JPH04338358A - Production of substituted benzocycloalkanoyl-2-acetic acid derivative - Google Patents

Abstract

PURPOSE:To industrially and economically produce the subject compound useful as an intermediate for medicines by reacting a tetralin derivative or an indanone derivative, etc., used as a raw material with glyoxylic acid in the presence of an acid and reducing the resultant compound in the presence of an acid. CONSTITUTION:A compound such as 1-indanone or alpha-tetralone expressed by formula I (m is 1 or 2; R<1> and R<2> are H, alkyl or alkoxy or R<1> and R<2> may form methylenedioxy) is reacted with glyoxylic acid in the presence of an acid such as sulfuric acid to provide a compound expressed by formula II (e.g. a compound expressed by formula III or IV), which is further reduced in the presence of an acid such as the sulfuric acid to afford a substituted benzocycloalkanoyl-2-acetic acid derivative expressed by formula V (e.g. a compound expressed by formula VI or VII). The aforementioned method can be applied even to use of an indanone derivative and is advantageous.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a compound of formula (III) useful as an intermediate for the production of pharmaceuticals.

0002

[C4]

(In the formula, m represents an integer of 1 or 2, and R1
and R2 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or together represent a methylenedioxy group. ) This invention relates to a novel method for producing substituted benzocycloalkanoyl-2-acetic acid derivatives represented by:

0004

[Prior Art] Conventionally, substituted benzocycloalkanoyl-
The 2-acetic acid derivative can be obtained by a method using a halogenated compound (J
．． O. C. , Vol. 26,3555,1961,J
．． C. S. , 4115, 1960, J. C. S. ,86
7, 1961, J. O. C. , Vol. 16,550
, 1951, J. Agr. Chem. Soc. , Jap
an, Vol. 23, 22, 1949), Arndt-
Method using Eistert reaction (Ann., Vol.
．． 627, 59, 1959, J. O. C. , Vol.
27, 4146, 1962), method for reducing naphthalene acetic acid (J.O.C., Vol. 14, 366, 194)
9), method using formaldehyde (J.O.C.,
Vol. 27, 4141, 1962), but none of these methods were necessarily satisfactory in terms of yield, number of steps, and in terms of operation and industrial production.

[0005]

[Problems to be Solved by the Invention] In addition, a method using glyoxylic acid in the presence of an alkali (J.O.C., Vo.
l. 23, 1832, 1958), a method is also known in which tetralone is reacted with glyoxylic acid in the presence of an alkali and the resulting intermediate is reduced with zinc amalgam.
The reagents used in the reaction are harmful, the yield is poor, and when an indanone derivative is used as a raw material, the desired product cannot be obtained, making it difficult to use industrially.

[0006]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors conducted extensive research and discovered a manufacturing method that can industrially and economically obtain substituted benzocycloalkanoyl-2-acetic acid. The invention has been completed. The present invention provides formula (I)

[0007]

[C5]

(In the formula, m represents an integer of 1 or 2, and R1
and R2 are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or together represent a methylenedioxy group. ) is reacted with glyoxylic acid in the presence of an acid to form formula (II)

[0009]

[C6]

[0010] After obtaining the compound represented by the formula (wherein m, R1 and R2 have the same meanings as above), the compound represented by the formula (III) is reduced in the presence of an acid.

[0011]

[C7]

Substituted benzocycloalkanoyl-2- (wherein m, R1 and R2 have the same meanings as above)
In the method for producing acetic acid derivatives.

The solvent used in the reaction between formula (I) and glyoxylic acid may be any solvent as long as it does not participate in the reaction, and examples thereof include water, dimethylformamide, tetrahydrofuran, tetrahydropyran, dioxane, etc., and preferred are water, dioxane or a mixed solvent thereof is used. A commercially available aqueous solution of glyoxylic acid can also be used. Examples of acids used in the reaction include organic acids such as acetic acid, trifluoroacetic acid, and oxalic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, and nitric acid. Preferably, sulfuric acid is used to reflux the solvent from room temperature. The reaction can be carried out over a range of temperatures. The reaction is completed in 1 to 24 hours and a compound represented by formula (II) is obtained.

The compound represented by formula (II) can be easily isolated and purified by conventional chemical operations such as filtration, washing, extraction, and recrystallization, and can be converted into an addition salt with an organic or inorganic base if desired. . Furthermore, in the production method of the present invention, the compound represented by formula (II) can be subjected to the next reduction reaction as a reaction mixture or crude crystal without being isolated and purified. This is an industrially and economically advantageous manufacturing method, as it does not require as much attention to the purity of the compound as in the past.

The solvent used for reducing the compound represented by formula (II) may be any solvent as long as it does not participate in the reaction, such as water, alcohols such as methanol, ethanol or isopropanol, and ethers such as dioxane or tetrahydrofuran. Alternatively, a mixed solvent thereof may be used, and dioxane is preferably used. Examples of acids used in the reaction include hydrochloric acid, sulfuric acid, periodic acid, trifluoroacetic acid, and oxalic acid, with sulfuric acid being preferred. The reaction temperature can be carried out in the range of room temperature to 80°C, preferably in the range of room temperature to 50°C. The reaction pressure can be in the range of normal pressure to 30 kg/cm2. Examples of the catalyst used in the reduction reaction include palladium on carbon, nickel, platinum, etc. Palladium on carbon is preferably used. Hydrogen or ammonium formate can be used as the reducing agent.

The thus obtained substituted benzocycloalkanoyl-2-acetic acid derivative represented by formula (III) can be easily isolated and purified by conventional chemical operations such as filtration, washing, crystallization, recrystallization, extraction, and distillation. If desired, it can be made into an addition salt with an organic or inorganic base.

The production method of the present invention uses, in addition to a tetralin derivative, which is one of the compounds represented by formula (I), as a raw material an indanone derivative that could not be applied by the above-mentioned known method. could also be applied, and succeeded in significantly improving the industrial value. Substituted benzocycloalkanoyl-2- obtained by the production method of the present invention
Acetic acid derivative (III) is disclosed in, for example, JP-A-2-2625.
It is useful as an intermediate for the pharmaceutical described in Publication No. 57, as well as a manufacturing intermediate for other pharmaceuticals.

[0018]

EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Example 1 2-indanyl acetic acid step 1 1-oxo-2-indanylidene acetic acid

[0019]

[Chemical formula 8]

[0020] To 364 g of 40% glyoxylic acid aqueous solution,
Add 200ml of dioxane and add 1-indanone 2.
00 g and 50 ml of 80% sulfuric acid were added and refluxed for 1 hour. After cooling, the precipitated crystals were collected by filtration, washed with isopropyl ether, and 1-oxo-2-indanilideneacetic acid 2
56g was obtained. Yield 90%. Melting point: 205-206°C (decomposition point) IR (KBr) cm-1: 3300-2800,171
5,1670,1635,1595,1400,130
0,1260,1205,1100 NMR (DMSO-d6) δ: 4.14 (2H, d,
J=2Hz), 6.82 (1H, t, J=2Hz), 7
．． 42 (1H, t, J = 8Hz), 7.53 (1H, d
, J=7Hz), 7.64 (1H, t, J=8Hz),
7.87 (1H, d, J = 7Hz) Step 2 2-indanyl acetic acid

[0021]

[Chemical formula 9]

1-oxo-2-indanilideneacetic acid 15
g was suspended in 150 ml of dioxane, and 2.4 ml of 98% sulfuric acid was added.
ml was added. Furthermore, add 10% palladium on carbon,
The mixture was stirred for 5 hours under conditions of 40-50°C and a hydrogen pressure of 3.5 kg/cm3. After cooling, palladium on carbon is filtered out.
The filtrate was distilled off under reduced pressure. 400 ml of water was added to the residual oil and stirred, the precipitated crystals were collected by filtration, and 2-indanyl acetic acid 1
2.3g was obtained. Yield 87%. Melting point: 88-90°C IR (KBr) cm-1: 3200-2750,168
0,1420,1400,1300,1245,123
0,1150,945,740 NMR (CDCl3) δ: 2.55 (2H, d, J=
7Hz), 2.67 (2H, dd, J=7Hz, 15H
z), 2.84 (1H, m), 3.17 (2H, dd,
J=7Hz, 15Hz), 7.12~7.22 (4H,
m) Example 2 (R,S)-5-methoxy-2-indanyl acetic acid Step 1 5-methoxy-1-oxo-2-indanylidene acetic acid

[
0023

[Chemical formula 10]

8 ml of dioxane was added to 11 g of a 40% glyoxylic acid aqueous solution, followed by 4.9 g of 5-methoxy-1-indanone and 1.1 ml of 80% sulfuric acid, and the mixture was refluxed for 4 hours. After cooling, 50 ml of water was added and the precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 5.6 g of 5-methoxy-1-oxo-2-indanilideneacetic acid. Yield 87%. Melting point: 212-219°C (decomposition) IR (KBr) cm-1: 3200-2400,168
0,1600,1420,1280,1240,110
0NMR (DMSO-d6) δ: 3.90 (3H, s
), 4.03 (2H, d, J = 3Hz), 6.47 (1
H, t, J=3Hz), 7.03(1H, dd, J=3
Hz, 9Hz), 7.19 (1H, d, J=3Hz),
7.73 (1H, d, J = 9Hz) Step 2 (R,S)-5-methoxy-2-indanyl acetic acid

00
25]

[Chemical formula 11]

5-methoxy-1-oxo-2-indanilideneacetic acid (5 g) was suspended in 50 ml of dioxane, and 1 ml of trifluoroacetic acid was added. Furthermore, 10% palladium on carbon was added, and under a hydrogen pressure of 3.5 kg/cm3,
The mixture was stirred at room temperature for 5 hours. Palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from a mixture of isopropyl ether and n-hexane to obtain (R,
4.2 g of S)-5-methoxy-2-indanyl acetic acid was obtained. Yield 89%. Melting point: 89-90°C IR (KBr) cm-1: 3200-2800,169
0,1490,1250,800 NMR (CDCl3) δ: 2.53 (2H, d, J=
7Hz), 2.58-2.69 (2H, m), 2.84
~2.95 (1H, m), 3.06 ~ 3.18 (2H,
m), 3.80 (3H, s), 6.69 (1H, dd,
J=8Hz, 3Hz), 6.75(1H, d, J=3H
z), 7.08 (1H, d, J = 8Hz) Example 3 5,6-methylenedioxy-2-indanyl acetic acid Step 1 5,6-methylenedioxy-1-oxo-2-indanylidene acetic acid

[0027]

[Chemical formula 12]

8 ml of dioxane was added to 11 g of 40% glyoxylic acid aqueous solution, and further 5.28 g of 3,4-methylenedioxy-1-indanone and 1.1 ml of 80% sulfuric acid were added.
1 was added and the mixture was refluxed for 2 hours. After cooling, 50 ml of water was added and the precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 6.4 g of 5,6-methylenedioxy-1-oxo-2-indanilideneacetic acid. Yield 91%. Melting point: >280°C (decomposed) IR (KBr) cm-1: 3200-2800,168
0,1605,1475,1305,1250,103
0NMR (DMSO-d6) δ: 3.94 (2H,b
rs ), 6.20 (2H, s), 6.43 (1H, b
rs ), 7.17 (2H, s) Step 2 5,6-methylenedioxy-2-indanyl acetic acid

00
29]

[Chemical formula 13]

5,6-methylenedioxy-1-oxo-
3.5 g of 2-indanilidene acetic acid and 50 ml of dioxane
and 1 ml of trifluoroacetic acid was added. moreover,
10% palladium on carbon was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen pressure of 3.5 kg/cm3. Palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with isopropyl ether to obtain 2.8 g of 5,6-methylenedioxy-2-indanyl acetic acid. Yield 85%. Melting point: 84-86°C IR (KBr) cm-1: 3200-2400,170
0,1500,1420,1210,800NMR(C
DCl3) δ: 2.54 (2H, d, J=6Hz),
2.57 (2H, dd,, J=6Hz, 16Hz), 2
．． 80-3.02 (1H, m), 3.06 (2H, dd
, J=6Hz, 16Hz), 5.90 (2H, d, J=
1Hz), 6.66(2H,s) Example 4 (R,S)-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid Step 1 1-oxo-1,2,3,4-tetrahydro -2-naphthylideneacetic acid

[0031]

[Chemical formula 14]

360 ml of dioxane was added to 380 ml of a 40% glyoxylic acid aqueous solution, followed by 200 g of α-tetralone and 60 ml of 80% sulfuric acid, and the mixture was refluxed for 5 hours. After cooling to room temperature, the crystals were further cooled on ice, the precipitated crystals were collected by filtration, and washed with ice water and isopropyl ether in this order.
210 g of 1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid was obtained. Yield 77%. Melting point: 186-188°C IR (KBr) cm-1: 3100-2800,169
0,1670,1630,1590,1410,129
0,1250,1200 NMR (DMSO-d6) δ: 2.98-3.03 (
2H, m), 3.29-3.34 (2H, m), 6.6
7 (1H, brs), 7.38-7.44 (2H, m
), 7.58-7.64 (1H, m), 7.95 (1H
, d, J=8Hz) Step 2 (R,S)-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid

[0033]

[Chemical formula 15]

14 g of 1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid was added to 200 m of dioxane.
1.5 g of 80% sulfuric acid was added. Furthermore, 1
0% palladium on carbon was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen pressure of 3.5 kg/cm3. Palladium on carbon was filtered off, and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in 100 ml of methylene chloride, and after washing with 50 ml of water,
Extracted twice with 50 ml of 10% sodium hydroxide. The extracts were combined, made acidic by adding hydrochloric acid, extracted twice with 100 ml of methylene chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The precipitated crystals were recrystallized from isopropyl ether to give (R,S)-1,2,3,4-
9.5 g of tetrahydronaphthalen-2-yl acetic acid was obtained. Yield 72%. Melting point: 85-87°C IR (KBr) cm-1: 3200-2700,170
5,1650,1430,1400,1280,124
5,1150,910,745 NMR (CDCl3) δ: 1.44-1.58 (1H
, m), 1.96~2.06 (1H, m), 2.21~
2.37 (1H, m), 2.52 (1H, dd, J=9
Hz, 16Hz), 2.82-2.98 (3H, m) Example 5 (R,S)-5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid Step 1 5 ,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid

[0035]

[Chemical formula 16]

Add 2 ml of dioxane to 3 ml of 80% glyoxylic acid aqueous solution, and add 5,7-dimethyl-1-
Oxo-1,2,3,4-tetrahydronaphthalene1.
74 g and 0.5 ml of 80% sulfuric acid were added and refluxed for 2 hours. After cooling to room temperature, the crystals were further cooled on ice, the precipitated crystals were collected by filtration, and washed with ice water and isopropyl ether in this order.
1.66 g of 5,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid was obtained. Yield 72%. Melting point: 205-206°C (decomposed) IR (KBr) cm-1: 3100-2700,169
5,1665,1625,1605,1471,140
5,1270,1210,1150 NMR (DMSO-d6) δ: 2.23 (3H, s)
, 2.31 (3H, s), 2.87 (2H, t, J=6
Hz), 3.28 (2H, t, J=6Hz), 6.59
(1H, s), 7.33 (1H, s), 7.64 (1H
,s) Step 2 (R,S)-5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid

[0037]

[Chemical formula 17]

5,7-dimethyl-1-oxo-1,2,
5 g of 3,4-tetrahydro-2-naphthylideneacetic acid was suspended in 50 ml of dioxane, and 0.8 ml of 80% sulfuric acid was added. Furthermore, add 10% palladium carbon to 3.5k
The mixture was stirred at room temperature for 5 hours under a hydrogen pressure of g/cm3. Palladium on carbon was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of methylene chloride and extracted twice with 30 ml of 10% sodium hydroxide. The extracts were combined, made acidic by adding hydrochloric acid, extracted twice with 50 ml of methylene chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The precipitated crystals were recrystallized from isopropyl ether to give (R,S)-5,7-dimethyl-1,2,3
, 4-tetrahydronaphthalen-2-yl acetic acid (4 g) was obtained. Yield 84%. Melting point: 92-93°C IR (KBr) cm-1: 3200-2700,170
0,1420,1290 NMR (CDCl3) δ: 1.44-1.59 (1H
, m), 2.02~2.10 (1H, m), 2.14~
2.34 (1H, m), 2.18 (3H, s), 2.2
5 (3H, s), 2.41 (2H, d, J=7Hz),
2.46-2.92 (4H, m), 6.75 (1H, s
), 6.82 (1H,s) Example 6 (R,S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid Step 1 6-methoxy-1-oxo-1, 2,3,4-tetrahydro-2-naphthylideneacetic acid

[0039]

[Chemical formula 18]

Add 3 ml of dioxane to 3 ml of 40% glyoxylic acid aqueous solution, and add 1.76 ml of 6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene.
g and 0.5 ml of 80% sulfuric acid were added thereto, and the mixture was refluxed for 3 hours. After cooling to room temperature, the precipitated crystals were filtered and washed with ice water and isopropyl ether to obtain 6-
1.65 g of methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid was obtained. Yield 71%
. Melting point: 179-180°C IR (KBr) cm-1: 3100-2700,168
0,1655,1590,1410,1270,121
0,1130 NMR (DMSO-d6) δ: 2.97 (2H, t,
J = 6Hz), 3.28 (2H, t, J = 6Hz), 3
．． 86 (3H, s), 6.63 (1H, s), 6.93
~6.96 (2H, m), 7.92 (1H, d, J=8
Hz) Step 2 (R,S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid

[0041]

[Chemical formula 19]

6-methoxy-1-oxo-1,2,3,
5 g of 4-tetrahydro-2-naphthylideneacetic acid was suspended in 50 ml of dioxane, and 0.8 ml of 80% sulfuric acid was added. Furthermore, 10% palladium on carbon was added, and 3.5 kg/
The mixture was stirred at room temperature for 6 hours under a hydrogen pressure of cm3. Palladium on carbon was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of methylene chloride and extracted twice with 30 ml of 10% sodium hydroxide. The extracts were combined, made acidic by adding hydrochloric acid, and then diluted with 50 ml of methylene chloride.
After extraction and drying over anhydrous magnesium sulfate, the solvent was distilled off. The precipitated crystals were recrystallized from isopropyl ether to obtain 3.9 g of (R,S)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl acetic acid. Yield 83%. Melting point: 94-95°C IR (KBr) cm-1: 3200-2700,170
0,1500,1420,1290,1250,103
5NMR (CDCl3) δ: 1.41-1.56 (1
H, m), 1.94-2.03 (1H, m), 2.18
~2.36 (1H, m), 2.42 (2H, d, J=7
Hz), 2.40-2.50 (1H, m), 2.79-
2.92 (3H, m), 3.77 (3H, s), 6.6
0 to 6.70 (2H, m), 6.97 (1H, d, J=
8Hz)

Claims (1)

[Claims] [Claim 1] Formula (I) [Formula 1] (wherein m represents an integer of 1 or 2, R1 and R2
are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or together represent a methylenedioxy group. ) is reacted with glyoxylic acid in the presence of an acid to obtain a compound represented by formula (II) [Chemical formula 2] (wherein m, R1 and R2 have the same meanings as above). , a substituted benzocycloalkanoyl-2- represented by the formula (III) (wherein m, R1 and R2 have the same meanings as above), characterized in that it is reduced in the presence of an acid. Method for producing acetic acid derivatives.