JPH03220180A - Isoxazoline derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> and R<2> are each H or lower alkoxy; R<3> is cyano or alkoxycarbonyl). EXAMPLE:5-Methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)-isoxazoline. USE:An intermediate for synthesizing (3,4-diarylisoxazol-5-yl)acetic acid derivatives useful as antiinflammatory agents, analgesics and antipyretics. PREPARATION:The objective compound of formula I can be obtained by cyclization of an alpha,beta-unsaturated ketoxime derivative of formula II. The compound of the formula II can be prepared by reaction between (1) a deoxybenzoin derivative of formula III and (2) an alkoxyacrylonitrile of formula IV (Z is lower alkyl) or alkoxyacrylic acid derivative in a solvent in the presence of a base to produce a compound of formula V which is then allowed to react with hydroxylamine (salt) in a solvent.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to novel inxacillin derivatives.

The inxacillin derivative of the present invention has a general formula (in the formula, 1''?1 and R2 are the same or different and represent a hydrogen atom or a lower flukoxy group) and are useful as anti-inflammatory agents, anti-inflammatory agents, and antipyretic agents. Represented (3.
It is useful as an intermediate in the production of 4-noaryl (xacyl-5-yl) acetic acid derivatives.

(Conventional I-Support) JP-A-56-59764 discloses (3,4-diallyl inxacyl-5-yl) acetic acid derivatives as compounds having anti-inflammatory, analgesic, and antipyretic effects. ,
The manufacturing method includes (1) the same publication and (2) JP-A-60-
A method described in Japanese Patent No. 75471 is known.

JP-A-56-59764 (in the formula, R1 and R2 are the same as above) 3.4-noaryl-5-methylinxazole was added to 7 tons of dry ice in a 7-ton run of tetrahydro under cold J''
A method of treatment with 11-butyllithium, followed by pouring the resulting reaction mixture into crushed dry ice, followed by acid treatment.

JP-A No. 75471 (wherein, A method in which 3,4-diaryl-5-cyanomethylinxazole is obtained by solvolyzing it.

The present inventors (3,4-diaryl ink
Although studies have been conducted on industrial methods for producing -yl)acetic acid derivatives, it has become clear that the methods shown in (1) and (2) have various problems.

That is, in method (1), 11-butyllithium, which is a synthetic reagent, is highly flammable, and if a large amount is used, there are problems in terms of fire and safety. Furthermore, use of highly humid dry ice for reactions that require anhydrous conditions, and -70
There are problems in working efficiency, including operability, when conducting the reaction at a low temperature of °C. Method (2) is more complicated than step (1) and also uses cyanide, so it is not preferred as an industrial production method from the viewpoint of safety.

(Problems to be Solved by the Invention) The purpose of the present invention is to produce an intermediate for producing a compound (A>) by a simple process, without using dangerous reagents, and by a method that is excellent in terms of safety and operability. An object of the present invention is to provide novel inxacillin derivatives useful as inxacillin derivatives.

(Means for Solving the Problems) The present invention provides: Formation (wherein R' and R? are the same or different, a hydrogen atom-1 lower alkoxy group, R' is a cya 7 group or an alkoxycarbonyl It pertains to an inxacillin derivative represented by the following.

In the above formula, R1 and R? Preferred lower alkoxy groups represented by are linear or branched alkoxy groups having 1 to 6 carbon atoms, specifically methoxy, ethoxy,
propoxy, 1so-propoxy, butoxy, ter
Examples include L-butoxy, pentyloxy, and hexyloxy groups.

Examples of the alkoxycarbonyl group represented by R3 in the above formula include me)9 dicarbonyl, ethoxycarbonyl, propoquinecarbonyl, and is.

-propoxycarbonyl, butoxycarbonyl, [I.
Examples include straight-chain or branched alkoxycarbonyl groups having 2 to 7 carbon atoms such as 1-1 toxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.

The inxacillin derivatives of the present invention are useful as anti-inflammatory agents, analgesics, and antipyretics and are represented by the general formula (wherein R1 and R2 are the same or different and represent a hydrogen atom or a lower alkoxy group) (3, 4-
g of diaryl inxacyl-5-yl) acetic acid derivative
It is useful as a synthetic compound.

Compound (1) of the present invention is produced by cyclizing an a,β-unsaturated ketoxime derivative represented by -formation (wherein R' R2 and R1 are the same as above).

Compound (II) used in this production method can be produced according to the following reaction scheme.

(B) (In the formula, [1 and R3 are the same as above. Z represents a lower alkyl group.) In the formula, the lower furkyl group represented by Z''Ch is, for example, methyl, ethyl, propyl, Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as inpropyl, butyl, Sl'e-butyl, LerL-butyl, pentyl, and hexyl groups.

Each step in the above reaction scheme is carried out in more detail as follows.

Step A> By reacting the deoxybenzoin derivative represented by the general formula (III) with the alkoxyacrylonitrile or alkoxy diacrylic acid derivative represented by the general formula (fV) in an appropriate solvent in the presence of a base, -formation (V)
A compound represented by is obtained. There are no particular restrictions on the solvent as long as it does not participate in the reaction, such as methanol,
Various organic solvents such as ethanol, t,er L-butanol, tetrahydrofuran, nooxane, benzene, toluene, xylene, carbon tetrachloride, chloroform, nochloromethane, 7cetonitrile, birinone, and trimethylformamide may be used singly or in combination. Can be used. As the base, for example, inorganic bases such as sodium hydroxide, sodium methoxide, potassium Lert-butoxide, and butyl lithium, and organic bases such as triethylamine and trimethylaminoviricun can be used.

The rate of reaction is - formation (IV) of the compound of general formula (Il
1 to 3 times the molar amount of the compound of formula (III) and a base of the general formula (III).
) is preferably used in an amount of 0.1 to 3 times the molar amount of the compound.

The reaction temperature is 200 DEG C. or less, preferably about 10 DEG C. to the boiling point of the solvent, and the reaction is usually carried out for about 0.5 to 20 hours.

and Step B.The compound represented by the general formula (V) obtained in Step B is
li'! , S in a solvent with hydroxylamine or a salt thereof to obtain a compound represented by -formation (n). The hydroxylamine salt used in the reaction is not particularly limited, and examples include hydrochloride and sulfate. There are no particular restrictions on the solvent as long as it does not interfere with the reaction, such as methanol, ethanol, 1. Zero reactions can be achieved by using various organic solvents such as prt-butanol, tetrahydrofuran, nooxane, benzene, toluene, xylene, carbon tetrachloride, chloroform, nochloromethane, acetonitrile, birinone, and trimethylformamide, either singly or in combination. It is preferable to use hydroxylamine or a salt thereof in an amount of 1 to 10 times the molar amount of the compound of general formula (V). The reaction temperature is 0 to 200°C, preferably 40°C to about the boiling point of the solvent, and the reaction is usually carried out for about 1 to 30 hours.

The compound of the present invention can be obtained by cyclizing the compound (■) obtained by the above reaction scheme in the presence of a catalyst in a suitable solvent or in the absence of a solvent.

The catalyst is not particularly limited, and examples thereof include acids and bases.

The acid is not particularly limited, and includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, and hydrobromic acid; ! ! Phosphoric acids such as phosphoric acid, polyphosphoric acid, etc. can be used alone or in combination.

There are no particular restrictions on the base, such as birinone, 4-
Organic bases such as dimethyl 7-minopyricune and triethylamine, and inorganic bases such as sodium hydroxide, sodium carbonate, sodium hydride, sodium amide, sodium methoxide, potassium Lert-butoxide, and 11-butyllithium can be used. Preferably, the acid and base are used in an amount of (1,1-, to times the molar amount of the compound in -formation (n).The reaction temperature is a). The reaction is usually completed at a temperature of about 1 to 1011).

The thus-obtained compound of the present invention can be separated into Rl by commonly known separation and purification steps and techniques (specifically, distillation, recrystallization, phosphoric column chromatography, etc.).

In the present invention, the isoxazoline derivative represented by the formula (1) includes isomers based on cis-lance isomerism of a monocyclic compound, and the present invention includes any isomers.

The compound of the present invention has an anti-inflammatory and analgesic effect expressed by the general formula (A) (1,4-noaryl inxacy-ru-5).
-yl) acetic acid derivative by the above-mentioned production method I)
The synthesized isoxazoline derivative represented by the general formula (+> is isolated or oxidized as it is in a suitable solvent without isolation; Noarylisoxazole-5-
This is achieved by converting the acetonitrile derivative into an acetonitrile derivative and then further solvolyzing or hydrolyzing it in the presence of an acid or a base. Examples of oxidizing agents include, but are not limited to, chlorine,
Bromine, iodine, halogenated compounds such as N-chlorosuccinimide and N-bromosuccinimide, inorganic oxidizing agents such as mandioxide and potassium permanganate, 2.7)-Fucloro-5,6-nocyanol 1.4 -Organic oxidizing agents such as penzoquinone, metachloroperbenzoic acid, and the like. There are no particular restrictions on the solvent as long as it does not participate in the reaction.
For example, nochloromethane, lyaaform, carbon tetrachloride, acetone, hexane, benzene, toluene, methanol,
Ethanol, ether, tetrahydrofuran, etc. can be used.

In the oxidation reaction described below, it is preferable to use the oxidizing agent in an amount of 1 to 10 times the molar amount of the inxacillin derivative represented by general formula (1). The reaction temperature is from 0 to 200°C, preferably from 0'C to the boiling point of the solvent. Solvolysis or hydrolysis is described in Japanese Patent Application Laid-Open No. 60-75471 using Ashigaru's solvation tR:lysis lj method, or for the time being defe 417 JTJ.
f) by the hydrolysis M method. Acids include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; bases include Tsubameisohanawa such as sodium hydroxide, potassium hydroxide, and sodium carbonate;
- Used for boat fishing.

(Examples) Next, the present invention will be explained in detail with reference to Examples and Reference Examples.

Reference example 1 Ethyl $, 5-bi(+-methoxyphenyl)-to-
Synthesis of oxdi-3-pentephate terl-buta-7-
Le 430111/1st grade, Te'oquin Anisoin 12
8 g of potassium L+/rL-butoxide, and 116 g of ethyl 3-7 toxyacrylate were added thereto, and the mixture was stirred at 70°C for 13 hours. After the reaction, add 11-hexane to the reaction mixture and leave it at room temperature.
child.

Collect the precipitate and add ethyl acetate 1000. After adding and dissolving p and 3N-sulfuric acid 300IIi', the organic layer was separated,
The frPP1 layer was washed with 3N sulfuric acid and saturated saline, and dried over anhydrous maghonsium sulfate. The organic layer was soaked under reduced pressure,
The title compound as an oil +53. (yield 90%).

This compound was a mixture of double bond-based isomers (approximately 6:4) from the NMR spectrum. This mixture was crystallized from hexane-ethyl acetate as necessary to isolate the isomer as white crystals.

Melting point 101~+03'C Infrared absorption spectrum (KBr) νwax (cm-') 17:'+2, 1640,
160ONMF? Spectrum ((j)C/,) δ
(p p 顛) 3J1 (2+1., J), 3.72 (3
11, s), 3.80 (311, S), 3, R5 (31
1, s), 6.37 (III, t), 6.90 (4H
, d), 7.2:1 (211, d), 7.89 (2+1
．． d) Furthermore, an oil which is an isomer of the above compound was obtained from the mother liquor.

Infrared absorption or vector (KRr) νi*ax(c+s-') +7:'12.1662
．． 1596N MR spectrum (Cr)C/3)
and (llll#l)]j5(2+1. (1), 1.
65 (311, S), 3°77 (311, S), a, 8
3 (311,・1), 6.30 (lit, t), 6
．． 6-7.1 (411, anger), 7.10 (211, d)
, 7.92 (211, J) Reference Example 2 4.5-bis(4-7toxyphenyl)-5-oxo-
Synthesis of 3-pentenenitrile The title compound, an oil, was obtained by reacting in the same manner as in Reference Example 1, using 3-methoxyacrylonitrile instead of 3-7 toxyacrylate.

Infrared absorption spectrum (NaCl') νIIHIX(clM-') 2250.1660
．． 1606NMR spectrum (CI)C,/co) δ
(ppm): t, +7(2+1.tJ), 1.78(
III, s), 3.85 (III, !;), 6.0
1 (:IH, t), 6.7-7.0 (4+1. import), 7.27 (211,, J), 7.90 (2+1.
tJ) Reference Example 3 Synthesis of methyl 4,5-diphenyl-5-oxo-3-pente/ate The oily form of the title compound was produced by reacting in the same manner as in Reference Example 1, using deoxybenzoin instead of deoxyanisoin. I got something.

NMR? Spectrum (cncIJ) δ(ll
llIbi):l, 18.3. :'10(2+1.cl
),3.65,:(,70(31(,S),6.46.
6.56 (III, t), 7.1-8.2 (IOH,
+*) Masr, spectrum M” (m/z) 280 Reference example 4 Synthesis of methyl 5-hydroxyimino-4,5-bis(4methoxyphenyl)-3-pentenoate Methyl obtained in Reference example 1 4,5 24.5 g of isomer mixture of -bis<4-/)xyphenyl-5-oxo-3-pente7ate and 51.5 g of hydroxylamine hydrochloride
was heated under reflux for 2 hours in 650 methanol and 72 ml of water. At this time, 0.g of sodium hydrogen carbonate was added to the reaction solution.
Equivalent amounts were added in portions as the reaction progressed. After the reaction was completed, methanol was distilled off under reduced pressure.

Water and ethyl acetate were added to the residue to dissolve it, and the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by chromatography (developing solvent: ethyl acetate-11-hexane) to obtain the title compound, oily substance 23.
6 (yield 90%) was obtained.

Infrared absorption spectrum (NoC1) Sea ax (cI--') +732.1608N
MR spectrum (CD CI,) δ (January I import): 1. I = 1.2 (211, +a), R, 65 (
311,fl), :1.76(3+1.ji),Ding+,77(3!+,・1),6.48(IH,t,),
6.81 (411, d), 7, :15 (211, tJ)
, 7.58 (411, cl), 8.72 (Nl, bs
) Reference Example 5 Synthesis of 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenenitrile Methyl 4,5
- Using 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenenitrile instead of bis(4-methoxyphenyl) 5-oxo-3-pentenoate, react in the same manner as in Reference Example 4. This gave the title compound as an oil.

Infrared rg! L yield spectrum (NJIC/) νnax (c
m-' ) 2252, 1596 NMR spectrum (CI) C13) δ (1111111) 3.12.3.
15 (211, da), 3.77 (311, s), 3.
78 (311, s), 6.18 (Ill, t), 6
．． l'14 (4H, d), 7.32 (211, d), 7
．． 55 (211,, J), 8.46 (III, bs)
Reference Example 6 Synthesis of methyl 5-hydroxyimine-4,5-no7-diru-3-pentenoate Methyl 4.5-bis(4-methoxyphenyl)-5-
Using 4,5-nophenyl-5-oxo-3-pentenoate in place of oxo-3-pente/ate, the reaction was carried out in the same manner as in Reference Example 4 to obtain the title compound as an oil.

NMR spectrum (CDC13) δ (ppm>3
．． 1-3.3 (2H, import), 3.64 (3H, s),
6.63 (Iff, t), 7.1-7.8 (101
1, request), 9.18 (III, bs) M a s
s spectrum" (+a/z) 295 Example 1 Synthesis of 5-7 toxycarbonylmethyl-3,4-bis(4-methoxyphenyl)-isoxazoline Methyl obtained in Reference Example 4 5-hydroxyimi/4,5- Bis(4-methoxyphenyl)-3-pente72-) 1,23.
in methanol 20-1 in the presence of 1.5 d of concentrated hydrochloric acid, 60
After the reaction was completed, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was removed under reduced pressure. After concentrating, the residue was separated and purified by silica sol column chromatography (eluent: ethyl llff acid-f1-hexane) to obtain the title compound, oily substance 16 (yield: 81%).

Infrared absorption spectrum (NaC/) νnax(c+n-') +7:16.161ON
Spectrum at Mr (CD C/3) δ (I beat 11) 2.0-2.8 (211, +*), 3.62,
:1,701111. s), 1.76(611,・1
), 4.5-5.2 (211, m), 6.7-7.1 (
411, 7.16 (211, J) Mass spectrum N11 (Import/z) 355 Example 2 Synthesis of 5-/)xycarbonylmethyl-3,4-no-7-functional nyl-inxazoline Methyl 5-hydroxy Methyl 5-hydroxyimi/-4,5-nophenyl-3-pente/ate obtained in Reference Example 6 was used instead of imino-4,5-bis(4-methoxyphenyl)-1-pente/ate. The title compound, a white powder, was obtained in the same manner as in Example 1 (yield: 85%).
).

Melting point 55-57℃ Infrared absorption spectrum (KBr) νI#ax(cscale-') 1734 NMR spectrum (C1)C/,) δ(p++m
)2.1~:1,0(2)1. ring), 3.59.3
．． 69(R1(,4E), 4.6-5.:1(2tl,
M), 6.9-7.4 (l (11, paid), 7.4-7
．． 8(21(, simple) Example 3 Synthesis of 5-cya7methyl-3,4-bis(4-methoxyphenyl)-isoxazoline 5-hydroxyimino-4,5bis(4
-methoxyphenyl)-3-pentenenitrile 322
8 g of sodium bicarbonate in 10 g of tetrahydro7 run solution: (2 J 6 'n 15, water 2.4 lead 1 't
Add 1 drop of potassium iodide, iodine 267'B, water 2,4 + n i' and strain for 90 minutes at room temperature.

After the reaction was completed, water was added and extracted with 1 portion of ethyl acetate, followed by CI
The rock layer was washed with a saturated saline solution and a saturated aqueous sodium thiosulfate solution, and dried over anhydrous magnesium sulfate. I.11 was concentrated under reduced pressure with F, and the residue was subjected to silica sol column chromatography (developing solvent: acetic acid 10-11-hexane).
Separate and refine with the title compound to obtain an oily substance 298)
i (yield 93%) was obtained.

Infrared absorption spectrum (NaC/) vlIlaW (CM-') 2252.1606N
MR spectrum (CD(1'3) δ(111
1111) 2.1-2.8 (211, m), : 1.78
(6H, 1), 4, 5-5. l (211, la),
6.7-7.0 (411, +*), 7.0-7.3 (2
+1. Mackerel), 7.4-7.7 (2+1. Mackerel) Mass spectrum M"4 rings 7y,) 322 Reference Example 7 Synthesis of 1:1,4-bis(4-methoxyphenyl)isoxazol-5-ylj acetic acid 5-methoxycarbonylmethyl-3,4 obtained in Example 1
-bis(4-methoxyphenyl)-inxacillin 0.
76@ was dissolved in 9 ml of carbon tetrachloride, and then 0.048 ml of N-bromoconolynimide 0,388.2.2'-7zobis-isobutyronitrile was added and the mixture was heated under reflux for 2 hours. After the reaction, water was added and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica sol column chromatography (developing solvent: ethyl acetate-n
-Hexane) to produce a white solid, 3,4-
Bis(4-7toxyphenyl)-isoxazole-5-
0 g (yield: 83%) of i'ff acid methic acid dithyl ester was obtained.

Melting point 67-68℃ Infrared absorption spectrum (KBr) C ax (Cm-') 173O NMR spectrum (Cr') CM and (llll
l) 3.7:1 (3H, s), 3.77 (211, s
), 3.79 (311+ s), 3.82 (3H* s
), 6,83 (211, d), 6.90 (2) 1. d
), 7.15 (2H, d), 7.40 (2H, tJ)”
The compound obtained in both cases was added to a 2% aqueous sodium hydroxide solution and stirred at 40°C overnight. After the reaction was completed, the reaction solution was washed twice with ether, then 10% hydrochloric acid was added under water cooling, extracted with ethyl acetate, and washed with saturated brine.
It was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound as a white solid (melting point 147-148°C).
I got it.

(Effects of the Invention) By oxidizing and hydrolyzing the inxacillin derivative of the present invention, it is possible to lead to (3,4-)7ly-inxazol-5-yl)acetic acid derivative in high yield.The present compound Synthesis of (3,4-diaryl-inxacyl-5-yl)acetic acid derivatives) j method does not use highly hygroscopic dry ice compared to the conventional method, so the manufacturing process can be shortened. C) It exhibits excellent effects, such as the fact that it is free from heat, and there is no danger of human accidents because it does not use butyllithium, which is highly flammable.

Procedural amendment March 14, 1991

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 and R^2 are the same or different and are a hydrogen atom, a lower alkoxy group, and R^3 is a cyano group or An isoxazoline derivative represented by (representing an alkoxycarbonyl group).