JPS584769A - Preparation of 1,4-dihydro-3(2h)-isoquinolone - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a raw material of o-(aminomethyl)phenylacetic acid which is an intermediate of a synthetic cephalosporin preparation, easily, by reacting phenylacetic acid amide with formaldehydes in the presence of a strong acid. CONSTITUTION:The phenylacetic acid amide of formulaIand formaldehyde or its equivalent substance, e.g. paraformaldehyde, or N-(hydroxymethyl)-phenylacetic acid amide of formula II obtained by the condensation of the above compounds at a molar ratio of 1:1, is heated at 80-90 deg.C in the presence of a strong acid to obtain the objective compound of formula III. The product can be converted to o-(aminomethyl)-phenylacetic acid by hydrolyzing without purification. The strong acid is preferably a mixture of sulfuric acid and acetic acid at a ratio of 1:2. The concentration of the phenylacetic acid amide in the strong acid is adjusted to 0.1mol.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 1,4-dihydro-3(2H)-isoquinolone.

1,4-dihydro-3(
2H)-isoquinolone corresponds to a lactam of o-(aminomethyl)phenylacetic acid, and 0-(aminomethyl)phenylacetic acid is obtained by hydrolysis as shown in the quadratic formula.
This amino acid is useful, for example, as an intermediate in one synthetic cephalosporin agent.

Conventionally, the method for producing 4-dihydro-3(2H)-isoquinolone was to produce 2-indanone from indene through several steps and then subject it to Schmidt reaction (Japanese Patent Application Laid-open No.
9-249'75) or its oxime through Beckmann rearrangement (Japanese Unexamined Patent Publication No. 49-275), however, the source of indene, which is the starting material, is limited, and the reagent for the Schmidt reaction is There are some difficulties in handling hydrogen azide.

-/ Also, as a method for producing 90-(aminomethyl)phenylacetic acid by opening the ring of a lactam, there is a method that goes through several steps from 0-methylphenylacetic acid ester (%
) is known, but it is difficult to shorten the process.

The applicant has already prepared N-substituted 1,4-dihydro-3(2H)-isoquinolones by reacting N-monosubstituted phenylacetamide and formaldehyde or a reagent capable of producing formaldehyde under the reaction conditions in the presence of a strong acid. (Japanese Unexamined Patent Application Publication No. 54-13)
857'i').

The present invention was achieved through the knowledge that 1,4-dihydro-3(2H)-isoquinolone can be produced by reacting phenylacetamide and formaldehyde or their equivalents in the presence of a strong acid. It is.
An equivalent of formaldehyde is paraformaldehyde.

In addition to reagents that can generate formaldehyde under the reaction conditions, such as trioxane, methylene diacetate, methylene sulfate, chloromethyl acetate, bis(acetoxymethyl) ether, and methylal, formaldehyde and phenylacetamide are mixed in advance in a molar ratio of 1=10. It is also possible to introduce formaldehyde into the reaction system in the form of N-(hydroxymethyl)phenylacetic acid amide obtained by condensation.

N-(hydroxymethyl)phenylacetamide is a crystal obtained almost quantitatively by, for example, reacting phenylacetamide with an aqueous formaldehyde solution under weak alkalinity. Using this crystal, it is easy to simultaneously introduce phenylacetamide and formaldehyde into the reaction system at a molar ratio of 1:1. The method of the invention therefore proceeds, for example, according to the steps of the following formula.

, H2CO /H+ In carrying out the present invention, formaldehyde and its equivalents are usually used at a concentration of 0 per mole of phenylacetamide.
．． 5-1.5 molar equivalents are used, preferably 0.9-1.1 molar equivalents. When N-(hydroxymethyl)phenylacetic acid amide is used, an effect equivalent to the addition of 1 molar equivalent of formaldehyde can be obtained.

Examples of the strong acid used in the present invention include sulfuric acid-acetic acid, sulfuric acid, trifluoroacetic acid, etc. Among them, sulfuric acid-acetic acid is advantageous, especially when the mixing ratio is 1:2.
Preferably. Note that the combined use of acetic anhydride, phosphorus pentoxide, or the like as a dehydrating agent during this ring-closing reaction may be effective in shortening one reaction time and improving yield. In this reaction, the concentration of phenylacetamide in a strong acid is 1 molar or less, preferably 0.1 molar, and the reaction temperature is room temperature to 100C, preferably 80 to 90C.
It is C.

In this ring-closing reaction, it is not preferable to use formaldehyde or its equivalent in excess than necessary or to carry out the reaction in an acidic medium at a high concentration, as this will result in the promotion of intermolecular polymerization.

The 1,4-dihydro-3(2H)-isoquinolone obtained in this reaction can be easily isolated and purified by conventional means, or it can be hydrolyzed without purification to give 0-
It can also lead to aminomethylphenylacetic acid.

The method of the present invention will be specifically explained below with reference to Examples.

Example 1 Phenylacetamide 2. 200m7 of a mixture of acetic acid and concentrated sulfuric acid (2:1) in 'i'r (20 mmol) and paraformaldehyde o, 63r (21 mmol)! Add.

Heat and stir at 85-90U for 6 hours. The reaction solution was poured into ice water and extracted with methylene chloride (soo, 4×3 times). The extract was washed with a 10% aqueous sodium carbonate solution and dried over sodium sulfate.

When the solvent was distilled off under reduced pressure, 2.61 of a yellow-green solid was obtained. This is Wako Gel 0-200 (Silica gel for column chromatography manufactured by Wako Tsumugi Co., Ltd.) 30? Column chromatography was performed using a benzene-ethyl acetate mixed solvent, the fractions containing the target product were collected, and the solvent was distilled off under reduced pressure.

1.67 crude crystals were obtained. This was recrystallized from inpropyl ether-benzene to give colorless needle-like 1.36f of 1°4-dihydro-3(2H)-isoquinolone (yield: 45%).
) was obtained. mp 144-145 c0 engineering R (KB
r): 3200, 3050, 1655, 1500,
1430°1395.1350,835.745m-0
NMR (DMSO-(161: δ(ppm)3.4
6 (2H, s), 4.37 (2H 1 day), '7.
29 (4H, s).

8.06 (LH,br,).

These physicochemical properties were completely consistent with those of the separately synthesized standard.

Example 2 N-hydroxymethylphenylacetic acid eamide 1.63
A mixture of acetic acid and concentrated sulfuric acid (2:
1) Add 100- and add 6 while stirring the mixture.
After heating to 85C for an hour, it is poured into 500 °C of ice water and extracted with methylene chloride (150 m/×3 times).
The extract was washed with a 10% aqueous sodium carbonate solution and dried over sodium sulfate.

The solvent was distilled off under reduced pressure, and the solid residue was crystallized 92 times from isopropyl ether-benzene to yield 4 units of 1,4-dihydro-3(2H)-isoquinolone (720 units (yield: 49%)). tli-6mp 140-144 t;'
0 The R and NMR spectra of this product matched those of the standard product.

The N-(hydroxymethyl)phenylacetic acid amide used in the reaction was prepared according to the method described in the literature (R, D, Haw-arth
etal, J. Ohem, Eloc, 19
50.1496), phenyl acetate amide and formalin were prepared.

Patent applicant: Banyu Pharmaceutical Co., Ltd. 　9　-

Claims (4)

[Claims] (1) A process for producing 2,4-dihydro-3(2H)-isoquinolone, characterized by reacting phenylacetamide and formaldehyde or their equivalents in the presence of a strong acid. (2) The method according to claim 1, wherein the formaldehyde equivalent is paraformaldehyde. (3) The method according to claim 1, wherein the phenylacetamide and formaldehyde or their equivalents are N-(hydroxymethyl)phenylacetamide. (4) The method according to claim 1, wherein the strong acid is a sulfuric acid-acetic acid type acid.