JPH0148897B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of o-(aminomethyl)phenyl acetate lactam and its homolog β-(o-aminomethylphenyl)propionate lactam. It is known that the lactam obtained according to the present invention is easily ring-opened by hydrolysis to give o-(aminomethyl)phenylacetic acid and β-(o-aminomethylphenyl)propionic acid. These amino acids are useful as intermediates in synthetic cephalosporin agents. Conventionally, methods for producing o-(aminomethyl)phenylacetic acid lactam include producing 2-indanone from indene and then subjecting it to Schmitt reaction (Japanese Patent Application Laid-Open No. 49-24975), or subjecting 2-indanone oxime to Beckman rearrangement. How to hang (Japanese Patent Application Laid-Open No. 49-275)
However, the starting material indene is expensive, and the process requires complicated operations such as the process from indene to 2-indanone using performic acid and the Schmidt reaction using hydrogen azide. , must handle hazardous reagents. In addition, the method for producing ring-opened o-(aminomethyl)phenylacetic acid involves several steps from 2-(o-methylphenyl)acetic acid ester (Japanese Unexamined Patent Application Publication No. 1989-1999).
-62991) is known, but it has disadvantages such as the difficulty in obtaining starting materials and the long manufacturing process. On the other hand, a method for producing β-(o-aminomethylphenyl)propionic acid lactam is a method by catalytic reduction of β-(o-cyanophenyl)propionic acid or o-cyanocinnamic acid or their esters (CA 68 , 77993n, CA 76 , 46063v) and the Betzkmann rearrangement of β-tetralone oxime (CA 73 , 110475y), but in addition to problems in obtaining starting materials, the latter method depends on the direction of the rearrangement. There is a possibility that a compound different from the target product will be produced. In order to overcome the above-mentioned drawbacks of the known methods, the present inventors conducted various studies and found that phenylacetonitrile or β-phenylpropionitrile, which is commercially available and easily available as a reagent, was combined with paraformaldehyde and a strong acid. O-(aminomethyl)phenylacetate lactam and β-
It was discovered that (o-aminomethylphenyl)propionic acid lactam can be produced, and the present invention was completed. The present invention provides a method for supplying o-(aminomethylphenyl)acetate lactam or β-(o-aminomethylphenyl)propionate lactam more advantageously than conventional methods. In carrying out the present invention, paraformaldehyde is usually used in an amount of 1 to 3 molar equivalents per mole of nitrile,
Preferably 1 to 1.1 molar equivalents are used. Examples of strong acids used in the present invention include sulfuric acid, sulfuric acid-acetic acid, trifluoroacetic acid, methanesulfonic acid, etc. Among them, sulfuric acid-acetic acid is advantageous, especially those with a mixing ratio of 1:2. is suitable. 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 the reaction time and improving the yield. The concentration of nitrile in strong acid in this reaction is
A suitable concentration is 1.5 molar or less, preferably 0.1 to 1 molar, and the reaction temperature is room temperature to 100°C, preferably 80 to 90°C. In this ring-closing reaction, it is not preferable to use paraformaldehyde in excess than necessary or to react nitrile at a high concentration in an acidic medium, as this will result in the promotion of intermolecular polymerization. The o-(aminomethyl)phenylacetic acid lactam and β-(o-aminomethylphenyl)propionic acid lactam obtained in this reaction can be easily isolated and purified by conventional means, or they can be hydrated without purification. It can also be isolated as a decomposed ring-opened amino acid. The method of the present invention will be specifically explained below with reference to Examples. Example 1 o-(aminomethyl)phenylacetic acid lactam phenylacetonitrile 1.14 ml (10 mmol),
A mixture of 315 mg (10.5 mmol) of paraformaldehyde and 100 ml of a sulfuric acid-acetic acid (1:2) mixture is stirred at 85-90° C. for 6 hours. Pour the reaction solution into ice water 500ml
ml and extract with methylene chloride (100ml x
3 times). The extract was washed with a 10% aqueous sodium carbonate solution.
The residue was dried with sodium sulfate and concentrated under reduced pressure, and the residue was subjected to column chromatography using 13 g of Wako Gel C-200 (silica gel for column chromatography, manufactured by Wako Pure Chemical Industries, Ltd., 100-200 mesh), and benzene-ethyl acetate (5:1) was used. →7:3) The fraction containing the target product was evaporated under reduced pressure, and the residue was crystallized from isopropyl ether-benzene to yield 700 mg of needle-shaped crystals of o-(aminomethyl)phenyl acetate lactam.
(yield 47.6%). Mp141-143℃. IR
(KBr): 3200, 2950, 1655, 1500, 1430, 1395,
1350, 1200, 1100, 835, 745 cm ^-1 . NMR
(DMSOd ⁶ ): δ3.46 (2H, s), 4.37 (2H, br.s),
7.29 (4H, s), 8.06 (1H, br.) These physicochemical properties were consistent with those of a specimen separately synthesized by a known method. Example 2 β-(o-aminomethylphenyl)propionic acid lactam 1.49 g (10 mmol) of β-phenylpropionitrile, 315 mg (10.5 mmol) of paraformaldehyde and 100 ml of a mixture of sulfuric acid and acetic acid (1:2). The mixture is stirred at 85-90°C for 6 hours. The reaction solution was poured into 500 ml of ice water and extracted with methylene chloride (100 ml of ice water).
ml x 3 times). The extract is washed with 10% aqueous sodium carbonate solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography on 13 g of Wakogel C-200, and benzene-ethyl acetate (5:1
→6:4). The fractions containing the target product were evaporated under reduced pressure, and the residue was crystallized from isopropyl etherbenzene to yield colorless needle-like β-(o-aminomethylphenyl)propionic acid lactam.
mg (yield 53%) was obtained. Mp127~129℃. IR (KBr): 3200, 1600, 1485, 1445, 1405,
1355, 1305, 1215, 1155, 1095, 795, 755, 710
cm ^-1 . NMR (DMSO-d6): δ2.62 (2H, m),
3.01 (2H, m), 4.29 (2H, br.s), 7.19 (4H, s),
7.91 (1H, br.) These physicochemical properties were consistent with those of a specimen separately synthesized by a known method. Example 3 o-(Aminomethyl)phenylacetic acid lactam Phenylacetonitrile 4.56 ml (40 mmol)
Add 80 ml of glacial acetic acid-concentrated sulfuric acid mixture (2:1) to 1.26 g (42 mmol) of paraformaldehyde,
Heat and stir at 85-90°C for 6 hours. Then under reduced pressure,
Distill the acetic acid and pour the concentrate into 500ml of ice water.
Extract with methylene chloride (100ml x 3 times) and extract the extract.
Wash with 10% sodium carbonate aqueous solution, dehydrate, and evaporate under reduced pressure. The residue was subjected to silica gel column chromatography using 13 g of Wakogel C-200, eluted with benzene-ethyl acetate (5:1 → 6:4), fractions containing the target product were collected, and the solvent was removed under reduced pressure. The crystalline residue was recrystallized from benzene-isopropyl ether to obtain 2.27 g of acicular o-(aminomethyl)phenylacetic acid lactam (yield 38.6).
%)Obtained. Mp141-143℃. The IR and NMR spectra matched those of the standard product. Examples 4 to 6 Phenylacetonitrile and paraformaldehyde were reacted in sulfuric acid-acetic acid (1:2) under the same reaction conditions as in Example 1 to obtain o-(aminomethyl)phenylacetic acid lactam. 【table】

Claims (1)

[Claims] 1 formula A compound represented by the formula [wherein n represents an integer of 1 or 2] and paraformaldehyde are reacted in the presence of a strong acid, A method for producing a compound represented by the formula [wherein n has the same meaning as above]. 2. The method according to claim 1, wherein the strong acid is a mixed acid of sulfuric acid and acetic acid. 3. The method according to claim 1, wherein n is 1. 4. The method according to claim 1, wherein n is 2.