CS200456B2 - Method of producing derivatives of benzoxazole - Google Patents

Description

(54) A method for producing benzoxazole derivatives

The invention relates to a process for the preparation of novel benzoxazole derivatives which have been found to have valuable pharmacological activity or are useful as intermediates for the preparation of such active compounds.

The invention therefore provides a process for the preparation of the novel benzoxazole derivatives of the general formula (I)

12 wherein the -CR R -COOH group is in the 5 or 6 position of the benzoxazole nucleus, R and R are each hydrogen or C 1 -C 4 alkyl and R ⁴ is cyclohexyl, furyl, thienyl, pyridyl or phenyl, optionally substituted in any available position by one or two halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl or amino, or optionally substituted at two adjacent positions by methylenedioxy groups.

The term alkyl of 1 to 4 carbon atoms, as used herein, means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, butyl, sec-butyl and tert. butyl. Similarly, the terms C 1 -C 4 alkoxy refer to C 1 -C 4 alkyl groups bonded via an oxygen atom.

The term C 1 -C 4 haloalkyl means the C 1 -C 4 alkyl groups substituted by at least one halogen atom, such as chloromethyl, bromomethyl, trifluoromethyl, 2-chloroethyl, pentafluoroethyl, 3-bromopropyl, 2-chlorobutyl and 4- bromo butyl.

In said group of compounds of formula (I), a subgroup preferred for the easy availability of the necessary starting materials comprises compounds wherein the -CR'r 2 -COOH group is in semi200456 of 5 or 6 benzoxazole nucleus, R ⁴ is alkyl of 1 to 4 carbon atoms, cyclohexyl, furyl, thienyl, pyridyl or phenyl optionally substituted at any available position with one or two groups selected from halogen, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl, pentafluoroethyl, C 1 -C 4 monohaloalkyl And R ¹ and R ² are independently hydrogen, methyl or ethyl, as well as their alkali, metal or alkaline earth metal, aluminum or ammonium salts.

Compounds of this type were tested for pharmacological activity and toxicity using a standard animal testing procedure. Such tests have revealed another class of compounds in which the combination of high potency, particularly anti-inflammatory potency, and low toxicity is most prominent. The particularly useful group of compounds having the formula II * * ΛΑζ ^"0 in which the -CH-COOH group is in position 5 or 6 of the benzoxazole nucleus, ^R4 is phenyl optionally substituted with one or two groups selected from halogen, trifluoromethyl, methyl, methoxy , and R ² is hydrogen or most preferably methyl, and includes non-toxic salts of these compounds.

Examples of compounds produced by the process of this invention are: 2- (2-methyl-6-benzoxazolyl) butyric acid 2- (2-n-butyl-6-benzoxazolyl) propionic acid 2-cyclohexyl-5-benzoxazolylacetic acid 2-cyclohexyl- 6-benzoxazolylacetic acid 2- (2-cyclohexyl-5-benzoxazolyl) butyric acid 2- [2- (fur-2-yl) -5-benzoxazolyl] -2-methylpropionic acid, potassium 2- (2- (fur-2) -yl) -6-benzoxazolyl] propionic acid 2- (2- (thien-2-yl) -6-benzoxazolyl] -2-ethylpropionic acid 2- (pyrid-4-yl) -5-benzoxazolylacetic acid 2- (2 2- (pyrazin-2-yl) -5-benzoxazolyl] propionic acid 2- (pyrazin-2-yl) -6-benzoxazolylacetic acid 2- [2- (pyrazin-2-yl) -5-benzoxazolyl] propionic acid 2- (4-Nitrophenyl) -5-benzoxazolylacetic acid 2- (4-aminophenyl-6-benzoxazolylacetic acid 2- [2- (4-3-chloroethylphenyl) -6-benzoxazolyl] propionic acid 2- [2- (4- tert-butoxyphenyl) -6-benzoxazolyl] butyric acid 2- (4-n-butylphenyl) -5-benzoxazolylacetic acid sodium salt.

Examples of preferred compounds produced by the process of the invention are:

A (I) 2-phenyl-5- and 6-benzoxazolylacetic acid

2- (4-chlorophenyl) -5- and 6-benzoxazolylacetic acid 2- (4-methylphenyl) -5- and 6-benzoxazolylacetic acid 2- (4-trifluoromethylphenyl) -5- and 6-benzoxazolylacetic acid 2- (4-methoxyphenyl) ) -5- and 6-benzoxazolylacetic acid 2- (4-bromophenyl) -5- and 6-benzoxazolylacetic acid 2- (4-fluorophenyl) -5- and 6-benzoxazolylacetic acid 2- (3-chlorophenyl) -5- and 6-Benzoxazolylacetic acid 2- (3-methylphenyl) -5- and 6-benzoxazolylacetic acid 2- (3-trifluoromethylphenyl) -5- and 6-benzoxazolylacetic acid 2- (3,4-dichlorophenyl) -5- and 6-benzoxazolylacetic acid 2- (2-Methylphenyl) -5- and 6-benzoxazolylacetic acid 2- (2-chlorophenyl) -5- and 6-benzoxazolylacetic acid 2- (2-methoxyphenyl) -5- and 6-benzoxazolylacetic acid 2- (3 , 4-dimethylphenyl) -5- and 6-benzoxazolylacetic acid

A (II) the sodium, potassium, aluminum and ammonium salts of the acids A (I) mentioned above.

Examples of the most preferred compounds produced by the process of the invention are:

Β (I) 2- (2- (phenyl-5- and 6-benzoxazolyl) propionic acid)

2- (2- (3,4-dimethoxyphenyl) -5- and 6-benzoxazolyl) propionic acid 2- (2- (3,4-methylenedioxyphenyl) -5- and 6-benzoxazolyl) propionic acid 2- (2- (2-chlorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- [2- (2-fluorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- [2- (2-methylphenyl) -5- and 6] -benzoxazolyl] propionic acid 2- [2- (3,4-dichlorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (3,5-dichlorophenyl-5- and 6-benzoxazolyl) propionic acid 2- (2- (2,4-dichlorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (3-chlorophenyl) -5- and 6-benzoxazolyl) propionic acid 2- [2- (3-trifluoromethylphenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (3-fluorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (3-methylphenyl) -5- and 6-benzoxazolyl) propionic acid 2- 2- (4-iodophenyl) -5- and 6-benzoxazolyl] propionic acid

2- (2- (4-chlorophenyl) -5- and 6-benzoxazolyl propionic acid)

2- [2- (2-hydroxy-4-chlorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- [2- (4-bromophenyl) -5- and 6-benzoxazolyl] propionic acid 2- [2- ( 4-nitrophenyl-5- and 6-benzoxazolyl] propionic acid 2- (2- (4-fluorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (3-nitro-4-chlorophenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (4-methylphenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (2-acetylphenyl) -5- and 6-benzoxazolyl) propionic acid 2- (2 - (4-Trifluoromethylphenyl) -5- and 6-benzoxazolyl] propionic acid 2- [2- (4-methoxyphenyl) -5- and 6-benzoxazolyl] propionic acid 2- (2- (4-methylsulfonylphenyl) -5- and 6-Benzoxazolyl] propionic acid 2- (2- (2-methoxyphenyl) -5- e 6-benzoxazolyl] propionic acid

(II) the sodium, potassium, aluminum and ammonium salts of the acids listed above under B (I).

The essence of the preparation of the abovementioned compounds of the general formula (1) by the process according to the invention is that the compound of the general formula (III) is hydrolyzed

R *

(III), wherein r ', R' and R 'are as defined above and a forged carboxyl group; p is R and / or R is hydrogen, optionally with 1, 2, wherein R and / or R is compounds of formula III are novel. their production in parallel application of the invention only in brief. Essentially, the compounds of the formula IV

A is a nitrile or esterifive group of the resulting product of formula (I) and the product is alkylated to the corresponding C 1 -C 4 alkyl compound.

They are described in detail together with method 170 166, and therefore, detailed formula-III produced by cyclization are given herein

XO crV-z (XV) wherein Z is A or a group that can be converted to A and X is either 5 hydrogen or R RCO- and Y is HjN-, or X is hydrogen and Y is R ^CO-NH or R ⁴ CH = N-, wherein in the case of. when X is hydrogen and Y is HgN-, cyclization is carried out in the presence of a cyclizing agent capable of imparting the desired group R * and then if Z in the resulting compound is not identical to group A, it is converted to group A in the usual manner.

When carrying out the preceding cyclization using a compound of formula IV in which X is hydrogen and Y is HgN-, it will be appreciated that if Z is also capable of reacting with the cyclizing agent, the reaction may take Although the undesirable products could be separated from the reaction mixture, it is desirable to use compounds of formula IV in which Z is a group which is not able to react with the cyclizing agent. Therefore, when Z is a group which can be converted to A, Z is preferably hydrogen or halogen and when Z is one of the groups included in group A, Z is preferably a nitrile or esterified carboxyl group.

The cyclization of a compound of formula IV wherein X is hydrogen and Y is R ⁴ CO-NH- or wherein X is R ⁴ CO- and Ϊ is HgN- can be accomplished by heat treatment and / or under acidic conditions, for example in the presence of hydrochloric acid or polyphosphoric acid.

When X is hydrogen and Y is R ⁴ CH = N-, the cyclization can readily be accomplished by treatment with an oxidizing agent such as lead acetate or nickel peroxide.

When using a compound of formula IV wherein X is hydrogen and Y is HgN-, cyclization is normally accomplished by mixing the cyclizing agent with a compound of formula IV, usually in a suitable solvent, which may be water or an organic solvent, for example pyridine, to of room temperature or lower, followed by heating to complete the reaction. Examples of suitable cyclizing agents which may be used are compounds of the formula R ⁴ COOH, (R ⁴ C0) 2 O, R ⁴ COC1 R ⁴ CCKH2, ^R4 CONHNH _2, R ^4, CN, R ⁴ C (OR ') = NH and R ⁴ CC 1 = NR ', wherein R' is alkyl of 1 to 4 carbon atoms.

As noted above, if Z is not a group A, the completion of the cyclization step must be followed by converting the group Z to the desired group A. As is well known to those skilled in the art, many different types of groups can be converted to A functions in the desired compounds produced according to the invention. However, for the purposes of the present invention, it is preferred that when Z is not A, it is hydrogen or halogen. When Z is hydrogen, the compound obtained by the cyclization reaction may be halogenated in a conventional manner, for example by treatment with chlorine, sulfuryl chloride, bromine or N-bromosuccinimide, preferably in the presence of a suitable solvent such as carbon tetrachloride to give the corresponding compound in which Z is halogen. This compound, or the same compound obtained directly from the above cyclization reaction, can then be reacted with an alkali metal cyanide in a suitable diluent or solvent, usually under heat treatment to give a compound of formula III wherein A is CN.

The latter compound, or the same compound obtained directly from the cyclization reaction, can be reacted in a number of ways to convert it to another compound of formula III. For example, nitrile can be reacted with a suitable alcohol under acidic conditions to give a compound of formula III wherein A is an esterified carboxyl group. Similarly, the nitrile can be hydrolyzed with, for example, sulfuric acid to give a compound of formula III wherein A is a carboxamide group. The product of formula (III) in which A is an esterified carboxyl group can be converted to a hydroxymic acid derivative by treatment with hydroxylamine. The acid of formula (I) or a salt thereof can be converted to an ester by treatment with an appropriate alcohol or by treatment with a halide of the appropriate ester moiety or salts thereof if the ester moiety contains a basic nitrogen atom. The acid of formula I or an ester thereof may also be converted to an amide of formula I by reaction with ammonia or an appropriate primary or secondary amine.

The ester of formula (III) may, of course, be hydrolyzed to the corresponding acid of formula (I) by treatment with a suitable hydrolytic agent, for example an inorganic base or an acid.

Hydrolysis of the nitrile or the aforementioned carboxamide with a strong base or acid, such as concentrated hydrochloric acid, yields a compound of formula I.

The acid of formula I can be converted into a salt by treatment with a suitable base such as ammonium, alkylammonium, aralkylammonium, aluminum, alkali metal or alkaline earth metal hydroxide, and of course the salt of formula I can easily be converted to the free acid by treatment with an acid such as hydrochloric acid. or sulfuric.

2

The product of formula I wherein R and / or R is hydrogen may be alkylated to give the corresponding compound of formula I wherein R and / or R is C 1 -C 4 alkyl. The alkylation can be carried out by interaction of an alkali metal derivative of the corresponding benzoxazole dihydrate with an alkyl halide, for example methyl or ethyl iodide.

The compounds of formula I are useful in that they are pharmacologically active.

In particular, these compounds have been shown to have low toxicity and analgesic, antipyretic and / or anti-inflammatory activity, as well as, in certain cases, the ability to inhibit prostaglandin synthesis or release. Previous efficacies have been demonstrated in an animal test generally with doses ranging from 0.1 to 250 mg / kg. For example, in the treatment of humans, doses ranging from 0.1 to 25 mg / kg may be administered, but doses outside this range may also be used by the physician treating the patient. The pharmacologically active compounds of formula (I) may be administered by the enteral or parenteral route, and for this purpose they will usually be formulated into pharmaceutical preparations containing the active ingredient in association with at least one pharmaceutically acceptable carrier. Such formulations will normally consist of the active ingredient mixed with a carrier or dilute carrier, or enclosed or surrounded by a carrier in the form of a capsule, sachet, capsule or other capsule. The carrier may be a solid, semi-solid, or liquid material that serves as a transporter, excipient, coating or environment for the active ingredient. Some examples of carriers that may be used are: lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum, calcium phosphate, liquid paraffin, cacao butter and oil, alginates, tragacanth, gelatin, methylcellulose, polyoxyethylene sorbitan monolauret, methyl- or propyl hydroxybenzoate, ethylcellulose oethanephthalate, low-viscosity acetylcellulose acetate, paraffin wax, mineral waxes, vegetable wax, vegetable gum, silicone rubber, such as liquid polydimethylsiloxane rubber, plasticized or non-plasticized polyvinyl ethyl ester, , crosslinked polyvinyl alcohol or crosslinked partially hydrolyzed polyvinyl acetate.

The compositions of the invention are preferably formulated in dosage units containing 1 to 1000 mg (preferably 25 to 500 mg) of active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories as well as drug dispersing systems, comprising the active ingredient contained in a flexible, unperforated polymeric material through which the drugs can be released by diffusion. More generally, the term dosage unit form *; as used herein means a physically discrete unit containing the active ingredient, generally in admixture with and / or surrounded by a pharmaceutical carrier, and wherein the amount of active ingredient is such that one or more units are normally required for a single therapeutic administration.

In addition to the active ingredient of formula (I), the compositions of the invention may also contain one or more pharmaceutically active ingredients, for example acetylsalicylic acid and its salts, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and indomethacin.

The compositions of the invention may, of course, be adapted to the mode of administration. For oral administration, for example, tablets, pills, capsules, solutions or suspensions may be used; a sterile injectable solution or suspension may be used for parenteral administration; suppositories may be used for rectal administration; creams, solutions or ointments may be used for topical administration. However, any of the foregoing preparations may be formulated in a delayed or sustained release form in a manner well known to those skilled in the art.

The following examples further illustrate the preparation of novel intermediates and novel end products of Formula I.

He did

2- (2-Phenyl-5-benzoxazolyl) propionic acid (a) 2- (4-Hydroxyphenyl) propionitrile

The finely ground 2- (4-aminophenyl) propionitrile (75 g, 0.5 mol) was suspended in concentrated hydrochloric acid (125 mL). The stirred suspension was diazotized at 0-5 ° C with a solution of sodium nitrite (36.23 g, 0.525 mol) in water (60 mL), which was added dropwise over 1-2 hours. The almost clear solution was stirred for an additional 20 minutes at 5-10 ° C, then poured into a stirred, boiling solution of concentrated sulfuric acid (250 mL) in water (2.5 mL).

After 6 minutes, it was cooled in an ice bath and then extracted (4x). The combined ether extracts were extracted with 2N sodium hydroxide solution (6x). The combined alkaline extracts were cooled in an ice bath, acidified with concentrated hydrochloric acid and extracted with ether (3x). The combined ether extracts were washed with brine (3x), dried (Na 2 SO 4) and evaporated to give a dark brown oil (66.7 g) which afforded 2- (4-hydroxyphenyl) propionitrile (59.58 g). mp 112-122 ° C, at a pressure of 16.6625 Pa, mp 41-46 ° C.

Analysis: Calculated: C, 73.44; H, 6.16; N, 9.51.

found: 73.19 «C, 5.91 # H, 9.31% N.

(b) 2- (3-Nitro-4-hydroxyphenyl) propionitrile

A solution of 2- (4-hydroxyphenyl) propionitrile (7.79 g, 0.053 mol) in acetic acid (10 mL) was added over 40 minutes at 7-10 ° C with stirring to 12N nitric acid (8 mL).

During this time, an additional volume of glacial oic acid (10 mL) was added. The resulting yellow suspension was stirred for an additional 30 minutes at 7 to 10 ° C, then an additional 30 minutes at -10 to -15 ° C. The suspension was diluted with water (approximately 90 mL). Filtration gave 2- (3-nitro-4-hydroxyphenyl) propionitrile as a yellow solid (8.43 g), mp 78-81 ° C.

Analysis: Calculated: C 56.24, H 4.19, N 14.57;

Found:% C, 56.29;% H, 4.24;% N, 14.47.

(c) (I) 2- (3-amino-4-hydroxyphenyl) propionitrile

2- (3-Nitro-4-hydroxyphenyl) propionitrile (123.8 g, 0.64 mol) was suspended in absolute ethanol (950 mL) and added over 20 minutes with cooling to a stannous chloride dihydrate solution (437.8 g, 1.94 mol) in concentrated hydrochloric acid (591 mL, 7 mol). The addition was rapid enough that the temperature of the reaction mixture did not exceed 20 ° C. The mixture was stirred for an additional 19 hours at room temperature. The resulting ice-mixed solution (1.75 kg) was added over 1 hour to a cooled solution of sodium hydroxide (650 g) in water (600 mL). The temperature of the reaction mixture was maintained at 15-20 ° C during the addition. The mixture was stirred for an additional hour and the pH was then adjusted to 6 by addition of concentrated hydrochloric acid. The resulting suspension was filtered, the filtrate was saturated with sodium chloride and then extracted with ether (6x). The combined ether extracts after drying (Na 2 SO 4) and evaporation gave a solid (69.15 g), which was suspended in chloroform and extracted with 2M hydrochloric acid (6x). The combined acid extracts were neutralized to pH 7-8 by addition of sodium bicarbonate. The resulting suspension was extracted with ether (4x). The combined ether extracts were washed twice with water, dried (Na ₂ SO 4) and evaporated to give 2- (3-amino-4-hydroxyphenyl) propionitrile as a light brown solid (62.85 g), mp 110-112 ° C.

% H, 6.21;% N, 17.27.

Found:% C, 66.45;% H, 6.09;% N, 16.99.

(c) (II) 2- (3-Amino-4-hydroxyphenyl) propionitrile was also prepared by the following method:

2- (3-Nitro-4-hydroxyphenyl) propionitrile (38.4 g, 0.2 mol) was suspended in absolute ethanol (250 mL) and hydrogenated at 0.4 MPa at room temperature to 10% palladium on carbon. Hydrogenation was complete in 3.8 hours. The catalyst was filtered off. Evaporation of the filtrate gave 2- (3-amino-4-hydroxyphenyl) propionitrile (17 g), m.p., 10 ° C.

(d) 2- (3-Benzamido-4-hydroxaphenyl) propionitrile

Benzoyl chloride (27.09 g, 0.19 mol) was added over 20 minutes while cooling to 0 to 3 ° C to a stirred solution of 2- (3-amino-4-hydroxyphenyl) propionitrile (28.35 g, 0.175 mol) in dry pyridine (200 mL). When the addition was complete, the reaction mixture was heated at 100 ° C for 1 hour. Evaporation under reduced pressure gave crude 2- (3-benzamido-4-hydroxyphenyl) propionitrile as an oil.

(s) 2- (2-Phenyl-5-benzoxazolyl) propionitrile

The oil mentioned in (d) above was boiled for 30 minutes so that the vapor temperature over the oil was raised to 130 ° C during this time. After cooling, the solution solidified. Recrystallization of the solid from methanol gave 2- (2-phenyl-5-benzoxazolyl) propionitrile (27.65 g), mp 118-120 ° C.

H, 4.87; N, 11.28.

Found: C, 77.33; H, 5.11; N, 11.34.

(f) 2- (2-Phenyl-5-benzoxazolyl) propionic acid

A solution of 2- (2-phenyl-5-benzoxazolyl) propionitrile (24-g, QP96 mol) in concentrated hydrochloric acid (220 mL) was refluxed for 2.5 hours. The mixture was poured onto ice with water (1 liter). The precipitated 2- (2-phenyl-5-benzoxazolyl) propionic acid was filtered off and washed well with water. The dry acid weighed 23 g and had m.p. 177-179 ° C.

Analysis: Calculated: C 71.89, H 4.90, 5.24 96 N;

Found: C, 72.13; H, 4.95; N, 5.39.

Example 2

In a similar manner to Example 1, the following compounds were synthesized:

(a) 2- (2-p-Fluorophenyl-5-benzoxazolyl) propionic acid acid, m.p. 162 to Mp 164 ° C. Analysis: calculated: 67.36% C, 4.24% H, 4.91% N; found: 67.58% C, 4.45% H, 5.07% N. (b) 2- (2-p-Chlorophenyl- 5-benzoxazolyl) propionic acid acid, m.p. 188 to 191 ° C. Analysis: calculated: 63.68% C 4.00% H, 4.64% N; found: 63.50% C, 4.16% H 4.72% N. (c) 2- (2-m-Chlorophenyl- 5-benzoxazolyl) propionic acid acid, m.p. 173 to 175 ° C. Analysis: calculated: 63.68% C, 4.00% H, 4.64% N; found: 63.50% C, 4.01% H, 4.75% N. (d) 2- (2-p-Methylphenyl) -5-benzoxazolyl) propionic acid acid, m.p. 166 to Mp 168 ° C. Analysis: calculated: 72.58% C, 5.37% H, 4.97% N; found: 72.36% C, 5.46% H, 5.40 96 N. (e) 2- (2-m-Methylphenyl) -5-benzoxazolyl) propionic acid acid, m.p. 155 to 157 ° C. Analysis: calculated: 72.58% C, 5.37% H, 4.97% M; found: 72.39% C, 5.61% H, 5.14% N. (f) 2- (2-o-Methylphenyl) -5-benzoxazolyl) propionic acid acid, m.p. 107 to Mp 110 ° C. Analysis: calculated: 72.58% C, 5.37% H, 4.97% N; found: 72.54% C 5.59% H, 4.77% N.

(g) 2- (2-p-Methoxyphenyl-5-benzoxazolyl) propionic acid, mp 189-191 ° C.

Analysis: calculated: found: 68.67% C, 68.42% C, H 5.08, H 5.36, 4.71 9 4.72 9 ί N; 6 N. Analysis: • calculated: 64.3% C, 3.7% H, 9.4% N; found: 64.1% C, 3.5% H, 9.5% N. Analysis: calculated: 60.5% C, 3.8% H, 4.4% N; found: 60.65% C, 4.06% H, 4.5% N.

(h) 2- (2-p-Chlorophenyl-5-benzoxazolyl) propionitrile, mp 150-153 ° C.

Analysis: Calculated: C, 67.96; H, 3.92; N, 9.90.

Found:% C, 67.57;% H, 3.96;% N, 9.25.

(i) 2- (2-p-Acetylphenyl-5-benzoxazolyl) propionic acid, mp 207-209 ° C.

Analysis: Calculated: C 69.90, H 4.85, N 4.53.

Found: C 69.72, H 4.75, K 4.50.

(j) 2- (2-Amino-5-benzoxazolyl) propionic acid, mp 225-229 ° C.

Example 3 (a) 2- (2-p-Bromophenyl-5-benzoxazolyl) propionic acid, one third hydrochloride.

This compound was prepared using the procedure described in Example 1. The product, m.p. 195-197 ° C, contained one third of the hydrogen chloride molecule.

Analysis: Calculated: C 53.60, H 3.46, N 3.90.

Found: C, 53.25; H, 3.37; N, 3.86.

(b) 2- (2-p-Bromo-phenyl-5-benzoxazolyl) -propionic acid sodium salt

2- (2-p-Bromophenyl-5-bertzoxazolyl) propionic acid, one third of the hydrochloride (4.3 g, 0.012 mol) was ground in 1N sodium hydroxide (20 mL). An equal volume of chloroform was added to the suspension. The suspension was stirred, then filtered. Recrystallization of the solid residue from aqueous ethanol gave 2- (2-p-bromophenyl-5-benzoxazolyl) propionic acid sodium salt, m.p. > 316 ° C.

H, 3.01; N, 3.8%.

Found:% C, 51.99;% H, 3.17;% N, 4.07.

Example 4

2- (5-Benzoxazolyl) propionic acid (a) 2- (3-Amino-4-hydroxyphenyl) propionic acid ethyl ester

A solution of 2- (3-amino-4-hydroxyphenyl) propionic acid (13.82 g, 0.076 mol) in absolute ethanol (50 mL) was saturated with hydrogen chloride gas. The solution was refluxed for 5.5 hours. Hydrogen chloride was introduced into the solution during the first 1.75 hours under reflux. Evaporation of the solution under reduced pressure gave an oil. The oil was dissolved in water (50 mL) and adjusted to pH 8 by addition of sodium bicarbonate. The solution was extracted with ether (3x). The combined ether extracts were dried and evaporated to an oil. Distillation of the oil afforded 2- (3-amino-4-hydroxyphenyl) propionic acid ethyl ester (8.43 g), m.p. 154-156 ° C / 33.3 Pa, mp 79-82 ° C.

H, 7.22; K, 6.69.

Found:% C, 62.48;% H, 7.24;% N, 6.79.

(b) 2- (3-Formamido-4-hydroxyphenyl) propionic acid ethyl ester

A solution of 2- (3-amino-4-hydroxyphenyl) propionic acid ethyl ester (2 g, 0.01 mol) in 98% formic acid (10 mL) was refluxed for 1.5 hours. The solution after evaporation under reduced pressure gave an oil. The oil was stirred in ether (10 mL). Filtration gave 2- (3-formamido-4-hydroxyphenyl) propionate ethyl ester. acid as a white solid (0.8 g), mp 102-104 ° C.

(c) 2- (5-Benzoxazolyl) propionic acid ethyl ester

2- (3-Formamido-4-hydroxyphenyl) propionic acid ethyl ester (11.39 g, 0.048 mol) was heated to 250 ° C * 5 ° C in an oil bath for 20 minutes. After cooling, the oil was dissolved in ethyl acetate. The solution was washed with 2N sodium hydroxide solution (4x) and then with water (2x). The solution after drying (Na ₂ SO ₄ ) and evaporation gave 2- (5-benzoxazolyl) propionic acid ethyl ester as an oil (6.55 g). (d) 2-5-Benzoxazolyl) propionic acid

A suspension of 2- (5-benzoxazolyl) propionic acid ethyl ester (5.75 g, 0.026 mol) in a solution of sodium hydroxide (1.04 g, 0.026 mol) in water (150 mL) was stirred at room temperature for 4.4 hours . The cloudy solution obtained was clarified by washing three times with ethyl acetate before the pH of the solution was adjusted to 4 by the addition of concentrated hydrochloric acid. The following cloudy solution was saturated with sodium chloride and then extracted with ethyl acetate (3x). The combined acetate extracts were washed once with aqueous sodium chloride solution, dried (Na 2 SO 4) and evaporated. The remaining solid was stirred in boiling carbon tetrachloride and the hot suspension was filtered. The filtrate by evaporation gave 2- (5-benzoxazolyl) propionic acid as a solid (1.24 g), mp 126-128.5 ° C.

Example 5

2-Phenyl-benzoxazolylacetic acid

A solution of 2-phenyl-5-benzoxazolylacetonitrile (8.9 g) - prepared according to the method described in Example 1 (e) - in concentrated hydrochloric acid (80 mL) was heated on a steam bath for 2.5 hours. The solution was then diluted with ice-water and allowed to stand. The solid product was crystallized from toluene to give white crystals of 2-phenyl-5-benzoxazolylacetic acid, mp 175 ° C.

For C ^ HH,,,,: C, 71.1; H, 4.4; N, 5.5; Found: C, 71.0; H, 4.4; N, 5.6.

Example 6

2-Phenyl-benzoxazolylacetic acid (a) 6-14-ethyl-2-phenylbenzoxazole

Benzoyl chloride (79 mL) was slowly added to a stirred suspension of 6-amino-m-cresol (83 g) in pyridine (600 mL). The temperature was kept below 5 ° C. The solution was refluxed for 2 hours, then evaporated to dryness to give an oil. This oil was extracted with aqueous 2N sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid. The solid N- (2'-hydroxy-4'-methylbenzanilide), m.p. 170 ° C, was filtered off. This product was heated when water was released. The resulting liquid was cooled, the solid product was pulverized and poured into petroleum ether. The solution was mixed with activated carbon and the filtrate evaporated to dryness to give 6-methyl-2-phenyl-benzoxazole, m.p. 93 ° C.

(b) 6-Bromomethyl-2-phenylbenzoxazole

N-Bromosuccinimide (25.9 g) was added to a cooled solution of 6-methyl-2-phenylbenzoxazole (30 g) in carbon tetrachloride (250 mL). After addition of benzoyl peroxide (500 mg), the mixture was refluxed for 3 hours in the presence of ultraviolet light. The solid residue was filtered off. The filtrate was evaporated somewhat, decolourised with charcoal and cooled. The crystals that formed were recrystallized from benzene to give 5-bromomethyl-2-phenyibenzoxazole, m.p. 162 ° C.

(c) 2-Phenyl-6-benzoxazolylacetonitrile

A mixture of 6-bromomethyl-2-phenylbenzoxazole (40 g) and sodium cyanide (7.4 g) in dry dimethylformamide (800 mL) was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate evaporated to dryness. The solid was recrystallized to give 2-phenyl-6-benzoxazolylacetonitrile as white crystals, mp, 144 ° C.

(d) 2-Phenyl-6-benzoxazolylacetic acid

A solution of 2-phenyl-6-benzoxazolylaoetonitrile (11 g) in concentrated hydrochloric acid200456

1.0 ml (100 ml) was heated on a steam bath for 1 hour. The solution was then cooled. The resulting solids were filtered and partitioned between aqueous sodium bicarbonate and chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The chloroform extract was evaporated to dryness. Recrystallization from toluene gave the residue white crystals of 2-phenyl-6-benzoxazolylacetic acid m.p. 170 ° C.

Analysis: for C, HH %NO vyp requires: C, 71.1; H, 4.4; N, 5.4; Found:% C, 71.0%;% H, 5.5%;

Example 7

2- (2-Phenyl-6-benzoxazolyl) propionic acid ethyl ester

A solution of 2-phenyl-6-benzoxazolylacetic acid ethyl ester (34 g) in ether (200 mL) was added to a stirred solution of KaNHg (from 3.2 g sodium) in liquid ammonia (500 mL). minutes, then a solution of methyl iodide (8.5 mL) in ether (10 mL) was quickly added. When the reaction mixture was decolorized, the reaction was quenched by addition of excess ammonium chloride. The mixture was evaporated to dryness and the residue was extracted with ether. The ether solution was evaporated to dryness to give white crystals of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester, mp 46 ° C.

Analysis: Calculated: C, 73.2; H, 5.8; N, 4.7; Found: 73.0% C, 5.7% H. 5.0% N.

A solution of the latter compound (15 g) in concentrated hydrochloric acid (150 mL) was heated in a water bath for 6 hours. The solution was cooled and the resulting crystals were filtered and recrystallized from ethanol / water to give 2- (2-phenyl-6-benzoyl-oxazolyl) -propionic acid, mp 132 ° C.

Analysis: Calculated: C, 71.9; H, 4.9; N, 5.2; Found: 71.7% C, 5.0% H, 5.3 «N.

Example 1 a d 8

2- (2-p-Chlorophenyl-6-benzoxazolyl) propionic acid (a) 2- (3-Hydroxy-4-aminophenyl) propionic acid hydrochloride

A solution of 2- (2-phenyl-6-benzoxazolyl) propionic acid ethyl ester (10 g) in concentrated hydrochloric acid (150 mL) was heated at 160 ° C for 24 hours. The resulting mixture was evaporated to dryness and the residue was dissolved in water. This solution was washed with chloroform then evaporated to dryness to give 2- (3-hydroxy-4-aminophenyl) propionic acid hydrochloride as a white powder, m.p. 170 ° C (dec.).

(b) 2- (3-Hydroxy-4-aminophenyl) propionic acid ethyl ester

A solution of 2- (3-hydroxy-4-aminophenyl) propionic acid (5 g) in ethanol (100 mL) was saturated with hydrogen chloride and the resulting solution was refluxed for 6 hours. The solution was evaporated to dryness, the residue was dissolved in ethanol and this solution neutralized with sodium hydroxide solution. The evaporation residue was dissolved in chloroform and the solution was washed with water. Evaporation of the chloroform solution gave 2- (3-hydroxy-4-aminophenyl) propionic acid ethyl ester, mp 114-115 ° C.

H, 7.2%; N, 6.7%. Found: C 63.2%, H 7.2%, N 6.9%.

1 (c) 2- (2-p-Chloro-phenyl-6-benzoxazolyl) -propionic acid ethyl ester

A solution of 2- (3-hydroxy-4-aminophenyl) propionic acid ethyl ester (2.5 g) in pyridine (15 mL) was mixed with p-chlorobenzoyl chloride (1.65 mL) at 5 ° C. After stirring at room temperature for 2 hours, the solution was evaporated to dryness.

The residue was heated to 220 ° C until water was released, then cooled. This gave 2- (2-p-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester.

(d) 2- (2-p-Chlorophenyl-6-benzoxazolyl) propionic acid

A solution of 2- (2-p-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester (4 g) in aqueous sodium hydroxide (30 mL) was heated on a steam bath for 1/2 hour. After cooling, the black solution was washed with chloroform. After acidifying the black solution with hydrochloric acid, the mixture was extracted with chloroform. This solution after evaporation gave 2- (2-p-chlorophenyl-6-benzoxazolyl) propionic acid, m.p. 196 ° C.

H, 4.0; N, 4.6; Cl, 11.8. Found: C 63.9%, H 4.2%, N 4.8%, Cl 12.0.

The following compounds were prepared in a similar manner:

(a) 2 - [2- (3,4-Methylenedioxyphenyl) -5-benzoxazolyl-3-propionic acid ethyl ester, m.p.

to 79 ° C.

Analysis; calculated: 67.25% C, 5.0% H, 4.1% N;

Found:% C, 67.1;% H, 5.05;% N, 4.4%.

(t) 2- [2- (3,4-Methylenedioxyphenyl) -5-benzoxazolyl] propionic acid, mp, 185-188 ° C.

Analysis: Calculated: C 65.5%, H 4.2%, N 4.5%;

found: C 65.4, H 3.9, N 4.7.

(c) 2- [2- (3,4-Dichlorophenyl) -5-benzoxazolyl] propionic acid, mp 169-173 ° C.

Analysis: Calculated: C 57.1%, H 3.3%, N 4.2%;

Found: C 56.9, H 3.4%, N 4.1%.

(d) 2- [2- (3,4-Dichlorophenyl) -5-benzoxazolyl] propionic acid, b, t, 151-153 ° C.

Analysis: Calculated: 57.1% 0. 3.3% H, 4.2% N;

Found: C 57.1%, H 3.3%, N 4.4%.

(e) 2- (2-p-Methylsulfonylphenyl-5-benzoxazolyl) propionic acid ethyl ester, mp 141-142 ° C.

Analysis: calculated: 61.1% C, 5.1% H, 3.75% N;

found; 61.2% C, 5.1% H, 3.6% N.

(f) 2- [2- (2-Furyl) -5-benzoxazolyl] propionic acid, mp 160-162 ° C.

Analysis: Calculated: C 65.4%, H 4.3%, N 5.4%;

Found: C 65.3, H 4.4, N 5.4%.

(g) 2- (2-Cyclohexyl-5-benzoxazolyl) propionic acid, mp 115-117 ° C.

Analysis: Calculated: C, 70.30; H, 7.00; N, 5.12.

Found:% C, 70.58;% H, 6.86;% N, 5.35.

(h) 2- (2-m-Trifluoromethylphenyl-5-benzoxazolyl) propionic acid, mp 144-147 ° C.

Analysis: calculated: 60.89% C, found: 61.05% C,

H, 3.60; N, 4.17; H, 3.87; N, 4.41.

(i) 2- [2- (2-Thienyl) -5-benzoxazolyl] propionic acid, m.p. 161-163 ° C;

Analysis:

calculated:

found:

, 52% C, 61.72% C,

H 4.05, H 4.19,

N, 5.12; 5.07% N.

(j) 2- (2-o-Chlorophenyl-5-benzoxazolyl) propionic acid, m.p. 101-103 ° C.

Analysis:

calculated:

found:

63.68% C, 63.80% C,

H 4.01, H 4.22,

4.64% N; 4.82% N.

(k) 2- (2-p-Trifluoromethylphenyl-5-benzoxazolyl) propionic acid, mp 165-168 ° C.

Analysis:

calculated: found ;:

60.89% C, 60.76% C,

3.60% H, 3.88% H,

4.17% N; 4.34% N.

(1) 2- (2-p-Iodophenyl-5-benzoxazolyl) propionic acid, m.p.

205 DEG-208 DEG.

Analysis:

calculated: found:

48.87% C, 48.91% C,

H 3.07, H 2.93,

32.27% I, 32.51% I,

3.56% N; 3.26% N.

(m) 2- (2-m-Fluorophenyl-5-benzoxazolyl) propionic acid, b

mp 135-141 ° C.

Analysis:

calculated: found:

67.36% C, 67.46% C,

H 4.24, H 4.37,

4.91% N; 5.11% N.

(n) 2- [2- (3,5-Dichlorophenyl) -5-benzoxazolyl] propionic acid, b, t

Mp 161-165 ° C.

Analysis: Calculated: C, 57.6; H, 3.29; N, 4.16.

Found: C 57.13, H 3.51, N 4.22.

(o) 2- (2-o-Fluorophenyl-5-benzoxazolyl) propionic acid, mp 180-183 ° C.

Analysis: Calculated: C, 67.36; H, 4.24; N, 4.91;

Found:% C, 67.16;% H, 4.50;% N, 4.91.

(p) 2- (2-p-Fluorophenyl-6-benzoxazolyl) propionic acid, mp 147 ° C.

Analysis: Calculated: C 67.4%, H 4.2%, N 4.9%, F 6.7;

Found: C 67.2%, H 4.4%, N 4.9%, F 6.8%.

(q) 2- (2-p-Chlorophenyl-5-benzoxazolyl) propionic acid, mp 188-191 ° C.

Analysis: calculated:

found:

63.68% C, 63.50% 0,

H 4.00, H 4.16,

4.64% N; 4.72% N.

Example 9

2- (2-o-Chlorophenyl-6-benzoxazolyl) propionic acid (a) 2- (2-o-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester

A solution of o-chlorobenzaldehyde (4.3 g) and 2- (3-hydroxy-4-aminophenyl) propionic acid ethyl ester (6 g) was heated in toluene (100 mL) while the water formed during heating was collected with use of Dean-Stark apparatus. After 30 minutes the solution was evaporated to dryness.

The residue was dissolved in acetic acid (100 mL), lead acetate (15 g) was added, and the solution was heated on a steam bath for 1 hour. The solution was poured into ice-water and extracted with ether to give an oil, 2- (2-o-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester, a sample of which gave a satisfactory microanalysis.

(b) 2- (2-o-Chlorophenyl-6-benzoxazolyl) propionic acid

The 2- (2-o-chlorophenyl-6-benzoxazolyl) propionic acid ethyl ester prepared according to (a) was stirred with sodium hydroxide solution (50 mL). After 1/2 hour the solution was evaporated to dryness. Acidification and recrystallization from ether gave 2- (2-o-chlorophenyl-6-benzoxazolyl) propionic acid, mp 108-110 ° C.

Analysis calculated for C18 H18 ClNO4: C, 63.7; H, 4.0; Found: C, 63.5;

4.6% N, 4.8% N,

11.8% Cl; 12.0% Cl.

Example 10

2- [2- (3-Pyridyl) -5-benzoxazolyl] propionic acid

In the same manner as described in Example 1, the above acid was prepared and recrystallized from dimethylformamide-ethanol, m.p. 197-200 ° C.

Analysis: Calculated: C, 67.2; H, 4.5; N, 10.4.

Found: C 67.3%, H 4.3%, N 10.3%.

The following compounds were prepared in the same manner:

(a) 2- [2- (4-Pyridyl) -5-benzoxazolyl] propionic acid, mp 247-250 ° C.

Analysis:

calculated: found:

2% C, 66.9% C,

4.5% H, 4.8% H,

10.4% N; 10.2% N.

(b) 2-? - (2-Pyridyl) -5-benzoxazolyl-3-propionic acid, m.p. 177-179 ° C.

Analysis:

calculated:

found:

67.2% C, 67.0% C,

4.5% H,

4.5% H,

10.4% N; 10.2% N.

(c) 2- (2-p-Chlorophenyl-5-benzoxazolyl) propionic acid, mp 241-242 ° C.

Analysis: Calculated: C 62.61, H 3.50, K 4.86;

Found:% C, 62.89;% H, 3.59;% N, 4.92.

They did

Sodium salt of 2- (2-p-chlorophenyl-5-benzoxazolyl) propionic acid monohydrate

Sodium bicarbonate (1.95 g) was added to a solution of 2- (2-p-chlorophenyl-5-benzoxazolyl) propionic acid (7 g) in a mixture of methanol (100 mL), chloroform (50 mL) and water (60 mL). ).

The resulting solution was evaporated to give a white solid. This solid was washed with chloroform (100 mL), filtered and dried to give the desired sodium salt monohydrate, mp 312-314 ° C.

Analysis: Calculated: C 56.23, H 3.83, N 4.09;

Found: C 56.65, H 3.50, N 3.99.

Example 12

2- (2-Methyl-5-benzoxazolyl) propionic acid (a) 2- (3-Acetamido-4-hydroxyphenyl) propionic acid ethyl ester

A solution of 2- (3-amino-4-hydroxyphenyl) propionic acid ethyl ester (10.46 g) and acetic anhydride (546 g) in dry pyridine (50 mL) was heated on a steam bath for 1.25 hours. The reaction mixture was poured into water (500 mL), leaving an oil. After cooling, the oil solidified. The solid was removed by filtration and washed with water. After drying, 2- (3-acetamido-4-hydroxyphenyl) propionic acid ethyl ester (8.25 g), m.p. 137-141 ° C, was obtained.

H, 6.82; N, 5.57. Found: C, 61.96. H, 6.63; N, 5.81.

(b) 2- (2-Methyl-5-benzoxazolyl) propionic acid ethyl ester

This compound was prepared according to the method described in Example 4 (c) from 2- (3-acetamido-4-hydroxyphenyl) propionic acid ethyl ester.

(c) 2- (2-Methyl-5-benzoxazolyl) propionic acid

This compound was prepared from 2- (2-methyl-5-benzoxazolyl) propionic acid ethyl ester using Method 4 (d), mp 115-117 ° C.

H, 5.40; N, 6.82. Found: C, 64.15; H, 5.43; M, 6.85.

Example 13

2- (2-Phenyl-5-benzoxazolyl) isobutyric acid

Reaction of 2- (2-phenyl-5-benzoxazolyl) propionitrile with methyl iodide as described above. in Example 7, 2- (2-phenyl-5-benzoxazolyl) isobutyronitrile was obtained, which was treated with concentrated hydrochloric acid as described in Example 1 (f). gave 2- (2-phenyl-5-benzoxazolyl) isobutyric acid, m.p. 92-95 ° C.

N, 10.7. Found: C, 77.6; H, 5.3; N, 10.45.

In the following examples of pharmaceutical compositions of the invention, the term medicament is used to refer to 2- (2-p-chlorophenyl-5-benzoxazolyl) propionic acid.

However, this compound may be replaced by any other active compound of formula I and the amount of medicament may be increased or decreased depending on the degree of effectiveness of the medicament.

Example 14

Tablets, each containing 100 mg of medicament, are prepared as follows:

medicament 100 mg potato starch 38 mg lactose 25 mg ethylcellulose (as a 20% solution in raw alcohol) 2 mg alginic acid 7 mg magnesium stearate 1 mg talc 2 mg

* total 175 mg

The medicament, starch and lactose are sieved through a No. 44 mesh B.S.S. e mixed together.

The ethylcellulose solution is mixed with the dust obtained and sieved through a No. 12 mesh B.S, S.

The obtained granules are dried at 50-60 ° C and then passed through a No. 16 mesh B.S.S. Alginic acid, magnesium stearate and talc, which are first passed through a No. 60 mesh B.S.S. are added to the granules, mixed and compressed on a tabletting machine weighing 175 mg.

Example, 5

Capsules each containing 200 mg of medicament are prepared as follows: lactose magnesium stearate

200 mg mg 2 mg

Medikament. The lactose n magnesium stearate is sieved through a No. 44 mesh B.S.S. and filled in 250 mg in hard gelatin capsules.

Example 16

Injectable solutions, one of them? each contains 100 mg of honey and cameras. ' in 5 ml of solution are prepared as follows.

me d i stove 100 mg h, v: oxide sodium (10% solution) 0.3. for injection to 5 ml K m <· tikám ·; ntu usp ^ n to ······ 'nu ’E water is added after drops while stirring solution b.yd sodium. ; octide medicament will not pass into solution. pH of the solution is adjusted to 8.0 to m.p.

The solution is filtered through a bacterial filter and filled into a pre-made solution. The ampoules are then hermetically sealed as well as those of the pellets.

Example 1 of ‘7 suppositories, each containing 25C mg of medicament, are prepared as follows!

medicament? 5C rag coke butter up to 2,000 mg

The medicament, after sieving through a No. 60 mesh B.S.S. sieve, is suspended in cocoa butter pre-thawed using as little heat as possible. The mixture is then poured into a chip, metal mold with a normal capacity of 2 g and allowed to cool.

Claims (1)

P 5 1 li * T OF THE INVENTION A process for the preparation of benzoxazole derivatives of the general formula I M— • A. «In — COOH Wherein the -CR R 1 -COOH group is in the 5 or 6 position of the benzoxazole nucleus, R and R are independently hydrogen or C 1 -C 4 alkyl and R * is cyclohexyl, furyl, thienyl, pyridyl or phenyl, optionally substituted in any free position by one or two halogen atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms or amino, or optionally substituted at two adjacent positions-methylenedioxy groups, and their nontoxic salts 200 (156) by hydrolyzing a compound of formula III N-cr'r ² -a (III); A in which R, R 'and R ⁴ are as defined above and A is a nitrile or esterified carboxyl group, and in the case where the resulting product of the formula I is S and / or R is hydrogen, the product is optionally alkylates to the corresponding compound (12) of formula (I) wherein R and / or R is C 1 -C 4 alkyl.