, and X is a halogen atom or a substituted sulfonyloxy group represented by OSO ₂ R ′). , R ′ is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms, NHCOR and X have a cis configuration, and may be an optically active substance or a racemic form. Is reacted under basic conditions to obtain a compound of the general formula (II)

[0019]

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(Wherein R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms), which is obtained by hydrolyzing the N-indenylamide derivative. Formula (III)

[0021]

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A method for producing 1-indanone represented by the formula:

The N-indenyl compound represented by the general formula (II) produced by the present invention is a novel compound.
That is, the present inventors have proposed a novel method for producing an N-indenylamide derivative represented by a new general formula (II), and a compound represented by a formula (III) in which this compound is easily useful by hydrolysis. The present inventors have found that 1-indanone is produced, and have completed the present invention.

[0024]

DESCRIPTION OF THE PREFERRED EMBODIMENTS N-Indanylamides represented by the general formula (I) include cis-1-acetamido-2
-Chloroindane, cis-1-acetamido-2-bromoindan, cis-1-acetamido-2-iodoindane, cis-1-benzamide-2-chloroindane,
Cis-1-benzamide-2-bromoindane, cis-
1-benzamide-2-iodoindane and the like. Also, cis-1-acetamido-2-methanesulfonyloxyindane, cis-1-benzamide-2-methanesulfonyloxyindane, cis-1-acetamido-2-p-toluenesulfonyloxyindane, cis-1-benzamide-2 Novel compounds such as -p-toluenesulfonyloxyindane are also included.

The present invention will be specifically described. In general,
An N-indenylamide represented by the general formula (II) is obtained by dissolving or suspending the N-indanylamide represented by the general formula (I) in a suitable solvent and stirring under basic conditions.

In order to obtain this basic condition, lithium methoxide, lithium ethoxide, lithium-tert-
Alkali metal alkoxides such as butoxide, sodium methoxide, sodium ethoxide, sodium-tert-butoxide, sodium-tert-pentoxide, potassium methoxide, potassium ethoxide, potassium-tert-butoxide side can be used.

Further, the dissociation constant of Bronsted acid (25
C./water) shows a value of pKa = 5 or more, aliphatic amine,
Amines such as aromatic amines, alicyclic amines, and heterocyclic amines can also be used. When an N-indanylamide represented by the general formula (I) is reacted with an amine, a reaction for producing an N-indenylamide represented by the general formula (II) by elimination of 1,2- amine is X group and S _N 2 nucleophilic substitution of 2-position reaction is expected to occur competitively. That is,
When the basicity of the amine is stronger than nucleophilicity, 1,2-elimination occurs preferentially, and when the nucleophilicity of the amine is stronger than basicity, the _SN 2 nucleophilic substitution reaction occurs preferentially. For example, pyridine has a pKa of 5.17 (Lange's Handbook).
k of Chemistry, 13th Ed. , M
cGraw-Hill, New York, 198
5. ), Wherein R is a methyl group, X is a bromine atom, NHCOR and X are in a cis configuration, and may be a racemic or an optically active compound. When N-indanylacetamide is reacted with pyridine, N-indenylacetamide represented by the general formula (II) (wherein R is a methyl group) is obtained, but is recovered by a side reaction. The rate drops. On the other hand, triethylamine has a pKa of 10.72, tert-butylamine has a pKa of 10.72, and morpholine has a pKa of 8.
In this case, since the basicity is higher than the nucleophilicity, the N-indenylamide derivative represented by the general formula (II) can be obtained in a high yield.

Further, lithium hydroxide, lithium carbonate,
Alkali metal hydroxides or carbonates such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate and potassium hydrogen carbonate can be used. However, when an alkali metal hydroxide or carbonate is used, water is generated by a neutralization reaction with an acid generated by the 1,2-elimination reaction. Therefore, N-indenylamides represented by the general formula (II) are hydrolyzed to 1-indanone. In contrast, when an alkoxide or an amine of an alkali metal is used, no water is generated, so that N-indenylamides represented by the general formula (II) can be isolated.

The amount of the basic compound to be used is preferably at least equimolar to the N-indanylamide represented by the general formula (I), and may be used in excess.

Examples of the solvent include water, protic polar solvents such as alcohols, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylenesulfonamide, and aliphatic hydrocarbons such as hexane, heptane, octane and decane. , Benzene, toluene, xylene, aromatic hydrocarbons such as mesitylene, dichloromethane,
Such as aliphatic halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, trichloroethylene, and tetrachloroethylene; aromatic halogenated hydrocarbons such as monochlorobenzene and dichlorobenzene; and aliphatic esters such as ethyl acetate, propyl acetate, and butyl acetate. Solvents that are inert to the reaction can be used. Further, these solvents may be used in combination. For example, when a miscible solvent is used in combination, the reaction proceeds in a homogeneous system, and when a hardly miscible solvent is used in combination, the reaction proceeds in a heterogeneous system. However, when water is used as the reaction solvent, the general formula (I
Since the production and hydrolysis of the N-indenylamides represented by I) occur in parallel, the product is 1-indanone.

This reaction can be carried out at a temperature of -10 ° C to 200 ° C, but is more preferably carried out at a temperature of 20 ° C to 120 ° C. If the temperature is lower than this, the reaction progresses slowly, and if the temperature is higher, the yield decreases due to side reactions.

The reaction product N- represented by the general formula (II)
After the completion of the reaction, cool the reaction solution to room temperature.If the reaction solvent is immiscible with water, and if the product has a high solubility in the solvent, remove the indenylamide by a conventional method after concentrating the solvent after washing with water. If the solubility is low, the crystals may be washed after filtering. When the reaction solvent is miscible with water, water may be added to the reaction solution, and the precipitated crystals may be filtered out or taken out by a conventional method such as solvent extraction.

The desired 1-indanone is obtained by hydrolyzing the N-indenylamide represented by the general formula (II) under basic conditions or acidic conditions. However, if hydrolysis is carried out under basic conditions, side reactions proceed simultaneously and the yield decreases, so that hydrolysis is preferably carried out under acidic conditions. To obtain this acidic condition, sulfuric acid, hydrochloric acid,
Phosphoric acid, acetic acid, and trifluoroacetic acid are preferably used. However, the present invention is not limited thereto, and a desired acidic substance such as perchloric acid, boron trifluoride, methanesulfonic acid, zeolite, or an ion exchange resin may be used. Condition can be obtained. The amount used is preferably at least equimolar to the amount of catalyst or N-indenylamides represented by the general formula (II). If the amount of the acid used is small, the reaction may not be completed. When sulfuric acid is used to obtain acidic conditions, the reaction can be performed at a sulfuric acid concentration of 0.001% or more, but 0.1%
The reaction is preferably carried out at a sulfuric acid concentration of from 50 to 50%. If the concentration is lower than this, the progress of the reaction is slow and the volume efficiency is deteriorated. If the concentration is higher than this, the yield decreases due to side reactions.

Examples of the solvent include water, protic polar solvents such as alcohols, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylenesulfonamide; and aliphatic hydrocarbons such as hexane, heptane, octane and decane. , Benzene, toluene, xylene, aromatic hydrocarbons such as mesitylene, dichloromethane,
Solvents that are inert to the reaction can be used, such as aliphatic halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, trichloroethylene and tetrachloroethylene, and aromatic halogenated hydrocarbons such as monochlorobenzene and dichlorobenzene. Further, these solvents may be used in combination. For example, when a solvent having high solubility of N-indenylamides represented by the general formula (II) is used in combination, the reaction proceeds in a homogeneous solution state, and when a solvent having low solubility is used in combination. The reaction proceeds in a heterogeneous slurry state.

This reaction can be carried out at a temperature of -20 ° C to 100 ° C, but is more preferably carried out at a temperature of 10 ° C to 80 ° C. If the temperature is lower than this, the reaction progresses slowly, and if the temperature is higher, the yield decreases due to side reactions.

After completion of the reaction, the reaction product, 1-indanone, may be cooled to room temperature. If the reaction solvent is immiscible with water, the reaction solution may be washed with water, concentrated and dried to remove. When the reaction solvent is miscible with water, it may be taken out by a conventional method such as solvent extraction.

[0037]

As described above, the present invention provides a compound of formula (III), which is a useful compound at a low cost by a simple operation of the N-indanylamide represented by the general formula (I), which was considered to be unnecessary in the past. Is a method of converting into 1-indanone, which is industrially valuable.

[0038]

The present invention will be described in more detail with reference to the following examples.

The analysis during the reaction in the following Examples was performed by high performance liquid chromatography (HPLC). The analysis of the product was performed by high performance liquid chromatography (HP
LC) or gas chromatography (GC).

The high-performance liquid chromatography (HPLC)
Analysis conditions column; YMC pack C8 A202 (4.6 ×
150 mm) Moving layer; Refer to the following gradient data Flow rate: 1 ml / min Detection: 254 nm Temperature; 40 ° C.

[0041]

[Table 1]

[0042] Gas chromatographic (GC) analysis conditions Column: Glass column (2.1 m) Filler; 5% Silicone OV-
17 60 / 80mesh Uniport HP detector; FID Range; 10 ² carrier _{gas; N 2 Inj / Det temp;} . 270 ℃ Initial time; 0 Final time; 10min Colum temp; 100 ℃ → 260 ℃ Program Rate; 10 ℃ / min example 1 (±) - cis - 2-bromo-1- Asetoa Mi
Doindan (I: R = CH ₃ , X = Br) as starting material
Using the 1-acetamide indene (II: R = CH ₃₎
(1) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three-necked flask.
12.7 g (0.05 mol) of (±) -cis-2-bromo-1-acetamidoindane was charged. It takes 7.5 minutes at 25 ° C. with stirring while stirring 7.58 of triethylamine.
g (0.075 mol) was added dropwise. Then 110 ° C
And stirred for 1 hour. After cooling to room temperature, at an internal temperature of 30 ° C., 350 ml of dichloroethane and 100 ml of water were added. The reaction solution was separated to obtain an organic layer. This was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-acetamidoindene (I
8.74 g (I: R = CH ₃ ) of light brown crystals (yield: 101)
%). The purity of this compound determined by high performance liquid chromatography (HPLC) was 99.0% (area percentage).

The physical properties are shown below.

Melting point: 131.5-133.6 ° C. 1H-NMR (CDCl ₃ , ppm, TMS); δ =
7.49 (1H, d, NH), 7.35 to 7.22 (4
H, m, arom), 6.87 (1H, t, CH),
3.46 (2H, d, CH ₂ ), 2.24 (3H, s,
CH _3).

IR (KBr, cm ^-1 ); 3287.0
(ΝNH), 1651.2 (νC = O), 1529.7
(ΝNH).

Elemental analysis: Calculated for C ₁₁ H ₁₁ NO: C 76.28%, H 6.40%, N 8.
09% Found: C 76.14%, H 6.45%, N 7.
95% Example 2 (±) - cis - 2-chloro-1 Asetoa Mi
Doindan (I: R = CH ₃ , X = Cl) as starting material
Using the 1-acetamide indene (II: R = CH ₃₎
A stirrer, a thermometer and a reflux condenser were attached to a 50 ml three-necked flask, and 20 ml of methanol was charged. While cooling to 8 ° C. in an ice bath and stirring, 0.41 g (7.5 mmol) of sodium methoxide was added. Upon addition of sodium methoxide, the internal temperature rose to 14 ° C.
The ice bath was removed and 1.05 g (5 mmol) of (±) -cis-2-chloro-1-acetamidoindane was added.
The mixture was further heated to 50 ° C. and stirred for 5 hours.

The reaction solution was cooled, and water was added to the reddish brown reaction solution.
After adding crystals to precipitate crystals and further cooling to 5 ° C., the crystals were filtered under reduced pressure. The crystals were washed with 20 ml of a cooled 50% aqueous methanol solution. The crystals collected by filtration were dried under reduced pressure to give gray crystals of 1-acetamidoindene 0.55.
g (63.6% yield). The purity of this compound determined by high performance liquid chromatography (HPLC) is 98.7%.
(Area percentage). The IR spectrum of this compound was obtained by examining the 1-acetamidoindene of Example 1 (II: R = CH
₃ ) The spectrum matched.

[0048] Example 3 (±) - Shea scan 2- Metansuru
Honiru-1- acetamide indane (I: R = C
H _3, X = with OSO ₂ CH ₃₎ as a starting material, 1-
Synthesis of acetamide indene (II: R = CH ₃ ) A 1 L _three - necked flask was equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser.
(±) -cis-1-amino-2-indanol 298 g
(2.0 mol). To this, 224.4 g (2.2 mol) of acetic anhydride was added dropwise over 2.5 hours while stirring under cooling in a water bath. After further aging at 30 ° C. for 2.5 hours, the slurry was filtered under reduced pressure. The crystals were washed twice with 100 ml of methylene chloride. The crystals collected by filtration were dried under reduced pressure to obtain 219.4 g (yield: 57.4%) of white crystals of (±) -cis-1-acetamido-2-indanol. High performance liquid chromatography of this compound (HPL
Purity according to C) was 97.9% (area percentage).
Physical properties are shown below.

Melting point: 162.1-162.9 ° C. 1H-NMR (CDCl ₃ , ppm, TMS); δ =
7.32 to 7.19 (4H, m, arom) 6.27
(1H, d, NH), 5.34 (1H, q, CH),
4.59 (1H, m, CH), 3.15 (1H, dd,
CH ₂ ), 2.93 (1H, dd, CH ₂ ), 2.58
(1H, d, OH), 2.08 (3H, s, CH 3). IR (KBr, cm ^-1 ); 3404.7 (νOH), 3
341.0 (νNH), 1616.5 (νC = O), 1
554.8 (νNH).

Elemental analysis: Calculated for C ₁₁ H ₁₃ NO ₂ : C 76.28%, H 6.40%, N 8.
09% Found: C 76.30%, H 6.44%, N 8.
Attach a stirrer, a thermometer, a dropping funnel, and a reflux condenser to a 500% four-necked flask with a concentration of 30% dichloroethane.
0 ml, (±) cis-1-acetamido-2-indanol 38.2 g (0.2 mol), triethylamine 2
2.3 g (0.22 mol) were charged. Add methanesulfonyl chloride 2 while stirring under cooling in a water bath.
5.2 g (0.22 mol) was added dropwise over 2 hours. After aging at 25 ° C. for 18 hours, 50 ml of water was added to the slurry and the mixture was stirred for 30 minutes. The crystals were filtered under reduced pressure and dried under reduced pressure to obtain 51.1 g (yield: 95.0%) of white crystals of (±) -cis-2-methanesulfonyloxy-1-acetamidoindane. The purity of this compound determined by high performance liquid chromatography (HPLC) was 99.1% (area percentage). Physical properties are shown below.

Melting point: 190.1-190.4 ° C. 1H-NMR (CDCl ₃ , ppm, TMS); δ =
7.32 to 7.22 (4H, m, arom), 6.20
(1H, d, NH), 5.65 (1H, dd, CH),
5.46 (1H, m, CH), 3.26 (2H, m, C
_{H 2), 2.98 (3H,} s, CH 3), 2.12 (3
H, s, CH _3).

IR (KBr, cm ^-1 ); 3279.3
(ΝNH), 1653.1 (νC = O), 1549.0
(ΝNH), 1338.7 (νS = O), 1188.3
(ΝS = O), 974.1 (νS-OC), 918.
2 (vS-O-C).

A 200 ml four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser.
l, (±) -cis-2-methanesulfonyloxy-1-
13.5 g (0.05 mol) of acetamidoindane was charged. While cooling to 5 ° C in an ice salt bath and stirring, 4.05 g (0.075 mol) of sodium methoxide was added.
Was added. Upon addition of sodium methoxide, the internal temperature rose to 14 ° C. Thereafter, the mixture was further stirred at room temperature for 1.5 hours, further heated at 40 ° C. for 5.0 hours, and stirred at 50 ° C. for 1.5 hours. The reaction was cooled and a brown slurry of water 10
0 ml was added, the slurry was cooled to 5 ° C. and filtered under reduced pressure. The crystals were washed with 20 ml of a cooled 50% aqueous methanol solution. The crystals were collected by filtration and dried under reduced pressure, 1-acetamide indene: to give a cream-colored needles 7.25g of _{(II R = CH 3) (} 83.8% yield). This compound had a purity of 9 by high performance liquid chromatography (HPLC).
It was 8.7% (area percentage). The IR spectrum of this compound was obtained by examining the 1-acetamidoindene (II:
(R = CH ₃ ).

[0054] Example 4 (±) - Shea scan 2- Metansuru
Honiru 1- benzamide indane (I: R = off
Enyl group, X ＝ O SO ₂ CH ₃ ) was used as starting material,
1-benzamide indene (II: R = phenyl group)
Stirrer , thermometer, dropping funnel in 1L four-necked flask,
Attach a reflux condenser, 300 ml of dichloroethane, 74.5 g (0.5 mol) of (±) -cis-1-amino-2-indanol,
55.7 g (0.55 mol) of triethylamine was charged. Stir in benzoyl chloride 7
7.3 g (0.55 mol) was added dropwise over 1.5 hours. After further aging at 25 ° C. for 1.5 hours, 50 ml of water was added to the slurry. After stirring for another 0.5 hours,
The crystals were filtered under reduced pressure. The crystals were washed with 100 ml of dichloroethane. The crystals collected by filtration were dried under reduced pressure to give (±) -cis-
White crystals of 1-benzamide-2-indanol 11
8.6 g (93.7% yield) was obtained. This compound had a purity of 9 by high performance liquid chromatography (HPLC).
It was 9.0% (area percentage). Physical properties are shown below.

Melting point: 154.1-155.5 ° C. 1H-NMR (CDCl ₃ , ppm, TMS); δ =
7.81 to 7.15 (9H, m, arom) 6.98
(1H, d, NH), 5.52 (1H, q, CH),
4.65 (1H, m, CH), 3.16 (1H, dd,
CH ₂ ), 2.95 (1H, dd, CH ₂ ), 2.89
(1H, d, OH). IR (KBr, cm ^-1 ); 3456.8 (νOH), 3
300.5 (νNH), 1631.9 (νC = O), 1
537.4 (νNH) A 500 ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser.
0 ml, (±) -cis-1-benzamide-2-indanol 25.3 g (0.1 mol), triethylamine 1
2.1 g (0.12 mol) was charged. While stirring, 13.7 g of methanesulfonyl chloride
(0.12 mol) was added dropwise over 10 minutes. After further aging at 25 ° C. for 3.5 hours, 100 ml of water was added to the slurry.
Was added and stirred for 0.5 hour. The crystals were filtered under reduced pressure, and the collected crystals were placed in a 300 ml beaker, and dichloroethane and water 100 were added.
After adding ml and stirring for 0.5 hour, the crystals were filtered under reduced pressure. The filtered crystals were dried under reduced pressure to obtain 22.0 g (yield: 66.4%) of (±) cis-1-benzamide-2-methanesulfonyloxyindane white crystals. The purity of this compound determined by high performance liquid chromatography (HPLC) was 99.4% (area percentage). Physical properties are shown below.

Melting point: 176.1% to 176.8 ° C. 1H-NMR (CDCl ₃ , ppm, TMS);
7.91 to 7.24 (9H, m, arom), 6.85
(1H, d, NH), 5.85 (1H, dd, CH),
5.57 (1H, m, CH), 3.33 (2H, m, C
_{H 2), 2.90 (3H,} s, CH 3).

IR (KBr, cm ^-1 ); 3248.4
(ΝNH), 1643.5 (νC = O), 1535.5
(ΝNH), 1344.5 (νS = O), 1167.0
(ΝS = O), 978.0 (νS-OC), 922.
1 (vS-O-C).

A 300 ml four-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser.
l, (±) -cis-2-methanesulfonyloxy-1-
16.6 g (0.05 mol) of benzamide indane was charged. 5.4 g (0.1 mol) of sodium methoxide was added while cooling to 2 ° C. in an ice salt bath and stirring. When sodium methoxide is added, the internal temperature becomes 13
° C. The mixture was further heated to 60 ° C. and stirred for 3.0 hours.

The reaction solution was cooled, and the brown slurry was treated with 10 parts of water.
After 0 ml was added, the mixture was further cooled to 5 ° C. and filtered under reduced pressure.
The crystals were washed with 20 ml of a cooled 50% aqueous methanol solution. The crystals collected by filtration were dried under reduced pressure, and 8.92 g of brown crystals of 1-benzamide indene (II: R = phenyl group) were obtained.
(Yield 75.9%) was obtained. The purity of this compound determined by high performance liquid chromatography (HPLC) is 96.9%.
(Area percentage). Physical properties are shown below.

Melting point: 167.2-168.9 ° C. 1H-NMR (CDCl ₃ , ppm, TMS); δ =
7.99 (1H, br, NH) 7.94 to 7.26 (9
H, m, arom), 7.05 (1H, t, CH),
_{3.51 (2H, d, CH 2} ).

IR (KBr, cm ^-1 ); 3287.0
(ΝNH), 1651.2 (νC = O), 1529.7
(ΝNH).

Elemental analysis: Calculated as C ₁₆ H ₁₃ NO: C 81.68%, H 5.57%, N 5.5.
95% found: C 81.84%, H 5.62%, N5.
83% Example 5 (±) - cis - 2-bromo-1- Asetoa Mi
Doindan (I: R = CH ₃ , X = Br) as starting material
Using the 1-acetamide indene (II: R = CH ₃₎
(2) A 100 ml three-necked flask was equipped with a stirrer, a thermometer, and a reflux condenser, and 50 ml of methanol, (±) -cis-
12.7 g of 2-bromo-1-acetamidoindane
(0.05 mol). Cool to 5 ° C in an ice bath, and stir while stirring with 4.05 g of sodium methoxide.
(0.075 mol) was added in three portions every 30 minutes. When sodium methoxide was added, the internal temperature of the reaction solution rose to 13 ° C. Thereafter, the mixture was stirred at 40 ° C. for 3 hours. After cooling to an internal temperature of 30 ° C. and adding 50 ml of water, pale yellow scale-like crystals were precipitated. The crystals were filtered under reduced pressure and 20 ml of a 50% aqueous methanol solution cooled to 5 ° C.
And washed it. The crystals collected by filtration were dried under reduced pressure at 40 ° C.
1-acetamide indene: was obtained (II R = CH ₃₎ of pale yellow crystals 7.51 g (86.8% yield). The purity of this compound determined by high performance liquid chromatography (HPLC) was 99.4% (area percentage).

[0063] Example 6 (±) - Shea scan 2-bromo-1
- acetate Toamidoindan _{(I: R = CH 3,} X = Br)
1-acetamidoindene (II:
R = CH ₃ ) (3) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three- necked flask, and 50 ml of toluene was added.
12.7 g (0.05 mol) of (±) -cis-2-bromo-1-acetamidoindane was charged. 4.36 g of morpholine with stirring at 25 ° C for 10 minutes
(0.05 mol) was added dropwise. Then, at 80 ° C.
Stir for 5 hours. Cool to room temperature and add 500 ml
Into 200 ml of dichloroethane and 20 ml of water.
0 ml was added. The organic layer was separated, further washed with water 200 ml, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 1-acetamide indene (II: R = CH ₃₎ of pale brown crystals 8.8 g (yield: 101. 7%). The purity of this compound determined by high performance liquid chromatography (HPLC) was 88.2% (area percentage).

[0064] Example 7 (±) - Shea scan 2-bromo-1
- acetate Toamidoindan _{(I: R = CH 3,} X = Br)
1-acetamidoindene (II:
R = CH ₃ ) (4) A 100 ml _three - necked flask was equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser.
ml, (±) -cis-2-bromo-1-acetamidoindane 12.7 g (0.05 mol), and tert-butylamine 5.12 g (0.07 mol) were charged. The mixture was stirred at 80 ° C. for 4.5 hours with stirring. After cooling to room temperature, the reaction solution was transferred to a 500 ml separating funnel, and 50 ml of dichloroethane and 100 ml of water were added. Separate the organic layer,
After further washing with 200 ml of water, drying over anhydrous sodium sulfate and concentration under reduced pressure, 1-acetamidoindene (II:
8.9 g (R = CH ₃ ) of light brown crystals (103.1 yield)
%). The purity of this compound determined by high performance liquid chromatography (HPLC) was 91.7% (area percentage).

[0065] Example 8 1-acetamide indene (I
I: Synthesis of 1-indanone by hydrolysis of R = CH ₃ )
(1) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three-necked flask, and 1.73 g (0.01 mol) of 1-acetamidoindene and methanol 20 were added.
ml and 10 ml of water. To this, 10 ml (0.01 mol) of 2N sulfuric acid was added dropwise over 36 minutes while stirring at 23 ° C. After further stirring for 1 hour, the reaction solution was added with 50 ml of water.
And 100 ml of benzene were added. The yellow organic layer was separated, and the aqueous layer was washed with 150 ml of benzene, combined with the previous organic layer, washed twice with 200 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-indanone tea. 1.31 g (yield 99.2%) of a yellow oil was obtained. The purity of the crystals by gas chromatography (GC) is 9
It was 9.5% (area percentage). The IR spectrum of this crystal was obtained using the FT-IR spectrum Aldrich library (The Aldrich Library of).
FT-IR Spectra, EDITION. , C
harles J. Pouchert, 1985).

[0066] Example 9 1 - benzamide indene (I
1-Indanone by hydrolysis of I: R = phenyl group)
A 100 ml three-necked flask was equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, and charged with 2.35 g (0.01 mol) of 1-benzamideindene, 20 ml of dichloroethane, 10 ml of water, and 20 ml of methanol. This was stirred at 23 ° C with 10 ml of 2N sulfuric acid (0.01 ml).
mol) was added dropwise over 6 minutes. After stirring for another 22 hours, 50 ml of water and 30 ml of dichloroethane were added to the reaction solution. The reddish-brown organic layer was separated, and the aqueous layer was washed with 30 ml of dichloroethane.
After washing twice with anhydrous sodium sulfate and drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 1.35 g of 1-indanone reddish brown oil.
(Yield: 102.2%). The purity of the crystals by gas chromatography (GC) was 89.6% (area percentage). The IR spectrum of this compound is shown in Example 8.
1-indanone.

[0067] Example 10 1-acetate preparative amide indene
(II: Conversion of 1-indanone by hydrolysis of R = CH ₃ )
Synthesis (2) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 200 ml three-necked flask, and 1.73 g (0.01 mol) of 1-acetamidoindene and 50 ml of water were charged. Add 0.4N sulfuric acid 5 with stirring at 21 ° C.
0 ml (0.01 mol) was added dropwise over 3 hours. After stirring for a further 2 hours, 50 ml of dichloromethane were added. The reddish brown organic layer was separated, and the aqueous layer was further washed with 50 ml of dichloromethane.
, Dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.32 g (yield 100%) of 1-indanone reddish brown oil. The purity of the crystals by gas chromatography (GC) is 99. 3% (area percentage)
Was.

[0068] Example 11 1-acetate preparative amide indene
(II: Conversion of 1-indanone by hydrolysis of R = CH ₃ )
Synthesis (3) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three- necked flask, and 1.73 g (0.01 mol) of 1-acetamidoindene and methanol 8.
6 ml, 17.3 ml of dichloroethane and 10 ml of water were charged. Add 2N sulfuric acid 10ml while stirring at 25 ° C.
(0.01 mol) was added dropwise over 26 minutes. After stirring for another 3 hours, the yellow organic layer was separated and 200 ml of water
, Dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.25 g (yield: 94.7%) of 1-indanone as a brownish-yellow oil. The purity of the crystals by gas chromatography (GC) was 99.7% (area percentage).

[0069] Example 12 1-acetate preparative amide indene
(II: Conversion of 1-indanone by hydrolysis of R = CH ₃ )
Synthesis (4) A 100 ml three-necked flask was equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser.
l, 10 ml of dichloroethane, 3.92 g of 50% sulfuric acid
(0.02 mol). To this, 1.73 g (0.01 mol) of 1-acetamidoindene was added with stirring at 24 ° C. After stirring for 1.5 hours, a pale yellow organic layer was separated and dried over anhydrous sodium sulfate.
Upon concentration under reduced pressure, brown crystals precipitated and oil was separated.
The crystals were filtered under reduced pressure, and the mother liquor was concentrated under reduced pressure to obtain 1.18 g (yield: 89.4%) of a 1-indanone brown yellow oil. High performance liquid chromatography of this crystal (HPL
The purity according to C) was 82.3% (area percentage).

[0070] Example 13 1-acetate preparative amide indene
(II: Conversion of 1-indanone by hydrolysis of R = CH ₃ )
Synthesis (5) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three-necked flask, and 1.73 g (0.01 mol) of 1-acetamidoindene, 20 ml of dichloroethane, and 10 ml of water were charged. To this, 10 ml (0.01 mol) of 2N sulfuric acid was added dropwise over 3 minutes while stirring at 23 ° C. After further stirring for 5 hours, the pale yellow organic layer was separated, and the aqueous layer was further washed twice with 20 ml of dichloroethane, combined with the previous organic layer, washed with 100 ml of water, dried over anhydrous sodium sulfate, and then dried under reduced pressure. After concentration, 1.30 g (yield 98.5%) of slightly yellow crystals of 1-indanone were obtained. The purity of the crystals by gas chromatography (GC) was 99.1% (area percentage).

[0071] Example 14 1-acetate preparative amide indene
(II: Conversion of 1-indanone by hydrolysis of R = CH ₃ )
Synthesis (6) A stirrer, a thermometer, a dropping funnel and a reflux condenser were attached to a 100 ml three-necked flask, and 1.73 g (0.01 mol) of 1-acetamidoindene and methanol 20 were added.
ml and 10 ml of water. While stirring at 26 ° C., 1.2 g of acetic acid (0.02 mol) dissolved in 10 ml of water was added thereto.
l) was added dropwise over 3 minutes. After heating to 50 ° C. and stirring for 7 hours, 50 ml of benzene was added to the reaction solution, and a yellow organic layer was separated. After washing twice with 200 ml of water, drying over anhydrous sodium sulfate and concentrating under reduced pressure, 1.28 g (yield 97.0%) of 1-indanone yellow oil was obtained. The purity of the crystals by gas chromatography (GC) is 9
It was 8.8% (area percentage).

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Shinya Otogi 1-133 Shimokawa-shi, Iwaki-shi, Fukushima Prefecture Inside Ichikawa Gosei Chemical Co., Ltd.

Claims (8)

[Claims] 1. A compound of the general formula (I) (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms, X is a halogen atom or a substituted sulfonyloxy group represented by OSO ₂ R ′, Is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms,
NHCOR and X have a cis configuration, and may be a racemic form or an optically active form) by reacting N-indanylamides represented by the following general formula (II): (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms) as an N-indenylamide derivative represented by the following formula: III) A method for producing 1-indanone represented by the formula: 2. In the general formula (I), R is CH ₃ , X is a bromine atom, and NH-COR and X are cis-1-acetamido-2-bromoindane having a cis configuration. The method for producing 1-indanone according to claim 1, wherein: 3. A compound of the general formula (II) (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms) N-indenylamide derivative represented by the formula: 4. A compound of the general formula (I) (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms, X is a halogen atom or a substituted sulfonyloxy group represented by OSO ₂ R ′, Is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms,
NHCOR and X have a cis configuration and may be a racemate or an optically active compound).
The reaction is carried out under anhydrous conditions and basic conditions.
I) (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms) A method for producing an N-indenylamide derivative represented by the following formula: 5. In order to obtain said basic conditions, lithium methoxide, lithium ethoxide, lithium-tert
-Using at least one alkoxide selected from the group consisting of butoxide, sodium methoxide, sodium ethoxide, sodium-tert-butoxide, sodium-tert-pentoxide, potassium methoxide, potassium ethoxide, and potassium-tert-butoxide side. The method for producing an N-indenylamide derivative according to claim 4, characterized in that: 6. An aliphatic amine, an aromatic amine, an alicyclic amine, or a heterocyclic amine, wherein the dissociation constant (25 ° C./water) of a Bronsted acid shows a value of pKa = 5 or more to obtain the basic condition. 5. A cyclic amine is used.
The method for producing the N-indenylamide derivative according to the above. 7. In order to obtain said basic conditions, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, n-butylamine, sec-butylamine, tert-butylamine, n-hexylamine, cyclohexylamine, 4-hexylamine,
The method for producing an N-indenylamide derivative according to claim 4, wherein at least one base selected from the group consisting of aminopyridine, morpholine, piperidine, and pyrrolidine is used. 8. A compound of the general formula (II) (Wherein, R is a substituted or unsubstituted phenyl group or a lower alkyl group having 1 to 8 carbon atoms) to produce an N-indenylamide derivative, which is hydrolyzed under acidic conditions. Formula (III) consisting of: A method for producing 1-indanone represented by the formula: