JPS5841864A - Novel preparation of isoindoline derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an anodyne, antipyretic, etc. extremely inexpensively and industrially efficiently by one process in high yield, by using an benzylidene derivative as a raw material obtained from o-phthalaldehyde-acid(ester derivative) and an aniline derivative, subjecting it to ring formation at room temperature. CONSTITUTION:An o-phthalaldehyde-acid(ester derivative) shown by the formulaI(R is H or lower alkyl) is reacted with an aniline derivative shown by the formula II (R<1> is H, lower alkyl, lower alkoxy, nitro, OH, trifluoromethyl, or halogen; n is 1-3; R<2> and R<3> are lower alkyl, or R<2> and R<3> together with N form pyrrolidine, piperidine, or morpholine ring) to give a benzylidene derivative shown by the formula III, which is used as a raw material, not isolated, and subjected to ring formation with a reducing agent (e.g., sodium boron hydride, etc.), to give an isoindoline derivative shown by the formula IV. Since one bath reaction can be carried out at room temperature, a reactor and operation are simple, and the recovery of solvent can be done easily. fuel and light expenses and labor cost are inexpensive.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1) (1) (wherein R is a hydrogen atom or a lower alkyl group, and R1 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group.

Nido O group + water s group,) lifluoromethyl group, halogen atom, n is an integer of 1 to 3, R2 and R3 each represent a lower alkyl group, or a pyrrolidine, piperidine or morpholine ring together with the nitrogen atom. General formula (II) (n) characterized by cyclizing a benzylidene derivative represented by (wherein R1, n, R2 and R3 have the same meanings as above) and the general formula (to) (m) (wherein R has the same meanings as above) 0 represented by )
-7 taraldehyde acid and 0-7 taraldehyde acid ester derivatives are reacted with an aniline derivative represented by the general formula (in the formula, R1, n, R2 and R3 have the same meanings as above). In general formula (■), which is characterized in that the intermediate represented by general formula (1) according to claim 1, which is produced by cyclization in the presence of a reducing agent, is cyclized without isolating The present invention relates to a novel method for producing the above-mentioned isoindoline derivative.

In addition, to specifically explain R, Hl, R2 and R3 in the general formula (1), the lower alkyl group of R is methyl, ethyl, propyl, butyl group,
R1 lower alkyl group hamethyl, ethyl, propylbutyl group, lower alkoxy group methoxy, ethoxy, propoxy, butoxy group, \rogen atom chlorine, fluorine,
Bromine, iodine, R2 and R3 each mean a lower alkyl group such as methyl, ethyl, propyl, butoxy group or a nitrogen atom and a bironodine, piperidine or morpholine ring. Isoindoline derivatives are already known in JP-A-56-922716, and compounds in the derivatives, such as 2-[4-(β-hyperolidinoethoxy)phenyl]isoindoline-1-one and 2
It has been reported that -(4-(β-piperidinoethoxy)phenyl)isoindoline-1-one has excellent analgesic, anti-inflammatory and antipyretic effects. However, isoindoline derivatives corresponding to general formula Regarding the manufacturing method, only the following method is described.

(V) (Vl) have the same meaning) In other words, in the known method, the isoindoline derivative of the general formula (1) is produced by reacting the compound of the general formula (g) with the compound of the general formula (to). More specifically, the reaction is carried out by heating and refluxing for 5 to 15 hours in water, ethanol, water and acetone, or other organic solvents that do not participate in the reaction.Preferably, a base such as sodium hydroxide is used.

It is carried out in the coexistence of potassium hydroxide, sodium alkoxide, etc.

The present inventors have conducted various studies regarding the method for producing the compound represented by the general formula (El), and have found a method superior to the above-mentioned known method, and have completed the present invention. That is, the present invention has the above general formula (2)
O-7 taraldehydic acid and ○-7 taraldehydic acid ester derivatives represented by the formula (I) and the amine derivative represented by the general formula are mixed in methanol, ethanol, or diglyme (methanol is particularly preferred) at room temperature or with heating. By doing this, the general formula (
The benzylidene derivative represented by 1) is produced, and then heated directly or after isolation at 0 to 100°C (especially 10 to 100°C).
General formula (It) can be obtained in high yield by reacting for 0.5 to 24 hours using a reducing agent (e.g., sodium borohydride, potassium borohydride, etc.) at a temperature of 1 to 3 times the mole at 45°C (preferably 45°C). The following isoindoline derivatives are obtained.

As described above, the present invention relates to 0-phthalaldehyde acid and 0-
A phthalaldehyde ester derivative [phase] and an IJ derivative represented by the general formula (foundation) are reacted in methanol, which is an inexpensive organic solvent, and a reducing agent is added without isolation, and the reaction is carried out in a single bath at room temperature. Therefore, the reaction apparatus and reaction operation are simple, and the methanol solvent can be easily recovered, making it possible to produce the target compound at a very low cost. Furthermore, there is no need for heating, there is little operational risk, and the utility and labor costs are also low, making it an extremely efficient, business-friendly and economical manufacturing method.

Next, the present invention will be specifically explained using examples.

Example 1 15 g of O-7 taraldehydic acid and 20.69 g of P-pyrrolidinoethoxyaniline were added to 200 g of methanol, stirred at room temperature for 30 minutes, and then 7.5 g of sodium borohydride was added while cooling in a water bath. I added it several times. Next, the temperature was returned to room temperature and the reaction was carried out for 3 hours, after which the solvent was distilled off under reduced pressure.

Add 200ml of water to the residue, collect the precipitated crystals, and after drying,
When recrystallized with benzene-petroleum ether, 2-[4-<
29.69 of β-pyrrolidinoethoxy)phenyl]isoindolin-1-one was obtained.

The melting point, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 130-132°C Mass spectrum M" 322 Elemental analysis value C20H22N202 Theoretical value Cnea4.Sl)j:6.
88 N: 8.69 Actual measurement value C near 4
．． 45 H: 6.81 N: 8.64 Example 2 0-7 taraldehyde acid methyl ester 16.49 and P
After adding 24.09 g of -piperidinoethoxyaniline to 200 g of methanol and stirring at room temperature for 1 hour, 5.4 g of borohydride was added in several portions while cooling in a water bath. After further reaction for 8 hours at room temperature, the solvent was distilled off under reduced pressure. Add 200 d of water to the residue, dry the precipitated crystals, and then recrystallize with ethanol to obtain 2
-I: 4-(β-piperidinoethoxy)phenyl]isoindolin-1-one 30.59 was obtained.

The melting point, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 141-143°C Mass spectrum M+336 Elemental analysis value C2□H21tN202 Theoretical value C near 4.97 H near, 19 N; 8
．． 33 Actual Measured Values C Near 4.81 H Near, 08 N: 8.31 Example 3 P-CN-(0-carboxybenzylidene)-aminocou 2-piperidinoethoxybenzene 3.59 suspended in methanol 200- Sodium borohydride 0 under cooling with water
．． 69 was added several times. Next, the mixture was returned to room temperature and stirred for 3 hours, and then the solvent was distilled off under reduced pressure. 200ml of water to the residue
- is added, the precipitated crystals are collected in a furnace, dried, and then recrystallized with ethanol! =2-(4-(β-Hiberidinoet'
xy)phenyl]isoindolin-1-one 3.19 was obtained.

The melting point, mass spectrum, and elemental analysis values of this substance were as follows.

Melting point 141-143°C Mass spectrum M” 336 Elemental analysis value C21H2LIN202 Theoretical value C near 4.97 H near, 19 N:8
．． 83 Actual Measured Values C Near 4.81 H Near 08 N: 8.31 The following compounds were synthesized according to the methods of Examples 1 to 3.

2-(4-Cβ-dimethylaminoethoxy)phenyl]
Isoindolin-1-one Melting point 139-141”C2-[4-
(β-diethylaminoethoxy)phenyl]isoindolin-1-one Melting point 88-89°C 2-(4-(β-morpholinoethoxy)phenyl]isoindolin-1-one Melting point 130-132°C 2-[3-chloro- 4-(β-dimethylaminoethoxy)phenyl]isoindolin-1-one Melting point
147-149°C 2-[3-chloro-4-(β-diethylamineethoxy)phenyl]isoindolin-1-one Melting point
119-121℃ 2,-[3-10rho 4-(β-morpholinoethoxy)
phenyl]isoindolin-1-one Melting point 1
65-167℃ 2-(3-10rho4-(β-piperidinoethoxy)phenyl)isoindolin-1-one Melting point 1
75-177°C 2-(3-chloro-4-(β-pyrrolidinoethoxy)phenyl)isoindolin-1-one Melting point 1
55-157℃

Claims (1)

[Claims] 1 General formula (1) (1) (In the formula, R is a hydrogen atom or a lower alkyl group, and R1 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group. =) O group, hydroxyl group,) represented by a fluoromethyl group or a halogen atom, n is an integer of 1 to 3, R2 and R3 each represent a lower alkyl group, or may form a pyrrolidine, piperidine or morpholine ring with the nitrogen atom) General formula (I) characterized by cyclizing a benzylidene derivative in the presence of a reducing agent
t) (In the formula, R1, n, R2 and R3 have the same meanings as above. O-phthalaldehydic acid and 0-7 having the same meaning as described in Section
A patent claim produced by reacting a taraldehyde acid ester derivative with an aniline derivative represented by the general formula 1 (IV) (wherein R't n t R2 and R3 have the same meanings as above) The range of the general formula described in item 1 (
A method for producing an isoindoline derivative represented by the general formula (■), which comprises cyclizing in the presence of a reducing agent without isolating the intermediate represented by 1).