SU612624A3 - Method of obtaining derivatives of amides of a-aminooxycarboxylic acids - Google Patents

Description

This invention relates to organic chemistry. A method is proposed for the preparation of derivatives of amC aC -agdine hydroxycarboxylic acids having anti-tuberculosis activity. A known method is to obtain amct derivatives of .ct-aminooxycarboxylic acids of the general formula A-HH-O-CHR-CO-NH-Z where A is hydrogen or acyl; C is hydrogen, alkyl or aryl; Z is alkyl, aryl or heterocyclic; and a radical that has tuberculostatic activity, consisting in the determination of amine formulas, where Z has the indicated values of amino-hydroxycarboxylic acid. .A-NH-0-CHR-COOH where A and R have the indicated meanings. Acylirovaks are carried out in dioxane at room temperature p, however, the activity of the compounds obtained by this method is low and amounts to 1 T / ml. The aim of the invention is to obtain derivatives of amides of oL-kyninooxy carboxylic acids, which have a higher anti-tuberculosis activity, in particular, an activity of 0.01-0.1 u / ml ... ... The proposed method of obtaining .prog derived amides of α-aminooxy-carboxylic acids of general formula 1 Y Х к - о - СЯ1 - С-N 1 «-R О« where X is an alkylidene or iaalko-alidene radical with 1-6 carbon atoms, which may be a phenyl residue or a phenyl residue substituted by one or more alkoxycarbonyl radicals with 1-3 carbon atoms a, with one or several chlorine atoms, hydroxy, hy-4H, n-, alkylamino groups with 1–4 carbon atoms, nitro and / or methoxy groups, furyl or nitrofuryl residue li — hydrogen, benzyl, dihydrogen or alkyl with 1–4 carbon atoms ; - hydrogen or alkvl with 1-4 atom.mi carbon; If - cyclohexyl, phenyl or feiyl, single or multiply substituted chloro

rum and / or methoxy groups. is that amide derivative xi. α-amino oxycarboxylic acid of formula 2

x

NgK-o-ns-tch,

R

BUT

where J, -R

and V have the indicated values,

or its salt is reacted with an oxo compound of general formula 3

X o

where X has the indicated values, in an aqueous medium or in an organic solvent medium or a mixture thereof at a temperature from to the boiling point of the solvent. Usually, dimethylformamide or pyridine is used as the organic solvent.

Preferred compounds are N-methyl-N -tsiklogeksilamid W- (5 -nitrofurfurilyden) aminooxyacetic acid, N - (2-metoksianilid) N- (5-nitrofurfuriliden) aminooxyacetic acid, N -tsiklogeksilamid N- (5-nitrofurfuriliden ) aminooxyacetic acid, -N- (2,4-dimethoxy-5-chloroanilide) N- {5-nitrofurfurylidene) - B - with (.- aminooxypropionic acid, N-cyclohexyl amide N- (benzal) aminooxyacetic acid, N-methyl N- (4-Itrobenzal) aminooxyacetic acid N-cyclohexylamide, N- (4-methylbenzyl) amide, N- (5-nitrofurfurylidene) aminooxyacetic acid you and - (4-fluoroanilide) N- {5-nirofurfurylidene) aminooxyacetic acid.

The proposed compounds have valuable pharmacological action. They are excellent anti-tuberculosis medications that are effective against various microbial strains. The most valuable representative of this group of compounds is N-methyl-N-cyclohexylamide N - {5-nitrofurfurylidene) aminooxyacetic acid.

A distinctive feature of the process is the use of compounds of formula 2. And 3 as starting materials, and the process is also carried out in an aqueous medium or in an organic solvent, dimethylformamide or pyridine, at-temperature, usually from the boiling point of the solvent.

 . The compounds obtained by the proposed method can be isolated and purified by conventional methods.

As the starting material, an optically active compound can be used.

The reaction is carried out mainly in the presence of inorganic acid acceptors or organic bases, in particular in the presence of tertiary ones. akinov.

four

The reaction is carried out mainly in an aqueous medium or in a mixture of organic solvent and water. Preferably, the reaction is carried out at a temperature ranging from reflux temperature to a solvent.

The salt of the amide derivative of o-aminooxycarboxylic acid of formula 2, predominantly a hydrohalide, is neutralized in an aqueous solution with an equivalent amount of an inorganic acid or organic acceptor. bases and then reacted with an oxo compound of formula 3 dissolved in a solvent miscible with water, preferably methanol, at -50 ° C, expediently at room temperature for 30 minutes to 24 hours, preferably 1-2 hours .

It is also possible to carry out the reaction between the amide derivative of the oC of the amino-carboxylic acid of the formula-2 or it. salts and the corresponding oxo compound of formula 3 in an organic solvent, mainly in pyridine, either in an aqueous medium or in a mixture of organic solvent and water at room temperature or at an elevated temperature, preferably at the boiling point of the solvent. In the Presence of an inorganic base: NIN or tertiary amine for from 3Q minutes to 24.hours, preferably within 1-2 hours If necessary, the precipitated salt is filtered off. The product is isolated by extraction, crystallization, or piping.

The value of T is determined by Shtahl on kieselgel G, in mobile quality; the phases are n-hexane: acetic acid (ice): chloroform in a ratio of 1: 1: 8, melting point on a Tottoli device.

Example I. t - {2-Methoxy-; anilide.) M-p-amino- - (methyl) 1 benzalvamooxyacetic acid.

2.32 g (0.010 mol) of 2-methoxy-anilide hydrochloride of aminooxy-acetic acid is dissolved in 15 cm of dimethylformamide, and 1.3 9 - cm (0.010 mol) of triethylamine are added to the solution, then 1.49 g (0.011 mol) t -aminoacetophenone. The reaction mixture was allowed to stand at room temperature. temperature for 16 hours. The triethnic amine hydrochloride is filtered off, the filtrate is evaporated under reduced pressure, and the residue is recrystallized from ethanol. Get 2,12 g (60% of theoretical) M- {2-methoxyanil .tsa) N- {h -amyne p-l- (methyl) 1 benzal aminooxyacetic acid-. lots, so pl. 114-116 C, 0.52. ,

Found,%: C 65.0; H 6.2; Ts13.2.

with „, OJ.N ... . .

Claims (2)

. Calculated,%: C 65.2; .N 6,1: N13, P p and measures 2. N - (- methoxyanilide) N - {P-hydroxybenzal) aminodasiacetic acid. : The compound is prepared according to the method described in Example 1. The yield is 78% of the theoretical. The product recrystallized from ethanol is m.p. 135-137 C, T 0.50. Found,%: C 63.3; H 5.5; N9.3. Calculated,%: C 64.0; H 5.4; N 9.3. Example 3, N-anilide N - (fur-furylidene) aminooxyacetic acid. The yield of the compound is 81% of the theoretical, so pl. after recrystallization from ethanol, 105-107 ° C, R 0.68. Found,%: C 56, G; H 5.7; M 8,6 iS ie e Z Calculated,%: C 56,0; H 5.6; .N8.7 Example 4. N - (2-Methoxyanilide) (5-nitrofurfurylidene) aminoacetic acid. Compound yield 84% of theoretical, after recrystallization from ethanol m.p. 115-116C, K 0.69. Found,%: C 52.6; H 4.1; N13.2 14 -1 ° b 3 Calculated,%: C 52.7; H 4.1; N13 Example 5. N-Anilide N-tl, 3- (dimethoxycarbonyl) isopropylidene Zoamine nooxyacetic acid. Compound yield 72% of theoretical, after recrystallization from ethanol m.p. 49-50 with 0.78. Found,%: C 56.1; H 5.7; N8.8 18 Calculated,%: C 56.0; H 5.6; N8, P. p. And Mer. 6. N-Anilide N- {2,5- (dimethoxy) benzal aminoacetic acid. Compound yield 65% of theory / after recrystallization from ethyl acetate. m.p. 84-86С, I | 0.65; Found: C, 67.4; H 6.5; N 9.0 20 4 2 Calculated,%: C 67.5; H 6.3; N8.7. Example 7. K - (2,4-Dimeterxy-5-chloroanilide) N- (5-nitrofurfurylidene) -J5 - cL-aminooxypropionic acid. 0.51 g (0.0016 mol) 2,4-dimetok si-5-chloroanilide 11 - c-aminooxypropionic acid and 0.14 g (0.0016 mol) of sodium acetate are dissolved in 3.0 cm of water and mixed with 0.23 g (0.0016 mol) 5-nitrofurfuryl 4.0 cm methanol. The reaction mixture is stirred or shaken for 2 hours at room temperature. Then the product is precipitated by adding 4.0 cm of water, filtered off and recrystallized from ethanol. 0.55 g (85% of theoretical) -2,4-dimethoxy-5-chloroanilide N - (5-nitrofurfurylidene) - D is obtained. α-hydroxypropionic acid, m.p. 150-152 ° C, Rf 0.60, LcCl2 5 +216 (s 1, dimethylformamide). Found,%: C 48.4; H 4.0; K 8,7 16 ъ Calculated,%: C 48.4; H 4.0; N8, Example 8. N-Methyl-N-cyclohexylamide N- (5-nitrofurfurylidene) aminooxyacetic acid. Compound yield 89% of theoretical after recrystallization from ethyl acetate m.p. 133-134 C, Tl 0.70; Found,%: C 54.3; H 6.5; N13.4. Calculated,% s C 54.2; H 6.5; W 13.5. , Example 9. N - (4-Chloranilide) .N - (5-nitrofurfurylidene) -3) -oL-oU "tHHOxypropionic acid. Compound yield 63% of theoretical, after recrystallization from ethanol m.p. 175-176 C, Rj 0.52. Found,% C 49.5; H 3.8; N12.5. Ci + HijOjNjCe Calculated,%: C 49.7; H 3.6; N12.4; Example 10. N-Anilide N- (5-nitrofurfurylidene) - 35 - oL-aminooxyphenylpropyric acid. The yield of the compound is 71% of the theoretical, after recrystallization from ethanol, m.p. 130-133 C, T | 0.74, + 109 ° (s 1, dimethylformamide). Found,%: C 63.4; H.4,7; N 11.2. S J Calculated,%: C 63.3; H 4.5; N11.1. Example 11. N-Cyclohexylamide M- (isopropylidene) aminooxyacetic acid. Compound yield 87% of 4ecKorOj theoret after recrystallization from ethanol, m.p. 63-64 ° C; T: 0.75. Found,%: C 62.2; H 9.2; N13.3. 2 Calculated,%: C, 62.4; H 9.4; N 13.4. Example 12. N-Cyclohexylamine N- (benzal) aminooxyacetic acid. The yield of the compound is 91% of the theoretical, after recrystallization from ethanol m.p. 88-90 0, T. 0.79. Found,%: C 69.2; H 7.6; N10.7. C “Calculated,%: C n 7.7; N10.8. Example 13. N-Methyl-N-cyclohexylamide n- (4-nitrobenzal) aminooxyacetic acid. Compound yield 77% of theory, after recrystallization from ethyl acetate m.p. 99-100C, 0.66. Found,%: C 59.9; H 6.5; N 13.3. - d c Calculated,%: C60,2; H 6.6; N13.2. Example 14. N-11iklogeksilamid - (5-nitrofurfurylidene) aminooxyacetic acid. Compound yield 93% of theoretical, after recrystallization from ethyl acetate m.p. 126-127s, R | 0.50. Found,%: C 52.5; H 6.1; N 14.0. C „H, O From Calculated,%: C 52.7; H 6.1; N14.2. Psimer 15. N-Cyclohexylamide N - (4-nitrobenzal) aminooxyacetic acid. Compound yield 78% of theoretical, after recrystallization from ethanol m.p. 92-94 with Rt 0.54. “Found,%: C 58.8; n 6.3; N13,7 C | jH ,, 04Нз. Calculated,%: C.59.0; H 6.2; N13 Example 16. N- (2-Methoxyanide) N- (2-chlorobenzal) aminooxyacetic acid, g (0.005 mol) of aminooxyacetic acid 2-methoxyanilide hydrochloride, dissolved in 20 cm of water. 0.70 g {0.005 mol of 2-chlorobenzaldehyde and 0.70 cm (0.005 mol) of triethylamine are added to the solution. The reaction mixture is boiled for 20 minutes. The raw product, precipitated from solution upon cooling, is filtered off, dried and recrystallized from ethanol. Obtain 1.10 g (69% of theoretical 2-methoxyanilide N- (2-chloro benzal) aminooxyacetic acid, mp. 84-85 C H 0.80. Naidenb,%: C 60.0; H 4.8 ; N 11.0 C "H.jO, Vyisleno,%: C 60.2; H 4.8; N11 Ex. Immer. 17. N - (2-Methoxy-anide) N - (4-nitrobenzal) aminooxyacetic acid. Compound yield 86% of theoretically after recrystallization from ethyl acetate: mp 128-130 ° C R 0.73 Found:% C 58.5; - H 4.7; N12, C, bN.5-0 , Hz Calculated,%: C 58.4; H 4.6; N 12.7. Example 18. N- (2-Methoxyanide) N (2-hydroxybenzal) aminooxyacetic acid. Compound yield 88% of theoretical, after recrystallization from ethyl cetata m.p. 98-100 ° C K 0.75. Found,% s с64, 1; H 5, 7; M9.4. C, eH ,, O.N2 Calculated. С 64.0; H 5 , 4; L9.3 Example 19. N - (2-Methoxyanilide) N - (4-dimethylaminobenzal) aminooxyacetic acid. The yield of the compound is 73% of theoretical, after recrystallization from ethyl acetate, mp 78--80 ° C, R, 0.54% Found: C 65.9; H 6.4; N12.6 C, 9 Calculated,%: C 66.1; H 6.4; N12, Example 20. N - (2-Methoxyamide) N - (3-nitrobenzal) aminoacetic acid. Compound yield 79% of theoretical, after recrystallization from ethyl acetate, m.p. 117-118 ° C, R 0.78 found,%: C 58.6; H 4.7; N12.4 Oj N, Vchisleno,%: C 58,5; H 4.6; N12 Example 21. N - (2-Methoxian lead) N - {l, 3- (dimethyl) -but 1-ylidene aminooxyacetic acid .. 2.32 g (O-, 010 mol) 2-methoxy-onean hydrochloride a, mono-acetic acid is dissolved in 15 cm of pyridine, and 2.0 g (0.010 mol) of methyl isobutyl ketone and 1.39 cm (0.0.10 mol) of triethylamine are added to the solution. . The reaction mixture is boiled for 1 hour and then the solvent is distilled off under reduced pressure. From the residue, the product is isolated by fractional distillation under reduced pressure. Obtain 1.72 g (62% of theoretical) of N- (2-methoxyanilide), 3- (dimethyl) -but-1-yliden aminooxyacetic acid, so pl. 198 ° C / 5 mmHg, RI 0.81. Found,%: C 64.8; H 7.9; N10.0. C yHjjOjNj Calculated,%: C 64.7; H 7.9 N 10.1. Example 22. N- (2-Methoxyanilide) N-l- (methyl-2,2- (dimethyl) et-1-ylidene-aminboxyacetic acid). Yield of the compound is 61% of theoretical, bp mm Hg, I {0.83. Found,%: G 63.7; H 7.8; N10.4 ... Calculated,%: C 63.6; H 7.6; N10.6, Example 23. N - (2-Methoxyanilide) N- {p-amino-i- (methyl) benzal aminooxyacetic acid (compound from example 1) Yield 67%, tons, mp li4-116 ° C. Claim 1. The method of producing amide derivatives of ct -aminoxycarbonic acids of the general formula -O -OH - C - I II .R O where X is alkylidene or isoalkyl; a new radical with 1-6 carbon atoms which may be substituted with a phenyl residue or a phenyl residue substituted with one or several alkoxycarbonyl1 and radicals with 1-3 carbon atoms, one m or several chlorine atoms, gi ;; roxy, amino, alkylamino groups with 1-4 carbon atoms, the cyto and., and. and. and the methoxy group, furyl nitrofuryl residue; and - hydrogen, benzyl radical or alkyl with 1-4 carbon atoms; P is hydrogen or alkyl with 1-4 carbon atoms; (- cyclohexyl, phenyl or phenyl, once or repeatedly, substituted by chlorine and / or methoxy groups, characterized in that 61 9 amide derivative of l-aminooxycarboxylic acid of the general formula xY NgK-O - cn-C-TsF. I 11 -R where "," L ", .. y" a., K.e values, or its salt is introduced into reaction with oxosoediacia of the general formula X.0 where X has the indicated values, in an aqueous medium or in an organic medium solvent or mixtures thereof at temperatures ranging from the boiling point of the solvent. 2. The method according to A.1. methylformamide or pyridine. . Sources of information taken into account in the examination: UK Patent 1329590, cl. C 07 C 103/30, 12.09.73.