JPS5936616B2 - Production method of isoindoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing compounds with analgesic and anti-inflammatory activity.

Pelkey Patent No. 774,985 by the present inventors describes the following general formula: where R is selected from the group consisting of hydrogen and lower alkyl groups containing 1 to 4 carbon atoms; and R, is hydrogen, lower alkyl containing 1 to 4 carbon atoms and general formula (CH2)n-N(?2
(wherein n is 1 or 2 and R2 and R3 are independently selected from the group consisting of hydrogen and lower alkyl having 1 to 4 carbon atoms) New compounds with analgesic and anti-inflammatory activity have been described.

Embodiments of the invention also include salts of compounds of general formula (1), in which R is hydrogen, with physiologically acceptable organic or inorganic bases, especially with 2(dimethylamino)ethanol. Ru.

The inventors hereby provide that the compounds of general formula (1) and their salts are each advantageously prepared by the following method, namely: (a) benzaldehyde is prepared from the general formula (where X is a cyano group or COOR'1 R',
is a lower alkynole group having 1 to 4 carbon atoms, R has the above definition) to produce a compound of the general formula (wherein X and R have the above definitions). , which is reduced to a compound of the general formula (wherein X and R have the above definitions), which is reacted with phosgene to form the following general formula (wherein X and R have the above definitions): A compound of the general formula (in which X and R
has the above definition), which is
If desired, saponification is carried out to produce a compound in which R of the general formula I) is hydrogen, and optionally converted to the corresponding ester by a conventional method, or (b) a compound of the above general formula... is monoxidized. A compound of the above general formula is produced by reacting with carbon, which is optionally saponified to produce a compound of the general formula (
I) in which R1 is hydrogen, which is optionally converted into the corresponding ester and optionally of the general formula (I).
It has been discovered that compounds in which R, in ) is hydrogen, can be prepared by reacting with a suitable base to form a physiologically acceptable salt.

From the series of reactions described above, if it is desired to obtain a compound of the general formula (C) in which R1 is an alkyl group,
When a compound according to the general definition is obtained which is OOR'1 (R'1 has the above definition), steps (a) and (b)
can be interrupted.

The reaction of this benzaldehyde with a compound of general formula () (which may be prepared by the method described in Pelkey Patent No. 774,985 by the present inventors) is preferably carried out in a non-polar solvent, preferably from about 50°C to about It is carried out at temperatures ranging between 200°C. The reduction of a compound of the general formula support) to a compound of the general formula [ is preferably carried out in a catalytic manner under pressure, for example using PtO2 under a pressure of about 3 to 4 atmospheres. The reaction of a compound of general formula with phosgene is preferably carried out in a non-polar solvent such as toluene, xylene dioxane, etc., and in the presence of a base such as pyridine, dimethylaniline, etc., and initially at about 20° to 50°C. range, then at a temperature in the range of about 70<0>C to 150<0>C. As a catalyst for the Friedel-Crafts reaction for converting compounds of general formula
nCl4 etc. can also be used.

As a solvent, a halogenated solvent such as dichloroethane,
Solvents commonly used in CCl4 as well as other Friedel-Crafts reactions can be used. The reaction of the compound of general formula (auto) with carbon monoxide is preferably carried out at an elevated temperature in the range of between about 250 and 350°C, and preferably between about 150 and 250°C.
It is carried out at pressures in the range between atmospheric pressure.

The final saponification of the compound of general formula "I" to form the compound of general formula (I) in which R1 is hydrogen is conventionally carried out by organic chemical methods, as is well known to those skilled in the art. ,
It can be carried out both in acidic and basic media.

The conversion of compounds of general formula (I) in which R1 is hydrogen to compounds of general formula (I) in which R1 is other than hydrogen can be carried out by conventional methods well known to those skilled in the art.

As mentioned above, it is well known to those skilled in the art to esterify the compound of general formula (1) in which R is hydrogen to form a compound of general formula (1) in which R is other than hydrogen, if desired. It is carried out by conventional organic chemical methods.

For example, an ester of a compound of general formula (0) with 2(dimethylamino)ethanol in which R1 is hydrogen is prepared by treating said compound with SOCl2 at a temperature of about 60°C to about 90°C, with or without solvent. The acid chloride so obtained can then be prepared by reacting at room temperature in a non-polar solvent such as dioxane, benzene or the like. Compounds of the general formula (0) in which R1 is hydrogen, as is well known to those skilled in the art, may optionally be prepared using their physiologically acceptable inorganic bases such as NaOH.Ca(0H)2 and others, or organic bases such as 2 (dimethylamino ) can be converted into salts with ethanol and others by conventional organic chemical methods.

For example, salts of compounds of the general formula (0) with 2(dimethylamino)ethanol in which R1 is hydrogen can be prepared by reacting these compounds at room temperature with an aqueous solution containing a stoichiometric amount of 2-(dimethylamizo)ethanol. The compounds of general formula 0) and their salts have already been disclosed in Pelkey Patent No. 7749.
As described in No. 85, it has a high degree of analgesic and anti-inflammatory activity. Particularly preferred are 1-oxo-2
-{p-[(α-methyl)monocarboxymethyl]-phenyl}-isoindoline compound. The following examples illustrate aspects of the invention, but are not intended to limit the invention.

Example 1 17.15y (0.16
2 mol) of benzaldehyde and 22.51 (0.15 mol) of benzaldehyde
A mixture containing 4 mol) of p-amino-(α-methyl)-phenylacetonitrile is heated in a back-current apparatus for 5 hours with removal of the water formed during the reaction as an azeotrope.

The toluene is then distilled in vacuo to give an oily residue which solidifies on standing. Crystallization from petroleum ether benzene gives 36t p)-(benzylidene)-amino-(α-methyl)-phenylacetonitrile, M5p. A temperature of 60 to 61°C is obtained.

Yield 100% o Example 2 23.47 (0.1 M
) of p-benzylidene-amino-(α-methyl)-phenylacetonitrile at 3 to 4 atmospheres at room temperature.
Hydrogenate in the presence of VPt02.

This compound is then separated from the catalyst, the EtOH is evaporated and the residue is distilled to give 20.57 p-benzylamino-(α-methyl)-phenylacetonitrile. B. p. l7O~175℃ (0.2mT
Example 3 To a solution containing 23.67 (0.1 M) p-benzylamino(α-methyl)phenylacetonitrile in 300 CC of anhydrous toluene was added 80.6 CC (0.1 M ) of anhydrous pyridine,
A flow of phosgene is then passed for 45 minutes at room temperature.

A precipitate forms and the temperature rises spontaneously to 40 degrees. This compound was then added for 1 hour, always with a constant phosgene flow.
Heat to 00°C for 2 hours. A stream of N2 is introduced to cool the compound and remove excess phosgene. Finally, the stream is washed with saturated aqueous NaCl solution. The compound is dried over Na2sO4 and the solvent is evaporated in vacuo. Distillation of this residue yields 23.

97 N-benzyl-N-[p-(α-methyl-carbonitrilemethyl)phenyl]monocarbamoyl chloride is obtained.

B. p. l98-203°C (0.3 mmHg pressure) yellow viscous fluid, yield 80% o Example 4 29.8 in 300 CC of anhydrous symmetrical dichloroethane
To a solution containing 7 (0.1 M) of N-benzyl-N-[p-(α-methyl-carbonitrilemethyl)phenyl]carbamoyl chloride was added 20 f1 (0.15 M) of anhydrous AlCl3, and with stirring 2 Heat in a back current apparatus for an hour.

The compound is then cooled, poured into ice and HCl, and the organic layer is separated. It is washed with water and then with NaHCO3 solution. The compound is dried over Na2sO4 and evaporated to dryness. When the solid portion is crystallized from EtOH, the 1-oxo-21{p-[(α-methyl)
~monocarbonitrilemethyl]-phenyl}-isoindoline, M. p. 192-194°C is obtained. Yield = 8
Working in a similar manner and starting from the derivatives described in detail in Example 3, the following compounds were obtained.

1-Oxo-2-[p-(carbonitrilemethyl)-phenyl]-isoindoline, M. p. 2Ol~202℃
1-oxo-2-{p-[(α-ethyl)-carbonitrilemethyl]-phenyl}-isoindoline, M. p.
l8l~182°C 1-oxo-2-{p-[(α-propyl)-carbonitrilemethyl]phenyl}-isoindoline, M. p. l74-1751-oxo-2-{p
-[(α-Butyl)monocarbonitrilemethyl]-phenyl}isoindoline, M. p. l6O~161℃Example 5 23.4V (0.IM) p in benzene of I00CC
A solution containing -benzylidene-amino-(α-methyl)-phenylacetonitrile and 1.0 V CO2 (CO)8 was placed in an autoclave filled with carbon monoxide at 200 atmospheres and stirred vigorously. Below, 320
Heat to ℃ for 1 hour.

The compound was cooled to room temperature, P separated from the resulting solid fraction, and crystallized from EtOH to give 18.4 V of 1-oxo-2-{p-[(α-methyl)monocarbonitrilemethyl]. -phenyl}-isoindoline is obtained.

M. p. l92-194°C, yield 70%0 Example 6 To 2.42 CC of concentrated H2SO4 and 7.4 CC of water, 2.
62y (0.0IM) of 1-oxo-2-{p-[(α
-methyl)monocarbonitrilemethyl]-phenyl}-isoindoline is heated for 16 hours in a bag-forcette apparatus.

The compound is then poured into 100 Cc of cold water, the solid fraction is separated and this is filtered. This compound is then reacted with 30 CC of 8% NaOH. This insoluble residue is removed by filtration. Add this P solution to 30CC of 8% H
Acidify with CI solution. This solid fraction was filtered and 95%
Crystallization from EtOH yields 2.39 v of 1-oxo-2-{p-[(α-methyl)carboxymethyl]-
phenyl}-isoindoline, M. p. 2l3~214
℃ is obtained. Yield: 85% o Working in a similar manner and starting from the derivative described in Example 4, the following compounds were obtained.

1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline, M. p. 2O8~209℃1-
Oxo-2-{p-[(α-ethyl)monocarboxymethyl]-phenyl}-isoindoline, M. p. l8O~
182℃1-oxo-2-{p-[(α-propyl)-
Carboxymethyl]-phenyl}isoindoline, M.
p. l6O~162℃1-oxo-2-{p-[(α-
butyl)monocarboxymethyl]-phenyl}-isoindoline, M. p. 145-147°C Example 7 7.86y (0.03M) of 1-oxo-21{p-[
(α-methyl)monocarbonitrilemethyl]-phenyl}
- isoindoline and 5. The mixture containing KOH of Iy is heated in a back current apparatus for 18 hours.

The mixture is diluted with water and washed with benzene. The aqueous phase was acidified with 8% HCI solution, the formed precipitate was filtered off, and crystallized from 95% EtOH.
Oxo-2-{p-[(α-methyl)monocarboxymethyl]-phenyl}-isoindoline, M. p. 2l3~
214°C is obtained. Yield = 80%. Operate in the same way,
Starting from the derivatives described in Example 4, the following compounds were obtained. 1-oxo-2-[p-(carboxymethyl)-
phenyl]-isoindoline, M. p. 2O8~209
C, 1-oxo-2-{p-[(α-ethyl)carboxymethyl]-phenyl}-isoindoline, M.C. p. l
80-182°C 1-oxo-2-{p-[(α-propyl)-carboxymethyl]-phenyl}-isoindoline, M. p. l6O~162℃1-oxo-2-{p[
(α-Butyl)monocarboxymethyl]-phenyl}-isoindoline, M. p. l45-147°C Example 8 In 200 CC of anhydrous toluene, 11.17 (0.10
5M) of benzaldehyde and 19.37 (0.1M)
The mixture containing p-amino-(α-methyl)-phenylethyl acetate is heated for 5 hours in a back current attachment with azeotropic removal of the water formed during the reaction.

The toluene is then evaporated in vacuo to yield 287 p-benzylideneamino-(α-methyl)-phenylethyl acetate. It has the appearance of a thick oil that is pure enough to be used in the next reaction. Yield 100%. Example 9 28.17 (0.1
M) ethyl p-benzylidene-amino mono(α-methyl)-phenyl acetate at room temperature under 3-4 atm.
．． 807 in the presence of PtO2.

The mixture is then stripped from the catalyst, the EtOH is evaporated, and the residue is distilled to give 247 ethyl p-
Benzyl-amino-(α-methyl)-phenylacetate is obtained. B. p. is 188-191℃ (0.1m
mHg pressure), yield 85%. Example 10 To a solution containing 28.37 (0.1 M) of ethyl p-benzylamino-(α-methyl)phenylacetate in 280 CC of anhydrous toluene was added 8.06 CC (0.1 M) of anhydrous pyridine. is added and then a flow of phosgene is introduced for a period of 2 hours.

The temperature rises naturally to about 40°C. The mixture is then cooled and a stream of N2 is introduced to remove excess phosgene. The benzene solution is washed with saturated aqueous NaCl and the mixture is dried over Na2sO4. The solvent is evaporated in vacuo. Distillation of this residue gives 31.27 N-benzyl-N-[[p-(α-methyl-carbethoxymethyl)phenyl]monocarbamoyl chloride. 'IO. p. l95~198°C (0.4mmH
g pressure), yield 90%. Example 11 6.97 (0
．． /47 (0.03M) of anhydrous AlC
13 is added and heated in a back current apparatus under stirring for 3 hours.

The mixture is then cooled and poured into ice and HCl. The organic layer was separated and finally the mixture was washed with water then NaH
Wash with CO3 solution, dry over Na2sO4 and evaporate to dryness. Crystallization of the residue from ligroin yields 4.647 1-oxo-2-{p-[(α-methyl)monocarfethoxymethyl]-phenyl}-isoindoline, M. p. 99-101E are obtained. Yield 7
Working in a similar manner and starting from the compound described in Example 10, the following compound was obtained.

1-oxo-2-[p-(carbethoxymethino)
-phenyl]isoindoline, M. p. l22-124
1-oxo-2-{p-[(α-ethyl)-carbuethoxymethyl]-phenyl}-isoindoline, M.C. p
．． lO7-109°C 1-oxo-2-{p-[(α-propyl)-carbethoxymethyl]-phenyl}-isoindoline, M. p. lO5-106°C, 1-oxo-2-{p-[(α-butyl)monocarbethoxymethyl]
-phenyl}-isoindoline, M. p. lO6~10
7°C Example 12 In 340cc of 95% EtOH23OCC water, 15
．． 97(0,05M) of 1-oxo-2-{p-[(α
-methyl)monocarbethoxymethyl]-phenyl}-isoindoline and 15.97 K2CO3 is heated in a back current apparatus for 8 hours.
It becomes a complete solution.

Evaporate the ethyl alcohol in vacuo and reduce the solution to 8%
When acidified with hydrochloric acid solution, a precipitate forms. The mixture was filtered, washed with water, and crystallized from 95% EtOH.
1.47 1-oxo-21{p-[(α-methyl)monocarboxymethyl]-phenyl}-isoindoline, M
．． p. 2l3-214°C is obtained. Yield 81% o Working in a similar manner and starting from the product described in Example 11, the following compound was obtained.

Claims (1)

[Claims] 1 Benzaldehyde is expressed by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, X is a cyano group or COOR'_1, and R'_1 is 1 to 4.
A lower alkyl group having 1 to 4 carbon atoms and R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms) is reacted with a compound of the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (III) (wherein X and R have the above definitions), which is then reduced to give the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (wherein X and R has the above definition) which is then reacted with phosgene to form a compound of the general formula ▲
There are chemical formulas, tables, etc. ▼ General formula consisting of a compound of (V) (in the formula, X and R have the above definitions) and intramolecular ring closure by Friedel-Crafts reaction ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ (VI)
A method for producing an isoindoline derivative (wherein X and R have the above definitions). 2 Benzaldehyde is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, X is a cyano group or COOR'_1, and R'_1 is 1 to 4
is a lower alkyl group having 1 to 4 carbon atoms, and R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms.
There are tables, etc. ▼ (III) A compound of (in the formula, X and R have the above definitions) is generated, and this is then converted into a ring to form the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV) (wherein X and R have the above definitions), which is then reacted with phosgene to produce the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (V) (wherein X and R have the above definitions). This compound is then subjected to intramolecular ring closure by Friedel-Crafts reaction to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (wherein, X and R have the above definitions). ), which is then saponified and optionally reacted with a suitable base to produce a physiologically acceptable salt.
General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) Process for producing isoindoline derivatives (wherein R has the above definition) and physiologically acceptable base addition salts thereof. 3 Benzaldehyde is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, X is a cyano group or COOR'_1, and R'_1 is 1 to 4
is a lower alkyl group having 1 to 4 carbon atoms, and R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms.
There are tables, etc. ▼ A general formula consisting of producing a compound of (III) (in which X and R have the above definitions) and then reacting this with carbon monoxide ▲ Numerical formulas, chemical formulas, tables, etc. There is a method for producing the isoindoline derivative of (VI) (wherein X and R have the above definitions). 4 Benzaldehyde is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, X is a cyano group or COOR'_1, and R'_1 is 1 to 4
is a lower alkyl group having 1 to 4 carbon atoms, and R is hydrogen or a lower alkyl group having 1 to 4 carbon atoms.
There are tables, etc. ▼ A compound of (III) (in the formula, X and R have the above definitions) is produced, and then this is reacted with carbon monoxide to form the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (VI) in which X and R have the above definitions, which is then saponified and optionally reacted with a suitable base to form a physiologically acceptable salt. becomes, general formula▲mathematical formula, chemical formula,
▼(I) Process for producing isoindoline derivatives (wherein R has the above definition) and physiologically acceptable base addition salts thereof.