JPH0211580B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an improved method for producing N-hydroxyamino acids. Conventionally, the synthesis method for N-hydroxyamino acids and their derivatives involves converting (E)-benzaldoxime to its isomer (Z)-benzaldoxime, and combining this aldoxime with α-halocarboxylic acids and their derivatives. A known method is to synthesize α-phenylnitrone and then subject this 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 (1967); J.Org.Chem., 41 ,
2092 (1976)]. 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.Cham., 33 , 4270]
(1968), Z.Chem., 16 , 17 (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 a formula that can be easily obtained selectively and in high yield from furfural and hydroxylamine in one step.

(Z)-Furfuraldoxime of [Formula] is highly stable and can be expressed in high yield by condensation reaction with an α-halocarboxylic acid derivative represented by the following general formula (). provide novel α-2-furylnitrones and exchange react the condensation reaction product with a hydroxyamine salt;
Alternatively, the inventors have discovered that the desired N-hydroxyamino acids represented by the following general formula () can be produced in high yield by a method of acid hydrolysis reaction, and have completed the present invention. That is, according to the present invention, the general formula () [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, R ³
represents a hydroxyl group, an amino group or a lower alkoxy group]
(Z)-furfuraldoxime and general formula [In the formula, X is a halogen atom, R ¹ , R ² and R ³
is the same meaning as above] is subjected to a condensation reaction with an α-halocarboxylic acid derivative represented by the general formula Producing a novel α-2-furylnitrone represented by [wherein R ¹ , R ² and R ³ have the same meanings as above],
This compound can then be produced by exchange reaction with a hydroxylamine salt or by acid hydrolysis. Regarding the above general formulas (), () and (),
The lower alkyl group represented by R ¹ and R ² is
1 to 4 carbon atoms, which may be straight chain or branched
Examples of the aryl group include a phenyl group (eg, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, etc.). The lower alkoxy group represented by R ³ is a straight-chain or branched alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec -butoxy, tert-butoxy, etc.). Furthermore, regarding the general formula (), examples of the halogen atom represented by X include chlorine, bromine, and iodine atoms. Next, the reaction between the raw material compound (Z)-furfuraldoxime and () is preferably carried out in a suitable solvent in the presence of a deoxidizing agent. As a deoxidizing agent,
For example, alkali metal alkoxides (e.g., potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide, etc.), tertiary amines (e.g., trimethylamine, triethylamine, pyridine, etc.), alkali metal hydrides (e.g., potassium hydride, etc.) , sodium hydride, etc.), and these can be preferably used. The reaction proceeds suitably under cooling or heating. As the reaction solvent, any solvent that does not interfere with the reaction is preferably used, such as alcohol (e.g., methanol, ethanol, n-propanol, iso-propanol, etc.), dimethylformamide, dioxane, acetonitrile, benzene, toluene, etc. I can do it. The thus produced compound () 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,
Acid hydrolysis reaction of compound () can be carried out using, for example, mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), organic acids (e.g.,
By carrying out the reaction under conditions such as formic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.), a compound () in which R ³ is a hydroxyl group is obtained. 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. Further, the exchange reaction between the compound () and the hydroxylamine salt proceeds suitably under cooling or heating, preferably at room temperature.
As the reaction solvent, water, alcohol (eg, methanol, ethanol, propanol, etc.), dimethylformamide, or a mixture of two or more thereof can be used as appropriate. Hydroxylamine salts used in this step include mineral salts (e.g., hydrochloride, sulfate, etc.), sulfonates (e.g., p-toluenesulfonate, methanesulfonate, etc.), and these When a monobasic acid salt is used in the salt of compound (), (Z)-
Furfuraldoxime is produced, 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 () or its salt thus produced can be easily obtained by appropriately using known processing means (e.g., filtration, concentration, extraction, recrystallization, chromatography, pH adjustment, etc.). isolation,
Can be purified. Examples of the salt of the compound () include acid addition salts corresponding to the hydroxylamine salt used in the reaction and alkali metal salts (eg, sodium salts, potassium salts) at the carboxyl group moiety. N- manufactured by the method described above
Hydroxyamino acids are compounds useful as intermediates in the production of antibiotics, benzodiazepines, emimycin, etc. [Biochemistry, Vol. 1, No.
2, 340 (1962); J. Heterocyclic Chem., 4 ,
647 (1967); Reference Example 6]. By the method of the present invention, N-hydroxyamino 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 An aqueous solution (150 ml) of sodium hydroxide (40 g) is added dropwise to an aqueous solution (250 ml) of furfural (96.1 g) and hydroxylamine hydrochloride (69 g) under ice cooling and stirring over 2 hours. After the dropwise addition was completed, the reaction solution was stirred for an additional hour. Filter the precipitated crystals and wash with cold water (300 ml). Drying the crystals over phosphorus pentoxide gives colorless needles of (Z)-furfuraldoxime (101 g, 91%). This product was used in the synthesis of the following nitrones. Melting point 89-91℃ (recrystallized from ether-hexane)
(Literature value melting point 89℃, 91-92℃) Reference example 2 Metallic sodium (4.6g) and methanol (100℃)
ml) and alcoholate solution prepared from (Z)-
Furfuraldoxime (12 g) and chloroacetic acid (9.5 g) were added, and the mixture was heated under reflux for 3 hours. 10 after cooling
Adjust the reaction solution to PH4 with % 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℃ Elemental analysis value C ₇ H ₇ NO ₄ Calculated value C49.71; H4.17; N8.28 Actual value C49.93; H4.29; N8.04 IRν ^KBr _nax cm ^-1 : 1715, 1630 PMR δ ^CDCl3 _ppn : 8.05 (1H), 4.73 (2H), 7.58 (1H)
,
6.63 (1H), 7.78 (1H), 10.7 (1H). Reference example 3 Sodium metal (0.7g) and ethanol (30ml)
(Z)-furfuraldoxime (3.4 g) and α-bromophenyl acetic acid ethyl ester (7.2 g) were added to the alcoholate solution prepared from
Stir at °C. After cooling, the solvent was distilled off under reduced pressure.
The residue is 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 needles of α-(2-furyl)-N-(ethoxycarbonyl(phenyl)methylnitrone (6.1 g, 74%). Melting point: 95-96°C Elemental analysis: C ₁₅ H ₁₅ NO ₄ Calculated value C65.92; H5.53; N5.13 Actual value C65.92; H5.45; N5.18 IRν ^KBr _nax cm ^-1 : 1740, 1595 PMR δ ^CDCl3 _ppn : 7.78 (1H), 7.47 ( 5H), 7.42 (1H)
,
7.32 (1H), 6.50 (1H), 5.74 (1H), 4.28 (2H),
1.27 (3H). Reference example 4 Sodium metal (11.5g) and methanol (300g)
ml) and alcoholate solution prepared from (Z)-
Add 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. Approximately 100ml of filtrate under reduced pressure
After cooling, the precipitated crystals are collected by filtration to obtain colorless acicular α-(2-furyl)-N-carbamoylmethylnitrone (71.4 g, 85%). Melting point 174-175℃ (recrystallized from methanol) Elemental analysis value C ₇ H ₈ N ₂ O ₃ Calculated value C50.00; H4.80; N16.66 Actual value C49.60; H4.56; N16.46 IRν ^KBr _nax cm ^-1 : 1705, 1695, 1620 PMR δ ^CDCl3 _ppn : 8.00 (1H), 7.78 (1H), 7.57 (1H)
,
7.32 (2H), 6.60 (1H), 4.57 (2H). Reference Example 5 The following compound is obtained in the same manner as in Reference Example 3.
α-(2-furyl)-N-methoxycarbonylmethylnitrone: Yield 77%, melting point 81℃ Elemental analysis value C ₈ H ₉ NO ₄ Calculated value C52.46; H4.95; N7.65 Actual value C52.55 ;H4.76;N7.71 IRν ^KBr _nax cm ^-1 : 1740, 1605 PMR δ ^CDCl3 _ppn : 7.77 (1H), 7.60 (1H), 7.47 (1H)
,
6.52 (1H), 4.67 (2H), 3.79 (3H). α-(2-furyl)-N-ethoxycarbonyl(methyl)methylnitrone: Yield 87%, melting point 111-112℃ Elemental analysis value C ₁₀ H ₁₃ NO ₄ Calculated value C56.86; H6.20; N6.63 Actual value C56.84; H6.14; N6.60 IRν ^KBr _nax cm ^-1 : 1740, 1595 PMR δ ^CDCl3 _ppn : 7.77 (1H), 7.63 (1H), 7.47 (1H)
,
6.52 (1H), 4.70 (1H), 4.23 (2H) 1.25 (3H),
1.71 (3H). α-(2-furyl)-N-ethoxycarbonyl(dimethyl)methylnitrone: Yield 89%, melting point 59℃ Elemental analysis value C ₁₁ H ₁₅ NO ₄ Calculated value C58.65; H6.71; N6.22 Actual value C58.74; H6.75; N6.37 IRν ^KBr _nax cm ^-1 : 1735, 1590 PMR δ ^CDCl3 _ppn : 7.75 (1H), 7.67 (1H), 7.47 (1H)
,
6.52 (1H), 4.23 (2H), 1.78 (6H), 1.26 (3H) α-(2-furyl)-N-ethoxycarbonyl(ethyl)methylnitrone: Yield 77%, melting point 72℃ Elemental analysis value C ₁₁ H ₁₅ NO ₄ Calculated value C58.65; H6.71; N6.22 Actual value C58.77; H6.79; N6.28 IRν ^KBr _nax cm ^-1 : 1735, 1595 PMR δ ^CDCl3 _ppn : 7.82 (1H), 7.67 (1H), 7.50 (1H)
,
6.54 (1H), 4.45 (1H), 2.6~1.9 (2H), 1.27
(3H), 1.00 (3H). Example 1 A methanol solution (50 g) of α-(2-furyl)-N-methoxycarbonylmethylnitrone (1.83 g)
ml) and hydroxylamine hydrochloride (0.69 g) and 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 ml each) to remove (Z)-furfuraldoxime produced by the reaction. After drying the residue under reduced pressure, ether is added to crystallize. ether
Reconsolidation from methanol (100:1) gives colorless needles of N-hydroxyglycine methyl ester hydrochloride (1.34 g, 95%). Melting point 90-91℃ Elemental analysis value C ₃ H ₈ ClNO ₃ Calculated value C25.45; H5.70; N9.90 Actual value C25.46; H5.90; N9.93 IRν ^KBr _nax cm ^-1 : 3400-3100 , 1740 PMR δ ^CDCl3 _ppn : 7.1~6.7 (2H), 3.83 (3H), 3.76
(2H). Example 2 Hydroxylamine hydrochloride (0.69 g) was added to a methanol solution (30 ml) of α-(2-furyl)-N-ethoxycarbonyl(phenyl)methylnitrone (2.73 g), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue.
Washed twice (30 ml each), the crude crystals were collected by filtration and recrystallized from methanol to yield colorless needle-like N-hydroxyphenylglycine ethyl ester hydrochloride (2.18 g, 94%).
is obtained. Melting point 135-137℃ Elemental analysis value C ₁₀ H ₁₄ ClNO ₃ Calculated value C51.84; H6.09; N6.05 Actual value C51.76; H6.11; N6.21 IRν ^KBr _nax cm ^-1 : 3500-3100 , 1740 PMR δ ^DMSO-d6 _ppn : 10.4 (2H), 7.47 (5H), 5.28
(1H), 4.20 (2H), 1.16 (3H). Example 3 Hydroxylamine hydrochloride (35 g) was added to a methanol solution (300 ml) of α-(2-furyl)-N-carbamoylmethylnitrone (84 g), and the mixture was heated at room temperature.
Stir for 30 minutes. The solvent was distilled off under reduced pressure, ether (300 ml) was added to the residue, and the precipitated crystals were collected by filtration. Drying over phosphorus pentoxide yields a colorless columnar N-hydroxyglycinamide hydrochloride (63 g, 99
%) is obtained. Melting point 138-140℃ Elemental analysis value C ₂ H ₇ ClN ₂ O ₂ Calculated value C18.98; H5.58; N22.14 Actual value C18.99; H5.47; N22.11 IRν ^KBr _nax cm ^-1 : 3350 , 3200, 1690, 1680 PMR δ ^DMSO-d6 _ppn : 11.5-10.6 (2H), 8.02 (1H),
7.50 (1H), 3.86 (2H). When the above ether filtrate is concentrated under reduced pressure (Z)
-Furfuraldoxime (53 g) is obtained. Example 4 Hydroxylamine hydrochloride (35 g) was added to an aqueous solution (200 ml) of α-(2-furyl)-N-carbamoylmethylnitrone (84 g), stirred at room temperature for 1 hour, and the reaction solution was cooled to 5°C for further 30 min. Stir for a minute. The precipitated crystals of (Z)-furfuraldoxime (51 g) were filtered off, the filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. Drying over phosphorus pentoxide yields N-hydroxyglycinamide hydrochloride (62.5
g, 98%) is obtained. Melting point: 138-140°C Example 5 α-(2-furyl)-N-carboxymethylnitrone (1.69g) was added to concentrated hydrochloric acid (7ml),
Heat to ℃ for 5 minutes. The reaction solution was concentrated under reduced pressure to obtain a pale yellow oil. Dissolve this oil in water (1 ml), adjust the pH to 5.6-6.0 with concentrated aqueous ammonia, and add ethanol (1 ml). The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain colorless needle-like N-hydroxyglycine (0.66 g, 72%). Melting point 138-139°C (literature value 139°C). Elemental analysis value C ₂ H ₅ NO ₃ Calculated value C26.38; H5.53; N15.38 Actual value C26.41; H5.49; N15.27 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 ₅ H ₁₂ ClNO ₃ Calculated value C35.41; H7.13; N8.26 Actual value C35.49; H7.21; N8.13 α-N-hydroxyamino-iso Butyric acid ethyl ester hydrochloride: Yield 89%, melting point 88-89℃ Elemental analysis value C ₆ H ₁₄ ClNO ₃ Calculated value C39.24; H7.69; N7.63 Actual value C39.15; H7.79; N7. 70 α-N-Hydroxyamino-butyric acid ethyl ester hydrochloride: Yield 88%, melting point 61-62℃ Elemental analysis value C ₆ H ₁₄ ClNO ₃ Calculated value C39.24; H7.69; N7.63 Actual value C39. 29; H7.73; N7.86 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℃) Elemental analysis value C ₃ H ₇ NO ₃ Calculated value C34.28; H6.71; N13.33 Actual value C34.47; H6.67; N13.28 α-N-Hydroxyamino- Isobutyric acid: yield 66
%, melting point 136-138℃ Elemental analysis value C ₄ H ₉ NO ₃ Calculated value C40.33; H7.62; N11.76 Actual value C40.27; H7.71; N11.79 α-N-Hydroxyamino-butyric acid : Yield 52%, melting point 126-129℃ Elemental analysis value C ₄ H ₉ NO ₃ Calculated value C40.33; H7.62; N11.76 Actual value C40.50; H7.81; N11.77 N-Hydroxyph Enylglycine: yield 39%,
Melting point 131-132℃ (Literature value 133℃) Elemental analysis value C ₈ H ₉ NO ₃ Calculated value C57.48; H5.43; N8.38 Actual value C57.49; H5.52; N8.22 Reference example 6 Nitrogen Add 20% glyoxal (17.6 ml) to an aqueous solution (400 ml) of N-hydroxyglycinamide hydrochloride (5.6 g) with stirring at 0° C. in a stream of air. Then add 5.5N sodium hydroxide (20ml) and stir for an additional 15 minutes. Immediately add 1N hydrochloric acid (50 ml) to the reaction solution and transfer to an activated carbon column (3.5 cm).
x 28cm). Wash with deionized water (90 ml) and mix (methanol: water: 28% ammonia water =
25:24:1) and fractionate. Thin layer chromatography (Merck DC-Fertigplatten)
Fractions showing a spot at Rf0.3 are collected using Kiselgel 60F-254 (developing solvent: ethyl acetate:methanol = 2:1), and the solvent is distilled off at 40°C or lower under reduced pressure.
Ethanol is added to the residue, the solid is crushed, filtered, and dried to form a pale brown powder of emimycin (4.48
g, 91%) is obtained. Melting point 245℃ (decomposed) (recrystallized from water) Elemental analysis value C ₄ H ₄ N ₂ O ₂ Calculated value C42.86; H3.60; N24.99 Actual value C42.86; H3.53; N24.89

Claims (1)

[Claims] 1. General formula [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, R ³
represents a hydroxyl group, an amino group or a lower alkoxy group] with a hydroxylamine salt. A method for producing a compound represented by the formula [wherein R ¹ , R ² and R ³ have the same meanings as above]. 2 General formula [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, R ³
represents a hydroxyl group, an amino group or a lower alkoxy group] A general formula characterized by acid hydrolysis of a compound represented by A method for producing a compound represented by the formula [wherein R ¹ , R ² and R ³ have the same meanings as above].