JPS5946244A - Hydroxamic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A hydroxamic acid derivative shown by the formula I (A is RXm; R is phenyl, pyrrolyl, thienyl, imidazolyl, or thiazolyl; X is halogen, lower alkyl, lower alkoxy, or nitro; m is 0-2; mX are the same or different; B is CHOH, CH, -O-, or -CO-; n is 2-10). EXAMPLE:7-(4-Dimethylaminophenyl)-7-oxoheptanohydroxamic acid. USE:Useful as an antiprotozoal agent, e.g., an antitrichomonal agent, or an intermediate for the antiprotozoal agents. PROCESS:A hydroxyamine salt is treated with an alkali in an organic solvent such as ethanol, etc., reacted with a carboxylic ester shown by the formula II(R<1> is lower alkyl), to give a compound shown by the formula I . The hydroxyamine salt used is preferably hydrochloride, and preferably the amount of it used is 1-3 equivalents based on the compound shown by the formula I , and the amount of the alkali used is 2-6 equivalents.

Description

Detailed Description of the Invention The present invention is based on the general formula [1] AB (CH2)n C0NHOH(IL [wherein,
A stands for RXm. R represents a phenyl group, pyrrolyl μ, chenyl group, imigzolyl group, or thiazolyl group;
This shows two characters, rr1 x (J can be the same ψ or different), B is -CHOH-, -CH-, -0-
and -〇〇-, and nlj: at of 2 to 10 is shown. ] The present invention relates to a hydroxamic acid derivative represented by C and a method for producing oil thereof.

According to the present invention, hydro+, Z, represented by general formula (1)
The b u derivative has the general formula [2] AB (CHJL)n C0OR['2] [wherein A represents RXm, and R represents a phenyl group, a pyrrolyl group, a chenyl group, an imidazolyl group, and a thiazolyl group,
X is a halogen atom.

It represents a lower alkyl group, a lower alkoxy group and a nitro group, 1m represents 0.1 or 2, and 5m X's can be the same or different. ), B is -CHOH-, -CH-
, -0- and -〇〇-, n represents an integer from 2 to 10, and R represents a lower alkyl group. υ
By doing so, fM can be produced.

More specifically, the hydroxyamine salt is digested with an alkali in an aqueous solution, then the carboxylic acid ester represented by the general formula [2] is added, and the reaction is carried out at room temperature for 30 minutes to 3 days under stirring at Vd. let One example of the salt of hydroxyamine is hydrochloride, and the organic solvent is not particularly limited, but lower alcohols such as ethanol are preferable, and the alkali is metal alkali such as potassium hydroxide, sodium hydroxide,・Rium methylate etc. are fine. The amount of H1'roxyam/hydrochloride used is 1 to 3 times as much as the carboxylic ester, and the - of the alkali is 2 to 6 times the amount of the carboxylic ester.
Double weight is preferable. After the completion of the reaction, to isolate the desired hydroxam U derivative, remove the by-products and inorganic substances, remove the solvent by distillation, add cold water, and dilute with diluted hydrochloric acid while stirring to pH 4 to 4.5. The target compound can be easily obtained by extracting it with a common organic solvent such as ethyl acetate, chloroform, or methylene chloride, or by breaking it apart if 1^n precipitates. The hydroxano, 6a derivative, which is a compound of the present invention, is prepared under strongly acidic conditions.
Since it is unstable under heating conditions, the reaction and post-treatment are preferably carried out at a temperature of 10° C. or lower i' and a pH of 4 or higher.

The hydroxamic acid derivative represented by the general formula [1] of the present invention can be used as an antiprotozoal agent 1, such as an anti-trichomoniacal agent, or as an intermediate for an antiprotozoal agent.

The compounds shown in Table 1 may be mentioned as the HI' a + samic acid salt conductors according to the present invention, but the present invention is not limited thereto.

""-Table 12: AB CCFIU)'n C0NHOHt,:
Oite A B
n phenyl
Co24-chlorophenyl
43-Bromophenyl
63-Me1xyphenyl 42-ethylphenyl 53-nitrophinyl 72.4-
Dichlorophenyl 52
．． 4-dimethoxinyl
52-chenyl
62-(5-chloronaeninori)
4A
B2-(5-methylchenyl)
CO52-(5-ethylchenyl)
72-(5-methylpyrrolyl) 55-imidazolyl
85-(2-ethyl imidazolyl) 57
enyl C, HOI (2 +0 4-chlorophenyl
44-Bromophenyl
64-fluorophenyl
5A
B5-71xophenyl
CHOH44-methylphenyl
54-methylphenyl
63-210 phenyl 1?4-dimethylaminophenyl 53.4-
Dichlorophenyl 44-
Chloro-2-methylphenyl 3
4-chloro-2,-bi-phenyl
52-chenyl
8”2-(5-chlorophenyl)
42-(5-methylchenyl)
52-pyrrolyl
71-pyrrolyl
52-(5-methylpyrrolyl) 55-
Imidazolyl 8
5-(2-methylimidazolyl)
5A
B5-(2-chloroimidazolyl)
CHOH65-(2-nitroimidazolyl)
5 phenyl
02 phenyl
3-chlorophenyl
52-Bromophenyl
43-Me)quinphenyl 74-Me)xyphenol 63.4-Dichlorophenyl 32.
4-dimethoxyphenyl
54-chloro-2-methylphenyl
64- (2-methyl-5-nitroimidazolyl) 55-(2-methylimidazolyl)
3A
B n phenyl
C11,24-chlorophenyl
44F Nitrophenyl
54-1-xyphenyl 94-dimethylamino-2-enyl 82.4-dichlorophenyl 42-(
5-methylchenyl) 4
2-chenyl
72-(5-ethylchenyl)
41-pyrrolyl
5l-(5-methylpyrrolyl)
42-(1-methylpyrrolyl) 6l-(2-methyl-
5-di-a-phenyl) 21-(2
-methylimidazolyl) 41
-imidazolyl
71 [1] Next, the compound of the present invention will be explained in more detail with reference to Examples, but: 4: The invention is not limited thereto.

Example 1 7-(4-dimethylaminophenyl)-7-'A+soheptanohydroxam 6a-T-9/
- Suspend 1.3 g of hydroamine jlf salt in Q rn I, stir vigorously at 3-5°C under nitrogen, and add 10.48 g of chlorine menal.
child. After stirring for 1 hour, 0.43 g of 7-(4-dimethylaminophenyl)-7-oxhebutanoic acid was added, and the mixture was stirred in room IB for 2 hours. Next, most of the ethanol is distilled off and then ethyl acetate is added.

30m of cold water each! Add them one by one and stir vigorously. The organic layer was removed, and the aqueous layer was adjusted to pH 4-ν4°5 with dilute hydrochloric acid, which turned cloudy. To the cloudy mixture, 50 ml of ethyl acetate was added and stirred vigorously. After drying the 4afm with anhydrous 4R potassium acid, the solvent was distilled off and dried to obtain 150 mg of a sticky eel liquid.

NMR (CDC13); δ 1jO (In, 611), 2.20 (
t, 2N) 2.97 (t, 211)
, 2. [i9 (s, 611)? , Q5.
7.3[+ (dcl 4+1)7.65 (
broad s 2tl)I R(neat);
3220+1655 cIn-'Hair Mass; m/z 2? [] (8M) In the same manner as in Example 1, the Hero + Sim derivatives of Examples 2 to 16 were added to fH7.

Large 1 Milk λ ■-Phenyl-7-1xohebbutanohydrochitum Acid Brown sticky fluid IR (neat); 16B5.1645 cm
-'Mass;rn/z 235 (M)17
5 (M-CONIION) Example 3 6-(4-chlorophenyl)-6-hydroxydenananohydrochilim white-resistant crystal, mpH 8-119°C? =JMR(DMSO-da); δ1.3
0 (m, 6N), 1.83 (t, 2H
)331 (broad s 2N) 4.40
(t, 111)7.29 (s, 4H
) I R(1(Br disk); 335
+1655 cm-'-harmful example'-5-phenyl-5-hyroxyphenylvalerohi+fi akizam GL & white crystal,
m p 57-59°C NMR (in DMSO-d): δ 1.115 <m, 4H), 3.20
(broad s 21) 4.4[1(t , ltl
), 7.20 (s, 511)I R(K
Br disk); 3450.2830.161
5cm-'Mass; m/z 209 (
6-phenyl-6-hydroxyhexanohydroxamic acid reddish brown viscosity P fluid NMR (DMSO-cls); δ 1.47 <m, 6H), 1.85 (t
, 2H) 3.42 (broa+:Is 211)
4.38 (t, 1N)? ,IO(S
, 511) I R (neat); 32511
．． 1640 cm-'Mass; m/z 223
(M+) 6't 1% 7-phenyl-6-hydroxyheptanohydroxa 1. Acid white crystal mp 95~96℃ NMR (cnc+3); δ 1.40~1.95 (In, 811.) 2.24
(t, 211) 4.7B (t, III)
7.41 (S,5N)IR(KBrd
isk) ; 3200,1625 cIn-'M
a s s; m/z 23704”) Separate W-
Example 8-phenyl-8-hydroxyoctanohydroxa 11 acid white crystals rnp 66-67°C NMR (DMSO-da); δ1.30
(m, 1011) 2.05 (t, 2N)4
．． 55 (t, ill) 7.25 (S,
511) I R (KBr disk): 324
11,1682 cm-'Mass; rn/
z 251 (M”) Example day 10-phenyl-10-hydroxydecanohyraxamic acid flame yellow I night NMR (DMSO-d(); δ 1.27 (m, 12H) 2.0 (t,
2H) 4.52 (t, 2fl) 7.26
(s-,511)IR(neat); 324
5,16436m-1M ass; rn/z
279 (H+) 111- 7-(4-methoxyphenyl)-7 monohydro-a-oxyheptanohydroxam I flame brown liquid NMR'(CDCIJ); δ1j7 (+
n, EIH) 3.73 (s, 3H) 4.52
(t, IH) 6. Bro,? , 23
(dd 4N)IR(neat); 34
50,1645 cm-'Mass; m/z
253 (M”) Cold Example 10 7-(4-dimethylaminophenyl)-7-hydroxyheptanohydroxamic acid brown liquid NMR (H9O-d, ), δ1.46
(Ill, 6ft) 2.63 (s, [i
ll ) 4.8? (t, 11+)
7.20 (broad s 4N) I
R(neat); 3200,1640 cm
-'M a s s ; m/ z
293 (N”) Example 11 6-(3-methoxyphenyl)-6-hydroxyhexanohydroxalic acid brown layer NMR (DNSO-dd); δ 3.75 (u+, 3tl) 4.78 1r
oads 2H) 6.53-7.20 (m,
411) I R(neat); 334
B, 1650 cm-'Mass; m/z 2!
i3 (M) (M-tlo) K-temperance 12 7-(5-methylchenyl)-7-hydro a+shiheptanohydroquinic acid brown liquor NMR (DMSO-dd); δ1.2 (
+n, 6N) 1.90 (t, 2
H) 3.45 (s, 211) 7.3
0 (s, 2H)IR(neat); 33
00,1640 cm-'Mass; m/z
25? (M”)*1”]-6-phenoxy hexamic acid I50 xamic acid white crystal m
p 69-70.5°C NMR (DMSO-dd); δ 1.56 (m, 6tl) 2.0 (t,
2H) 3.40 (s, 1N) 3.94
(t, 2H) 6.95-7.31 (m, 5N)
IR (KBr disk); 3150,165
0.1241cm-'Mass; m/z
223 (N+) Example 14 4-chlorophenylhexanohydroxamic acid residue brown viscous I#I fluid N IJI R (DMSO-dd); δ1.32
(m', 6N) 1.9[1(t, 211
)2.5[] (m, 2+1)'
? ,20(S,4N)IR(neat)
; 1645cm-'Mass; m/
241 (M+)
．． 5z+96'cNMR (DNSO-dd); δ 1.97 <m, 2tl) 2.22 (S,
311) 3.1? (broads III)
, 3.76 (t , 211 ) 8.15 (s, IN
) 8.59 (broads [1) I R (KBr di
sk) ; 3211], 1640, 154 [1cm
-' 11 cusp Example 16 6-(2-Methyl-5-210.rMidazolyl)hexanohivroquim6σ Reddish-brown liquid NMR (Illi5od,); δ2.
23 (8,3H) 2.22 (t, 2H)3.
83 (t, 2N) 7.10 (s, IH)
In (broad s 18)I R(
KBr disk); 1620cm-'Mas
s; m/z 256 (M”) Patent applicant Nissan Kaji Koitobu Nikai

Claims (2)

[Claims] (1) General formula [1] AB (CH2)n C0NHOHN) [wherein A is R
Xm, where R represents a phenyl group, a pyrrolyl group, a chenyl group, an imidazolyl group, or a thiazolyl group;
represents a halogen atom, an alkyl group 5, a lower alkoxy group and a nitro group; 5m represents 0, 1 or 2;
The 11 X's can be the same/different. )1
B is -CHOH-, -CH-, -0- and -CO-
, and n represents an integer of 2 to 10. ] A hydroxamic acid derivative represented by 'C. (2) General formula [2] AB (CH2)n C0OR (2) [In the formula, A represents RXm, R represents a phenyl group, pyrrolyl group, chenyl group, imidazolyl group, and thiazolyl group, and X represents halogen atom. Lower alkyl arithmetic, lower alkoxy group and nitro group, 1m indicates 0, 1 or 2, rn number of X is the same -t
or can be different. ), B is -CH0'H-, -
CH-, -0- and -co-4, n represents Mu of 2 to 1O, and R represents a lower alkyl group. [1] AB (CHI ) rI C0NHOH (1) [In the formula, A represents RXm, and R is phenyl] group, pyrrolyl group, chenyl group, imidazolyl group, and thiazolyl group, X represents a halogen hW atom, lower alkyl group, lower alkoxy group, and 2-4 group;
, and 1m X's are the same - violet/ko are different. ), B is -CHOH-+ -crr-, OJ3.
1: rF co-, n represents 2 to 10 U sharks. ] ≠Hydro+Sam h■＾Production method of S form.