Derivative oxazole

 

(57) Abstract:

Usage: in medicine, in particular as substances inhibiting the aggregation of blood platelets. The essence of the invention: derivatives of oxazole f-ly 1, where R1phenyl or thienyl; R2is hydrogen or lower alkyl or together with "=(O)=O - ' - tetrazol - 1 - yl; X is a divalent linking radical selected from the group CH=CH, CH2CH2CH2O; Y is a divalent linking radical, attached in the 3 or 4 position of the phenyl ring and is selected from the group: OCH2CH2-CH2CH-CH, 2 tab.

The invention relates to heterocyclic carbon compounds that have medicinal and biosdecode properties and to their preparation and use. In particular, the invention is associated with derivatives oxazole, which are inhibitors of the aggregation of blood platelets.

The known chemistry of sterilisation formula

CHCH

in which R is hydrogen, para-methoxy-, ortho-hydroxy - 3,4-methylendioxy group.

Known class oxazol-2-paliperidone aliphatic monocarboxylic acids, ALLROUNDER in position 4 and/or 5 oxazoline ring formula

R1< / BR>nalnyh, naftalina, thienyl and fueling radicals, substituted by substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy-, nitro - and triptorelin radicals and in which R1is selected from the group consisting of carboxialkilnuyu and carboxylating radicals, each containing from 2 to 5 carbon atoms, and amides, derivatives of hydroxamic acid, lower alilovic esters and lower alkanoyloxy lowest alilovic esters of them. Compounds known patent include an effective in-clinic anti-inflammatory agent, usually known as oxaprozin (R2=R3=phenyl, R1=(CH2)2COOH).

The famous series of derivatives of 2,3-dihydro-2-oxo-1H-imidazo [4,5-b]-rhinolining simple ester of the formula

O which by the way R1and R2are hydrogen, and "alk-Y" is a residue alanovoy acid and ether complex.

Known compounds having cyclic monophosphate (AMP) fosfodiesterazu inhibitory activity and which are useful as inhibitors of the aggregation of blood platelets and/or as charitonenko funds.

The known range triphenylene the P>6each is H, halogen, alkyl, alkoxy group and trifluoromethyl; n is an integer from 1 to 10, and R7is H, alkali metal ions, alkyl or benzyl group. These compounds are useful in the treatment of thromboembolic, inflammatory and/or atherosclerotic disease in humans. Especially preferred member of the series, in which R1to R6is hydrogen, n is 7, and R7is sodium (identifiable in the field of technology as ottimista sodium), described as having protivoraketnoi activity and is being developed in the clinic as antihyperlipidemic tools.

In its fullest particularly the invention relates to a derivative of oxazole formula 1

X

in which R1, R2X, Y are defined below and which are inhibitors of adenosine and induced collagen aggregation of human plasma platelet-rich, and are particularly useful as inhibitors of the aggregation of blood platelets mammals

Another example embodiment of the invention relates to alkali salts of carboxylic acids listed derivatives oxazole, where R2is hydrogen the mule 1

X

in which R1the phenyl or Tienam;

R2hydrogen, lower alkyl or together with CO2tetrazol-1-yl;

X divalent binding group selected from the group consisting of CH2CH2CH=CH and CH2O;

Y divalent binding group attached at the 3 - or 4-position of the phenyl selected from the group consisting of OCH2- CH2CH2and CH=CH;

or when R2hydrogen, alkali metal salt.

The term "lower alkyl" refers to branched or unbranched saturated hydrocarbon chain containing 1-4 carbon atoms, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and tertiary butyl. The term "lower alkanol" means an alcohol having 1-4 carbon atoms and defined by the term "lower alkyl". The term "alkali metal salt" includes alkali metals and most preferably sodium and potassium. When the "divalent binding group X is CH2O, carbon covalently associated with oxazolam, and oxygen covalently bound to a substituted phenyl group.

When the "divalent binding group Y is CH2O, oxygen covalently bound to the phenyl and Cerezuela formula 1

X

(a) hydrolysis of compounds of formula Ia< / BR>
X

in which R2ais lower alkyl; and R1X and Y are such as defined above, to the corresponding acid; or (b) esterification of the compounds of formula Iin< / BR>
X

in which R1X and Y are as defined above, lower alkanol; or

(C) the restoration of the compounds of formula (II)

CHCH

in which R1, R2and Y are as defined above, to obtain the compound of formula (III)

CH2CH

in which R1, R2and Y are as defined above;

(d) alkylation of the compounds of formula (IV)

X

in which R1and X are as defined above, and IT is attached in position 3 or 4 of the phenyl usingrCH2R2ain which R2ais lower alkyl to obtain a compound of formula (V)

X

in which R2ais lower alkyl; R1is the same as defined above, and X is CH2CH2CH=CH; or

(d) alkylation of 3 - or 4-substituted phenyl of the formula (VI)

YaCO2Ra2in which Ya is CH2Oh or CH2CH2and R2
Y

in which R1and R2are as defined above, and Yais CH2Oh or CH2CH2;

(e) reaction of interaction triftormetilfosfinov of ester compounds of the formula (IX)

CH2CH

in which R1is phenyl or Tienam, and IT is attached at the 3 - or 4-position of the phenyl with H2C=CHCOOR2ain which R2ais lower alkyl to obtain a compound of formula (X)

CH2O

in which R1is phenyl or Tienam, and R2alower alkyl;

(g) the reaction of interaction of the compounds of formula (XI)

CH2O

in which R1is phenyl, formyl group is attached at position 3 or 4 of the phenyl with trimethylphosphate derived CH2COOR2ain which R2ais lower alkyl to obtain a compound of formula (XII)

CH2O in which R1and R2andare as defined above;

(C) reaction of interaction of the compounds of formula (XIII)

OCH2CO2Ra2< / BR>
in which R2ais lower alkyl, and the sides of the>
< / BR>
in which R1is phenyl or Tienam, to obtain the compound of formula (XV)

CHCH

in which R1is phenyl or Tienam, and R2alower alkyl;

(and) treatment of compounds of formula (XVI)

X

in which X and Y are as defined above;

(K) azide tri-n-butyanova to get tetrazol formula (XVII)

X

in which X and Y are as defined above.

The following schemes receive exemplary compounds of formula I explain in the following way.

< / BR>
Scheme I depicts the formation of compounds of formula I, obtained from phenylpropionate and okresni acids. Alkylation of the sodium salt hydroxyphenylpropionic acid (2) or hydroxycortisol acid (3) desipramine (1), followed by the formation of oxazole providing phenols (4) and (5), which were alkylated with the help of ester 2-romancenovel acid, to obtain the ester (6) and (7) respectively.

Subsequent hydrolysis with aqueous alkali gives the corresponding acid (8) and (9). Saturated compounds (6) and (8) were synthesized from unsaturated precursors (7) and (9) by hydrogenation, preferably ka the EMA 2 represents an alternative method of obtaining esters (7), comprising the reaction mix dimethylphosphate (11), obtained from the bromide (10) via the Arbuzov reaction, as described by Schroeder and others (D. C. Schroeder. et al J. Org. Chem. 27, 1098-1101 (1962), functionalized with aldehyde (12). Proton NMR data show that the unsaturated compounds were predominantly, if not exclusively, in the TRANS configuration.

< / BR>
Scheme 3 represents the formation of compounds of formula I, including an oxygen atom in the relationship between aryl and oxazolines cycles. Bromination of 4,5-diphenyl-2-methoxazole according to modification methodology Aldous and others (D. L. Aldous et. al. J. Org.Chem. 25, 1151-1154 (1060) using II-bromosuccinimide in carbon tetrachloride at reflux in the presence of 2,2l-azobis-(2-methylpropionitrile), bromide (13). Alkylation of hydroxybenzaldehyde (14) with bromide (13) in the presence of potassium carbonate by boiling under reflux gives the aldehyde (15), which was converted into ester (16) by modification of Wadsworth-Emmons Wittig reaction, according to Wadsworth (W. S. Wadsworth, Org.Raections, 25, 73-252 (1978). Conventional alkaline hydrolysis of ester (16) gives the carboxylic acid (17). Saturated ester (18) and acid (19) were synthesized by alkylation ptx2">

< / BR>
Scheme 4 represents the formation of compounds of the formula I, in which the linking moiety Y is CH2CH2"and X is CH2CH2or CH=CH. Triplet (triftorbyenzola) (22) was synthesized from oxazol-phenol (21) by treating the anhydride triftormetilfullerenov acid in pyridine. The reaction of complex triftormetilfosfinov ether (22) with the ethyl ester of acrylic acid in the presence of PD-catalyst leads to the formation of ester cinnamic acid (23). Induced by base hydrolysis of the compound (23) gives the acid (26). Catalytic hydrogenation of ester cinnamic acid (14) gives the saturated ester (24), which was converted to the acid (25) under aqueous alkaline conditions.

< / BR>
Figure 5 shows the formation of compounds of formula I, when X linking group" is CH2O, and Y is a side chain of the linking group" OCH2. Monoacetate of resorcinol (27) was alkylated with methyl ether bromoxynil acid to obtain (28), which was dissolved in a methanol solution of hydrogen chloride, to obtain a phenol (29). Alkylation of phenol (29) with bromide (10) gives the ester of oxazole (30), which was hydrolyzed to the carboxylic acid (31): vtoroy two phenyl cycle substituted thiophene cycles in two possible regioisomeric forms. Derivatives of 2-methyl-4,5-(2 - or 3-thienyl)-oxazole (32) were obtained according to the method of Davidson (D. Davidson et al. J. Org.Chem. 2, 329-334 (1037) from 2 - or 3-thiophene-carboxaldehyde. Metallcia connection (32), using n-utility, which requires the addition of benzyl bromide (33), gives the oksazolov (34). Phenolic protective group, dimethyl-(1,1-dimethylethyl)-silane was removed by using a fluoride n-butylamine to get phenols (35). Conventional alkylation using methyl ester bromoxynil acid gives esters (36), which were hydrolyzed to carboxylic acid (37) using an aqueous solution of the hydroxide.

< / BR>
Scheme 7 shows the formation of compounds of the formula I, in which the carboxylic acid residue is replaced with tetrazolium the heterocycle. Treatment of phenol (21) bromoacetonitrile and potassium carbonate gives the nitrile (38), which was converted into tetrazol (39) with azide tri-n-butyanova.

Alkali metal salts of carboxylic acids of formula I are generally obtained by dissolving the acid in a suitable solvent, such as methanol, adding a molar equivalent of an alkaline base such as sodium methoxide, and deposition of sediment salt or by evaporating the solvent.

As communication is the firmness of the inhibitors of the aggregation of blood platelets (thrombocytes).

Platelet aggregation is part of a complex physiological mechanism of formation of a blood clot in the vascular system. Thromboembolic phenomenon, i.e. the formation of blood clots, associated with hemostasis and a number of painful conditions in mammals, including thrombophlebitis, phlebothrombosis, cerebral thrombosis, coronary thrombosis, and retinal vascular thrombosis. The increase in the propensity for platelet aggregation, sometimes called adhesiveness ("tack") platelets, occurs after childbirth, surgery, such as bypass surgery coronary artery, organ transplantation, plastic surgery on the blood vessels, artificial heart valves, not to mention the other, and in ischemic heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolia and hyperlipemia; Poplawski and others (A. Poplauski et. al. J. Artjerosclerosis Research, 8, 721 (1968). Thus, the compounds of the invention, which have anti-platelet properties (inhibit aggregation of blood platelets), are useful for the prevention or treatment of conditions involving platelet aggregation and thrombosis, such as mentioned above. It is also believed that the compounds being considered and the properties of the considered compounds can be demonstrated by conventional in vitro and in vivo biological tests such as the following.

INHIBITION OF AGGREGATION OF HUMAN PLATELETS IN VITRO.

Aggregometer (a device for measuring aggregation) was used according to the method of born (C. V. R. Born J. Physiol (London), 1962, 162, 67-68), which modified the Mustard and others (Mustard J. F. et. al. J. Lab.Ghem.Med. 1964, 64, 548-599) to evaluate the in vitro activity of various compounds on inhibition of adenosine diphosphate (ADP) and collagen induced platelet aggregation. The hand of a volunteer donor is cleaned with 70% ethyl alcohol. Sterilized syringe with a volume of 20 ml and needle were used to select 20 ml of blood. The blood is immediately added to the tube for testing, containing 3.8% sodium citrate to prevent clotting of blood (1 CH citrate at 9 o'clock the blood).

Platelet-rich plasma (OTP) was separated by centrifugation for 10 min with a speed of 10,000 rpm (140 Ho) of citrate (3.8 per cent) human blood. All glassware used to obtain the OTP, treated silicone. ADP at a final concentration of 0.5 μg/ml or 0.05 ml of the collagen suspension obtained according to the method described by Evans and others (Evanas G. et. al. J. Exp.Med. 1968, 128, 877-894), was used to induce aggregation. Different epitheliale plasma, would give the desired concentration for testing. Control tests with filler were carried out and compared with the aggregation induced in platelet-rich plasma containing different concentrations of the tested compounds. The curves of the response to the dose received and the magnitude of the Inhibitory Concentration (IC50) were calculated or percent inhibition at 32 µg/ml was observed. In this test, the value of the IC50for dipyridamole in the clinic anti-platelet funds are 512 µg/ml against ADP and 245 µg/ml against collagen.

The results are presented in table.1 and 2 below for the various compounds and related prototype compounds.

INHIBITION OF THROMBOSIS INDUCED BY LASER IN VIVO.

Method of thrombosis induced by the laser, is a modification of the method developed by Sanders and others (Sanders, A. G. Brit. of Exp.Pathol, 1954, 35, 331) and Grant and others (Grant, L. et. al. in Proc.Soc.Exp.Biol.Med. 1965, 119, 1123). A detailed description of this method is described by Fleming and others (Fleming J. S. et. al.) in the book of Platelets and Thrombosis, the publishers Serabyn and sherry, Baltimore, Wagon Park Press,247-262, 1974 (in Plateles and Thrambosis A. Scriabane and S. Sherry. the ads. Baltimore, Univ Park Press) and is hereby incorporated by reference.

Hearing the us in a relaxed supine state in a position of supination. Lokalizovannoe microvascular damage was caused by focusing single ruby laser beam through the microscope into the cavity (lumen) of the vessel with a diameter of 10-60 μm. This causes the formation of small blood clot consisting of platelets, assembled around a core of one or two damaged erythrocytes. Area of blood clots was determined by two perpendicular measurements made by using the eyepiece micrometer. The middle area of the thrombus (μm2) obtained for 10 trials of each rabbit, is used as the control value. The test compound was administered orally and posledujuwie tests were carried out at selected periods of time. Pharmacological activity was evaluated by comparing before and Paleozoic neighboring areas of blood clots.

In the above bilateral models of thrombosis compound of example 6 shows 53% inhibition of thrombosis in oral dose of 10 mg/kg, 38% inhibition at the dose of 3 mg/kg and 23% inhibition at the dose of 1 mg/kg of live weight.

The dosage used in therapeutic methods of the invention varies with the change of the form of the introduction of specifically selected compounds tested subjectional and 0.05-10 mg/kg of body weight parenterally (for the most part are characterized as subcutaneous, intramuscular and intravenous injections). It is assumed that the effective uniform dose for humans varies in the range of 1-100 mg, preferably 0.5 to 20 mg, administered one to three times a day. In accordance with accepted clinical practice, the effective dose can be determined by introducing the compounds of formula I at a dose significantly lower than the dose of a compound, which should be effective, and then increase the dosage with minor increases up until not achieved the desired effect.

When carrying out the review here therapeutic methods of the active ingredient of the formula I or alkali metal salts of carboxylic acids of formula I are preferably introduced together with a pharmaceutically acceptable carrier. Suitable dosage forms for oral administration are tablets, dispersible powders, granules, capsules, syrups and elixirs. Examples of parenteral dosage forms are solutions, suspensions, dispersions, emulsions and the like. Compositions for oral use may contain one or more conventional adjuvants, such as podslushivaet substances, substances imparting taste and aroma, casalegno (grace). Tablets may contain the active ingredient in a mixture with conventional pharmaceutically acceptable excipients, including inert diluents such as calcium carbonate, sodium carbonate, lactose and talc; granulating and dezintegriruetsja tools, such as starch and alginic acid; binders, such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a long lasting effect over an extended period of time. Similarly, suspensions, syrups and elixirs may contain the active ingredient in a mixture with any of the common fillers used for such compositions, such as suspendresume means (for example methylcellulose, tragakant and sodium alginate), wetting agents (e.g. lecithin, polyoxyethylenated) and preservatives, such as ethyl ester of para-hydroxybenzoic acid. Capsules may contain the active ingredient alone or mixed with an inert solid diluent, such calisti equipment, and may contain appropriate dispersing or wetting agents and suspendiruemye means identical or similar to those mentioned above.

The following examples are presented to show, and should not be construed as limiting the invention in any way, because many variations of the invention are possible within the invention.

In the following examples, all temperatures are presented in degrees centigrade scale. The melting points were recorded on the instrument Thomas-Hoover capillary determine the melting point and are uncorrected. Proton nuclear magnetic resonance spectrum (1H-NMR) were recorded on a spectrometer Bruker AM 300, Bruker W 360 or Varian Gemini. All spectra were determined in CDCl3or DMSO-d6unless otherwise noted, and chemical shifts are reported in units of Delta shifted in a weak field from the internal standard tetramethylsilane (TMS), and constant interaction between the protons are reported in Hertz. Types of cleavage are indicated as follows: s, singlet; d, doublet; T. triplet; sq Quartet; m, multiplet; ush, broadened peak and DD, doublet of doublets.

B>CO2CH3< / BR>
A mixture of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenol (3,41 g, 10 mmol), potassium carbonate (1.52 g, 11 mmol), potassium iodide (catalytic amount), methyl ester bromoxynil acid (1.68 g, 11 mmol) and acetonitrile (32 ml) is stirred while boiling under reflux in a nitrogen atmosphere. After 90 min the mixture is cooled, filtered and concentrated to obtain residue oil, which is subjected to chromatography on a column of silica gel. Elution using a mixture of hexanol, ethyl acetate and triethylamine (75: 25: 1) to give methyl ester 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy] -acetic acid (3,59 g, 86%) as a viscous oil.

Analysis: for C26H23NO4:

Calculated: C 75,54; H 5,61; N 3,39.

Found: C 75,57; H 5,67; N 3,41%

IH-NMR (CDCl3) : 3,14 (4H, c); 3,76 (3H, c.); 4,60 (2H, c.); to 6.75 (1H, DD. J=8 Hz, Jl=2,5 Hz); 6.90 to (1H, d, J=8 Hz); to 7.15 to 7.40 (7H, m), and from 7.50 to 7.75 (4H, m).

P R I m e R 2. 2-[3-[2-(4,5-Diphenyl-2-oxazolyl)-ethyl]-phenoxy]-acetic acid

CH2CHOCH2CO2H

A mixture of methyl ester 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy] -vinegar-Noah acid (2.25 g, 5.5 mmol), 3N solution of sodium hydroxide (5.5 ml) and methanol (50 ml) is heated to boiling with reverse refrigerators is their network solution which is diluted with 1 N hydrochloric acid to pH 3, to obtain an oily residue. The mixture is extracted with CH2Cl2and the organic extracts washed twice with water and once with saturated sodium chloride solution. Concentration after drying over sodium sulfate gives a remainder of a pale yellow solid, which is recrystallized twice from a mixture of hexanol and CH2Cl2(2:1) to obtain 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenoxy]-acetic acid (1,74 g, 80%), so pl. 153,3-154,5aboutC.

Analysis: for C25H21NO4:

Calculated: C 75,18; H And 5.30; N 3,51.

Found: C 75,15; H 5,35; N 3.30% PER

IH-NMR (DMSO-d6) : of 3.12 (4H, m); with 4.64 (2H, s); of 6.73 (1H, DD. J=8gts, Jl= 2 Hz); to 6.88 (2H, m); then 7.20 (1H, T. J=8 Hz); 7,30-7,50 (6N, m) and 12,98 (1H, ush.S.).

Sodium metal (0,58 g, 25 mg/atom) is dissolved in methanol (10 ml) and 1 ml of this solution was diluted with methanol (20 ml). Add 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy]-acetic acid (100 g, 2.5 mmole) and the mixture is stirred at room temperature for 18 hours Evaporation of the solvent gives a residue solid beige CVT, sodium salt 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenoxy] -acetic acid (1.06 g, 100), 30; H2O 0,85.

Found: C 70,46; H 4,75; N 3,32; H2O 0,60% I

IH=NMR (D2) : To 2.55 (4H, ush.C.); 4,19 (2H, s); of 6.20 (1H, d, J=7.5 Hz); 6,45-6,70 (5H, m); 6,79 (1H, T. J=7.5 Hz) 6,90-7,30 (7H, m).

P R I m e R 3. Methyl ester 2-[4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy] acetic acid

CH2CHOCH2CO2CH3< / BR>
A mixture of 4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenol (6,00 g, 17 mmol), methyl ester bromoxynil acid (2,96 g and 1.83 ml, 19 mmol), potassium carbonate (2.91 in g, 21 mmol), potassium iodide (catalytic amount) and acetonitrile (80 ml) is stirred while boiling under reflux. After 1 h the mixture is cooled, filtered and the solvent is removed to the residue to obtain a crystalline solid that is ground to powder using hexanol and filtered to obtain methyl ester 2-[4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenoxy] -acetic acid (7,27 g, 100%). An analytical sample obtained by recrystallization of a sample in 2.25 g of methanol to obtain 1.70 g of pure substance, which has so pl. 122-125aboutC.

Analysis: for C26H23NO4:

Calculated: C 75,53; H 5,61; N 3,39.

Found: C 75,30; H 5,86; N 3,39%

IH-NMR (Cl3) : 3,11 (4H, s); of 3.77 (3H, s); 4,60 (2H, s); at 6.84 (2H, d J=]-acetic acid.

CH2CHOCH2CO2H

A mixture of methyl ester 2-[4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy] -vinegar-Noah acid (5 g, 12 mmol), 5 N sodium hydroxide solution (7,26 ml) and methanol (100 ml) is heated on a steam bath for 45 minutes the Solution is concentrated under vacuum, diluted with water and 2 N HCl and the white solid filtered off. Recrystallization from methanol gives 2-[4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy]-acetic acid (2,88 g, 59% ), so pl. 147-149aboutC.

Analysis: for C25H21NO4:

Calculated: C 75,17; H And 5.30; N 3,51.

Found: C 75,03; H 5,50; N 3,44%

IH-NMR (DMSO-d6) : 3,11 (4H, ush.C.); and 4.68 (2H, s); 6.90 to (2N, ush.C.); from 7.24 (2H, d J=6 Hz); from 7,30 to 7.90 (10 H, m); and 13,10 (1H, ush.S.).

P R I m e R 5. Ethyl ester 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenyl]-2-propanolol acid

CH2CH

A mixture of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenyltrichlorosilane (11.8 g, 25 mmol), ethyl ester of acrylic acid (5,01 g, 50 mmol), triethylamine (10,12 g, 100 mmol), palladium acetate 11 (0.28 g, 1.25 mmole), 1,3-bis-(diphenylphosphino)-propane (0.52 g, 1.25 mmole) and DMF (100 ml) was stirred at 90aboutC in nitrogen atmosphere. After 2 and 6 hours add an additional palladium acetate 11 (0.28 g, 1.25 mmole) and 1,3-bi the United extracts washed three times with water and once with saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The residual oil chromatographic on a column of silica gel using a mixture of hexanol and ethyl acetate (3:1) as eluent, to obtain ethyl ester 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenyl]-2-propanolol acid (9,37 g, 88%) as oil.

Analysis: for C28H25NO3:

Calculated: C 79,41; H 5,96; N 3,31.

Found: C 79,20; H 6,21; N 3,45%

IH-NMR (l3) : of 1.31 (3H, so J=7 Hz); 3,17 (4H, m); 4,24 (2H, sq J=7 Hz); 6,41 (1H, d J=16 Hz); 7,20 is 7.50 (1H, m); 7,50-7,80 (5H, m).

P R I m e R 6. Hexane MES hydrate 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenyl]-2-propanolol acid

CH2CH

A mixture of ethyl ester 3-[3-[2-(405-diphenyl-2-oxazolyl(-ethyl]-phenyl]-2-prop-new acid (1.50 g, 3.5 mmole), 3 N sodium hydroxide solution (3.5 ml) and methanol (100 ml) is heated on a steam bath. After 25 min the mixture is cooled, concentrated, diluted with water and with dilute hydrochloric acid to make pH 1. The mixture is extracted three times with CH2Cl2. The combined extracts are washed with saturated NaCl solution, dried on sodium sulfate and the solvent is evaporated. The residual oil chromatographic on a column of silica gel using a mixture of chlorosilane (1,400 g 100%) in the form of hydrated hexane MES after recrystallization from a mixture of hexanol and CH2Cl2(3:1), so pl. 114-115aboutC.

Analysis: for C26H21NO30,6 C6H14x x0,2H2O:

Calculated: 78,88; H 6,67; N 3,11; H2O 0,70.

Found: C 78,54; H 6,86; N 3.04 from; H2O 0,21%

IH-NMR (l3) , 0,86 (3H, so J=7 Hz); 1,25 (4H, m); 3,19 (4H, s); 6,44 (1H, d J=16 Hz); from 7.25 to 7,70 (14 H, m) and 7.75 (1H, d J=16 Hz).

P R I m e R 7. Ethyl ester of 3-[2-(4,5-diphenyl-2-oxazole)-ethyl]-benzoylpropionic acid

CH2CH

A solution of ethyl ester of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenyl-2-propene - howl acid (1,02 g, 2.4 mmole) in ethyl acetate (50 ml) hydronaut over 10% palladium on charcoal (0.06 g) at a pressure of 35 pounds/inch2(2,4584 ATM. ). After 27 h, the mixture is filtered, concentrated and the residue is subjected to chromatography on a column of silica gel using a mixture of ethyl acetate and hexanol (9: 1) as eluent. Elution gives the ethyl ester of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-benzoylpropionic acid (0,92 g, 90%) as oil.

Analysis: C28H27NO3:

Calculated: C 79,04; H 6,40; N 3,30.

Found: C 79,12; H 6,72; N 3.30% PER

IH-NMR (l3) : to 1.22 (3H, triplet, J=7 Hz); at 2.59 (2H, so J)-ethyl]-benzoylpropionate acid

CH2CH

A mixture of ethyl ester of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-benzoylpropionic acid (1.85 g, 4.3 mmole), 3N solution of sodium hydroxide (4.4 ml) and methanol (100 ml) is heated on a steam bath. After 20 min the mixture was concentrated, diluted with water and 1 N hydrochloric acid to pH 1 and extracted with CH2Cl2. The combined extracts dried over sodium sulfate and the solvent is evaporated, to the residue to obtain a white solid. Recrystallization from a mixture of hexane and CH2Cl2gives 3-[2-(4,5-diphenyl - 2-oxazolyl)-ethyl]-benzoylpropionate acid (1,58 g, 91%), so pl. 119-120aboutC.

Analysis: for C26H23NO3:

Calculated: C 78,57; H Of 5.84; N 3,53.

Found: 78,61; H 5,96; N 3,31%

IH-NMR (l3) : of 2.64 (2H, so J=8 Hz); at 2.93 (2H, so J=7 Hz); 3,14 (4H, s); 7,05 is 7.50 (10H, m); 7,50 to 7.75 (4H, m).

P R I m e R 9. Methyl ester [3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy]-UK - susei acid

CHCHOCH2CO2CH3< / BR>
Sodium metal (260 mg, 11 mg/atom) is dissolved in methanol (50 ml) and added dropwise dimethyl ether [(4,5-diphenyl-2-oxazolyl)-methyl]-phosphinic acid (to 3.89 g, 11 mmol) followed by methyl ether (3-formylphenoxy)-acetic acid (2 g, 10 mmol). See what PR HCl. The mixture is extracted with CH2Cl2, the organic phase is dried over sodium sulfate and the solvent is evaporated to obtain the residue, a yellow oil. This oil combines with raw substance from the reaction carried out with 2 g of the phosphonate and 985 mg of aldehyde, and chromatographic on the competition with silica gel. Elution using a mixture of hexanol and diethyl ether (3: 2) gives methyl ester [3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenoxy] -acetic acid in the form of MES diethyl ether (2,92 g, 46%) after recrystallization from diethyl ether, T. pl. 79-82aboutC.

Analysis: for C26H21NO40,4 C4H10O:

Calculated: 75,34; H 5,58; N 3,23.

Found: C 75,35; H vs. 5.47; N 3,17%

IH-NMR (l3) : 1,26 (1,25 N, so J=7 Hz); 3,53 (0,75 N, sq J=7 Hz); 3,88 (3H, s); to 4.73 (2H, s); 6,94 (1H, DD. J=7.5 Hz, Jl=2 Hz); 7,06 (1H, d J= 16 Hz); 7,14 (1H, so J=2 Hz); 7,20-of 7.55 (8H, m); of 7.60 (1H, d J=16 Hz) and 7,70-of 7.90 (5H, m).

P R I m e R 10. [3-[2-(4,5-Diphenyl-2-oxazolyl)-ethynyl]-phenoxy]-acetic acid

CHCHOCH2CO2H

A mixture of methyl ester [3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenoxy] -vinegar - Noah acid (1,00 g, 2.5 mmole), 5N solution of sodium hydroxide (2 ml) and methanol (15 ml) is heated on a steam bath for 10 min before the reaction product, made of 1.46 g of ester using 3 ml of 5 N NaOH in 40 ml of methanol. Recrystallization from ethanol gives [3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenoxy] -acetic acid (1.70 g, 70%), so pl. 213-215aboutC.

Analysis: for C25H19NO4.

Calculated: C 75,56; H 4,82; N 3,53.

Found: 75,37; N TO 4.87; N 3,43

IH-NMR (DMSO-d6) : of 4.75 (2H, s); make 6.90 (1H, m); 7,20-of 7.70 (13H, m); and 13,02 (1H, ush.S.).

P R I m e R 11. Methyl ester [4-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl] -phenoxy]-acetic acid

CHCHOCH2CO2CH3< / BR>
Sodium metal (570 mg, 25 mg/atom) is dissolved in methanol (50 ml) and added dropwise dimethyl ether [(4,5-diphenyl-2-oxazolyl)-methyl]-phosphinic acid (7,80 g, 22 mmol). The mixture is stirred for 10 min before add methyl ester (4-formyl-phenoxy)-acetic acid (of 4.00 g, 20 mmol). After stirring at room temperature for 1 h the mixture is diluted with water and the yellow solid is filtered off and dried in air to obtain a crude reaction product (3.80 g, 44%). This reaction product combine with 3.50 g, held earlier experience and recrystallized twice from methanol to obtain analytically pure methyl ester [4-[2-(4,5-WPPT is B>NO4:

Calculated: C 75,90; H 5,15; N 3,41.

Found: C at 76.00; H 5,16; N 3,44%

IH-NMR (DMSO-d6) : 3,70 (3H, s); is 4.85 (2H, s); 6,97 (2H, d, J=10 Hz); was 7.08 (1H, d, J=13 Hz); 7,30-7,55 (6N, m); 7,55-7,80 (7H, m).

P R I m e R 12. [4-[2-(4,5-Diphenyl-2-oxazolyl)-ethynyl]-phenoxy]-acetic acid

CHCHOCH2CO2H

A mixture of methyl ester [4-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenoxy] -vinegar - Noah acid (2.00 g, 5 mmol), 5 N sodium hydroxide solution (2,90 ml), water (40 ml) and methanol (10 ml) is heated on a steam bath to obtain a solution. The mixture is cooled, diluted with 2 N hydrochloric acid to pH 1 and filtered. Recrystallization from ethanol gives [4-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenoxy]-acetic acid (1,34 g, 69%), so pl. 223-225aboutC.

Analysis: for C25H19NO4:

Calculated: C 75,56; H 4,82; N 3,53.

Found: C 75,47; H 4,79; N 3.55% OF

IH-NMR (DMSO-d6) : 4,74 (2H, s); to 6.95 (2H, d J=8.5 Hz); was 7.08 (1H, d J= 16 Hz); 7,20-7,50 (6N, m); 7,50-of 7.70 (5H, m); of 7.69 (2H, d J=8.5 Hz) and 13.08 (1H, ush. C.).

P R I m e p 13. Methyl ester [3-[3-(4,5-diphenyl-2-oxazolyl)-methoxy] -phenyl]-propanoic acid

CH2O

A mixture of 2-methyl bromide-4,5-diphenyloxazole (10.0 g, 3 mmole), methyl ester 3-(3-hydroxyphenyl)-propanoic acid (5.73 g, 3 mmole), CT and the boiling temperature under reflux. After 30 min the mixture is filtered, concentrated under vacuum and the residual oil chromatographic on a column of silica gel. Elution using a mixture of hexanol and diethyl ether (3:1) gives methyl ester [3-[3-(4,5-diphenyl-2-oxazolyl)-methoxy] -phenyl]-propanoic acid (10,34 g, 78%) as oil. An analytical sample get, exposing 4 g of the sample chromatography under the conditions described above, to obtain a pure substance in the form of butter.

Analysis: for C26H23NO4:

Calculated: C 75,53; H 5,61; N 3,39.

Found: C 75,11; H ceiling of 5.60; N 3,33%

IH-NMR (l3) : 2,62 (2N, so J=8 Hz); 2.95 and (2N, so J=8 Hz); the 3.65 (3H, s); 5,19 (2H, s); 6,80-7,05 (3H, m); 7,20-of 7.55 (7H, m); and 7.60-7,80 (4H, m).

P R I m e R 14. 3-[3-[(4,5-Diphenyl-2-oxazolyl)-methoxy]-phenyl]-propanoic acid

CH2O

A mixture of methyl ester of 3-[3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenyl] -disappear - new acid (6 g, 14.5 mmol), 5 N sodium hydroxide solution (8.7 ml) in methanol (150 ml) is heated to boiling under reflux on the steam bath. After 20 min the mixture was concentrated, diluted with water (200 ml) and 2 N hydrochloric acid to pH 1. After filtering and drying in air overnight, the solid is recrystallized from a mixture of hexanol and CH2C.

Analysis: for C25H21NO40,11 H2O:

Calculated: C 74,84; H 5,33; N 3,50; H2O 0,45.

Found: C 74,49; H 5,31; N 3,31; H2O 0,05%

IH-NMR (l2) : to 2.67 (2H, so J=8 Hz); 2.95 and (2N, so J=8 Hz); 5,22 (2H, s ); 6,80-to 7.00 (3H, m) 7,15 is 7.50 (7H, m); 7,55-7,80 (4H, m) and 10,71 (1H, ush.S.).

P R I m e R 15. Methyl ester of 3-[4-[(4,5-diphenyl-2-oxazolyl)-methoxy] -phenyl] propanoic acid

CH2O

The reaction of 2-methyl bromide-4,5-diphenyloxazole and methyl ester of 3-(4-hydroxyphenyl)-propanoic acid according to the method of example 17 gives the above-named connection, so pl. 92-95aboutC.

Analysis: for C26H23NO40,3 H2O:

Calculated: C 74,56; H of 5.68; N 3,35; H2O 1,29.

Found: C 74,37; H of 5.81; N 5,81; HO20,13.

P R I m e R 16. 3-[4-[(4,5-Diphenyl-2-oxazolyl)-methoxy]-phenyl]-propanoic acid

CH2O

Methyl ester of 3-[4-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenyl]-propanoic acid hydrolyzing an aqueous solution of sodium hydroxide by the method of example 18, to obtain the above-mentioned connection, so pl. 124-127aboutC.

Analysis: for C25H21NO4:

Calculated: C 75,18; H And 5.30; N 3,51.

Found: 74,73; N 5,38; N 3,49%

P R I m e R 17. Methyl ester of 3-[3-[(4,5-diphenyl-2-oxa) washed with hexane, cover dimethyl ether (250 ml) and add parts trimethyl-phosphonoacetate (timetravel ether farinosus acid) (10,71 g, 9,52 ml, 50 mmol). The mixture is stirred for 15 min and a solution of 3-[(4,5-diphenyl-2-oxazolyl)-methoxy] -Ben - zaldehyde (19,00 g, 53 mmol) in dimethylformamide (50 ml) is added in one step. The mixture is stirred for 30 min to obtain a solution of amber before it is diluted with water and extracted with CH2Cl2. The combined extracts dried over sodium sulfate and the solvent is evaporated, to the residue to obtain the oil, which crystallizes when crushed into a powder using a mixture of hexanol and diethyl ether to obtain methyl ester of 3-[3-[(4,5-diphenyl-2-oxazolyl)-methoxy] phenyl]-2-propanolol acid (27,20 g, 78 ). An analytical sample obtained by recrystallization of 1.40 g of the substance from isopropyl alcohol to obtain 0.85 grams of a pure substance with so pl. 88-90aboutC.

Analysis: for C26H21NO4:

Calculated: C 75,90; H 5,15; N 3,41.

Found: 75,80; N IS 5.18; N, 3.43% OF

IH-NMR (l3) : of 3.85 (3H, s); at 5.27 (2H, s); of 6.49 (1H, d J=16 Hz); 7,10-of 7.55 (10H, m); 7,60-7,80 (5H, m).

P R I m e R 18. 3-[3-[(4,5-Diphenyl-2-oxazolyl)-methoxy]-phenyl]-2-protowall acid (3 g, 7.2 mmol), 5 N sodium hydroxide solution (4,40 ml) and methanol (60 ml) is heated at the boil under reflux. After 30 minutes the mixture is cooled, concentrated, diluted with water and acidified to pH 1 with 2 N hydrochloric acid. The yellow solid is filtered off and recrystallized from a mixture of hexanol and CH2Cl2to obtain 3-[3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenyl]-2-propanolol acid (2,25 n, 77%), so pl. 145-147aboutC.

Analysis: for C25H19NO40,1 H2O:

Calculated: 75,22; H is 4.85; N 3,51; H2O 0,45.

Found: C 74,94; H a 4.86; N 3,42; H2O 0,11%

IH-NMR (l3/DMSO-d6) : of 5.24 (2H, s); only 6.64 (1H, d J=16 Hz); to 7.09 (1H, DD. J= 8 Hz, Jl=2 Hz); 7.18 in (1H, d, J=8 Hz); of 7.25 (1H, d J=2 Hz); 7,30 is 7.50 (7H, m); and 7.60-7,80 (5H, m)

P R I m e R 19. Methyl ester of 3-[4-[(4,5-diphenyl-2-oxazolyl)-methoxy] -phenyl]-2-propanolol acid

CH2O

The reaction of trimethyl-phosphonoacetate and 4-[(4,5-diphenyl-2-oxazolyl)-methoxy] -benzaldehyde according to the method of example 21 gives the above-named connection, so pl. 159-161aboutWITH

Analysis: for C26H21NO40,3 H2O:

Calculated: C 74,92; H 5,23; N 3,37; H2O 1,30.

Found: 74,96; H 5,04; N 3,35; H2O 0,03%

P R I m e R 20. 3-[4-(4,5-diphenyl-2-oxazo]-phenyl-2-propanolol acid hydrolyzing aqueous sodium hydroxide according to the method of example 22, to obtain the above-mentioned connection, so pl. 205-207aboutC.

Analysis: for C25H19NO40,1 H2O:

Calculated: C 75,22; H is 4.85; N 3,51; H2O 0,45.

Found: C 75,14; H a 4.86; N 3,47; H2O 0,20%

P R I m e R 21. Methyl ester [3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenoxy] acetic acid

CH2OOCH2CO2CH3< / BR>
A mixture of 2-methyl bromide-4,5-diphenyl-oxazole (of 6.68 g, 21 mmol) methyl ether (3-acetoxyphenyl)-acetic acid (a 3.87 g, 21 mmol), potassium carbonate (3,52 g, 25 mmol), potassium iodide (catalytic amount) and acetonitrile (125 ml) is stirred while boiling under reflux. After 40 min the mixture is cooled, filtered and the solvent is evaporated, to the residue to obtain the oil. Chromatography on a column of silica gel using a mixture of hexanol and diethyl ether (3:1) as eluent, gives hydrated methyl ester [3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenoxy]-acetic acid (6,45 g, 72%) as oil.

Analysis: for C25H21NO50,2 H2O:

Calculated: 71,66; H 5,15 l N 3,35; H2O 0,86.

Found: C 71,56; H 5,49; N 3,44; H2O 0,60%

IH=NMR (l3) : of 3.77 (3H, s); br4.61 (2H, s); of 5.17 (2H, s); 6,55 (1H, DD. J= 8 Hz, Jl=2 Hz); of 6.65 (1H, m is sapolil)-methoxy]-phenoxy]-acetic acid

CH2OOCH2CO2H

A mixture of methyl ester [3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenoxy] -vinegar - Noah acid (5,85 g, 14 mmol), 5 N sodium hydroxide solution (8,45 ml) and methanol (100 ml) is heated at the boil under reflux. After 10 min the mixture is cooled, the solvent is evaporated and the residue diluted with water and 2 N HCl solution to pH 1. The yellow solid is filtered off and recrystallized from a mixture of chloroform, diethyl ether, methanol and hexanol to get gidratirovannuyu [3-[(4,5-diphenyl-2-oxazolyl)-methoxy]-phenoxy]-acetic acid (2.70 g, 47), so pl. 133-135aboutC.

Analysis: for C24H19NO50,6 H2O:

Calculated: C 69,93; H 4,84; N 3,40; H2O 2,62.

Found: to 69.61 l H 4,79; N 3,35; H2O 0,21%

IH-NMR (DMSO-d6) : 4,47 (2H, s); of 5.29 (2H, s); is 6.54 (1H, d, J=8 Hz); of 6.68 (2H, m); then 7.20 (1H, T. J=8 Hz); 7,30-7,80 (14N, m).

P R I m e R 23. Ethyl ester 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl] -phenyl]-2 - propanolol acid

CHCH

The reaction of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl] -phenyltrichlorosilane obtained by the reaction of the anhydride triftormetilfullerenov acid with 3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenol according to the method of example 37 ethyl ester, acrylic KIS who were zolyl)-ethynyl]-phenyl]-2-Papanova acid

CHCH

Hydrolysis of ethyl ester 3-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethynyl]-phenyl] -2 - propanolol acid with sodium hydroxide, similarly to the method of example 10, gives the above-named connection.

P R I m e R 25. Methyl ester [3-[2-[4,5-di-(3-thienyl)-2-oxazolyl]-ethyl]-phenoxy]-acetic acid

CH2CHOCH2CO2CH3< / BR>
A mixture of 3-[2-[4,5-di-(3-thienyl)-2-oxazolyl] -ethyl] -phenol (2.00 g, 5.6 mmol), methyl ester bromoxynil acid (1.04 g, 6.8 mmol), potassium carbonate (0,94 g, 6.8 mmol), potassium iodide (catalytic amount) and acetonitrile (100 ml) is stirred while boiling under reflux in a nitrogen atmosphere. After 15 h the mixture is cooled, filtered and concentrated and the residue is subjected to chromatography on a column of silica gel. Elution using a mixture of hexanol and ethyl acetate (7:2) gives methyl ester [3-[2-[4,5-di-(3-thienyl)-2-oxazolyl] -ethyl] -pheno - XI] -acetic acid (1,95 g, 80%) as oil.

Analysis: for C22H19NO4S2:

Calculated: C 62,10; H 4,51; N 3,30.

Found: C 62,39; H with 4.64; N 3,37%

IH-NMR (l3) : 3,10 (4H, s); of 3.78 (3H, s); 4,60 (2H, s); 6,74 (1H, DD. J=8 Hz, Jl=2,5 Hz); for 6.81 (1H, ush.C.); 6,89 (1H, d Jl=8 Hz); 7,10-7,40 (5H, m); and 7.50-of 7.70 (2H, m).

P R and m is the return methyl ester [3-[2-[4,5-di-(3-thienyl)-2-oxazolyl]-ethyl]-phenoxy] -acetic acid (1.40 g, 3.3 mmole), 3 N sodium hydroxide solution (3.3 ml) and methanol (50 ml) is heated on a steam bath for 20 minutes the Solvent is evaporated, the residue diluted with water and 1 N HCl solution to pH=1 and extracted with CH2Cl2. The combined extracts dried over sodium sulfate and concentrated to obtain a solid beige color. Recrystallization from a mixture of hexanol and CH2Cl2(5:3) gives gidratirovannuyu [3-[2-[4,5-di-(3-thienyl)-2-oxazolyl]-ethyl]-phenoxy]-acetic acid (1,16 g, 85%), so pl. 154-156aboutC.

Analysis: for C21H17NO4S20,4 H2O:

Calculated: C 60,25; H 4,29; N 3,35; H2O 1,72.

Found: C 60,11; H 4,20; N 3,25; H2O 1,06%

IH-NMR (DMSO-d6) : a 3.06 (4H, m); br4.61 (2H, s); 6,72 (N, DD. J=8 Hz, Jl= 2,5 Hz); 6.87 in (2H, m); 7,17 (1H, T. J=8 Hz); of 7.25 (2H, m); 7,60-of 7.90 (4H, m); and 13,03 (1H, ush.S.).

P R I m e R 27. Methyl ester [3-[2-[4,5-di-(2-thienyl)2-oxazolyl]-ethyl]-phenoxy] acetic acid

CH2CHOCH2CO2CH3< / BR>
The reaction of 3-[2-[4,5-di-(2-thienyl)2-oxazolyl] -ethyl] -phenol with methyl ether bromoxynil acid according to the method of example 29 to give the above compound.

P R I m e R 28. [3-[2-[4,5-Di-(2-thienyl)-2-oxazolyl]-ethyl]-venexiana acid

ssnoi acid with aqueous sodium hydroxide gives the above hydrated compound, so pl. of 105.5-107aboutC.

Analysis: for C21H17NO4S20,3 H2O:

Calculated: 60,51; H 4.26 deaths; N 3,36; H2O 1,29.

Found: C 60,40; H 4,29; N 2,95; H2O 1,26%

P R I m e R 29. Obtaining intermediates scheme (29-1)

HO(CH2)2CO2H

A solution of 3-hydroxycortisol acid (20,00 g, 122 mmol) in methanol (200 ml) hydronaut over 100 palladium on charcoal (1.25 g) at a pressure of 45-50 pounds per square inch (3,16-3,51 ATM.), using a Parr apparatus for hydrogenation. After 4 h the mixture is filtered through Celite and the solvent is evaporated to obtain the residue reddish-brown solid, which was used without further purification.

IH-NMR (SD3OD) : 2,32 (2N, so J=7.5 Hz); of 2.68 (2H, so J=7.5 Hz); from 6,30 to 6.50 (3H, m); and PC 6.82 (1H, T. J=8,5 Hz).

P R I m e R 29. 3-[2-(4,5-Diphenyl-2-oxazolyl)-ethyl]-phenol (29-2)

CH2CHOH

Sodium metal (2,69 g, 9,12 g/atom) is dissolved in absolute ethanol (250 ml) and a solution of 3-(3-hydroxyphenyl)-propionic acid (19,38 n, 120 mmol) in absolute ethanol (125 ml) is added. The mixture is heated briefly boiling under reflux, cooled and added dropwise concentrated sulfuric acid (5 drops) in absolute ethanol (5 ml), followed by sledlike within 5,57 h, cooled and concentrated under vacuum. To the residue add glacial acetic acid (600 ml) and ammonium acetate. (45,09 g of 0.58 mmole) and the mixture heated to boiling under reflux in a period of 10.5 hours the Cooled reaction mixture is divided into parts between water and CH2Cl2the organic phase is separated, washed with water (three times) and saturated NaCl solution. After drying over sodium sulfate, evaporation of solvent gives a residue painted in Golden color solid. Recrystallization from a mixture of hexanol and CH2Cl2(2:1) to give 3-[2-(4,5-diphenyl)-2-oxazolyl)-ethyl]-phenol (29,35 g, 73%), so pl. 146-147,5aboutC.

Analysis: for C23H19NO20,05 H2O:

Calculated: C 80,70; H 5,63; N 4,10; H2O 0,26.

Found: 80,45; H 5,69; N 3,92; H2O 0,11%

IH-NMR (l3) : 3,05 (4H, m); 6,60 (2H, m); of 6.68 (1H, d, J=7.5 Hz); 7,05 (1H, T. J=7.5 Hz); 7,20 was 7.45 (6N, m); 7.5-7,80 (5H, m).

P R I m e R 29. 4-[2-(4,5-Diphenyl-2-oxazolyl)-ethyl]-phenol (29-3)

CH2CHOH

Sodium metal (1,00 g, 43 mg/atom) is dissolved in ethanol (125 ml) and add 3-(4-hydroxyphenyl)-propionic acid (6,04 g, 36 mmol) to obtain white loose sediment. The mixture is heated briefly with stirring and add konzi). The mixture is heated at the boil under reflux for 2 h, cooled, concentrated and diluted with water. The mixture is extracted with CH2Cl2the combined extracts dried over sodium sulfate and concentrated to obtain an oil which is dissolved in acetic acid (250 ml). Add ammonium acetate (14,00 g, 180 mmol) and the mixture heated to boiling under reflux. After 100 min, the solution is cooled, diluted with water and extracted with CH2Cl2. The combined extracts dried over sodium sulfate and the solvent is evaporated to obtain the residue, the solid that is ground to a powder using a mixture of hexanol and diethyl ether and filtered to obtain 4-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenol (8.00 g, 64% ). An analytical sample obtained by recrystallization 1.5 g of a substance from a mixture of hexanol and CH2Cl2to obtain 1.20 g of pure substance, so pl. 142-144aboutC.

Analysis: for C23H19NO40,1 H2O:

Calculated: C 80,50; H 5,64; N 4,04; H2O 0,53.

Found: C 80,16; H 5,80; N 4,16; H2O 0,06%

IH-NMR (l3) : 3,30 (4H, m); to 6.80 (2H, d J=8.5 Hz); to 7.15 (2H, d J= 8.5 Hz); 7,35-7,70 (6N, m); 7,20-of 7.90 (4H, m); and to 7.95 (1H, ush.S.).

Analysis: for C23H17NO2.

Calculated: C 81,40; H Of 5.05; N 4,13.

Found: C 81,02; H 4,94; N 3,93%

IH-NMR (DMSO-d6) : 6,77 (1H, d, J=7.5 Hz); 7,00-to 7.35 (4H, m); 7,35-7,50 (6N, m); 7,53 (1H, d J=16 Hz); 7,60-of 7.70 (4H, m); and 9.58 (1H, s).

P R I m e R 30. Di is OCH3)2< / BR>
A mixture of 2-methyl bromide-4,5-diphenyloxazole (26,72 g, 85 mmol) obtained according to Aldous and others (D. L. Aldous et.al. J. Org.Chem. 25, 1151 (1960) and trimethylphosphite (80 g, 84 ml, 645 mmol) is heated with stirring at 120aboutC in nitrogen atmosphere. After 90 min the excess trimethylphosphite removed under vacuum and the residue chromatographic on a column of silica gel. Elution with a mixture of diethyl ether and methanol (49:1) gives 6,13 g yellow solid and 18,90 g of oil with the same characteristics TLC. Recrystallization of 1.3 g of solid substance from hexane gives analytically pure dimethyl ether [(4,5-dimethyl-2-oxazolyl)methyl]-phosphinic acid of 1.15 g, so pl. 54-57aboutC.

Analysis: for C18H18NO4P:

Calculated: C 62,98; H Of 5.29; N, 4.09 To.

Found: C 62,88; H 5,26; N 4,00%

IH-NMR (l3) : 3,48 (2H, d, J=21 Hz); 3,81 (6N, D. J= 11 Hz); 7,20-7,35 (6N, m); and 7.50-of 7.70 (4H, m).

P R I m e R 31. Obtaining intermediate circuit 3.

3-[(4,5-Diphenyl-2-oxazolyl)-methoxy]-benzaldehyde

CH2OCHO

A mixture of 2-methyl bromide-4,5-diphenyloxazole (26,72 g, 85 mmol) obtained according to Aldous and others (D. L. Aldous et. al. J. Org.Chem. 2, 228-334 (1937)), 3-hydroxybenzaldehyde (9,34 g, 76 mmol), potassium carbonate (12,92 g, 93 mmol), potassium iodide (0.5 g) and di is jut diethyl ether (three times). The combined extracts washed with water (three times), dried over sodium sulfate and concentrate under vacuum to obtain an oil, which chromatographic on a column of silica gel. Elution using a mixture of hexanol and diethyl ether (2:1) gives the 3-(4,5-diphenyl-2-oxazolyl)-methoxy-benzaldehyde (21,16 g, 70%). An analytical sample is recrystallized from a mixture of CH2Cl2and hexanol and has so pl. 72-75aboutC.

Analysis: for C23H17NO3:

Calculated: 77,74; N. Of 4.83; N 3,95.

Found: C 77,49; H 4,90; N A 3.87%

IH-NMR (l3) : 5,28 (2H, s); 7,30-7,80 (14N, m); and 9.99 (1H, s).

P R I m e R 32. Obtaining the intermediate circuit 4. 3-[2-(4,5-Diphenyl-2-oxazolyl)-ethyl]-phenyltrichlorosilane

CH2CHOSO2CF3< / BR>
Anhydride triftormetilfullerenov acid (16,55 g, 58 mmol) is added to a stirred solution of 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenol (10,00 g, 29 mmol) in pyridine (60 ml) maintained at 0aboutC. the Mixture was allowed to stand in the refrigerator overnight before it was poured on ice water and extracted with diethyl ether (three times). The combined extracts are washed four times with water, dried over anhydrous magnesium sulfate and end the ethyl acetate (17:3), gives 3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl] -phenyltrichlorosilane (12,54 g, 90%) as oil.

Analysis: for C24H18NO4:

Calculated: C 60,89; H 3,84; N 2,96.

Found: 60,97; H 3,93; N 3.21% OF

IH-NMR (l3) : 3,18 (4H, m); 7,10-to 7.50 (10H, m); and 7.50-of 7.70 (4H, m).

P R I m e R 33. Obtaining the intermediate circuit 5.

Methyl ether (3-hydroxyphenoxy)-acetic acid

HOOCH2CO2CH3< / BR>
A mixture of monoacetate of resorcinol (20,00 g of 0.13 mmole), methyl ester bromoxynil acid (21,14 g of 13.05 ml of 0.14 mmole), potassium carbonate (21,80 g, 0.16 mmole) and acetonitrile (350 ml) is stirred while boiling under reflux. After 30 min the mixture is filtered and the solvent is removed under vacuum to obtain the residue oil was dissolved in methanol (350 ml). Add concentrated hydrochloric acid (2 ml) and the mixture is stirred while boiling under reflux. After 20 minutes the solution is concentrated, diluted with water and extracted with CH2Cl2to obtain the oil, which is distilled under reduced pressure to obtain methyl ether (3-hydroxyphenoxy)-acetic acid, with so pl. 154-180aboutC/1.5 mm (15,98 g, 66% ).

P R I m e R 34. Getting InterMedia is H

n-Utility (0.518 g, 8 mmol) in hexano (3,24 ml) are added to a solution of Diisopropylamine (0,82 g, 8 mmol) in dry tetrahydrofuran (20 ml) maintained at 0aboutC. in the nitrogen atmosphere. After 20 min the mixture is cooled to -78aboutC and a solution of 2-methyl-4,5-di-(3-thienyl)-oxazole (1.60 g, 6.5 mmol) obtained similar to Davidson and others (D. Davidson et. el. J. Org.Chem. 2, 328-334 (1937)) in tetrahydrofuran (10 ml) is added dropwise to a slurry of red-orange color. The mixture was stirred at -78aboutC for 2 h before adding a solution of 3-(methyl bromide)-phenoxy-dimethyl-(1,1-dimethylethyl)-silane (2,44 g, 8 mmol) in tetrahydrofuran (5 ml). After stirring at -78aboutC for 4 h the mixture was poured on a saturated solution of ammonium chloride and extracted with diethyl ether. The combined extracts washed twice with a saturated solution of ammonium chloride, once with saturated NaCl solution and dried over magnesium sulfate. The solvent is evaporated and the residue chromatographic on a column of silica gel using a mixture of hexanol and ethyl acetate (19:1) as eluent to obtain 2-[2-[3-dimethyl-(1,1-dimethylethyl)-siloxy] -phenyl] -ethyl-4,5-di-(3-thienyl)-oxazol (1,33, 43%) as oil.

IH-NMR (l3) : 0,14 (6N,-2. 3-[2-[4,5-Di-(3-thienyl)-2-oxazolyl]-ethyl]-phenol

CH2CHOH

To a solution of 2-[2-[3-[dimethyl-(1,1-dimethylethyl)-siloxy]-phenyl]-ethyl]-4,5 - di-(3-thienyl)-oxazole (4.26 deaths g, 9 mmol) in tetrahydrofuran (185 ml) add a solution of Tetra-n-butylammonium fluoride (2,98 g, 11 mmol) in tetrahydrofuran (11,40 ml). The mixture is stirred at room temperature under nitrogen atmosphere. After 30 min the mixture was diluted with diethyl ether and a saturated solution of ammonium chloride. The organic phase is separated, washed twice with a saturated solution of ammonium chloride and once with saturated solution of NaCl before being dried over sodium sulfate and concentrate under vacuum. Chromatography of the residue on a column of silica gel using a mixture of hexanol and ethyl acetate (3:1), in the amount of eluent, to give 3-[2-[4,5-di-(3-thienyl)-2-oxazolyl] -ethyl]-phenol (2,45 g, 76%). An analytical sample obtained by recrystallization 0.45 g of a substance from a mixture of hexanol and CH2Cl2(2: 1) and has so pl. 143,5-145aboutC.

Analysis: for C19H15NO2S2:

Calculated: 64,57; N 4,28; N 3,97.

Found: C 64,65; H to 4.41; N, 3.89% OF

IH-NMR (DMSO-d6) : of 3.00 (4H, m); to 6.58 (1H, DD. J=8 Hz, Jl=2 Hz); 6,67 (2H, m ); 7,07 (1H, T. J=8 Hz); of 7.25 (2H, m); 7,60-of 7.90 (4H, m); and of 9.30 (1H, s).

aboutC in nitrogen atmosphere. After 20 h the mixture is cooled, diluted with ethyl acetate (300 ml) and 1 N HCl solution (200 ml) and the mixture is stirred for 2 hours the Aqueous phase is removed and the organic phase is added to a 0.1 M solution of potassium fluoride. After stirring overnight the organic layer was separated, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrate under vacuum. The remainder chromatographic on a column of silica gel using a mixture of chloroform and methanol (10:1) as eluent, to obtain 5-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]-phenoxy]-methyl-1H-tetrazol (1.18 g, 66) after recrystallization from a mixture of hexanol and CH2Cl2so pl. on 138.5-140aboutC.

Analysis: for C25H21NO5O2:

Calculated: C 70,91; H 5,00; N 16,54.

Found: C 70,83; H of 5.05; N 16,49%

IH-NMR (l3+DMSO-d6) : only 2.91 (4H, s); 5,13 (2H, s); 6,55-6,70 (3H, m); 6.90 to-7,20 (7H, m); and 7,30 is 7.50 (4H, m).

DERIVATIVE OXAZOLE General formula

< / BR>
where R1phenyl or thienyl;

R2hydrogen, lower alkyl or together with CO2tetrazol-1-yl;

X divalent linking group selected from CH2Red ring and selected from the group consisting of OCH2CH2CH2or CH CH.

 

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