DE1445916B - Process for the preparation of compounds of the oxazole series - Google Patents

Description

a) a process in which o-aminohydroxylbenzene and a carboxylic acid in the presence of Poly- or pyrophosphoric acid are heated (E. Nyilas et al, Journal Am. Chem. Soc. 82 [1960], p. 609; U.S. Patent 3,095,421, British Patent specification 902 058),

b) a method in which o-acyl-aminohydrobenzene is heated with poly- or pyrophosphoric acid (British patent specification 902 059),

c) a process in which o-aminohydroxybenzene and a carboxylic acid are heated with boric acid under a nitrogen atmosphere (US Pat. No. 3,095,422),
d) a process in which a Schiff base derived from o-aminohydroxybenzene and an aldehyde compound are oxidized (FF Stephens et al, Journal Chem. Soc. [1949], p. 2971, and [1950], p. 1722, [German Patent specification 827 949]),

e) a method in which o-aminohydroxybenzene is heated with an aldehyde compound

(A. M. Osman et al, Journal Org. Chem. 27 [1962], p. 558),

f) the method according to F. Heinrich (Ber. dtsch.

Chem. Ges., 54 [1921], p. 2493); the method according to M. Schubert (Ann. 558 [1947], p. 10), and G. L. J e η k i η s et al., Journal Org. Chem. 26 [1961], p. 274. It was found that the the second process mentioned, in which o-haloaminobenzene is used as the starting material will entail considerable difficulties in carrying out the reaction. Currently only one process is common, in which o-haloaminobenzene in liquid ammonia with sodium amide is treated (J. F. B u η η e 11 et al, Journal Am. Chem. Soc, 80 [1958], p. 2021, 83 [1961], p. 1691, and Journal Org. Chem., 28 [1963], p. 1).

The above-mentioned process starting from o-aminohydroxybenzene generally has the disadvantage that the o-aminohydroxybenzene and its derivatives tend to oxidize, resulting in a low yield and an impure product. o-aminophenol, for example, is on the one hand in the presence of water at ordinary temperature and, on the other hand, even in an organic solvent still readily oxidized at a temperature below 100 ° C., The production of o-Hydroxyacylamino compounds and / or the preparation of the oxazole compounds derived therefrom usually carried out with the exclusion of air or in an inert gas atmosphere in order to obtain ejne To prevent the product from darkening due to oxidation by atmospheric oxygen. .

If the procedure is not carried out under such precautions, the formation of the stained Product usually unavoidable.

In contrast, o-HalogenaminobenzoIe, such as o-chloroaniline or o-bromoaniline, which in the second process is used as the starting material for production The oxazole compounds used can be very persistent and if they are atmospheric Exposed to oxygen, not affected by harmful oxidation.

A particularly pure oxazole compound can in this way using the o-haloaminobenzene can be obtained as a starting material.

However, since liquid ammonia must be used as the reactant, the process requires J. F. B u η η e 11 et al a low temperature and the use of a closed container to keep the Ensure implementation of the reaction. This makes the procedure difficult when im economic yardstick should be used.

We have now found a process for the preparation of compounds of the oxazole series which the no longer has the disadvantages mentioned above.

The process of the invention is now characterized in that an acylamino compound | _{v of} the general formula II

^25th

Ii

NHCOR

wherein the ring A is substituted as indicated above and R has the meaning given and X is a chlorine or bromine atom, in an inert solvent and in the presence of a catalytic amount of metallic copper or a copper compound on ■ :, ■■; ..

a) a temperature in the range from about 150 to 200 ⁰ C in the presence or absence of an inorganic alkali salt as an acid binder or

b) a temperature in the range of 130 to 15O ⁰ C in the presence of an organic base as acid binder

heated.

The compound of the general formula II can be prepared in that a monocarboxylic acid of the general formula III

HOOC - R

III

wherein R has the meaning given or its functional derivative, e.g. B. an ester or an acid halide of which, with an o-aminohalobenzene-. '*? Compound of the general formula IV

IV

NH,

55

60

is reacted, in which the ring A is substituted as indicated above and X has the meaning given has.

The method according to the invention is distinguished from the previously known in that the desired product easily with a high yield and economically with a considerable amount high purity is achieved.

It is also very advantageous that after the process according to the invention, the end product through simple cooling of the reaction mixture can be obtained in an almost pure state and the im In contrast to the products obtained by conventional processes without further purification can be used directly for many commercial purposes.

The compounds according to the process of the invention can, for. B. as intermediates in the Manufacture of dyes, ultraviolet absorbers, light stabilizers, optical brighteners, Dyeing auxiliaries and pharmaceutical substances are used.

Than that of the amino group in o-haloaminobenzene neighboring, the bromine atom is preferably used because it favors the reaction more than that Chlorine atom; consequently, oxazole ring formation can be more effective according to the method of the present invention are executed.

The acylamino compounds of the general formula II can readily by known methods, z. B. be prepared by one of the above-mentioned carboxylic acid chlorides in one inert organic solvent can react with an o-haloaminobenzene, the desired Product can be obtained in good yield and with high purity.

The acylamino compound thus obtained, which has the halogen atom on that adjacent to the amino group Place contains, is then brought into contact with a copper (I) or copper (II) salt, for example with copper acetate, copper sulfate, copper (I) or copper (II) chloride or copper oxide. Powdered copper is particularly suitable as a catalyst.

It has also been found that an active copper catalyst can advantageously be obtained when one in situ in the reaction medium, for example, copper (II) acetate with metallic zinc or lead brings in touch. A good result is also achieved when the copper compounds are in anhydrous Shape can be used.

An acid-binding agent can advantageously be used, although this is at least in the case of a higher one The temperature for the reaction is not always necessary to neutralize the hydrogen bromide or hydrogen chloride, which is released as a result of the ring formation of the oxazole.

An alkali metal salt of inorganic or organic compounds can preferably be used as the acid binder Acids such as sodium carbonate, sodium acetate, or potassium acetate can be used as well as an organic one basic compound like "eiiu * aliphatic amine, z. B. butylamine, dibutylamine, triethylamine and especially pyridine, picoline, lutidine and quinoline, the are obtained as coal tar fractions. The organic acid binder is better than the inorganic one Acid binder for use, suitable because the former not only reacts faster than the latter, but also its reactivity already unfolds at lower temperatures and the product therefore is obtained with a high degree of purity.

Although the above J. F. Bunnett method uses the same starting material as is used in the process according to the invention, there must be the reaction with sodium amide in liquid Ammonia are carried out, whereas according to the process according to the invention, an inorganic one

Substance such as alkali metal salts or an organic base, e.g. B. pyridine, find use. The known procedure would not expire if the liquid ammonia acted as a reactant by an acid-binding agent Means of the kind used in the method according to the invention would be replaced. From this is It can be clearly seen that the process according to the invention can be achieved by using other reactants differs significantly from the J. F. Bunnett method.

It is assumed that a complex salt formation of the copper compound with the basic used Connection takes place. The oxazole formation can therefore be effected in the same way if, for. B. a separately prepared complex salt or a complex such as copper (II) ammonium acetate + copper (II) pyridine sulfate instead of adding a copper salt catalyst and an acid binder separately is used in the system.

It is also advantageous that a copper-containing complex salt of the oxazole compound and the Copper or the copper salt is formed immediately in the formation of the oxazole compound. That so formed complex salt can be separated and recovered if the oxazole ring formation without Use of an acid binding agent was effected or with an acid binding agent in such a way small amount that this is insufficient to neutralize the hydrogen halide which is split off from the reactants.

In this case, the oxazole compound can be removed from the salt thus separated by treating it either with a basic compound, e.g. B. ammonia or pyridine or with sodium carbonate or concentrated sulfuric acid.

The suitable to carry out the reaction temperature range when using an inorganic acid-binding agent is from about 150 to about 200 ⁹ C. In this case, can be used with a boiling point above 150 ° C as the solvent an organic substance, such as nitrobenzene, o-dichlorobenzene , Trichlorobenzene, naphthalene and dimethylformylamide; the petroleum distillates with high boiling points can also be used. The reaction takes place very quickly even at a temperature below 150 ^° C. if an organic basic substance is used as the acid-binding agent. If the reaction is carried out without an acid-binding agent, a suitable reaction temperature is in the range from 150 to 200 ^° C.

The invention is illustrated by the following examples. All percentages are based on weight. - ; .-. ν:

example 1
10 parts of the acylamino compound of the formula

H, C

Br

NHCO

NO,

kept at this temperature. The whole thing was then cooled to a temperature below 10 ° C and the precipitated product was collected by filtration, washed with benzene and dried. The product was treated with a mineral acid to give 5.1 parts of a pale yellow Powder of the following formula

H, C

NO,

The yield of the product was 67.0% of theory. A pale yellow crystalline compound with a melting point of 207 to 208 ° C was obtained by recrystallization from ethyl alcohol.

The same product is obtained without copper (II) oxide. The speed of reaction is there but a little less.

The acylamino compound used as the starting material in this example was prepared as follows: 9.3 parts of 3-bromo-4-aminotoluene were placed in 82.5 parts of monochlorobenzene. The under Stirring heated mixture was for 35 minutes and at a temperature of 120 to 130 ° C a Solution added previously by dissolving 9.3 parts of p-nitrobenzoyl chloride in 33 parts of monochlorobenzene had been made.

The whole was reacted at a temperature of 130 to 132 ° C for 4 hours. 70 parts of the monochlorobenzene were distilled off, and the remainder of the reaction mixture was cooled ^{to below 10 ° C.} The mass which crystallized out was filtered, squeezed out well, washed with a little benzene and dried. 15.7 parts of the acylamino compound having a melting point of 159 to 160 ° C. were thus obtained as a pale yellow crystalline substance.

The yield was 93.4% of theory. The different, acylamino compounds used as starting materials in the following examples were also made in the same way.

Eg game 2

A mixture of 9.55 parts of the acylamino compound of the formula

Br

-CONH

NO,

0.1 part copper (I) chloride and 2.37 parts anhydrous; Sodium carbonate was refluxed in 75 parts of trichlorobenzene for 4 hours. That so educated The reaction product was treated according to the procedure of Example 1.

4.8 parts of a pale yellow powder of the formula were obtained

NO ₂

0.1 part of copper (I) chloride, 0.25 part of copper (II) oxide and 5 parts of anhydrous sodium acetate were in

Given 110 parts of nitrobenzene. The yield obtained was 67.2% of theory. The

mixture was heated to 200 ° C and for 10 hours product was recrystallized from ethyl alcohol, and

pale yellow crystals with a melting point of 181 to 182.5 ° C. were obtained.

Example 3

18.2 parts of anhydrous were added to a mixture of 370 parts of dimethylformamide and 98 parts of pyridine Copper (II) acetate was added and the whole was heated with stirring to obtain a clear solution to obtain. At about 90 ° C, 39.2 parts were given by the formula

Br

set. The reaction mixture was cooled to a temperature below 10 ° C; the secreting ones Crystals were filtered off, squeezed well, successively with 50 parts of cold ethyl alcohol, Parts of 5% aqueous ammonia solution and a little water and washed and dried. One received 27.8 parts of pale yellow crystals of the formula

H, C

NHCO

CH = CH- ^ rX The yield was 89.3% of theory. The product was recrystallized from ethyl alcohol, and the pale yellow crystals with a melting point of 179 to 180 ^° C. were obtained.

shown acylamino compound of the solution. Further examples were carried out in a manner analogous to

type, and the resultant mixture was performed at a 20 Example 3 above and shown in the nachfol temperature 140-142 ⁰ C for 4 hours environmentally constricting table.

example

Structural formula melting point
( ⁰ C)

yield

Appearance of the product

O ₂ N

H, CO

H, C0

to 242

83.7

to 123

90.1

Yellowish brown

Pale yellow

to 84

80.3

Colorless

until 196

87.1

Pale yellow

to 210

85.6

Pale yellow

91.5 to 92

86.9

Colorless

to 217

94.8

Pale yellow

209 534/560

continuation

10

example Structural formula H ₃ CO - / "" V "C O H _ä CC \ /
O NO ₂ / Melting point Out
prey Look
of the product N N CC) ■ (%) N / "S-CH ₁ - / ^N 11th ρ \ /
O 184 to 185 94.0 Colorless N CH ₃ 12th \ /
O O 71 to 72 85.7 Colorless N V NO ₂ / = \ y ^x
\ -? \. 13th \ /
O λ ι 225 to 226 97.2 Colorless ? ^H N NO ₂ 14th \ /
O 149 to 150 99.1 Colorless N V NO ₂ 15th 216 to 217 92.2 Colorless NO ₂ 16 O 151 to 152 91.5 Pale yellow \
OH 17th ö 153 to 154 88.4 Colorless O

Example 18 ,,. _t ".

• ο 1.82 parts of anhydrous copper (II) acetate were added to a liquid mixture containing 13.6 parts of dimethylformamide and 4.8 parts of pyridine. The whole was heated with stirring until a clear solution was obtained.
2.90 parts of the acylamino compound of the formula

H, C Br

After 2 hours of reaction at a temperature of 135-140 ⁰ C, the resultant was reac-tion mixture was diluted by pouring it into water. The solid which separated out was collected by filtration, washed with 5% strength aqueous ammonia and dried. In this way, 2.1 parts of a compound of in the form of a light brown powder of the formula were obtained

6o

NHCO

H ₃ C

65

and 0.33 part of powdery metallic zinc was added to the solution, and the whole was heated. The yield was almost quantitative.
After recrystallization from 50% ethyl alcohol it became a white substance with a melting point

obtained from 94 to 94.5 ° C. You get higher yields, when Examples 4 to 17 are carried out by the same procedure as in the present example will. The product insoluble in the reaction medium used was purified by the method of Example 3 treated further.

Example 19

To a mixture of 43.7 parts of dimethylformamide and 19 parts of a-picoline were 4.66 parts of Acylamino compound of the formula

NHCO

OH

y ν

OCH,

OH

OCH,

IO

given; To this mixture, 0.64 part of finely powdered metallic copper, which was prepared by reacting copper sulfate with powdered metallic zinc, was added. The whole was allowed to react with stirring for 12 hours at a temperature of 137 to 14O ⁰ C. The reaction mixture was cooled to a temperature below 10 ° C.

The solid which separated out was filtered off, washed with cold ethyl alcohol and dried. The copper-containing compound of brown color obtained in this way was thoroughly ground and with ten times the volume of concentrated aqueous ammonia at ambient temperature for 5 hours treated for a long time in order to dissolve the copper contained in the product. The mixture was made by adding diluted with water, and the separating material was filtered off with 5% aqueous ammonia and then washed with water and dried. 3.27 parts of the compound were obtained formula

The yield was 85.0% of theory. The color obtained after recrystallization from n-butanol

loose connection had a melting point of 148 to 148.5 ° C.

The yields of the compounds achieved by Examples 4 to 18 can still increase if the procedures are carried out under the same reaction conditions as in this example.

Example 20
33.5 parts of an acylamino compound of the formula

H ₃ C

Br

NHCO

y ν

NO ₂

were in a solution of 158 parts of dimethylformamide cast, in which 16.0 parts of anhydrous copper (II) sulfate were dissolved. The whole thing was heated with stirring and reacted at a temperature of 150 to 152 ° C for 4 hours. The reaction mixture was cooled and, at a temperature below 10 ° C., the separating became Solid obtained by filtering off, successively with cold ethyl alcohol, 5% aqueous Ammonia and water washed and dried.

In this way, 21.2 parts of the compound of the formula were obtained

NO,

40 The yield was 83.3% of the theoretically attainable value.

A pale yellow crystalline material was obtained

with a melting point of 208-209 ° C when the product was recrystallized from ethyl alcohol.

A similar result was obtained in this example using 18.2 parts of anhydrous cupric acetate achieved in place of the anhydrous copper (II) sulfate.

Claims (1)

I 445 916 Claim: Process for the preparation of compounds of the oxazole series of the general formula I. wherein the ring A is unsubstituted or has one or more halogen atoms by one or more halogen atoms Alkyl, alkoxy, nitrile, nitro, phenyl, carboxyl or sulfonyl radicals is substituted and R is a Alkyl, benzyl, or one having a nitro, styryl, alkyl, alkoxy group or a halogen atom and / or a hydroxyl group substituted or unsubstituted phenyl radical or one with a Nitro group-substituted or unsubstituted styryl radical, a pyridyl or 2-furyl or 2-thiophene radical means, characterized by the fact that an acylamino compound is used of the general formula II NHCOR wherein the ring A is substituted as indicated above and R has the meaning indicated and X means a chlorine or bromine atom, in an inert solvent and in the presence of one catalytic amount of metallic copper or a copper compound a) a temperature in the range of about 150 to 200 ° C in the presence or absence of a inorganic alkali salt as an acid binder, agent or b) a temperature in the range from 130 to 150 ° C. in the presence of an organic base as an acid binder heated. The invention relates to a process for the preparation of compounds of the oxazole series general formula I. C-R wherein the ring A is unsubstituted or one or more alkyl, Alkoxy, nitrile, nitro, phenyl, carboxyl or sulfonyl radicals and R is an alkyl, Benzyl or one with a nitro, styryl, alkyl, alkoxy group or a halogen atom and / or a hydroxyl group substituted or unsubstituted phenyl radical or one with a nitro group substituted or unsubstituted styryl radical, a pyridyl or 2-furyl or 2-thiophene radical. The previously known method for the production of Benzoxazole compounds can generally be divided into two groups, one of which is the o-aminohydroxybenzene compound and the other starting from the o-haloaminobenzene compound. The first method has been the most widely used to date; there are numerous in this context Embodiments described in the literature. These are, for example: '