JPS6044304B2 - Method for producing phenylpropionic acid derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing a novel lath compound.

Furthermore, the present invention relates to a method for producing a compound that is effective in treating inflammation and also exhibits strong analgesic and antipyretic effects. More particularly, this invention relates to a process for the preparation of 2-[4-(benzoxazol-2-yl)phenyl]propionic acid, its non-toxic pharmaceutically acceptable salts. A novel benzoxazole phenylpropionic acid for use in the treatment of conditions symptomatically evidenced by pain, fever, and inflammation occurring as an essential or incidental phenomenon is represented by the following formula: H-°C ■ River Formula I This compound is a highly potent anti-inflammatory agent.

Regarding this compound, in addition to the racemate and levorotatory isomer, what is interesting is the 'd' (dextrorotatory) isomer;
(d)-2-[4-(benzoxazol-2-yl)phenyl]propionic acid.

It should be noted that in addition to the free acids, belonging to a more preferred embodiment of this invention are the corresponding pharmaceutically acceptable addition salts. The term pharmaceutically acceptable addition salts refers to salts derived from pharmaceutically acceptable inorganic and organic bases.

Suitable salts include alkali metal salts such as sodium, potassium, lithium, magnesium, calcium,
Alkaline earth metal salts such as ammonium and ethylamine, triethylamine, ethanolamine, diethanolamine, diethylaminoethanol, ethylenediamino, pentylamino, procaine, pyrrolidine, piperidine, morpholine, 1-ethyl-piperidine, 2
- Organic amino acids such as piperidine, ethanol, etc. are included. The benzoxazole phenylpropionic acid of the present invention has high anti-inflammatory, analgesic and antipyretic effects.

It is of value in the treatment of arthritic and dermatological diseases or similar situations in response to anti-inflammatory drugs. Generally it is needed in a wide variety of situations where one or more symptoms of inflammation, fever, or pain are displayed. This category includes diseases such as osteoarthritis, osteoarthritis, gout, infectious arthritis, rheumatic fever and inflammatory conditions of the ocular system. For these purposes, the compounds of the invention may be administered orally, topically, parenterally, by inhalation spray, in unit dosage amounts containing non-toxic, pharmaceutically acceptable common carriers, adjuvants and excipients. It is taken by formula or rectally.

The term parenteral as used herein refers to subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques. includes. In addition to treating warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the invented compounds are useful for treating humans. Pharmaceutical compositions containing the active ingredient are in a form suitable for oral use.

For example, tablets, lozenges, confections! tablets, aqueous or oily suspensions, dispersions and granules, emulsions, hard or soft capsules, syrups, elixirs. Compositions intended for oral use may be prepared by any method known in the art of pharmaceutical formulation;
It is a pharmaceutically elegant and palatable preparation containing one or more from the group of flavorants, fragrances, colorants, preservatives, etc. Tablets contain the active ingredient in admixture with excipients which are non-toxic, pharmaceutically acceptable and suitable for the manufacture of tablets. These additives include, for example, inactive excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, thickening and disintegrating agents such as corn starch, alginic acid, starch, gelatin, and gum arabic. binders such as magnesium stearate, stearic acid, and lubricants such as talc. The tablets may be uncoated or coated by known techniques to delay disintegration (disintegration in the gastrointestinal tract) and absorption, thereby prolonging their action. For example, glyceryl monosteare! time delay substances such as glyceryl distearate are used. Forms for oral use are also labeled as hard or soft gelatin capsules.

In the former, the active ingredient is mixed with inactive solid excipients, such as, for example, calcium carbonate, calcium phosphate, kaolin, while in the latter, the active ingredient is mixed with water or, for example, peanut oil,
Mixed with an oily medium such as peanut oil, liquid baraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.

Such additives are, for example, suspending agents such as carboxymethylcellulose, sodium, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidine, tragacanth, gum arabic; dispersing agents or wetting agents are lecithin; naturally occurring phospholipids such as polyoxyethylene stearate, condensation compounds of alkylene oxide and fatty acids such as polyoxyethylene stearate, condensation compounds of ethylene oxide and long chain aliphatic alcohols such as heptadecaethylene oxycetanol, polyoxyethylene 3 is a condensation compound of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as sorbitol monooleate; It is a condensation compound with a partial ester. The aqueous suspensions described above may also contain one or more preservatives, such as ethyl, n-propyl, p-hydroxybenzoic acid, coloring agents, flavoring agents, and sweetening agents such as sucrose and saccharin. Oily suspensions are formed by suspending the active ingredients in a vegetable oil, such as arachis oil, olive oil, coma oil or coconut oil, or in a mineral oil such as liquid paraffin.

Oily suspensions contain a thickening agent such as peace wax, hard paraffin, and cetyl alcohol. Sweeteners and flavoring agents such as those mentioned above may be added to create a palatable oral preparation. These formulations are preserved with the addition of antioxidants such as ascorbic acid. Dispersible powders and granules suitable for preparation of aqueous suspensions by the addition of water are prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional additives such as sweeteners, flavoring agents, and coloring agents may also be added. The formulations of the invention also take the form of oil-in-water emulsions.

The oil phase is a vegetable oil such as olive oil, peanut oil or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth, naturally occurring phospholipids such as soybean lecithin, esters and partial emulsifiers derived from fatty acids and hexitol anhydrides such as sorbitan monooleate. esters, as well as the aforementioned partial esters such as polyoxyethylene sorbitan monooleate and -
It is a condensation compound with ethylene oxide. Emulsifiers can also include sweeteners and flavoring agents. Syrups and elixirs are formed with sweetening agents such as glycerol, sorbitol, and sucrose.

The formulation may also contain laxatives, preservatives, flavoring agents, and coloring agents.The formulation takes the form of a sterile injectable preparation, eg, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents such as those mentioned above. formed by. The sterile injectable preparation is also a sterile injectable solution or suspension in a nontoxic parenterally acceptable excipient or solvent. For example, 1.
There is a solution in 3-butanediol. Among the acceptable excipients and solvents used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are generally employed as a solvent or suspending medium. For this purpose, a variety of bland fixed oils may be employed including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are utilized in injectable formulations. Compounds of the invention may also be administered in the form of rectal suppositories.

These formulations are prepared by mixing the drug with suitable non-irritating excipients. The excipient is solid at room temperature but liquid at rectal temperatures, where it dissolves and releases the drug. Such substances are cocoa milk fat and polyethylene glycols. For topical use, creams, ointments, jellies, solutions, suspensions, etc. containing anti-inflammatory agents are used. 1
Doses of 0.5 m9 to 140 mg/kg body weight per day are effective in the treatment of the pathologies indicated above.

(25 mg to 7 yTrL per patient per day), e.g.
Administration of about 0.1 to 50 mg of the compound per kg of body weight per day effectively treats inflammation and produces antipyretic and analgesic effects. (5mg to 3mg per patient per day)
5fTn. s) Effectively about 1W per kg of body weight per day! 9
A dose of about 15 m9 shows great efficacy. (50 mgs to 1f1Tr per patient per day!) The amount of active ingredient that is combined with the carrier material to produce a single dose will vary depending on the subject being treated and the particular mode of administration.

For example, formulations intended for oral administration to humans contain 5m9 to 5ym of active agent in a suitable amount of carrier material, which varies from about 5 to 95% of total tissue. Unit dose formats generally range from about 25 mg to about 50
Contains 0m9 of active ingredient. However, the specific dosage level for each individual patient will depend on the activity of the specified compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug binding, and the particular disease being treated. It can be seen that it depends on various factors such as the weight of the

The present invention relates to the following method for producing the above-mentioned target compound. A method of hydrolyzing a compound with the following structural formula:

The novel compounds of this invention are prepared, for example, as shown by the following scheme.

Below is a detailed description of each of the above steps.

Step A: A suitable O-aminophenol and p-ethylbenzoyl chloride are reacted in pyridine at ambient temperature for 1 to 1 hour to obtain 4-ethyl-2''-hydroxybenzanilide.

Step B: The temperature is high enough to cause ring closure of the anilide formed in Step A above to the benzoxazole.
One hour of heating below the melting point at a temperature of 240-250°C is usually sufficient.

Step C: The 2-(4-ethylphenyl)benzoxazole and N-bromosuccinimide formed in Step B are refluxed in carbon tetrachloride, preferably in the presence of a catalytic amount of dibenzole peroxide, to give 2-[ 4-(1-bromoethyl)phenyl]benzoxazole is obtained.

Step D: 2-[4-(1-bromoethyl)phenyl]benzoxazole formed in Step C and sodium cyanide are mixed in methanol or DMSO at 60-70°C for 1 hour.
A treatment of ~3 hours yields 2-[4-(benzoxazol-2-yl)phenyl]probionitrile.

Step E: Acidic hydrolysis of the probionitrile formed in Step D is carried out by heating for 1 hour at 85 to 95 °C in concentrated hydrochloric acid to obtain the desired 2-[4-(benzoxazol-2-yl)phenyl]propionic acid. obtain.

Non-toxic benzoxazole phenylpropionic acid addition salts can be prepared from the acid by any well known metathesis procedure.

For example, an acid is reacted with an inorganic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, barium hydroxide, and the like. Next, an example will be given and explained.

These examples should not be construed as limiting the invention. In addition, Examples 2 to 4 are shown as reference examples. Example 1 2-[4-(benzoxazol-2-yl)phenyl]
Propiozoic acid A ethyl-7-hydroxybenzanilide O-aminophenol in 70 cc dry pyridine 8.2
A solution of p-ethylbenzoyl chloride (prepared from 10 fm. p-ethylbenzoic acid and thionyl chloride) in 20 cc of benzene is added to the solution of dam.

An exothermic reaction occurs and the reaction mixture is stirred at ambient temperature overnight. The mixture was concentrated in vacuo and the mixture of benzene and ether 11
Mixture and 2.5N hydrochloric acid. The organic layer is washed with saturated sodium bicarbonate solution, water, then dried and concentrated. Recrystallization from benzene-hexane gave 4-ethyl-7-hydroxybenzanilide, M. p. lO3~
At 105°C, 10.5f (yield 65.4%) is obtained.
B2-(4-ethylphenyl)benzoxazone 4-
Ethyl-7-hydroxybenzanilide (10.2yT
L) is heated in a Wood metal bath at 235-245°C for 1 hour.

The reaction mixture was cooled and diluted with ethanol-ether (1:1).
Add to the mixed solution and wash with diluted sodium hydroxide. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel 500q and elution with ethereal petroleum ether (1-2%) yielded 2-(4-ethylphenyl)benzoxazole, M.I.
p. 7.3y (yield 77.3%) is obtained at 84-86°C. C2-[4-(1-bromoethyl)phenyl]benzoxazole In a solution of 7.1f17n of 2-(4-ethylphenyl)benzoxazole in 125cc of carbon tetrachloride, 6.2ym of N-bromosuccinimide and benzoyl peroxide were added. Add 50m9.

Reflux the mixture for about 30 minutes. N-bromosuccinimide reacts completely in that time. After clearing, concentrate the liquid,
2-(4-[1-bromoethyl]phenyl)benzoxazole, M. p. 10.1y (yield 100%) was obtained at 128-131°C. D2-[4-(benzoxazol-2-yl)phenyl]propionitrile dimethyl sulfoxide in 100 cc, sodium cyanide 2.45
A solution of 2-[4-
(1-bromoethyl)phenyl]benzoxazole 10
．． Add 0q.

The color of the reaction mixture turns reddish-brown. The reaction mixture is poured into ice water and thoroughly extracted with methylene chloride. The combined methylene chloride extract is washed well with water, dried and concentrated to obtain the crude product. Silica gel 400ym
Chromatography of the crude material and elution with methylene chloride yielded pure 2-[4-(benzoxazol-2-yl)phenyl]probionitrile, M.P. p.
116-117°C, 2.2 mg (yield 26.8%) is obtained. (methylene-chloridehexane)E2-[
1.8 qrn of 2-(4-[benzoxazol-2-yl]phenyl)probionitrile 4-(benzoxazol-2-yl)phenyl]propionic acid, and 20 c of concentrated hydrochloric acid.
Heat the mixture in c on a steam bath for 1 hour.

The mixture is then passed through a calcined glass filter to 200 ml of ice water.
The resulting precipitate is filtered and air-dried to obtain a crude product. Recrystallized 2-[4-(benzoxazol-2-yl)phenyl]propionic acid from methanol, M.
p. 1.5 f (yield 77.5%) is obtained at 174-178°C. υExample 2 2-[4-(benzoxazol-2-yl)phenyl]
Resolution of propionic acid 1 monoisomer 2-[4-(benzoxazol-2-yl)phenyl] in 200 cc of a mixture of ether and methylene chloride (1:1)
(-)-α- in a solution of propionic acid (3.0yw1,)
Add 3.0 ml of methylpentylamine.

The resulting salt precipitates and is collected by filtration to yield 4.0y of the amine salt of the acid. By repeated recrystallization from acetone (5 times from 100 to 150 cc of acetone), 0.66
6 fwL of salt is obtained. If the salt is dissolved in methanol-water and treated with concentrated hydrochloric acid, 1-2-[4-(benzoxazol-2-yl)phenyl]propionic acid, M. p
．． l75-177℃, 0.429g (yield 28.6%)
[α]o=-45.1±0.8 is obtained. d-rich 2-[4-(benzoxazol-2-yl)phenyl]propionic acid obtained from the mother liquor of the above recrystallization of the d monoisomer,
2.0f771. and cinchonidine 2.5yr! 1. The mixture is heated in 500 cc of chloroform until a solution results, then concentrated in vacuo to give a pale yellow solid.

1.6 by repeated recrystallization from acetone (5 times)
A salt of vTrL is obtained. If the salt is placed between a benzene-ether mixture and dilute hydrochloric acid, d-2-[4
Mono(benzoxazol-2-yl)phenyl]propionic acid is obtained. By recrystallization from methanol-water,
Pure product, M. p. l75-178℃, 0.692
y (yield 46%) [α]o=+44.2±00 is obtained. Since the α-methylphenylacetic acid compound of the present invention has upwardly symmetrical carbon atoms, it usually exists in the form of a racemic mixture.

Resolution of such racemates can be accomplished by a large number of known methods. Thus, some racemic mixtures can be readily separated into mixed crystals (and then precipitated as eutectics). In some cases selective precipitation is used.General chemical methods are used in which diastereomers are formed from racemic mixtures by reaction with optically active resolving agents. In this way, the optically active base is reacted with the carboxyl group.Due to the difference in solubility of the diastereomers formed, selective crystallization of one type can be achieved, and the optically active acid can be regenerated from the mixture.However, there is much promise. There is a third division method, which is
This is a chemical production method using selective enzymatic reactions.
When asymmetric oxidase or decarboxylase is applied to racemic acid, these enzymes destroy one form by oxidation or decarboxylation, leaving the other form unchanged. Of interest is the use of hydrolytic enzymes on derivatives of racemic mixtures to selectively form one form of the acid. Thus, when an esterase acts on an acid ester or amide, the esterase selectively saponifies one side of the symmetrical crystal, leaving the other unchanged. Furthermore, it should be noted that the above-described resolution method is used for intermediates having asymmetric carbon atoms in various steps of synthesis.

As I pointed out earlier, what is particularly interesting is that 2-[4-(
It is the (d) isomer of benzoxazol-2-yl)phenyl]propionic acid.

The desired (d) isomer of the free acid can be prepared by any of the resolution methods described above, preferably from the free acid as a starting material. For example, diastereomers of amides or salts of free acids include quinine, purusin, cinchonidine, cinchonine, hydroxyhydrindamine, methylamine, morphine, α-phenylethylamine, phenyloxynaphthylmethylamine, quinidine, I-phenythylamine, It is formed from basic amino acids such as strychnine, lysine, and arginine, and optically active amines such as amino acid esters. Similarly, free ester diastereomers are formed with optically active alcohols such as borneol, menthol, 2-octanol, and the like. Particularly preferred is the use of synwonidine to form easily degradable diastereomeric salts. The salt can then be dissolved in a solvent such as acetone, separated, the solvent distilled at atmospheric pressure until crystals begin to precipitate, and the mixture allowed to cool to room temperature to continue crystallization, resulting in two symmetrical crystals. (left and right crystals) can be separated. The (d) acid is then regenerated from the (d) salt by extracting the salt between ether and an inorganic solvent such as dilute hydrochloric acid. In short, the partitioning of the acid into its "゜d゛" and "゜゜1" forms is accomplished using well-known techniques.

Stereochemistry of one-carbon compounds. JE. L. Ellel, M.C.
See M. Graw Hllll (1962), pages 47-85.

The dividing method used in the embodiments of the invention and incorporated herein by reference is shown here. Examples of such methods include: (a) Resolution by mechanical separation of crystals (b) Resolution by formation of diastereomers (C) Resolution by asymmetric transformation equilibrium (d) Resolution by mechanical asymmetric transformation (e ) Biochemical asymmetric transformations (f) Completely asymmetric syntheses (g) Asymmetric syntheses involving symmetric compounds The preparation of the corresponding acids by hydrolysis of benzoxazole phenylprobionitriles in the present invention can be carried out by any method known in the art. , for example, by conversion of the nitrile to an acid by acid- or base-catalyzed hydrolysis.

However, the hydrolysis of nitriles can be carried out under acidic conditions using mineral acids, preferably sulfuric acid, with or without the use of inert solvents, at elevated temperatures (preferably the reflux temperature of the system). Preferably, the reaction is carried out until the reaction is substantially complete (at or near completion). However, it should be noted that prolonged heating with strong acids may result in cleavage of the benzoxazole ring. Example 3 2-[4-(benzoxazol-2-yl)phenyl]
A mixture consisting of 250 parts propionic acid, 2(1) parts corn starch, and 30 parts alginic acid is mixed with a sufficient amount of a 10% aqueous paste of corn starch and granulated.

The granules are dried in a stream of hot air, the dry granules are passed through a 16 mesh sieve, mixed with 6 parts of magnesium stearate and compressed into tablets to yield tablets suitable for oral administration. Example 4 (1) Capsule Nibenzoxazole 2507F! One hundred (1) two-piece hard gelatin capsules for oral use containing 9 were prepared from the following ingredients:

Gram (d) 2
-[4-(Benzoxazol-2-yl)phenyl]propionic acid 2500 Lactose, U. S.
PlOOOO Starch・0・S-P3OO Talc, U. S. P65 Calcium stearate 25 milled benzoxazole mixed with starch-lactose mixture;
It was then mixed with talc and calcium stearate.

The final mixture was encapsulated in the usual manner. In the above configuration, capsules containing 25, 50 and 100 mg of benzoxazole 1 are added to 100, 250 mg for 2500 g.
, 500 and 1000y were replaced. ).
) Soft Toxic Capsules A one-piece soft elastic capsule for oral administration containing 200 mg of benzoxazole is first ground in the usual manner with the active material in sufficient corn oil to facilitate encapsulation of this material. It was manufactured by dispersing it in

Claims (1)

[Claims] 1. In a method for producing a compound having the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, the compound having the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is hydrolyzed. A method characterized by: