JPS63183548A - Production of n-hydroxyamino acids - Google Patents

Abstract

PURPOSE:To advantageously obtain the titled compound useful as an intermediate of antibiotic, benzodiazepins, emimycin, etc., in high yield by subjecting novel alpha-2-furilnitrons to exchange reaction with a hydroxylamine salt or to acid hydrolysis. CONSTITUTION:A novel substance expressed by formula I (R1 and R2 are H, lower alkyl or aryl; R<3> is OH, NH2 or lower alkoxy) is subjected to exchange reaction with a hydroxylamine salt or acid hydrolysis to provide the aimed compound expressed by formula II via a stable intermediate advantageously in industrial scale and high yield. The above-mentioned novel substance can be readily and selectively produced from furfural and hydroxylamine in one process and high yield and produced in high yield by condensation reaction of (Z)-furfuraldoxime expressed by formula III which is rich in stability with a alpha-halocarboxylic acid derivative expressed by formula IV (X is halogen) and the resultant product may be used as the above-mentioned raw material without isolation and purification.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing N-hydroxyamino acids.

Conventionally, as a method for synthesizing N-hydroxy amino acids and their derivatives, (E)-penzaldoxime is converted to its isomer (Z)-benzaldoxime, and this aldoxime is synthesized from α-halocarboxylic acid and its derivatives. α−
A known method is to synthesize phenylnitrone and then subject the nitrone to an exchange reaction with a hydroxylamine salt or to an acid hydrolysis reaction to obtain the desired product [
J,Org,Chem,,32,265 (+967)
;J,Org,Chem,,41,2092 (197
6)]. Although this method has a wide range of applicability and is widely used, it also has the following drawbacks. That is, in the first step, the highly hygroscopic and unstable hydrochloride of (Z)-benzaldoxime and the unstable (Z)-benzaldoxime must be isolated, and therefore a complicated and delicate process is required. [Reference J, Org, Cheml, 1 supra.

4.270 (1968), Z, Chem, 16°+
7 (1976)]. The use of compounds that inherently lack stability or in reactions makes it extremely difficult to handle large amounts of them, and therefore it cannot be said to be suitable as an industrial means.

As a result of various studies, the present inventors found that (Z)-furfuraldoxime can be easily produced from furfural and hydroxylamine in one step with high stability and also with the following general formula (
The condensation reaction with the α-halocarboxylic acid derivative represented by n) produces a novel α- represented by the following general formula (I) in high yield.
The target N-hydroxyamino acids represented by the following general formula (I) can be highly synthesized by providing 2-furylnitrones and then subjecting the condensation reaction product to an exchange reaction with a hydroxyamine salt or acid hydrolysis reaction. The present invention was completed by discovering that it can be produced with high yield.

That is, according to the present invention, general formula (I) HONH-C
-COR' (III)■ [In the formula, R1 and R2 are the same or different and represent a hydrogen atom, a lower alkyl group or an aryl group, R3 is a hydroxyl group,
N represents an amino group or a lower alkoxy group]
-Hydroxy amino acids are (Z)-furfuraldoxime and an α-halocarboxylic acid represented by the general formula % () [wherein, X is a halogen atom, and R', R2 and R3 are as defined above] A new α-2-furylnitrone represented by the general formula [wherein R1, R2 and R3 have the same meanings as above] is produced by condensation reaction with the derivative, and then this compound is subjected to an exchange reaction with a hydroxylamine salt. It can be produced by hydrolysis or acid hydrolysis.

Regarding the above general formulas (I), (II) and (1), R1
The lower alkyl group represented by butyl, tert-butyl, etc.), and the aryl group includes a phenyl group. Further, the lower alkoxy group represented by R3 has 1 to 4 carbon atoms and may be linear or branched.
alkoxy groups (e.g., methoxy, ethoxy, n-propoxy, 1so-propoxy, n-butoxy).

5ec-butoxy, tert-butoxy, etc.). Furthermore, regarding the general formula (II), examples of the halogen atom represented by X include chlorine, bromine, and iodine atoms.

Next, the raw material compound (Z)-furfuraldoxime and (n
) is preferably carried out in a suitable solvent in the presence of a deoxidizing agent. Examples of deoxidizers include alkali metal alkoxides (eg, potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide, etc.), and tertiary amines (eg, trimethylamine, triethylamine).

pyridine, etc.), alkali metal hydrides (eg, potassium hydride, sodium hydride, etc.), and these can be preferably used. The reaction proceeds suitably under cooling or heating. Examples of the reaction solvent include alcohol (eg, methanol).

ethanol, n-propertool, 1so-propertool, etc.), dimethylformamide, dioxane.

Any substance such as acetonitrile, benzene, toluene, etc. that does not interfere with this reaction can be suitably used.

Compound (1) thus produced is a novel compound that has not been described in any literature, and can be isolated and purified or subjected to the next reaction without being isolated and purified. That is, the acid hydrolysis reaction of compound (1) can be carried out using, for example, mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), organic acids (e.g., formic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.). ), a compound (■) in which R3 is a hydroxyl group is obtained (6).

This reaction proceeds suitably at room temperature or under heating. Further, as the reaction solvent, water, alcohol (eg, methanol, ethanol, etc.), organic acid (eg, formic acid, acetic acid, etc.), or a mixture of two or more thereof can be used as appropriate. In addition, the exchange reaction between compound (1) and hydroxylamine salt is
The process is suitably carried out under cooling or heating, preferably at room temperature. As the reaction solvent, water, alcohol (eg, methanol, ethanol, propatool, etc.), dimethylformamide, or a mixture of two or more thereof can be used as appropriate. Hydroxylamine salts used in this step include mineral acid salts (eg, hydrochloride).

sulfates, etc.), sulfonates (e.g., p-toluenesulfonate, methanesulfonate, etc.), and when monobasic acid salts are used among these salts, the compound (I
(Z)-furfuraldoxime is produced together with the salt of II), and this aldoxime has an industrial advantage in that it can be isolated and recovered in high yield and reused in the process of the present invention.

The target compound (III) or its salt thus produced can be treated by known processing means (e.g., filtration, concentration, extraction,
Easily isolated by appropriate use of methods (recrystallization, chromatography, pH adjustment, etc.).

Can be purified. Examples of the salt of compound (III) include acid addition salts corresponding to the hydroxylamine salt used in the reaction and alkali metal salts in the carboxyl group (e.g.
Examples include sodium salt, potassium salt), etc.

The N-hydroxyamino acids produced by the method described above are compounds useful as intermediates for the production of antibiotics, benzodiazepines, emimycin, etc. [B
iochemistry.

Vol.1. No. 2, 340 (1962); J, H
eterocyclic Chem,,Sat.

647 (1967); Reference Example 6].

71 By the method of the present invention, N-hydroquine amino acids can be produced industrially advantageously and in high yields via stable intermediates.

The present invention will be explained in more detail below using reference examples, examples, etc., but the scope of the present invention is not limited thereto.

Reference Example 1 A solution of sodium hydroxide (40 g) was added to an aqueous solution (250 m12) of furfural (96.1 g) and hydroxylamine hydrochloride (69 g) under water cooling while stirring.
0 mρ) was added dropwise over 2 hours.

After the dropwise addition was completed, the reaction solution was stirred for an additional hour. The precipitated crystals are collected by filtration and washed with cold water (300 mf2).

When this crystal is dried over phosphorus pentoxide, colorless needle-like (Z)-
Furfuraldoxime (101 g, 91%) is obtained. Honjima was used for the synthesis of the following nitrones.

Melting point: 89-91°C (recrystallized from ether-hexane) (
Literature value melting point 89℃, 91-92℃) Reference example 2゜ Sodium metal (4.6g) and methanol (100mf
Add (Z)-furfuraldoxime (12 g) and chloroacetic acid (9.5 g) to the alcoholade solution prepared from 2) and heat under reflux for 3 hours.

After cooling, the reaction solution was adjusted to pH 4 with a 10% hydrochloric acid-methanol solution. The reaction solution is heated to 50°C, and the precipitated sodium chloride is filtered off. When the filtrate is cooled, colorless needle-like α-(
2-furyl)-N-carboxymethylnitrone (10,
8 g, 64%) is obtained.

Melting point 177-180°C Elemental analysis value: C7H7NO.

Calculated value C49,'7L, H4,17, N L28
Actual value C49.93, H4.29, N 8.046.
63 (LH), 7.78 (If (), 10.7 (IH)
.

Reference example 3゜Metal sodium (0.7g) and ethanol (30mρ)
Add (Z)-furfuraldoxime (3.4 g) and α-bromophenyl acetic acid ethyl ester (7.2 g) to the alcoholade solution prepared from and stir at 40°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was extracted with dichloromethane. Dichloromethane is washed with water, dried over sodium sulfate, and then distilled off to obtain crude crystals. Recrystallization from ether gives colorless acicular α-(2-furyl)-N-ethoxycarbonyl(phenyl)methylnitrone (6, Ig,
74%) is obtained.

Melting point 95-96°C Elemental analysis values: C, 5H, 5NO.

Calculated value C65,92, H5,53, N 5.13 Actual value C65,92, H5,45, N 5.187.32
(II(), 6.5(1(1)1), 5.74(1)
1) 4.28 (2H), 1.27 (3H).

Reference example 4゜ Sodium metal (11.5g) and methanol (300m
(Z) ~ Furfuraldoxime (67 g) and chloroacetic acid amide (47 g
) and stir at 40'C for 2 hours. After the reaction is completed, the solution is heated to 55-60'C and the precipitated sodium chloride is filtered off. The filtrate was concentrated under reduced pressure to a volume of approximately 100 ml, and after cooling, the precipitated crystals were collected by filtration, yielding colorless needle-like α-(
2-furyl)-N-carbamoylmethylnitrone (71
4 g, 85%) is obtained.

Melting point 174-1.75°C (recrystallized from methanol) Elemental analysis value C7H,N,03 Calculated value C50,00, H4,80, N 16.66 Actual value C49,60, H4,56, N 16.467 ．．
32 (2H), 6.60 (IH), 4.57 (2H).

Reference example 5 The following compound is obtained in the same manner as in Reference Example 3.

=11-α-(2-furyl)-N-methoxycarbonylmethylnitrone, yield 77%, melting point 818C Elemental analysis value C8H
gNO4 Calculated value C52,46, H4,95, N 7.65 Actual value C52,55, H4,76, N 7.716.52
(IH), 4.67 (2H), 3.79 (3H).

α-(2-furyl)-N-ethoxycarbonyl(methyl)methylnitrone, yield 87%.

Melting point III - 112°C Elemental analysis value CIO813N O4 Calculated value C56,86, H6,20, N 6.63 Actual value C56,84, H6,14', N 6.606
．． 52 (IH), 4.70 (IH), 4.23 (2H)
1.25 (3H), 1.71 (3F ().

α-(2-furyl)-N-ethoxycarbonyl(dimethyl)methylnitrone: Yield 89%.

Melting point 59℃ Elemental analysis value CIIHr s N O4 calculation value C58
,65,H6,71,N 6.22 Actual value C58,7
4, H6,75, N 6.376.52 (IH), 4.
23 (2H), 1.78 (6H) 1.26 (3H) α-(2-furyl)-N-ethoxycarbonyl(ethyl)methylnitrone, yield 77%.

Melting point 72°C Elemental analysis value C+ IH,5N O4 Calculated value C58,65, H6,71,, N 6.22 Actual value C5g,77, H6,79, N 6.286
．． 54 (iH), 4.45 (IH), 2.6-1.9 (
28), 1.27 (3H), 1.0O (3+1).

Example 1 Hydroxylamine hydrochloride (0°69 g) was added to a methanol solution (50 mρ) of α-(2-furyl)-N-methoxycarbonylmethylnitrone (1.83 g), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was thoroughly washed with ether three times (30 mσ each time) to remove (Z)-furfuraldoxime produced by the reaction. After drying the residue under reduced pressure, ether is added to crystallize. Reconsolidation from ether-methanol (100:1) gives colorless needles of N-hydroxyglycine methyl ester hydrochloride (1.34 g, 95%).

Melting point 90-91°C Elemental analysis value C3H, CσN 03 Calculated value C25,45, H5,70, N 9°90 Actual value C25,46,')l 5.90, N 9.9
3 (2H).

Example 2 A methanol solution of α-(2-furyl)-N-ethoxycarbonyl(phenyl)methylnitrone (2,73 g) (
Hydroxylamine hydrochloride (0.69g
) and stir at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue three times (30 ml each).
The washed crude crystals were collected by filtration and recrystallized from methanol to obtain colorless needle-shaped N-hydroxyphenylglycine ethyl ester hydrochloride (2.18 g, 94%).

Melting point 135-137°C Elemental analysis value C1,H,4CQNO3 Calculated value C51,84, H6,09, N 6.05 Actual value C51,76, H6,11, N 621 (LH),
4.20 (2H), 1.16 (3H).

Example 3 Hydroxylamine hydrochloride (35 g) is added to a methanol solution (300 mσ) of α-(2-furyl)-N-carbamoylmethylnitrone (84 g), and the mixture is stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with ether (
300 mρ) and filter the precipitated crystals. Drying over phosphorus pentoxide gives colorless columnar N-hydroxyglycinamide hydrochloride (63 g, 99%).

Melting point 138-140°C Elemental analysis value C2H7CσN2O2 Calculated value CI8.98, H5.58, N 22.1
4 Actual measurement value C1g, 99, H5, 47; N22
．． 117.50 (LH), 3.86 (2H).

The above ether filtrate was concentrated under reduced pressure to obtain (Z)-furfuraldoxime (53 g).

Example 4 Hydroxylamine hydrochloride (35 g) was added to an aqueous solution (200 m) of α-(2-furyl)-N~carbamoylmethylnitrone (84 g), stirred at room temperature for 1 hour, and the reaction solution was cooled to 5°C. Stir for 30 minutes. Filter off the precipitated crystals of (Z)-furfuraldoxime (51 g), concentrate the filtrate under reduced pressure, and collect the precipitated crystals by filtration. When dried over phosphorus pentoxide, N-hydroxyglycinamide is obtained. The hydrochloride salt (62.5 g, 98%) is obtained.

Melting point 138-140°C Example 5 α-(2-furyl)-N-carboxymethylnitrone (
Add 1,69g) to concentrated hydrochloric acid (7mQ) and heat at 80-90℃.
Heat for 5 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow oil. Dissolve this oil in water (ImQ), adjust the pH to 5.5-6.0 with concentrated aqueous ammonia, and add ethanol (1 mf2). The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain colorless needle-shaped N-hydroxyglycine (0.66 g, 72%).

Melting point 138-139°C (literature value 139°C) Elemental analysis value C2H5NO3 Calculated value C2G, 38. H5,53, N 15.3g
Actual value C26,41, H5,49, N 15.27 Example 6 The following compound is obtained in the same manner as in Example 1.

N-hydroxyalanine ethyl ester hydrochloride: yield
93%, melting point oil elemental analysis value C”, Hl 2 CρNO3 calculated value C
35,41,H7,13,N 8.26 Actual value C35
,49,H7,21,N 8.13α-N-hydroxyamino-isobutyric acid ethyl ester hydrochloride: Yield 89%
, melting point 88-89°C Elemental analysis value Ca HI 4
CσNO3 calculated value C39, 24, H7, 69, N 7
．． 63 actual measurement value C39, 15, H7, 79, N 7.7
0α-N-Hydroxyamino-butyric acid ethyl ester hydrochloride: Yield 88%, melting point 61-62°C Elemental analysis CaH
+4CρNO3 Calculated value C39,24, H7,69, N 7.63 Actual value C39,29, H7,73, N 7.86 Example 7 The following compound is obtained in the same manner as in Example 5.

N-hydroxyalanine: yield 56%, melting point 147°
C (literature value 146-147°C) Elemental analysis value C, H?
NO3 Calculated value C34,28; H6,71,N 13.33
Actual value C34,47, H6,67, N 13.28α
-N-Hydroxyamino-isobutyric acid: Yield 66%, melting point 136-138°C Elemental analysis C4H11NO3 Calculated value C40,33; H7,62, N 11.76
Actual value C40, 27,)l 7. n; N 11.7
9α-N-Hydroxyamino-butyric acid・Yield 52%, melting point 126-129°C Elemental analysis value
C4Hs N O3 Calculated value C40,33,H7,62,N 11.76Actual value C40,50,H7,81,N 11.77N-
Hydroxyphenylglycine, yield 39%.

Melting point 131-1328C (literature value 133℃) Elemental analysis value C3H9NO3 Calculated value C57,48, Hs, 4a; N 8.3g Actual value C57,49, H5,52, N 8.22 Reference example 6 In nitrogen stream, 0 An aqueous solution (400 mi2) of N-hydroxyglycinamide hydrochloride (5.6 g) was stirred at °C.
) and add 20% glyoxal (17°6mρ).

Then add 5.5N sodium hydroxide (20ml) and stir for an additional 15 minutes. IN hydrochloric acid (50
m12) and immediately add an activated carbon column (3.5cm
28 cm). Deionized water (90m12)
Wash with a mixture of (methanol: water. 28% ammonia water)
Elute and fractionate with 25.24 l). Thin layer chromatography 20- Roughy (Merck & Co., Ltd. D C-Fertigplat)
Fractions showing a spot at RfO,3 are collected using Kiselgel 60 F-254 (developing solvent: ethyl acetate:methanol-2=1), and the solvent is distilled off at 40° C. or lower under reduced pressure. Ethanol was added to the residue, the solid matter was crushed, filtered, and dried to give a light brown powder of emimycin (4,4
8 g, 91%) is obtained.

Melting point: 245℃ (decomposed) (recrystallized from water) Elemental analysis value
C4H, N, 0°

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom, a lower alkyl group, or an aryl group, and R^3 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R ^1, R^2 and R^3 have the same meanings as above]
A method for producing a compound represented by