7-examinerlawrence heterocyclic amides or their stereoisomers as receptor antagonists of thromboxane

 

(57) Abstract:

Usage: in medicine, as receptor antagonists of thromboxane. The inventive product: 7-examinerlawrence heterocyclic amides of f-crystals I, or stereoisomers, where m is 1,2 or 3; n is 0,1,2,3 or 4,Z is CH2-CH2- or CH=CH-, provided that when Z is - CH=CH-, n is 0; R is carboxyl, its alkali metal salt, carboxy - (C1-C8) - alkyl, CONHSO2(C1-C8) - alkyl, CONHSO2- phenyl, CONHSO2- benzyl or CH2-5-tetrazolyl; X Is O, S, or NH; R1-C1-C16- alkyl, possibly substituted C3-C8- cycloalkyl or phenyl, which may contain a halogen atom; C3-C8- cycloalkyl or phenyl which may be substituted with halogen; R2- H or C1-C8- alkyl, or R1and R2taken together with the adjacent nitrogen atom, form a 5-8-membered ring. table 2., 1 Il. Connection structure of f-crystals 1.

The invention relates to 7-examinerlawrence heterocyclic Amida - analogues of prostaglandins, which are receptor antagonists AND thromboxane a2(THA2or combined receptor antagonists AND thromboxane a2- (inhibitors which give a long duration of action. These compounds have the following structural formula:

< / BR>
(I) including all stereoisomers, where m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

Z represents -(CH2)2- or-CH=CH-, provided that when Z represents-CH=CH-, where n is not 0;

R - carboxyl, its alkali metal salt, carboxy (C1-C8)-alkyl, CONHSO2(C1-C8)-alkyl, CONHSO2is phenyl; CONHSO2-benzyl or CH2-5-tetrazolyl; X Is O, S or NH;

R1- C1-C16-alkyl which may be substituted WITH3-C8-cycloalkyl or phenyl, which may contain a halogen atom; C3-C8-cycloalkyl; phenyl which may be substituted with halogen;

R2is hydrogen or C1-C8-alkyl, or R1and R2taken together with the adjacent nitrogen atom, form a 5-8-membered ring.

Thus, the compounds of formula I include compounds of the following types:

IA

IB

IC

Preferred are those compounds of formula I in which Z represents-CH=CH - in the CIS-configuration, m is 1, n is 2 or 3, R is a CO2H, R1represents a substituted phenylalkyl or cyclohexylethyl, and R2is hydrogen or methyl.

Predni as follows.

Compounds in which Z represents-CH=CH-, preferably in the CIS-form and X represents O, get, based on oxymethylene connection

< / BR>
(II) (get it, as described in U.S. patent N 4143054), which is subjected to oxidation by Jones, when compound II is reacted with Jones reagent (CrO3dissolved or suspended in the aqueous sulfuric acid solution made as described in the book: Fisher and Fisher, "Reagents for organic synthesis", T. I, S. 142 (1967)), in the presence of acetone, in an inert atmosphere, such as argon, at a temperature from - 10 to 20aboutWith formation of the corresponding carboxylic acid

< / BR>
(III)

Then, in an inert organic solvent, such as tetrahydrofuran, conduct the reaction of the carbodiimide linking acid III with amidol A

--N in the presence of dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC and 1-oxibendazole in an inert atmosphere, such as argon, using a molar ratio A:III from 1.2:1 to 1:1, receiving oxiband

< / BR>
(IV)

Oxiband IV then subjected to cyclodehydration at which the solution IV in an inert organic solvent, for example tetrahydrofuran is eXplorist carbon in the presence of an amine, for example trimethylamine, getting oxazoline.

< / BR>
(V)

In another embodiment, oxiband IV is treated with sulphonylchloride, such as methanesulfonamido, and an amine, such as triethylamine, followed by treatment with potassium carbonate in acetone, getting oxazoline V.

Oxazoline V oxidize, processing, manganese dioxide, or Nickel peroxide, preferably the latter, receiving oxazol IA

< / BR>
In another embodiment, oxazol IA can be obtained from the acid III

carbodiimide coupling, as described above, with the replacement of A by A', getting VI,

H2N - A

< / BR>
(VI) where Pro represents a suitable protecting group.

Oxime VI then subjected to cyclodehydration and oxidation as described for IV and V, receiving VII.

< / BR>
(VII)

Protecting group in compound VII can be removed with the formation of the corresponding acid VIII

< / BR>
(VIII) which when processed by excess oxalicacid in the presence of an inert organic solvent, for example toluene, methylene chloride or chloroform, and possibly a catalytic amount of dimethylformamide, with stirring in an inert atmosphere, such as argon, give the crude acid chloride IX,

the Finance, such as triethylamine, in an inert atmosphere, such as argon, using a molar ratio IX:A" is from 0.5:1 to 1:1, preferably from 0.8:1 to 1:1, receiving IA'.

< / BR>
I A'

The compounds of formula I in which Z represents transisomer-CH= CH-, can be obtained on the basis of oxymethylene of compound II, which contains a double bond in the CIS-form. Compound II is treated with a protecting compound such as tert-butyldimethylsilyl or other silyl protecting group, as described above, in the presence of imidazole or triethylamine and an inert organic solvent, for example methylene chloride or tetrahydrofuran, receiving a secure connection X.

< / BR>
(X)

A solution of protected alcohol X in an inert organic solvent, for example methylene chloride or acetone, is treated with excess ozone at low temperature from - 78 to - 60aboutC, followed by treatment with an excess of dimethyl sulfide (molar ratio X:(CH3)2S is from 1:100 to 1:5), or triphenylphosphine, receiving the aldehyde XI.

< / BR>
(XI)

For the claimed compounds in which Z represents-CH=CH - TRANS-form and n = 2, the aldehyde XI is then treated with a mixture of bromide or lithium chloride and ti chloroform, receiving ester XII.

< / BR>
(XII)

A solution of ester XII in an inert organic solvent, such as tetrahydrofuran, simple ether or dimethoxyethane, cooled to a temperature of from 78 to 0aboutWith and carry out its reaction with diisobutylaluminium in an aromatic solvent, for example toluene, in the course of from 0.5 to 4 hours, getting alcohol XIII.

< / BR>
(XIII)

Alcohol XIII is treated with patrimonialisation (obtained by adding bromine to triphenylphosphine in toluene or other aromatic solvent in an inert atmosphere, for example argon, at reduced temperature from - 10 to 10about(C) in the presence of pyridine and toluene, at low temperatures from - 10 to 10aboutC receives bromide XIV.

< / BR>
(XIV)

Alkilany ester of acetic acid, such as tert-butyl acetate or ethyl acetate, is treated with a solution GAVE (diisopropylamide lithium) in an inert organic solvent, for example tetrahydrofuran, at low temperatures from - 78 to - 60aboutWith, for from 0.5 to 2 h, followed by the addition of a solution of bromide XIV in an inert organic solvent, for example tetrahydrofuran; the result ester XV (where n = 2).

about 1,3 or 4, conducting the reaction of the aldehyde XI with postnasal salt of the formula R.

(C6H5)H2)n+1-CH2-OH (P)

In the presence of a strong base such as tert-Aminata potassium in toluene or NaH/DMSO, receiving XIII',

< / BR>
(XIII') which oxidizes and atrificial, using methods known to experts in the field of technology, receiving an ester XV (where n = 1,3 or 4).

Then with a complex ester XV remove the protection, processing XV in methanol in an inert atmosphere, for example argon, is treated with hydrochloric acid in methanol (obtained by adding acetylchloride to methanol) to give the alcohol XVI

< / BR>
(XVI)

XVI can then be used instead of II as an initial matter, following the above described method, to obtain the acid IIIA,

< / BR>
(III A), and then obtain the claimed compound IA in the TRANS configuration.

< / BR>
(IA")

The claimed compounds IB, where Z represents-CH= CH-, and X represents S, can be obtained on the basis of the acid III or IIIA, as follows.

Conducting the reaction of the acid III or IIIA with oxalylamino, possibly in the presence of catalytic amounts of dimethylformamide, methylene chloride, to obtain the corresponding chlorohydrate carry out the reaction of the acid III or IIIA with alkylchlorosilanes in the presence of an amine, such as triethylamine, receiving a mixed anhydride, which lidiruyut, by reaction with a solution of ammonia in methanol or with a concentrated aqueous solution of ammonia, getting amide XVII.

Then amide XVII is treated with pentasulfide phosphorus or reagent Lawesson [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-divos - Patan-2,4-disulfide], getting the appropriate thioamide XVIII,

< / BR>
(XVIII) which is treated bronirovochnoy acid

(Br-CH2--CO2H) in a polar solvent, for example dimethylformamide, in the presence of a weak base, such as K2CO3using the molar ratio XVIII: bronirovannaja acid from 1:1 to 1:1.5, the receiving of thiazolin XIX

< / BR>
(XIX)

Then thiazolin XIX dehydration, processing sulphonylchloride, such as methanesulfonamido, in the presence of a base, such as triethylamine, getting Diatlovo acid XX;

< / BR>
(XX)

Then carry out the reaction of the carbodiimide linking of this acid with the amine

HR1< / BR>
(A"') in the presence of DCC or WSC in an inert atmosphere, for example argon, using a molar ratio A':XX from 1:1 to 2:1, receiving amide IBa< / BR>
< / BR>
IBa< / BR>
The proposed connection of the IC, in which X represents with the NCH2-COOPrO

(B) where BOC is a tert-butyloxycarbonyl and PrO represents a protecting group, for example, preferably, -CH2CH2Si(CH3)3in the presence of a binding agent, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-oxybisethanol (OVT) and methylene chloride using a molar ratio of III or IIIA: B from 1.2:1 to 1:1, within 12 to 90 h of the amide Obtained is subjected to reaction tonirovania, treating him reagent Lawesson in the presence of benzene at a temperature of from 50 to 75aboutC for 1 to 4 hours, receiving ester XXI.

< / BR>
(XXI)

Ether XXI subjected to cyclization by treatment of a solution of the XXI in an inert solvent, for example acetonitrile, chloroform or tetrahydrofuran, triphenylphosphine (using the molar ratio XXI:triphenylphosphine from 0.8:1 to 1: 1) and carbon tetrachloride in the presence of an amine, such as triethylamine or diisopropylethylamine, getting imidazolin XXII.

< / BR>
(XXII)

Then imidazoline XXII remove protection, removing the protecting group Pro, which use appropriate methods, for example treatment triperoxonane acid in the presence of methylene chloride, and get acid XXIII.

< / BR>
(XXIV)

Amide XXIV oxidize, processing oxidant, such as manganese dioxide, in the presence of an inert solvent, for example chloroform, receiving ester ICa.

< / BR>
ICa< / BR>
Esters IA', IA", IBaand ICacan be converted into the corresponding acid, namely in the I1,

< / BR>
(I1) processing these esters base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide to give the corresponding alkali metal salts, followed by neutralization of the acid, for example dilute hydrochloric or oxalic acid, resulting in the proposed acid compounds.

The compounds of formula I in which Z represents -(CH2)2- can be obtained from the acid I1by subjecting it to hydrogenation, using for this purpose, for example, catalytic hydrogenation, such as, for example, palladium or charcoal, in the presence of an inert organic solvent such as ethyl acetate (EtOAc) or acetic acid (AcOH)in which R represents CONHSO2R3namely I3,

< / BR>
I3get treating acid I1or I2a sulfonamide of the formula

H2N-R3< / BR>
(C) in the presence of a binding agent, such as carbonyldiimidazole or WSC, in the presence of an amine, such as 4-dimethylaminopyridine, in an inert atmosphere, for example argon, using the molar ratio of C:I1or I2from 0.8:1 to 1.2:1, receiving the result of the sulfonamide I3.

Acid I1or I2can be converted into the corresponding esters, treating acid I1and I2the corresponding alcohols in the presence of an acid catalyst with the production of esters.

The claimed compounds in which R represents a CH2-5-tetrazolyl, and Z represents -(CH2)2-, i.e., I4,

< / BR>
I4get subjecting the esters IA',IA",IBaand ICaor esters of the acids of the I1, restore hydride reagent such as lithium borohydride or sodium borohydride, receiving alcohol XXV

< / BR>
(XXV) which is then converted into the bromide treatment triphenylphosphine in an inert solvent, for example toluene. Then the bromide is converted into a nitrile XXVI processing)

Then the nitrile XXVI subjected to a cycloaddition reaction, processing XXVI sodium in the presence of ammonium chloride, dimethylformamide and lithium chloride at a temperature of from 100 to 130aboutC receives the result of the I4.

The proposed compounds in which R represents-CH2-5-tetrazolyl, and Z is-CH=CH-, i.e., I5,

< / BR>
I5receiving, processing Polyacetal D (obtained as described in U.S. patent N 4654356)

< / BR>
(D) a Wittig reagent of the formula E

(C6H5)CH2)

(E) in the presence of a base, such as tert-butoxide sodium or sodium hydride - dimethyl sulfoxide, using the molar ratio of D:E of 1:1 to 0.2:1, receiving oxymethylene connection XXVII,

< / BR>
(XXVII) which is treated with a protecting compound F, where Pro-halogen, for example prommetalservis ether, in the presence of a base, getting protected tetrazol XXVIII,

< / BR>
(XXVIII)

Protected tetrazol XXVIII can then be used instead oxymethylene of compound (II) to obtain various compounds of formula XXIX, where X represents O,S or NH,

< / BR>
(XXIX) in which protection is removed by treatment with an aqueous solution of an acid, for example aqueous hydrochloric acid solution, getting UP> is not a hydrogen atom, can be obtained from the corresponding acids of the I6,

< / BR>
I6treating acid I6(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide - house in the presence of dimethylformamide, 1-examensarbete and organic bases such as triethylamine, and Amin G

HNHR3a(G) with the formation of amide I7< / BR>
< / BR>
(I7) where R3arepresents lower alkyl, aryl or aralkyl.

The compounds of formula I in which R represents CONH2can be obtained from the corresponding acids of the I6using the above method to obtain the amide I7except that to obtain the amide I8instead Amin G use ammonium chloride,

< / BR>
I8< / BR>
The compounds of formula I in which R represents a CH2OH, can be obtained from the corresponding complex ester of the I9,

< / BR>
I9which is treated with a reducing agent such as lithium borohydride (LiBH4) in an inert solvent, for example diethyl ether or tetrahydrofuran, getting the alcohol I10.

< / BR>
(I10)

The proposed compounds have four asymmetric centers, which in the formula I marked the star represent all possible stereoisomers of the corresponding compounds. All the different stereoisomeric forms included in the scope of the invention.

The various stereoisomeric forms of the inventive compounds, namely CIS-Exo, CIS-endo, all TRANS-forms and stereoisomeric pairs can be obtained using the original connection, and following the methods described in U.S. patent N 4143054. Examples of such stereoisomers below.

< / BR>
(Ia)

< / BR>
(Ib)

(Ic)

(Id)

In each of the inventive compounds of the core reasons of convenience shown as follows:

It should also be noted that the core of the claimed compounds can be represented in the following form:

< / BR>
The claimed compounds are antagonists of thromboxane receptor, and therefore can be used as inhibitors of processes mediated by thromboxane receptor. The term "antagonist of the thromboxane receptor" includes compounds that are so-called receptor antagonists of thromboxane A2, antagonists of thromboxane A2, antagonists of thromboxane A2/endoperoxide prostaglandins, antagonists TR-receptor or antagonists of thromboxane.

The inventive compounds are also inhibitors of thromboxane synthase, and can therefore in order to use as inhibitors of platelet function, i.e. for the prevention and treatment of thrombosis, both full and partial, such as thrombosis of arteries, including thrombosis of the coronary arteries, cerebral arteries, ophthalmic artery, arteries, liver, peritoneum, kidneys, peripheral arteries or grafts vessels or organs, for the prevention and treatment of acute angina attacks, coronary disease, or intermittent claudication. They can be used for prevention of thrombosis caused by damage to blood vessels caused during diagnostic or therapeutic procedures, such as, for example, endarterectomy or angiography. These compounds can be used for treatment or prevention of disorders associated with the consumption and/or platelet activation, including activation of platelets, their dysfunction and/or loss during extracorporeal circulation, the use of radiographic contrast agents, thrombotic thrombocytopenic Purpur, disseminated intravascular coagulation, purple lightning, disorders associated with blood transfusion, or hemolytic uremic syndrome, systemic lupus caused by cyclosporine renal toxicity, pulmonary hypertension, side mastubate or blockage of veins, including obstruction of the pulmonary veins, deep vein thrombosis, venous thrombosis of the hepatic vein thrombosis and kidney.

The proposed connection can be used as inhibitors of narrowing of the arteries or veins. Accordingly, they can be used to prevent the narrowing of blood vessels associated with acute angina, chronic angina and its varieties, angina pectoris Prinzmetal, syndrome Ranada, migraine, spasm of the coronary arteries, cerebral arteries, eyes, liver, peritoneum, liver, peripheral arteries or grafts vessels, and damage to blood vessels in the result of surgery or injury. Pregnancy-induced hypertension, hepatorenal syndrome, and pulmonary hypertension are additional examples related to vasoconstriction of diseases that can be cured with the use of the claimed compounds.

Such compounds can be used as inhibitors of bronchospasm, i.e., increased airway responsiveness, allergic bronchospasm, asthma, as well as bronchospasmolytic reactions to environmental exposure, infections, poisons and mechanical impact.

The proposed connection may be that the th muscle, skin, brain, gallbladder, kidney; however, they can be used in pure form or in combination with other substances capable of restoring the blood flow. For example, these compounds can be used to improve postischemic myocardial function and to reduce the size of myocardial infarction. Ischemia caused by reduced blood flow during diagnostic or therapeutic procedures, can be eliminated by the use of these compounds; for example, they accelerate the recovery of myocardial function after bypass surgery. In addition, they can be used for injuries caused by tissue damage.

The claimed compounds can be used for the prevention and treatment of other conditions, including burns, diabetic retinopathy, tumor metastasis and late dyskinesia. These compounds can be used to enhance the action of diuretics.

In addition, the claimed antagonists of thromboxane receptor can be used with thrombolytic agents, such as t-PA, streptokinase, urokinase, PUK or Anatolievna activator complex, and the plasminogen-streptokinase (APSAC) during the first 6 h of myocardial infarction. In this case, thrombolytic Agay the COC to reduce the postischemic myocardial damage.

The claimed compounds can enter the oral or parenterally to various mammalian species affected by these diseases, such as humans, cats, dogs, etc. in an effective amount within the dosage range from 0.1 to 100 mg/kg, preferably from 0.2 to 50 mg/kg, more preferably from about 0.5 to 25 mg/kg (or from 1 to 2500 mg, preferably from 5 to 2000 mg) once or 2-4 times a day.

Declare derivative oxazole, namely the compounds of formula I in which X represents oxygen, have a particularly long duration of action; these connections, if you prefer, you can enter in the above doses, once a day, once in two days or if it is desirable, once a day twice a week.

In table. 1 presents indicators of activity in relation to inhibition of platelet aggregation when compared to the actions of the representatives of known compounds and declared, designated as 33 SQ 640. The results testify to the apparent 10-fold excess of activity of the latter.

In addition, the drawing shows a graph comparing the duration of action for compounds 33 SQ 640 known and SQ 31 491, which shows the closest properties. Even sudden death (see drawing).

Description of the testing methods described below.

Aggregation of human platelets.

Venous blood was collected from antecubital (elbow) Vienna person not taking any medications within 2 weeks. Blood was collected in vials with a capacity of 150 liters, containing the anticoagulant sodium citrate. PRP was prepared by centrifugation of blood containing citrate, 200g for 10 min at 25aboutC. PRP identified PRP by centrifugation for 3 min at 25aboutC.

Accumulation of platelets in the PRP was studied photometrically using aggregometry Chronologist with a linear recorder. 10 mm methanolic standard solution sample was dissolved in 0.5 ml of PRP and held preincubation for 2.5 min at 37aboutTo make the aggregator, and then for 3 min recorded value of the optical transmittance. The rate of increase in the past, which in turn is a measure of the rate of aggregation was determined by the slope of the steep portion of the curve aggregation.

Death caused by U - 46 619 in mice.

This effect was determined using the modified methods of Kohler.

Males weighing 20-25 g after preliminary sutochnie) for 30 min before treatment of the animals with the use of U - 46 619 (2 mg/kg) intravenously.

These concentrations lethal outcome was observed in all specimens. The duration of action was studied in animals pre-exposed to test compounds at a concentration of 0.2 mg/kg, orally before protivozavitok with the use of U - 46619 (2 mg/kg) intravenously at the indicated intervals.

The active compound can be applied in the form of a tablet, capsule, solution or suspension containing from about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formula I, or apply an external path for the healing of wounds (0.01 to 5% by weight of compounds of formula I, from 1 to 5 times a day). These compounds can be mixed in the usual way with a physiologically suitable filler or carrier, binder, preservative, stabilizer, Corrigendum and so on, or with a carrier for topical treatments, such as Plastibase (mineral oil gelled with polyethylene), as provided by common pharmaceutical practice. Moreover, as follows from the above, certain members of the listed groups in addition are intermediates for other members of the group.

The claimed connection of megacolony in the form of a cream or ointment.

The following examples illustrate preferred embodiments of the present invention. Unless otherwise noted, all temperatures are given in degrees Celsius.

P R I m e R 1. {1S-[1 ,2 (Z),3 ,4 ]}- 6-{3-[4-(4-cyclohexylmethyl)amino] Carbo - Neil-2-oxazolyl}-7 - oxabicyclo[2.2.1-heptyl-2]-4-hexenoic acid

A.[1,1-dimethylmethoxy)carbonyl]-N-(4 - cyclohexylmethyl)-L-Suriname

To a solution of 575 mg of the hydrochloride of 4-cyclohexylethylamine (3.0 mmol), 615 mg of tert-butoxycarbonyl-L-serine (3.0 mmol, 1 EQ.), 405 mg of 1-oxybenzenesulfonate (3.0 mmol, 1.0 equiv. and 387 mg diisopropylethylamine (3.0 mmol, 1 EQ. ) in 10 ml dry tetrahydrofuran (THF) with stirring in an argon atmosphere at 0aboutTo add 618 mg of 1,3-dicyclohexylcarbodiimide (3.0 mmol, 1.0 EQ.) in one portion. Slowly precipitate. After one hour the mixture is heated to room temperature and stirred for 4 hours After dilution with ethyl acetate the mixture is filtered, and the filtrate is washed with saline solution with pH = 1 (obtained by mixing water, brine and 1M aqueous HCl). Then twice washed with 1M solution of NaHCO3, dried over Na2SO4and evaporated, obtaining 1.1 g of the crude target amide.

Hydrochloric acid cyclo - hexylphthalate 0,27 Target amide 0,47

B. N-(4-cyclohexylmethyl)-L-Suriname

To a solution of 1.1 g of the crude amide (section A) in 4 ml of CH2Cl2at room temperature add 4 ml triperoxonane acid. The mixture is stirred for 4 h After evaporation of the solvent remaining triperoxonane acid is removed in the form of an azeotrope with CHCl3on a rotary evaporator. Flash chromatography (150 g l ioxy - Yes silicon, 10% [10% aqueous NH3in CH3OH] CH2Cl2) gives, after azeotropic distillation with toluene and vacuum simulation, 495 mg of pure target amine in the form of a white solid, the yield of the desired amine is 68% in terms of the hydrochloride of 4-cyclohexylethylamine.

TX (10% [10% aqueous NH3in CH3OH] CH2Cl2- anisaldehyde): amide (section A) 0,47 target amide 0,17

13C NMR (67,8 MHz in CDCl3):

173,4, 64,6, 56,3, 39,1, 37,3, 36,9, 33,1, 29,6, 26,5, 26,2, 24,0.

C.[1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-(oxymethyl)-7-oxabicyclo[2.2.1]heptyl-2]-4-GCSE-new acid, methyl ester

To a solution of 36,27 g (4R-[4a , 5, 8, 8 )]-octahydro-5,8-epoxy-1H-2-benzopyran-3-ol (obtained as described in U.S. patent N 4143054) (0.23 mol) and 3-carboxypropylbetaine-Mead (127,34 g and 0.37 mol) in 600 ml of dry THF in an argon atmosphere for 3aboutWith PR is wolnego solution). First, the reaction temperature reaches a maximum value of 8aboutWith, then reduce to 4aboutWith to add the rest of the base. After that, the reaction is carried out at room temperature for 90 minutes the Reaction container is placed in an ice bath (0aboutC), and stop the reaction by adding for 30 min 152 ml of glacial acetic acid. In vacuum to remove the solvents (in the form of an azeotrope with toluene). Add water (640 ml) and 50 ml of concentrated HCl at a pH of 2.6. Dilute the mixture of 640 ml of ethyl acetate, add 149 g of NaCl and a few crystals of 3-carboxypropylbetaine-Mead (the seed), then intensively stirred for 15 minutes the Precipitate was separated by filtration and washed with two portions of ethyl acetate (each serving 320 ml). Separate an ethyl acetate layer, the aqueous layer was extracted with ethyl acetate (2 x 200 ml); the collected an ethyl acetate layers dried over MgSO4and concentrate. Add 507 ml of a 5% K2CO3then intensively stirred for 1 h sediment is not observed. The reaction mixture is concentrated to a pasty condition and suspended in 508 ml of water. With vigorous stirring for several hours the sediment does not occur. Water deciveria suspended particulate matter OTDELA have by filtration and washed several times with water. The collected aqueous layers extracted 5 times with a mixture of toluene/ether (1: 1, 230 ml per extraction). After cooling the collected aqueous layer in an ice bath to 0aboutTo add concentrated HCl to a pH of 2.5, then extracted once 460 ml and 2 times 230 ml of ethyl acetate. Collected an ethyl acetate layers dried over MgSO4and evaporated in vacuum, obtaining 49,74 g butter amber color. Rubbing with 330 ml of ether (room temperature, overnight) remove from oil phosphorus-containing by-products. The ether solution is decanted from the dark red oil into a separating funnel, from which oil is poured, captured by decanting (1.56 g). Evaporation of the ether solution gives 43,08 g of [1S-[1 ,2 (Z),3 ,4 ]]-6-(3-oxymethyl)-7-oxabicyclo[2.2.1]heptyl-]-4-hexenoic acid as a viscous yellow oil.

1H NMR shows that the molar ratio of the product:triphenylphosphine: ether is 23:1:1,8 (wt.%: 93:4,7-2,2). A drop of ether and triphenylphosphine gives an output equal to 72.5% (40,06 g).

At room temperature in an argon atmosphere to 80 ml of methanol are added dropwise acetylchloride (5,20 ml, 0,073 mmol). The solution acetylchloride in methanol type (single addition) to a solution of 42,98 g (0.18 mol) in 700 ml of methanol. Peremeshivayu 300 ml of ethyl acetate and 150 ml of water. After separation of the layers the aqueous layer was extracted with 150 ml of ethyl acetate, collected an ethyl acetate layers washed with brine, dried over Na2SO4and evaporated in vacuum, obtaining 43,06 g of a viscous tan oil. Flash chromatography on 1350 g of silica gel (E. Merck Kieselgel 60) (240-400 mesh, 75/25 ether/hexane, and then the ether after the target product begins to flow from the column) gives 35,74 g target of ester in the form of a viscous oil is light yellow in color, does not contain (according to NMR) triphenylphospine).

1H NMR (CDCl3standard tetramethylsilane was - TMS): 5,41-5,38, m (2H); 5,49, d, I = =4,69 Hz (1H); 4,22, d, I = 4,69 Hz (1H); to 3.73 at 3.69, m (1H); 3,67, S. , (3H); 3,60 m (1H); 2,37, sh.with. (4H); 2,12-1,99, m (3H); 1,97-1,85 m (1H); 1,72, m (2H); 1,46, m (2H).

13C NMR (CDCl3standard 77,00): 173,50, 130,42, 128,63, 80,23, 79,22, 61,74, 51,49, 48,95, 46,45, 33,86, 29,69, 29,31, 25,94, 22,92

D. [1S-[1 , 2 (Z),3 ,4 ]]-6-[3-(carboxy)-7-oxabicyclo[2.2.1]-heptyl-2-]-4-GCSE - new acid, methyl ester

To a solution 2,43 g containing impurities of the alcohol obtained in section C (purity 80% , of 1.94 g, 7.6 mmol alcohol, impurity - triphenylphosphine), in 40 ml of acetone, in an argon atmosphere at 0aboutSlowly add 8 ml of Jones reagent (concentration of Cr" - 2.6 M). The red coloration of the reagent persists until the end dobavleniya-2 to bind excess reagent. At 0aboutWith stirring, add 3M aqueous solution of NaHCO3to dissolve all salts. Add the brine, and then the mixture is shaken out three times with ethyl acetate. After drying the extracts over Na2SO4and solvent evaporation spend pulse chromatography (150 g silica, 25-45% 5% acetic acid in ethyl acetate in a gradient of hexane), which, after azeotropic distillation of acetic acid with toluene, gives 1,91 g of oily product. This oily product is a mixture containing impurities of the target acid (purity 80%, of 1.53 g of the target product, impurity - triphenylphospine), obtained with a yield of 75%.

TX (50% [5% acetic acid in ethyl acetate] in a mixture of hexanediamide): Alcohol (section C) 0,33 Target acid 0,35

13C NMR (67,8 MHz in CDCl3)

175,3, 173,1, 129,1, 128,8, 78,0, 78,0, 51,6, 51,1, 47,4, 33,5, 28,8, 28,5, 26,9, 22,5

E. [1S-[1 , 2 , ( Z), 3 (R+),4]]-6-[3-[[[2-[(4-cyclohexylmethyl)amino[1-(oxymethyl)-2-oxoethyl] amino] carbonyl]-7-oxabicyclo[2.2.1] heptyl-2]-4-hexenoic acid, methyl ester

To a solution of 733 mg containing impurities acid obtained in section D (purity 80%, 586 mg, 2.2 mmol, 1.1 EQ., impurity - triphenylphosphine), in 4 ml of dry THF in an argon atmosphere add 356 mg EMA sediment add 5 ml of THF and the mixture is gently heated, receiving solution (m / V detects the presence of stable elliminate). After stirring for 30 min add a solution of 495 mg of the amine obtained in section B (2.0 mmol) in 10 ml of dry THF; in addition use even 5 ml of THF for quantitative transfer of Amin. TX homogeneous mixture obtained after 1 h stirring at room temperature, shows the course of a very slow reaction. Therefore, the THF is removed, passing through the mixture during the night argon, up until its volume is not reduced to 2 ml and precipitation. Adding 5 ml of THF is dissolution of the precipitate. After 5 h stirring, the mixture is evaporated; flash chromatography (150 g silica, 50 to 100% ethyl acetate gradient in hexane, then from 0 to 10% CH3OH the gradient of ethyl acetate) to give 230 mg of pure target exibility in the form of oil. The yield of the target exibility is 23%.

Also highlighted isomer of aminopyralid (27%) and the adduct composition 2:1 (16% ). These by-products can be a good solution to turn into a target oxiband by interesterification using KCN in CH3OH at room temperature, although aminopyralid may also undergo spontaneous isomerization.

TX (50%imidazole 0,18 Target oxiband 0,22 of Aminopyralid 0,04 Adduct of 2:1 to 0.33

13C NMR (67,8 MHz in CDCl3):

173,3, 172,8, 170,4, 129,2, 129,0, 78,9, 78,8, 62,7, 54,0, 53,8, 51,3, 47,9, 34,9, 37,3, 33,6, 33,1, 29,5, 29,4, 28,6, 27,2, 26,4, 26,1, 24,0, 22,6

F. [1S-[1 ,2 (Z),3 (R+),4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)-amino] carbonyl] -4,5 - dihydro-2 - oxazolyl]-7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester

The methodological approach described by M. J. Miller, P. G. Mattingly, M. A. Morrison, J. F. Kerwin, J. Am.Chem.Soc. 1980, 102, 7026.

To a solution of 240 mg of pure exibility obtained in section E (0.48 mmol) in 3 ml of dry THF in an argon atmosphere at room temperature add 189 mg of triphenylphosphine (to 0.72 mmol, 1.5 equiv.) 73 mg of triethylamine (0,72 mmol, 1.5 EQ.) and 89 mg CCl4(of 0.58 mmol, 1.2 equiv.) and the resulting mixture is refluxed. After 1 h, add another aliquot CCl4triethylamine, and after 2.5 h another aliquot of these reagents. After 2 h, add another aliquot CCl4triethylamine and half aliquots (95 mg) triphenylphosphine. After another 2 h TX indicates total expenditure exibility obtained in section E, and initially colorless, homogeneous mixture of saliva, which then darkens. After evaporation of the solvent carry pulse chromatography (silica, 15% acetone in toluene), cotoran-anisaldehyde): Oxiband (section E) 0,07 Target oxazoline 0,29

13C NMR (67,8 MHz in CDCl3):

173,1, 171,2, 169,1, 129,3, 128,9, 79,0, 78,9, 69,6, 68,3, 51,3, 48,2, 46,3, 39,0, 37,4, 36,9, 33,7, 33,1, 29,6, 29,5, 28,7, 27,1, 26,5, 26,2, 24,0, 22,7

G.[1S-[1 , 2 (Z),3 , 4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)-amino]carbonyl] -2-oxa - zolyl]-7 - oxabicyclo[2.2.1]heptyl-2-4-hexenoic acid, methyl ester

The methodological approach described in D. L. Evans, D. K. Minster, U. Jordis, S. M. Hecht, A. L. Mazzu. Jr., A. I. Meyers, J. Org.Chem., 1979. 44, 497.

To a solution of 190 mg of pure oxazoline obtained in section F, (0.40 mmol) in 10 ml of CHCl3add 200 mg Mitrofanova NiO2and the resulting heterogeneous mixture was stirred at room temperature. Method TX shows that within the first hour of the reaction, however, then the reaction stops. After 1 day add five additional aliquot of reagent until then, until the reaction is complete. The mixture is diluted with ethyl acetate, and then mixed with a 3M aqueous solution of NaHSO3to the disappearance of black color NiO2and dissolution of the greater part of the solid components. The mixture is extracted three times with ethyl acetate, after which the extract is dried over Na2SO4and evaporated. Flash chromatography (silica, 25 to 35% ethyl acetate gradient in hexane) to give 90 mg of pure target oxazole in the form of a solid veslemoy oxazol 0,81

13With NMR (67,8 MHz in CDCl3):

173,2, 163,8, 160,5, 140,4, 136,0, 129,4, 128,5, 79,5, 79,3, 51,4, 49,6, 46,6, 39,0, 37,4, 37,0, 33,7, 33,3, 29,8, 29,7, 28,9, 27,8, 26,6, 26,6, 26,3, 24,1, 22,7.

H. [1S-[1 , 2 , (Z),3 ,4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)-amino] carbonyl] -2-oxa-zo - Lil] -7 - oxabicyclo[2.2.1] heptyl-2]-4-hexenoic acid.

To 90 mg of pure oxazole (0,19 mmol) in 4 ml of CH3OH, at room temperature, add 2 ml of 1M aqueous solution of NaOH. After stirring the mixture for 1,3 h add 1M aqueous HCl solution, reducing the pH to 1. The mixture is extracted three times with ethyl acetate. The extracts are dried over Na2SO4and the solvent is evaporated, obtaining the crude acid target. Flash chromatography (25 to 50%, 5% acetic acid in ethyl acetate, gradient hexane) gives, after azeotropic distillation of acetic acid with toluene, 71 mg of pure acid target in the form of solids. The yield of the desired acid is 81%.

TX (50%, 5% acetic acid in ethyl acetate, the mixture hexanediamide): Oxazol (section G) 0,43 Target acid 0,25

13With NMR (67,8 MHz in CDCl3):

176,9, 163,9, 160,7, 140,9, 135,7, 129,5, 128,4, 79,5, 79,3, 49,6, 46,5, 39,1, 37,4, 36,9, 33,7, 33,2, 29,7, 29,7, 28,8, 27,8, 26,6, 26,2, 24,1, 22,5.

P R I m m e R 2. [1S-[1 , 2 (Z),3 . ,4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)methylaminomethyl]- the methyl(-L-serine, 2-(trimethylsilyl) ethyl ester.

The methodological approach is described P. Sieber, Helv.Chim.Acta (1977), 60, 2711

To a solution of 20.7 g of N-tert-butoxycarbonyl-O-benzyl-(L)-serine (70 mmol), and 11.0 g of pyridine (139 mmol, 2.0 EQ.) and 9.9 g of 2-trimethylsilylethynyl (84 mmol, 1.2 EQ.) in 50 ml of dry CH3CN, stir at 0aboutIn argon atmosphere, add to 15.8 g of 1,3-dicyclohexylcarbodiimide (76 mmol, 1.1 EQ.) in one portion. A precipitate. After 3 h the mixture is heated to room temperature and stirred for 12 hours Add a solution of 1.4 g of dihydrate of oxalic acid (11 mmol, of 0.15 EQ.) in 3 ml of dimethylformamide (DMF) and stirred the mixture for 1 h before being filtered. The filter cake is washed with ethyl acetate to total absence in the filtrate of the target ester. The filtrate is washed twice 1M aqueous HCl solution and brine, and double - aqueous solution of NaHCO3(1M). Drying over Na2SO4and evaporation gives to 34.8 g of the crude target of ester (purity 79%, the content of the target product of 27.6 g, impurity - solvent and 2-trimethylsilylethynyl) in the form of an oil; yield 100%.

TX (50%, 5% acetic acid in ethyl acetate, the mixture hexanediamide):

N-tert-butoxide - boil-O-benzyl-(L)-serine 0,40 Target complex epidemeology)carbonyl] -L-se - Rin, 2-(trimethylsilyl)ethyl ester.

To a solution of 34.8 g of the crude ester obtained in section A (purity 79% , of 27.6 g of 100% of an ether, an impurity - solvent and 2-trimethylsilylethynyl, 70 mmol) in 200 ml of ethyl acetate and 300 ml of acetic acid at room temperature in an argon atmosphere, add 10 g of Pd catalyst (10%) on coal. Then the resulting mixture is stirred in hydrogen atmosphere for 4 days. Method TX indicates an almost complete transformation. The mixture is filtered through a polycarbonate membrane, and after evaporation of the solvent the remaining acetic acid is removed by azeotropic distillation with toluene and CH2Cl2. Flash chromatography (750 g silica, 10-30% ethyl acetate gradient in hexane) to give 3.58 g of pure source materials, yield 13%, and 16,49 Mr. clean target dibenzylamino of ester in the form of oil. The yield of the target of ester is 78%.

TX (25% ethyl acetate in a mixture of hexane-anisaldehyde): ester (section A) 0,61

The target ester (section B) 0,28

13With NMR (67,8 MHz in CDCl3): 170,9, 155,6, 79,9, 63,8, 63,0, 55,8, 28,1, 17,2-1,7.

C. Monohydrochloride 2-(trimethylsilyl) ethyl ester of L-serine.

The methodological approach is described P. Sieber, R. H. Andreatta, K. Eliser, R. Kamber, the York (1977), S. 543-545.

To a solution of 10.4 g of the ester obtained in section B (to 34.1 mmol) in 200 ml of diethyl ether is added 40 ml of a solution of approximately 6.5 M HCl (methanol/methyl acetate, 260 mmol). (This solution is prepared by adding 42 g acetylchloride (0.54 mmol) dropwise to 35 g of methanol (1.1 mmol, stirring the mixture at 0aboutC and then at room temperature for 2 h). The mixture is then stirred for 4 h, with honey - Lenna produces gas. Under stirring at room temperature carefully in small portions add 32,8 g NaHCO3(390 mmol), to be able to control the allocation of gas for neutralization. The mixture is then filtered through a glass filter; the filter cake washed with 50% solution of methanol in diethyl ether. After evaporation of the solvents get 8.06 g semisolid crude almost pure target hydrochloric acid amine. This substance can only be partial salt, but, assuming that the net salt 1:1, the resulting output is 98%.

TX (10%, 10% concentrated aqueous NH3H CH3OH, in a mixture of CH2Cl2- anisaldehyde): ester (section B) 0,63 Amin (section C) 0,22

13With NMR (67,8 MHz in CDCl3): 171,3, 63,9, 61,9, 55,5, 17,1-1,8.

D. [1S-[1 , 2 (Z),3 (R*

To a solution 9,40 g of the acid obtained in section D of example 1 (purity of 85% to 7.99 g, to 29.8 mmol), of 8.04 g of the crude, almost pure hydrochloric acid amine, obtained in section (purity 95%, of 7.60 g of 31.6 mmol, 1.06 EQ. ), 4,43 g 1-oxybenzenesulfonate was 32.8 mmol, 1.1 equiv.) and 4,24 g diisopropylethylamine was 32.8 mmol, 1.1 EQ.) in 50 ml of dry THF, stirred in an argon atmosphere at room temperature, one portion add approximately 6.8 g of 1,3-dicyclohexylcarbodiimide (33 mmol, 1.1 EQ.). Slowly, a precipitate may form. After 16 h the solvent is evaporated and flash chromatography (silica, 30 to 100% ethyl acetate gradient in hexane) gives the oil containing solid component. This substance is transferred into diethyl ether, in which a solid component is dissolved, and filter the mixture. Evaporation gives of 9.45 g of almost pure target amide (purity 90%, 8,54 g 100% of the target product) in the form of a light oil. The yield of the desired amide is 63%.

TX (50%, 5% acetic acid in ethyl acetate, the mixture hexanediamide): Acid (section D of example 1) 0,42 Target amide 0,36

13With NMR (67,8 MHz in CDCl3): 173,5, 172,4, 170,3, 129,4, 129,1, 79,2, 79,1, 63,9, 63,2, 54,6, 54,5, 51,4, 47,8, 33,7, 29,7, 28,5, 27,3, 22,7, 17,2, - 1,7.

E. [1S-[1 ,2 (Z),3 (R*),4 ]]-6-, milovy ether.

To a solution of 8.3 g of almost pure amide, obtained in section a purity of 90%, and 7.5 g of 16.6 mmol) in 150 ml dry CH3CN, in an argon atmosphere at room temperature (bath with room temperature) is added to 13.1 g of triphenylphosphine (50 mmol, 3.0 equiv.) 6.4 g of diisopropylethylamine (50 mmol, 3.0 equiv.) and 7.7 g CCl4(50 mmol, 3.0 EQ.). After stirring for 2 h to a mixture of 1M aqueous solution of NaHCO3and thrice extracted with a mixture of methylene chloride. The extract is dried over Na2SO4evaporate the solvent and spend pulse chromatography (silica, 20-50% ethyl acetate gradient in hexane); obtain 5.9 g of almost pure target oxazoline (purity 90%, with 5.3 g of 100% of the target product) in the form of oil. The output oxazoline is 73%.

TX (50% ethyl acetate in a mixture of hexane-anisaldehyde): Amide (section D) 0,20 Target oxazoline 0,44

13With NMR (67,8 MHz in CDCl3): 172,7, 170,7, 169,0, 129,0, 128,8, 78,3, 78,3, 69,0, 67,5, 63,2, 50,9, 48,1, 46,0, 33,4, 29,3, 28,4, 26,7, 22,4, 16,8-2,0.

F. [1S-[1 2 ( Z),3, 4 ]]-6-[3-[4-[[2-(trimethylsilyl)etoxycarbonyl]-2-oxazo-Lil]-7 - oxabicyclo[2.2.1]heptyl-2] -4-hexenoic acid, methyl ester

The methodological approach described in D. L. Evans, D. K. Minsten, U. Jordis, S. M. Hecht, A. L. Mazzu, Jr., and .A.I. Meyers, J. Org. Chem. (1979), 44, 497.

Cl2added to 10.1 g Mitrofanova NiO2and the resulting heterogeneous mixture was stirred at room temperature. (Esotericist reaction leads to some self-heating of the mixture). Method TX shows that after 1 h the reaction is almost over. Then add an additional aliquot of NiO2(2.0 g). After 30 min the reaction is finished; add 150 ml of ethyl acetate. For recovery and dissolution of salts of Nickel was added 100 ml of 3M aqueous solution of NaHSO3and 200 ml of 1M aqueous solution of triacrylate. Under stirring all the solid components are dissolved and the mixture is heated. The mixture twice separated and extracted with etilize - Tatum (TX shows the complete extraction of the target oxazole), then the extract is dried over Na2SO4and evaporated. Purification of 3.8 g of the crude product by pulsed chromatography (150 g silica, 20-75% ethyl acetate gradient in hexane) gives 2,60 g of pure target oxazole in the form of oil. The output oxazole is 57%.

TX (50% ethyl acetate in a mixture of hexane-anisaldehyde): Oxazoline (section E) 0,34 Target oxazol 0,58

13With NMR (67,8 MHz in CDCl3): 172,9, 164,5, 161,0, 143,3, 133,0, 129,1, 128,4, 79,0, 78,9, 63,0, 51,1, 49,5, 46,8, 33,5, 29,5, 28,7, 27,6, 22,5, 17,2, 1,8.

ptx2">

The methodological approach is described P. Sieber, R. H. Andreatta, K. Eliser, B. Kamber, B. Riniker and A. Rink

Peptides: Proceedings of the Fifth American Symposium on peptides, M., editors: M. Goodman, I. Meienhofer, new York, (1977), S. 543-545.

To a solution of 3.1 g of pure oxazole obtained in section (7.1 mmol) in 20 ml of dry DMF in an atmosphere of argon is added 12.0 g of tetrabutylammonium on the silicon dioxide (Huka of 13.9 mmol, 1,96 equiv.) and the resulting heterogeneous mixture was stirred at room temperature for 6 hours the Mixture is diluted with 20 ml of 1% triperoxonane acid, 1% methanol, 98% ethyl acetate, and filtered using 40 ml of the same solvent for washing the precipitate on the filter. The filtrate is evaporated and spend three times the azeotropic distillation with toluene to remove DMF. The crude product is purified on ion-exchange resin: after washing the column with 250 g AG 50 W-X8 (hydrogen form) with water and then 50% CH3OH in water until the discoloration of the elution solvent, the crude product is dissolved in 40 ml of 50% methanol in water, is injected into the column and elute in the same solvent. Obtain 2.65 g of almost pure target oxazolone acid (purity 90%, of 2.38 g of 100% of the target product) in the form of oil. Output oxazolone acid is 100%.

TX (1% triperoxonane acid, Hz in CDCl3): 175,0, 166,7, 163,8, 145,6, 134,2, 130,4, 129,7, 80,7, 52,0, 50,7, 47,7, 34,6, 30,5, 29,7, 28,9, 23,8.

N. Monohydrochloride N-methyl-4-cyclohexylethylamine

To a solution of 750 mg of hydrochloric acid 4-cyclohexylethylamine (3.9 mmol) and 1.08 g of triethylamine (10,8 mol, 2.8 EQ.) in 10 ml of dry THF, stirred in argon atmosphere at 0aboutTo add 584 mg ClCO2C2H5(5.4 mmol, 1.4 EQ.). After heating to room temperature, the heterogeneous mixture is stirred for 3 hours After dilution with diethyl ether, the mixture is washed (twice) 1M aqueous solution of HCl. The organic layer is dried over Na2SO4and evaporated, getting 950 mg of crude intermediate ethylcarbamate in the form of oil, containing the admixture of a certain amount of imide.

To a solution of 950 mg of crude intermediate ethylcarbamate in 10 ml of dry THF under stirring in an argon atmosphere at 0aboutWith added 950 mg sociallyengaged (25 mmol, 6,4 EQ.). There is a selection of gas. The mixture is then refluxed for 2 hours After cooling to 0aboutWith and introduction 20 ml of diethyl ether, carefully add 1.0 ml of water to bind the excess hydride. The mixture is again warmed to room temperature and under vigorous stirring is tre (10% , 10% concentrated aqueous NH3in CH3OH) in diethyl ether, and the filtrate evaporated. The substance is subjected to evaporation in the presence of CH3OH several times to remove NH3), and then acidified with concentrated aqueous HCl solution. Azeotropic distillation of water with toluene and CH3OH gives, after evacuation to a high vacuum, 830 mg of the crude hydrochloric secondary amine (80% purity, 660 mg, impurity - hydrochloric acid tertiary amine) in the form of solids. The yield is 83%; the product is used without purification.

TX (10% , 10% concentrated aqueous ammonia in CH3OH in a mixture of CH2Cl2anisaldehyde): 4-Cyclohexylethylamine 0,07

Intermediate CT - bamat 0,89 Target Amin 0,11

1. [1S-[1S, 2 (Z), 3 , 4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)methylamino] carbonyl] - 2-oxazolyl]- 7-oxabicyclo [2.2.1] heptyl-2]-4-hexenoic acid, methyl ester.

Sample containing impurities oxazolone acid obtained in section G (impurity - tetrabutylammonium, the sample is in the form of the free acid, 0.20 mmol), dried by azeotropic distillation with dry THF and toluene (procedure was repeated twice, using high vacuum). The resulting substance is transferred in 2 ml of toluene, and Yes (1.0 mmol, 5 EQ. ). There is a selection of gas. After 1 h, add 127 mg oxalicacid. Again there is a selection of gas. The mixture is stirred over night. Method TX shows complete conversion to the acid chloride acid bearing the name: methyl ether [1S-[1, 2 (Z), 3 , 4 ]]-6-[3-[4-(chlorocarbonyl)-2-oxazolyl] -7-oxabi - cyclo-[2.2.1] heptyl-2]-4-hexenoic acid. The solvent is evaporated, then add and again evaporated toluene for complete removal of oxalicacid.

To the crude acid chloride acid (section G) add 4 ml of CHCl3. Complete dissolution of the substance does not occur. Under stirring in an argon atmosphere at room temperature add 100 mg containing impurities secondary amine, obtained in section N (purity 80%, 80 mg, impurity - hydrochloric acid tertiary amine, 0,39 mmol, 2 equiv.) and 145 mg of triethylamine (1.4 mmol, 7 EQ.). After stirring at room temperature for 1 h the mixture is diluted with ethyl acetate, add water and extracted twice with ethyl acetate, and then dried extract over NaSO4and evaporated. Get 120 mg containing impurities of the target amide resin. The crude product is used without further purification.

TX (1% triperoxonane acid, 1% methanol, 98% utilized (section I) of 0.64

Y. [1S-[1 , 2 ( Z), 3 , 4 ]-6-[3-[4-[[(4-cyclohexylmethyl)-methylamino] carbonyl] - 2-oxazolyl - 7-oxabicyclo [2.2.1] heptyl-2-]4-hexenoic acid.

To 120 mg obtained in the separation of amide I in 6 ml of CH3OH at room temperature, add 2 ml of 1.0 M aqueous NaOH solution. After stirring the mixture for 3 hours, add 1M aqueous HCl solution, reducing the pH to 1. Then the extraction is carried out with ethyl acetate (three times). The extracts are dried over Na2SO4and after evaporation of the solvent to obtain the crude acid target. Flash chromatography (50-100%, 5% acetic acid in ethyl acetate, gradient hexane) gives, after azeotropic distillation of acetic acid with toluene, 70 mg of pure desired product as oil. The yield of the target product is 72% per oxazolone acid obtained in section G.

TX (50%, 5% acetic acid in ethyl acetate in a mixture of hexane-anisaldehyde): Amide (section I) 0,36 Target product 0,20

13With NMR (67,8 MHz in CDCl3. There are two conformations. Lines that apply only to a single conformation, are given in parentheses):

177,0, 163,1, (162,3), (162,0), 142,5, 136,4, 129,6, 128,5, 79,5, 79,4, (50,4), 49,7, (48,7), 46,7, 37,5, 37,0, (36,4), 34,1, 33,3, 29,7, 29,0, 27,9, (27,2), 26,6, 26,3, (24,2), (23,7), 22,9.

P R I m e R 3. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(1-pyrrolidinyl) is of IMT]-L-seryl]pyrrolidin

To a solution of pyrrolidine (1,11 g, 15.7 mmol), tert-butyloxycarbonyl (SIDE) - (L)-serine (3,22 g, 15.7 mmol), 1-oxybenzenesulfonate (2,12 g, 15.7 mmol) and diisopropylethylamine (2,73 g, 15.7 mmol) in 30 ml THF under stirring in argon atmosphere add 1,3-dicyclohexylcarbodiimide (3,23 g, 15.7 mmol). The resulting mixture was stirred at room temperature for 17 h and concentrated in vacuo. The mixture is then diluted with 200 ml ethyl acetate and filtered off the precipitate. The precipitate is washed with ethyl acetate (3 x 40 ml). The collected filtrate was washed with 1 N. aqueous solution of NA (3 times with 70 ml) and a saturated solution of NaHCO3(2 x 80 ml). The organic layer is dried over MgSO4, filtered and concentrated in vacuo. Product chromatografic on 140 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2and obtain 1.64 g (41%), the target amide.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,24, Cl(SO4)2.< / BR>
13With NMR (67,5 MHz, CDCl3) : 169,4, 155,6, 79,7, 62,8, 53,5, 46,5, 45,9, 28,0, 28,0, 28,0, 25,7, 23,8.

B. [1S-[1 , 2 , (Z), 3 (R*), 4 ] ]-6-[3-[[[(1-(oxymethyl)-2-oxo-2-(1-pyrrolidinyl)-ethyl-] amino] carbonyl] -7-oxabicyclo [2.2.1]-heptyl-2]-4-hexenoic acid, methyl ester.

To osphere argon at 0aboutWith add 5 ml triperoxonane acid (TFUC). The mixture was stirred at 0aboutC for 2 h and diluted with 50 ml of toluene. The resulting mixture was concentrated in vacuo. To a solution of the obtained amine salt with TFUK, 1-oxybenzenesulfonate (0.50 g, 3.73 mmol) and 5 ml of triethylamine in 20 ml of DMF with stirring solution of the acid obtained in section D of example 1 (a 1.00 g, 3.73 mmol) in 10 ml DMF. Then to this mixture is added ethyl-3(3-dimethylamino)-propellerpowered in the form of its hydrochloric acid salt. The reaction mixture was stirred at room temperature for 19 h and concentrated in vacuo. The mixture is diluted with 400 ml ethyl acetate and washed with 1 N. HCl solution (3 times 30 ml), and 0.2 N. NaOH solution (2 x 30 ml) and brine (1, 60 ml). The organic layer is dried over MgSO4, filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 50 g of silica gel 60 (Merck), using as eluent solutions of 2% and 4% CH3OH in CH2Cl2(0.4 l of each solution), and obtain 320 mg (22%) of the target alcohol.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,22, CE(SO4)2< / BR>
13With NMR (67,5 MHz, CDCl3): : 173,4, 172,2, 168,8, 129,3, 129,2, 78,9, 78,9, 63,5, 54,3, 52,2, 51,4, 48,0, 46,6, 45,9, 33,7, 29,5, 28,8, 27�cyclo [2.2.1] heptyl-2]-4-hexenoic acid, methyl ether.

To a solution of the alcohol obtained in section B (305 mg, 0.75 mmol), and diisopropylethylamine (of 0.39 ml, 2,24 mmol) in 10 ml of CH2Cl2under stirring in an argon atmosphere at 0aboutWith add methanesulfonanilide (0,07 ml, 0.90 mmol). The resulting mixture was stirred at room temperature for 4 h and concentrated in vacuo. The crude mesilate dissolved in 30 ml of acetone and combined with 0,60 g K2CO3. The resulting mixture was refluxed for 4 h, cooled to room temperature, and diluted with 100 ml of acetone. The precipitate is filtered and washed with acetone (3 x 40 ml). The filtrate was concentrated in vacuo and chromatographic on 50 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2obtain 210 mg (72%) of the target oxazoline.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,20, Ce(SO4)2.

13With NMR (67,5 MHz. CDCl3) : 173,4, 168,2, 167,7, 129,5, 129,1, 78,9, 78,9, 68,7, 67,5, 51,4, 48,4, 46,5, 46,4, 46,1, 33,9, 29,7, 28,8, 27,1, 25,9, 24,1, 22,8.

D. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(1-pyrrolidinyl)carbonyl]-8-oxazolyl] -7-oxa-bicyclo [2.2.1] heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section With oxazol the room temperature for 3 h, then add another 200 mg NiO2. This mixture is stirred for another 1 h, and add another portion 200 mg NiO2. The resulting reaction mixture was stirred at room temperature for 17 h and diluted with 80 ml of ethyl acetate. To the resulting mixture add 5 ml of 3M solution of NaHSO3and 40 ml of 1M solution of sodium citrate. Separate the organic layer, the aqueous layer was extracted with ethyl acetate (3 x 70 ml). The collected organic extracts are dried over MgSO4, filtered and concentrated in vacuo. The resulting product chromatografic on 18 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2get 69,2 mg (35%) target of ester.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,24, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,2, 163,1, 160,3, 142,2, 137,1, 129,3, 128,7, 79,4, 79,1, 51,4, 49,6, 48,2, 46,7, 46,6, 33,7, 29,7, 28,9, 27,8, 26,4, 23,7, 22,7.

E. [1S- [1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(1-pyrrolidinyl)carbonyl] -2-oxazolyl-7-OK - sabillo [2.2.1] heptyl-2]-4-hexenoic acid.

To the solution obtained in section D of ester (69,0 mg, 0.18 mmol) and 2 ml of water in 12 ml of THF with stirring, add 2 ml of 1 n LiOH solution. The resulting mixture within 10 mi the N. HCl, and saturated NaCl. The THF layer was separated, the aqueous layer was extracted with ethyl acetate (4 x 60 ml). The collected organic extracts are dried over MgSO4, filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 10 g of silica gel 60 (Merck), using as eluent a 10% CH3OH in CH2Cl2get 26 mg (39%) of the target acid.

TX: silica gel, 6%: CH3OH in CH2Cl2, Rf= 0,22, Ce(SO4)2.

13With NMR (67,5 MHz, DMSO - d6) : 175,1, 163,2, 159,6, 142,2, 136,3, 130,5, 127,6, 78,8, 78,4, 48,8, 47,7, 46,3, 45,8, 29,3, 28,4, 27,5, 25,9, 23,3, 23,2, 22,8.

P R I m e R 4. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(cyclohexylamino)carbonyl] -2 - oxazolyl]- 7-oxabicyclo [2.2.1] Gail-2] -4-hexenoic acid.

A. [(1,1-Dimethylmethoxy)carbonyl]-N-cyclohexyl-L-Suriname.

To a solution of cyclohexylamine (1,11 g, 15.7 mmol), BOC-(L)-serine (3,22 g, 15.7 mmol), 1-oxybenzenesulfonate (2,12 g, 15.7 mmol) and diisopropylethylamine (2,73 ml, 15.7 mmol) in 30 ml THF under stirring in an argon atmosphere at 0aboutTo add 1,3-dicyclohexylcarbodiimide (3,23 g, 15.7 mmol). The resulting mixture was stirred at room temperature for 18 hours the Mixture is diluted with 200 ml ethyl acetate and the precipitate is filtered off. Sediment promyvaem solution of NaHCO3(2 x 80 ml). The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The resulting product chromatografic on 140 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2; obtain 1.64 g (41%), the target amide.

TX: silica gel: 4% CH3OH in CH2Cl2; Rf= 0,24, Ce(SO4)2.

13C NMR (67,5 MHz, CDCl3) : 170,1, 156,1, 80,2, 62,7, 48,1, 32,6, 32,6, 28,1, 25,3, 24,5, 24,5, 24,5.

B. [1S-[1 , 2 (Z), 3 (R*), 4 ]]-6-[3-[[[(2-cyclohexylamino)-1-(oxymethyl)-2-oxoa-Tyl] amino] carbonyl]-7-oxabicyclo [2.2.1]-heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section A of amide (1.06 g, 3.73 mmol) in 20 ml of dry methylene chloride under stirring in an argon atmosphere at 0aboutWith add 5 ml TFUCK. The mixture was stirred at 0aboutC for 2 h and diluted with 50 ml of toluene. The resulting mixture was concentrated in vacuo. To a solution of the obtained amine salt with TFUK, 1-oxybenzenesulfonate (0.50 g, 3.73 mmol) and 6 ml of triethylamine in 20 ml of DMF was added with stirring a solution obtained in section D of example 1 acid and 1.00 g, 3.73 mmol) in 10 ml of DMF. To the resulting mixture then add the hydrochloric acid salt of ethyl-3-(3-dimethylamino)-propylbromide. The mixture is diluted with 400 ml ethyl acetate and washed with 1 N. HCl solution (3 x 40 ml), and 0.2 N. NaOH solution (2 x 30 ml), a saturated solution of NaHCO3(1, 30 ml) and brine (1, 100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Cleaning is carried out using pulsed chromatography on silica gel 60 (60 g, Merck, using as eluent 2% CH3OH in CH2Cl2obtain 690 mg (42%) of the target alcohol.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,30, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,3, 173,0, 169,6, 129,4, 129,0, 79,1, 78,9, 62,7, 54,4, 53,7, 51,4, 48,2, 48,0, 33,7, 32,6, 32,6, 32,6, 29,5, 28,6, 27,5, 25,3, 24,6, 24,6, 22,7.

C. [1S-[1 , 2 (Z) 3 , (R*), -6-[3-4-(cyclohexylamino)-carbonyl] -4,5"-dihydro-2-oxazolyl-7 - oxabicyclo [2.2.1] heptyl-2]-4-hexenoic acid, methyl ester

To the solution obtained in section B of alcohol (680 mg, 1.56 mmol) and diisopropylethylamine (of 0.82 ml, and 4.68 mmol) in 20 ml of methylene chloride under stirring in an argon atmosphere at 0aboutWith add methanesulfonanilide (0,13 ml of 1.63 mmol). The resulting mixture was stirred at room temperature for 1 h and concentrated in vacuo. The crude mesilate was dissolved in 20 ml of acetone and connecting is mperature and diluted with 100 ml of acetone. The precipitate is filtered and washed with acetone (3 times 50 ml). The filtrate was concentrated in vacuo and chromatographic on 50 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2get 540 mg (83%) of the target oxazoline.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,42, Ce(SO4)2.< / BR>
13With NMR (67,5 MHz, CDCl3) : 173,2, 170,4, 169,2, 129,5, 128,9, 79,1, 79,0, 69,7, 68,4, 51,4, 48,4, 47,8, 46,4, 33,8, 33,0, 32,8, 29,6, 28,9, 27,3, 25,4, 24,7, 24,7, 22,8.

D. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(cyclohexylamino)carbonyl]-2-oxazolyl] -7 - oxabicyclo [2.2.1] heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section C of oxazoline (530 mg, of 1.26 mmol) in 5 ml of methylene chloride was added with stirring 1.06 g NiO2. The reaction mixture was stirred at room temperature for 3 h, after which add 530 mg NiO2. The resulting mixture was stirred at room temperature for 1 h and add 530 mg NiO2. This mixture is stirred for 80 min and diluted with 120 min of ethyl acetate. To the resulting mixture are added 10 ml of a 3M solution of NaHSO3and 70 ml sodium citrate (1M). Separate the organic layer and extracted the aqueous layer with ethyl acetate (2 times their vacuum. The resulting product chromatografic on 40 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2; obtain 370 mg (70%) target of ester.

TX: silica gel, 4% CH3OH in CH2Cl2, Rf= 0,64, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,2, 163,7, 159,6, 140,6, 136,1, 129,4, 128,5, 79,5, 79,3, 51,4, 49,6, 47,8, 46,6, 33,7, 33,0, 33,0, 29,7, 28,8, 27,8, 25,4, 24,9, 24,9, 22,7.

E. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(cyclohexylamino)carbonyl] -2-oxazolyl]-7 - oxabicyclo [2.2.1] heptyl-2]-4-hexenoic acid.

To the solution obtained in section D of ester (360 mg, 0.86 mmol) and 10 ml of water in 60 ml of THF was added with stirring 10 ml of 1 n LiOH solution. The resulting mixture for 10 min, rinsed with argon and stirred at room temperature for 7 hours, the Mixture is acidified to pH 2 by adding 1 n HCl and saturated with NaCl. The THF layer was separated; the aqueous layer was extracted with ethyl acetate (4 x 80 ml). The collected organic extracts are dried (MgSO4) filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 40 g of silica gel 60 (Merck), using as eluent 4% CH3OH in CH2Cl2receive 300 mg (86%) of the target acid.

TX: silica gel, 6% CH3OH at C5, 79,5, 79,5, 48,1, 46,6, 33,7, 32,9, 32,9, 29,7, 28,9, 27,9, 25,5, 24,9, 24,9.

P R I m e R 5. [1S-[1 , 2 (Z), 3 , 4 ]] -6-[3-[[4-[[(2-cyclohexylethyl)aminocarb-Neil] -2-oxazolyl]-7 - oxabicyclo [2.2.1] heptyl-2-]-4-hexenoic acid.

A. [(1,1-dimethylmethoxy)carbonyl-N-(2-cyclohexylethyl)-L-Suriname.

To a solution of 2-cyclohexylethylamine (2.00 g, 15.7 mmol), BOC-(L)-serine (3,22 g, 15.7 mmol), 1-oxybenzenesulfonate (2,12 g, 15.7 mmol), and diisopropylethylamine (2,73 ml, 15.7 mmol) in 40 ml of THF with stirring in an argon atmosphere at 0aboutTo add 1,3-dicyclohexylcarbodiimide (3,23 g, 15.7 mmol). The resulting mixture was stirred at room temperature and add 10 ml of DMF. Then the reaction mixture was stirred at room temperature for 18 hours the Mixture is diluted with 300 ml of ethyl acetate, and the precipitate is filtered off. The precipitate is washed with ethyl acetate (3 x 40 ml). The collected filtrate was washed with 1 N. HCl solution (3 x 70 ml), and saturated solution of NaHCO3(2 x 80 ml). The organic layer is dried (MgSO4)filtered and concentrated in vacuo. The resulting product chromatographic on silica gel 60 (Merck) 160 g), using as eluent a mixture of hexane - diethyl ether (1:4), receive 1,91 g (39%), the target amide.

TX: silica gel, 4% CH3OH in CH35,2, 33,1, 33,1, 28,3, 28,3, 26,4, 26,4, 26,1.

B. [1S-[ 1 , 2 (Z), 3 (R*), 4 ]]-6-[3-[[[2-[2-(cyclohexylethyl)amino] -1-(oxymethyl)- 2-oxoethyl]- amino]carbonyl]-7-oxabicyclo [2.2.1] heptyl-2-4-hexenoic acid, methyl ester.

To the solution obtained in section A of amide (1.28 g, 3.73 mmol) in 20 ml of dry methylene chloride under stirring in an argon atmosphere at 0aboutWith add 5 ml TFUCK. The resulting mixture was stirred at 0aboutC for 2 h and diluted with 50 ml of toluene. The mixture was concentrated in vacuo. To a solution of the obtained amine salt with TFUK, 1-oxybenzenesulfonate (0.50 g, 3.73 mmol) and 5 ml of triethylamine in 20 ml of DMF was added with stirring a solution obtained in section D of example 1 acid and 1.00 g, 3.73 mmol) in 10 ml of DMF. Then to this mixture, add the hydrochloric acid salt of ethyl-3-(3-dimethylamino)-propylbromide (0.55 g, 3.73 mmol). The reaction mixture was stirred at room temperature for 17 h and concentrated in vacuo. The mixture is diluted with 400 ml ethyl acetate and washed with 1 N. HCl solution (3 x 40 ml), 0.2 to dissolve rum NaOH (2 x 30 ml), a saturated solution of NaHCO3(1, 30 ml) and brine (1, 100 ml). The organic layer is dried (MgSO4), filtered and concentrated in vacuo. Cleaning is carried out using pulsed chrome is,00 g (54%) of the target alcohol.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,30, Ce(SO4)2.< / BR>
13With NMR (67,5 MHz, CDCl3) : 173,4, 172,9, 170,4, 129,3, 129,0, 79,0, 78,9, 62,7, 54,2, 53,7, 51,4, 48,0, 37,3, 36,6, 35,3, 33,7, 32,9, 32,9, 29,5, 28,6, 27,3, 26,3, 26,0, 26,0, 22,7.

C. [1S-[1 ,2 (Z),3 (R*),4 ]]-6-[3-[4-[[(2-cyclohexylethyl)amino] carbonyl]-4,5-di - hydro - 2-oxazolyl]-7-oxabicyclo[2.2.1]-heptyl-2-4-hexenoic acid, methyl ester. To the solution obtained in section B of alcohol (890 mg, of 1.80 mmol) and diisopropylethylamine (0,94 ml, 5.40 mmol) in 30 ml of methylene chloride under stirring in an argon atmosphere at 0aboutWith add methanesulfonanilide (0,14 ml of 1.80 mmol). The resulting mixture was stirred at room temperature for 1 h and concentrated in vacuo. The crude mesilate dissolved in 30 ml of acetone and combined with the 0,77 g K2CO3. This mixture is refluxed for 4 h, cooled to room temperature and diluted with 100 ml of acetone. The precipitate is filtered and washed with acetone (3 times 50 ml). The filtrate was concentrated in vacuo and chromatographic on 60 g of silica gel 60 (Merck), using as eluent 25% CH3OH in CH2Cl2obtain 480 mg (54%) of target compound.

TX: silica gel, 4% CH3OH in CH2Cl23, 51,4, 48,3, 46,3, 36,9, 36,8, 35,2, 33,7, 33,0, 32,9, 29,6, 28,8, 27,2, 26,3, 26,1, 26,1, 22,8.

D. [1S-[1 , 2 (Z),3 , 4 ]]-6-[3-[4-[[(2-cyclohexylethyl)amino]carbonyl] -2-oxa-zolyl] -7 - oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester. To the solution obtained in section C of oxazoline (480 mg, 1.01 mmol) in 20 ml of methylene chloride was added with stirring 480 mg NiO2. The reaction mixture was stirred at room temperature for 1 h, then add another 480 mg NiO2.

The mixture is stirred at room temperature for another 3 h and add another 480 mg NiO2. This mixture is stirred for additional 15.5 hours, and add another portion of NiO2(480 mg). The reaction mixture is stirred for another 1.5 h and diluted with 100 ml of ethyl acetate. To the resulting mixture are added 20 ml of a 3M solution of NaHSO3and 30 ml of 1M solution of sodium citrate. Separate the organic layer and extracted the aqueous layer with ethyl acetate (2 times 100 ml). The collected organic extracts washed with brine (1 x 50 ml), dried (MgSO4) filtered and concentrated in vacuo. The resulting product chromatografic on 45 g of silica gel 60 (Merck) using as eluent 2% CH3OH in CH2Cl2receive 200 mg (42%) target of ester.

TX: silica gel, 4% CH3O, 40,3, 136,0, 129,3, 128,4, 79,4, 79,3, 51,3, 49,6, 46,6, 36,9, 36,7, 35,2, 33,6, 33,0, 33,0, 29,7, 28,8 27,7, 26,4, 26,0, 26,0, 22,7.

E. [1S-[1 ,2 (Z),3 , 4 ]]-6-[3-[4-[[(2-cyclohexylethyl)-amino]carbonyl]-2-oxazolyl]-7 - oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid.

To the solution obtained in section D of ester (190 mg, 0.40 mmol) and 4 ml of water in 30 ml of THF with stirring, add 4 ml of 1 n LiOH solution. The resulting mixture for 10 min, rinsed with argon and stirred at room temperature for 5 hours the Mixture is acidified to pH 2 by adding 1 n HCl and saturated with NaCl. The THF layer was separated, the aqueous layer was extracted with ethyl acetate (4 x 25 ml). The collected organic extracts are dried (MgSO4), filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 20 g of silica gel 60 (Merck), using as eluent 4% CH3OH in CH2Cl2get 106,7 mg (59%) of the target acid.

TX: silica gel, 6% CH3OH in CH2Cl2; Rf= 0,32, Ce(SO4)2.

13With NMR (67,5, MHz, CDCl3) : 176,9, 163,9, 160,7, 140,8, 135,7, 129,4, 128,4, 79,5, 79,4, 49,6, 46,5, 36,9, 36,8, 35,2, 33,7, 33,0, 33,0, 29,6, 28,8, 27,8, 26,4, 26,1, 26,1, 22,6.

P R I m e R 6. [1S-[1 ,2 (Z),3 4 ]]-6-[3-[4-[[[2-(4-chlorophenyl)-ethyl]amino]carbonyl]-2-OK-sapolil]-7 - oxabicyclo[2.2.1]-heptyl-4-hexanolactone)ethylamine (2,44 g, 15.7 mmol), BOC-(L)-serine (3,22 g, 15.7 mmol), 1-oxybenzenesulfonate (2,12 g, 15.7 mmol) and diisopropylethylamine (2,73 ml, 15.7 mmol) in 30 ml THF under stirring in an argon atmosphere at 0aboutTo add 1,3-dicyclohexylcarbodiimide (3,23 g, 15.7 mmol). The resulting mixture was stirred at room temperature and add 10 ml of DMF. Then the reaction mixture was stirred at room temperature for 18 hours the Mixture is diluted with 200 ml ethyl acetate and the precipitate is filtered off. The precipitate is washed with ethyl acetate (3 x 40 ml). The collected filtrate was washed with 1 N. aqueous solution of HCl (3 x 70 ml) and a saturated solution of NaHCO3(2 x 80 ml). The organic layer is dried (MgSO4) filtered and concentrated in vacuo. The resulting product chromatografic on 160 g of silica gel 60 (Merck) using as eluent a mixture of hexane-diethyl ether (1:4), gain of 2.56 g (48%), the target amide.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,34, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,1, 157,6, 139,2, 133,1, 131,4, 131,4, 129,4, 80,8, 63,3, 58,0, 41,7, 35,7, 34,7, 28,7, 28,7, 28,7.

B. [1S-[1 ,2 (Z),3 (R*),4 ]]-6-[3-[[[2-[[2-(4-chlorophenyl)-ethyl] amino] -1-(oxymethyl)-2 - oxoethyl]amino]carbonyl]-7-oxanilic-lo [ 2.2.1] heptyl-2]-4-hexenoic acid is ethene under stirring in an argon atmosphere at 0aboutWith add 5 ml TFUCK. The mixture was stirred at 0aboutC for 2 h and diluted with 50 ml of toluene. The resulting mixture was concentrated in vacuo. To a solution of the obtained amine salt and TFUK, 1-oxybenzenesulfonate (0.50 g, 3.73 mmol) and 5 ml of triethylamine in 20 ml of DMF was added with stirring a solution obtained in section D of example 1 acid and 1.00 g, 3.73 mmol) in 10 ml of DMF. To the resulting mixture then add hydrochloric ethyl-3-(3-dimethylamino)propellerblade-MFA (0.55 g, 3.73 mmol). The reaction mixture was stirred at room temperature for 17 h and concentrated in vacuo. The mixture is diluted with 400 ml ethyl acetate and washed with 1 N. HCl solution (3 x 40 ml), and 0.2 N. NaOH solution (2 x 30 ml), a saturated solution of NaHCO3(1, 30 ml) and brine (1, 100 ml). The organic layer is dried (MgSO4), filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 60 g of silica gel 60 (Merck) using as eluent 2% CH3OH in CH2Cl2get 1,00 g (54%) of the target alcohol.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,30, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,5, 172,9, 170,6, 137,2, 132,1, 130,0, 130,0, 129,3, 129,1, 128,5, 128,5, 79,0, 78,9, 62,7, 54,1, 53,9, 51,4, 48,0, 40,8, 34,8, 33,7, 2�yl]-7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ether.

To the solution obtained in section B of alcohol (890 mg, of 1.80 mmol) and diisopropylethylamine (0,94 ml, 5.40 mmol) in 30 ml of methylene chloride under stirring in an argon atmosphere at 0aboutWith add methanesulfonanilide (0,14 ml of 1.80 mmol). The resulting mixture was stirred at room temperature for 1 h and concentrated in vacuo. The crude mesilate dissolved in 30 ml of acetone and combined with 0,77 g K2CO3. The resulting mixture was heated under reflux for 4 h, cooled to room temperature and diluted with 100 ml of acetone. The precipitate is filtered and washed with acetone (3 times 50 ml). The filtrate was concentrated in vacuo and chromatographic on 60 g of silica gel 60 (Merck) using 2% CH3OH in CH2Cl2as eluent; obtain 480 mg (54%) of the target oxazoline.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,42, Ce(SO4)2.

13With NMR (67,5, MHz, CDCl3) : 171,6; 169,4; 169,3; 137,0; 132,3; 130,0; 130,0; 129,5; 129,0; 128,6; 128,6; 79,1; 79,0; 69,6; 68,3; 51,5; 48,2; 46,3; 40,0; 34,8; 33,8; 29,6; 28,9; 27,2; 22,8.

D.[1S-[1 ,2 (Z),3 ,4 ]]-6-[3-[4-[[[2-(4-chlorophenyl)ethyl]aminocarbonyl] -2-oxazo - Lil] -7 - oxabicyclo[2.2.1]heptyl-2-4-hexenoic acid, methyl ester.

To a solution of the floor of the UB>2
. The reaction mixture was stirred at room temperature for 1 h, then added 480 mg NiO2. This mixture was stirred at room temperature for 3 h, and add another 480 mg NiO2. The resulting mixture was stirred for additional 15.5 hours and add another portion of NiO2(480 mg). The reaction mixture was stirred for 1.5 h and diluted with 100 ml of ethyl acetate. To the resulting mixture are added 20 ml of a 3M solution of NaHSO3and 30 ml of 1M solution of sodium citrate. Separate the organic layer and extracted the aqueous layer with ethyl acetate (2 times 100 ml). The collected organic extracts washed with brine (1 x 50 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting product chromatografic on 45 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2; receive 200 mg (42%) target of ester.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,60, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,2, 169,3, 160,6, 140,5, 137,2, 135,8, 132,2, 130,0, 130,0, 129,4,128,6, 128,6, 128,5, 79,5, 79,3, 51,4, 49,6, 46,6, 40,1, 35,2, 35,2, 33,7, 29,7, 28,9, 27,8, 22,7.

E.[1S-[1,2 (Z),3 ,4 ]]-6-[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7 - oxabicyclo[2.2.1]heptyl-2]-4-sextgp with stirring, add 4 ml of 1 N. the LiOH solution. The resulting mixture was rinsed for 10 minutes with argon and stirred at room temperature for 5 hours the Mixture is acidified to pH 2 by adding 1 N. HCl, and saturated NaCl. Separate the layer of THF, the aqueous layer was extracted with ethyl acetate (4 x 25 ml). The collected organic extracts are dried (MgSO4) filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 20 g of silica gel 60 (Merck) using as eluent 4% CH3OH in CH2Cl2get 106,7 mg (59%) of the target acid.

TX: silica gel, 6% CH3OH in CH2Cl2; Rf= 0,32, CE(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 176,9, 175,4, 164,0, 160,9, 140,9, 137,2, 130,1, 130,1, 129,4, 128,6, 128,6, 79,6, 79,5, 49,6, 46,6, 40,2, 35,1, 33,7, 29,7, 28,9, 27,9, 22,6.

P R I m e R 7. [1S-[1 ,2 (Z),3 ,4 ]]-6-[3-[4-[[[(4-chlorophenyl)amino] carbonyl]-2-oxa-zolyl]-7-oxabicyclo [2.2.1]-heptyl-2]-4-hexenoic acid.

A.[(1,1-dimethylmethoxy)carbonyl]-N-(4-chlorophenyl)-L-Suriname

To a solution of 4-Chloroaniline (2.00 g, 15.7 mmol), BOC-(L)-serine (3,22 g, 15.7 mmol), 1-oxybenzenesulfonate (2,12 g, 15.7 mmol) and diisopropylethylamine (5.40 ml, and 31.2 mmol) in 40 ml of DMF under stirring in argon atmosphere add hydrochloric ethyl-3(3-dimethylamino)propellerpowered (2,31 the Mixture is diluted with 400 ml ethyl acetate and washed with 1 N. aqueous solution of HCl (3 x 70 ml), and saturated solution of NaHCO3(2 x 70 ml). The organic layer is dried (MgSO4) filtered and concentrated in vacuo. The resulting product chromatografic on 80 g of silica gel 60 (Merck) using as eluents mixture of hexane-diethyl ether composition 1:3 and 1:4 (1 l of each mixture); get 1,02 g (21%), the target amide.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,34, Ce(SO4)2.

B. [1S-[1S, 2 (Z), 3 (R*), 4 ]]-6-[3-[[[2-[(4-chlorophenyl)amino]-1-(oxymethyl)-2-oxoethyl] amino] carbonyl]-7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section A of amide (1,02 g, 3,24 mmol) in 12 ml of dry methylene chloride under stirring in an argon atmosphere at 0aboutWith add 3 ml TFUCK. The mixture was stirred at 0aboutC for 3 h and diluted with 50 ml of toluene. The mixture was concentrated in vacuo. To a solution of this amine salt and TFUK, 1-oxybenzenesulfonate (0.50 g, 3.73 mmol) and 5 ml of triethylamine in 20 ml of DMF was added with stirring a solution obtained in section D of example 1 acid and 1.00 g, 3.73 mmol) in 10 ml of DMF. Then to the resulting mixture add hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction dare 400 ml ethyl acetate and washed with 1 N. HCl solution (3 times 30 ml), and 0.2 N. NaOH solution (2 x 30 ml) and brine (1, 100 ml). The organic layer is dried (MgSO4) and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 80 g of silica gel 60 (Merck), using as eluent 2% CH3OH in CH2Cl2; obtain 380 mg (22%) of the target alcohol.

TX: silica gel; 4% CH3OH in CH2Cl2; Rf= 0,31, Ce(SO4)2,

C. [1S-[1 ,2 ,(Z),3 (R*),4 ] ]-6-[3-[4-[[(4-chlorophenyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]- 7-oxabicyclo][2.2.1]-heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section B of alcohol (370 mg, 2,39 mmol) and diisopropylethylamine (0,42 ml, 2,39 mmol) in 5 ml of chloroform under stirring in an argon atmosphere at 0aboutWith add methanesulfonanilide (0,068 ml, 0.88 mmol). The resulting mixture was stirred at room temperature for 30 min and concentrated in vacuo. The crude mesilate dissolved in 10 ml of acetone and combined with 0.70 g K2CO3. This mixture is heated under reflux at a temperature close to the boiling temperature for 3 h, cooled to room temperature and diluted with 100 ml of acetone. The precipitate is filtered and washed with acetone (3 times in the 2% CH3OH in CH2Cl2getting 210 mg (59%) of the target oxazoline.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,68, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,2; 170,0; 169,6; 135,8; 129,5; 129,4; 128,9; 128,5; 120,9; 120,9; 79.2; 69,4; 68,7; 51,4; 48,3; 46,4; 33,7; 29,6; 28,8; 27,2; 22,8.

D. [1S-[1 , 2 (Z),3 , 4 ]]-6[3-[4-[[(4-chlorophenyl)amino]carbonyl]-2-oxazolyl] -7 - oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section C of oxazoline (200 mg, 0.45 mmol) in 3 ml of methylene chloride was added with stirring 200 mg NiO2. The reaction mixture was stirred at room temperature for 1.5 hours, then add another 200 mg NiO2. This mixture was stirred at room temperature for 1.5 h, and add another 200 mg NiO2. The resulting mixture was stirred for another 1.5 h and introducing another portion (200 mg).

The reaction mixture was stirred for 2 h and diluted with 100 ml of ethyl acetate. To the resulting mixture add 5 ml of 3M NaHSO3and 30 ml of 1M sodium citrate. The organic layer was separated; the aqueous layer was extracted with ethyl acetate (2 x 200 ml). The collected organic extracts are dried (MgSO4), filtered and concentrated in vacuo. The resulting product chromium is t 140 mg (70%) target of ester.

TX: silica gel, 4% CH3OH in CH2Cl2; Rf= 0,76, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 173,2, 164,2, 158,4, 141,4, 136,0, 135,9, 129,5, 129,3, 128,9, 128,9, 128,4, 121,1, 79,6, 79,4, 51,4, 49,6, 46,6, 33,7, 29,7, 28,9, 27,9, 22,8.

E. [1S-1 , 2 (Z),3 , 4 ]]-6-[3-[4-[[(4-chlorophenyl)amino]carbonyl] -2-oxazolyl]-7-oxabicyclo [2.2.1]heptyl-2]-4-hexenoic acid.

To the solution obtained in section D of ester (135 mg, 0.03 mmol) and 3 ml of water in 15 ml of THF with stirring, add 3 ml of 1 n LiOH solution. The resulting mixture for 10 minutes, rinsed with argon and stirred at room temperature for 5 hours. The mixture is acidified to pH = 2 by adding a solution of 1 N. HCl and saturated with NaCl. Separate the THF layer; the aqueous layer was extracted with ethyl acetate (4 x 15 ml). The collected organic extracts are dried (MgSO4), filtered and concentrated in vacuo. Cleaning is performed by pulsed chromatography on 15 g of silica gel 60 (Merck) using as eluent 4% CH3OH and CH2Cl2; get the 79.2 mg (61%) of the target acid.

TX: silica gel, 6% CH3OH in CH2Cl2; Rf= 0,36, Ce(SO4)2.

13With NMR (67,5 MHz, CDCl3) : 179,0, 177,6, 164,2, 141,7, 136,0, 135,9, 129,4, 128,5, 121,2, 79,7, 79,5, 49,6, 46,6, 33,6, 32,3, 29,7, 28,9, 27,9, 22,6.

A. [1S-[1 , 2 (Z),3 , 4 ]]-6-[3-[4-[[[4-(4-chlorophenyl)butyl]amino] carbonyl] -2-oxa-zolyl] - 7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

0.21 g containing impurity compounds obtained in section G of example 2 (purity 50%, 0.11 g, 0.33 mmol), stirred in 4 ml of toluene and add 0.1 ml (1,14 mmol) oxytrichloride. Add one drop of DMF and the resulting mixture was stirred for 2 h at room temperature, after which, according to traditional chronology, the reaction ends. The reaction mixture was concentrated in vacuo; the residue is twice re-concentrate 2 ml of toluene, getting orange oil, namely methyl ether [1S-[1 , 2 (Z),3 ,4 ]]-6-(4-chlorophenyl)-2-oxazolyl)-7-oxabicyclo[2.2.1] Hep-Tyl-2] -4 - hexenoic acid. To this oil is added about 3 ml of chloroform, and then of 0.11 ml (0.08 g, 0.78 mmol) of triethylamine and 0.13 g (0.71 mmol) of 4-(4-chlorophenyl)butylamine and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water, separate the organic layer and the aqueous layer was twice extracted with 20 ml ethyl acetate. The organic layers are collected together, washed with brine, dried over MgSO4and concentrated in vacuo, obtaining of 0.43 g of orange oil. This oil is subjected to pulse the spruce methyl ester (purity 50% , of 0.13 g of the desired product in the form of oil. The yield is 78%.

13With NMR (67,8 MHz, CDCl3) : 172,8, 163,6, 160,3, 140,2, 135,7, 131,0, 129,4, 129,1, 128,2, 128,0, 79,2, 79,1, 51,1, 49,4, 46,3, 38,4, 34,4, 33,5, 29,4, 28,6, 28,1, 27,6, 22,5.

B. [1S-[1 2 (Z),3 ,4]]-6-[3-[4-[[[4-(4-chlorophenyl)butyl]-amino] carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptyl-2]-4-GCSE - new acid.

0.26 g containing impurities of ester obtained in section A. (purity 50%, of 0.13 g, 0.26 mmol), stirred in about 30 ml of 1 N. NaOH and 2 ml of THF for 8 h at room temperature. The reaction mixture was concentrated to remove THF for 8 h at room temperature. The reaction mixture was concentrated to remove THF and acidified to pH 2 by adding concentrated HCl. Add ethyl acetate and the separated organic layer. The aqueous layer was twice extracted with about 20 ml of ethyl acetate. The organic layers are collected together, washed with a saturated solution of NaCl, dried over MgSO4and concentrated in vacuo, receiving 0.2 g of light oil. The resulting product chromatographic (silicon dioxide, 0,50% CH3OH, 0.25% OF CH3CO2H, 99,25% ethyl acetate) to give 0.10 g of the pure product. The yield is 79%.13With NMR (67,8 MHz, CDCl3) : 178,4, 164,4, 161,4, 141,0, 140,4, 135,6, 131,3, 129,6, 129,3, 128,5, 128,3, 79,5, Neal] -2 - thiazolyl]-7 - oxabicyclo[2.2.1]-heptyl-2]-4-hexenoic acid.

A. [1S-[1, 2 (Z),3 ,4 ]]-6-[3-(aminocarbonyl)-7-oxabicyclo[2.2.1] heptyl-2]-4-Huck - Senova acid, methyl ester.

To the solution obtained in section D of example 1 acid (2,45 g, 9,13 mmol) in dry benzene (100 ml) dropwise over 10 min add oxalicacid (of 0.96 ml, 11 mmol). After stirring for 5 h the reaction mixture was concentrated and dissolved in dry THF (10 ml) and added dropwise over 5 minutes are added to a solution of concentrated ammonium hydroxide (3 ml) in THF (100 ml) having a temperature of 0aboutC. Then the reaction mixture was concentrated in vacuo. The remaining solid is separated between ethyl acetate (150 ml) and 0.25 M K2CO3(25 ml). The aqueous layer was extracted with ethyl acetate (25 ml). The collected organic layers are dried (Na2SO4) and concentrated in vacuo. The residue (2.2 g) is suspended in boiling simple ether (100 ml). Add ethyl acetate (about 10 ml) to obtain a solution. The mixture is concentrated to about 50 ml on a steam bath, cooled to room temperature, make the seed and raids!! during the night. Clean the target amide (1.19 g, 49% ) receive filtering. Another portion of the target amide (145 mg) are obtained by concentrating the mother liquor is diluted to 15 ml (after which crystallization products is th ether.

To the solution obtained in section A of amide (267 mg, 0,999 mmol) in dry toluene (10 ml) at a temperature of 60aboutTo add the reagent Lawesson (222 mg, 0.55 mmol). The reaction mixture was stirred at 60aboutC for 30 min, diluted with diethyl ether (50 ml) and washed polysystem solution of NaHCO3(2 times 5 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo. The residue is passed through a thin layer of silicon dioxide, using a mixture of 50% ethyl acetate-hexane, and receives a yellow solid (249 mg, 88%).

C. [1S-[1 , 2 (Z),3 ,4 ]]-6-[3-(4-carboxy-2-thiazolyl)-7-oxabicyclo[2.2.1]heptyl-2-] -4 - hexenoic acid, methyl ester.

To the solution obtained in section B thioamide (400 mg, of 1.41 mmol) and powdered anhydrous K2CO3(390 mg, 2.82 mmol) in dry DMF (10 ml) in several portions add bronirovannogo acid (water content of 0.4 mol per 1 mol of the acid, 295 mg, was 1.69 mmol). The reaction mixture was stirred at room temperature for 30 minutes, after this time add to 29.5 mg bronirovochnoy acid. After one hour the solvent is removed in vacuum at a temperature below 30aboutC. the Residue is partially suspended, partially sulfonylurea (0.33 ml, 4.2 mmol). After stirring for 5 min the reaction mixture was diluted with diethyl ether (40 ml). The organic layer is extracted with 0.5 M solution of K2CO3(9 times 10 ml). The collected organic layers are acidified to a pH of 1.5 by adding 6 n HCl solution and extracted with diethyl ether (6 times 25 ml). Then the organic layers are dried (Na2SO4) and concentrated in vacuo. The yield of acid is 212 mg (43%).

D. [1S-[1 , 2 (Z),3 ,4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)-amino] carbonyl] -2-thiazo - Lil] -7 - oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

To the solution obtained in section C acid (42,0 mg, 0,120 mmol) in dry DMF (1 ml) is added 1,1'-carbonyldiimidazole (20,3 mg, 0.125 mmol). The reaction mixture was stirred for 1 h Then add a solution of hydrochloric acid cyclohexylmethyl)-amine (23,4 mg, 0,131 mmol) and triethylamine (at 0.020 ml, 0.14 mmol) in dry DMF (0.5 ml). The reaction mixture was stirred for 1 h, and concentrated by removing DMF. The residue is transferred in diethyl ether (20 ml) and 0.5 n HCl solution (5 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo. The obtained amide (46.8 mg, 81%) chromatographic (silicon dioxide: 50% ethyl acetate-hexane), getting to 37.1 mg (64% ) target of ester sabillo[2.2.1]heptyl-2]-4-hexenoic acid.

To the solution obtained in section D amide in methanol (1 ml) add 2 N. KOH (0.3 ml). The reaction mixture is stirred for 2 hours Enter another 0.3 ml of KOH. After another 1 h, the reaction mixture was concentrated by removing the methanol. The residue is dissolved in water (1 ml) and adjusted pH to 2 by adding 1 N. HCl. The mixture is extracted with methylene chloride (3 times 5 ml). The collected organic layers are dried (Na2SO4) and concentrated in vacuo, obtaining an oily product (34.7 mg, 96%).

P R I m e R 10. [1S-[1 ,2 (Z),3 ,4 ]]-6-[3-[5-[[(4-cyclohexylmethyl)amino] carbonyl-1H-imidazol-2-yl] - 7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

A. 2-{[(1,1-Dimethylmethoxy)carbonyl]AMI - but}-3-{[(phenylmethoxy)carbonyl] amino}propanoic acid.

N-BOC-asparagine (18.0 g, 77.5 mmol) are added to a solution of bis (triptoreline) iodopirazol (50.0 g, 116,3 mmol) in a mixture of DMF - H2O (1: 1, 620 ml). After 15 minutes, add pyridine (12.5 ml, 155, 1mm mmol). Dark yellow solution is stirred for 16 hours the Resulting pale yellow solution was concentrated in vacuo at a temperature below 40aboutC. the Residue is diluted with water (600 ml), washed with diethyl ether (6 times 400 ml) and concentrated in vacuo. The crude product is dissolved in water (100 m the th mixture with vigorous stirring, added dropwise to benzylchloride (purity 80%, according to NMR analysis; and 19.8 g, 93,0 mmol), dissolved in 50 ml of THF. Add another portion of a solution of Na2CO3to maintain the pH value in the main area (determined by the indicator paper pH from 5 to 10). After 1 h the addition finished, the reaction mixture is concentrated by removing THF. The residue is extracted with diethyl ether (3 x 200 ml). the pH of the aqueous layer was adjusted to 2 by addition of concentrated sulfuric acid. The mixture is extracted with diethyl ether (4 x 200 ml). These latter extracts dried (Na2SO4) and concentrated in vacuo. The chromatography was carried out (80% ethyl acetate/hexane containing 1% acetic acid), gives to 4.23 g (16%) of the desired product containing a small amount of impurities.

Rf(silica, ethyl acetate + 0.5% of acetic acid) of 0.27.

B. 2-(Trimethylsilyl)ethyl-2-{ [(1,1-dime-teletaxi)carbonyl]-amino}- 3-{ [(phenylmethoxy)carbonyl]amino}propanal.

To the solution obtained in section A acid (3,96 g, 11.7 mmol) in dry THF (50 ml) at 0aboutWith added 1,1-carbonyldiimidazole (2,08 g, 12.9 mmol). After 1 h, type 2-(trimethylsilyl)ethanol (3.4 ml). Then the reaction mixture was kept at 70aboutC for 1 h, After cooling, the reaction mixture conze is 3.08 g (60%) target of ester as a clear oil; Rf(silica, 25% ethyl acetate - hexane) 0,32.

C. 2-(Trimethylsilyl)ethyl ester of 3-amino-2-{ [(1,1-dimethylmethoxy)carbonyl]AMI - but}propanolol acid.

To the solution obtained in section B of the Z-amine (2,89 g, 6,60 mmol) in a mixture of propanol-2/water (65 ml/6 ml) is added ammonium formate (2,08 g, 33.0 mmol) and then the suspension of Pd/C (10%, 0.5 g) in propanol-2 (4 ml). The mixture is stirred at room temperature for 1 h, the Reaction mixture was filtered through Celite and concentrated in vacuo. The residue is transferred into 70 ml of ethyl acetate and 30 ml of saturated NaCl solution containing 8 ml of 5 N. NaOH. Next, the aqueous layer was extracted with ethyl acetate (2 x 70 ml). The collected organic layers are dried (Na2SO4) and concentrated in vacuo, obtaining the target compound in the form of oil (1.85 g, 92%).

Rf(silica, 10% methanol/chloroform) to 0.75.

D. [1S-[1,2 (Z),3 ,4 ]]-6-[3-[[[2-[[(1,1-dimethylmethoxy)-carbonyl] amino] -3-oxo-3-[2 - trimethylsilyl)ethoxy]propyl]-amino]taxometer]-7-oxabicyclo [2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

WSC (1.18 g, x 6.15 mmol) are added to a solution of methyl ester [1S-[1 , 2 (Z), 3,4 ]]-6-[3-(carboxy)-7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid (1.65 g, x 6.15 mmol), the compound obtained in section C (1) - Rev. izbavlyayut methylene chloride (300 ml), extracted (50 ml of 1 N. HCl 1 times, 50 ml of a saturated solution of NaHCO31 times (50 ml water, 1 time), dried (Na2SO4) and concentrated in vacuo. The chromatography was carried out (pulse mode, silicon dioxide, diameter 50 mm, 40% ethyl acetate - hexane, 2 l; 60% ethyl acetate, 1 l) gives an oily product number 2,11 g (63% ); Rf(silica, 10% methanol/chloroform) to 0.67.

Thus obtained amide (1,94 g, 3.50 mmol) was stirred at 65aboutWith in benzene (40 ml) with a reagent of Lawesson (850 mg, 2.10 mmol) for 1.5 hours the Reaction mixture is cooled and diluted with diethyl ether (250 ml). The mixture was washed (2 times 50 ml of 0.5 N. NaCO3), dried (Na2SO4), concentrated in vacuo and chromatographic (pulse mode, silicon dioxide, diameter 50 mm, 25% ethyl acetate - hexane), receiving of 1.61 g (80%) of target compound in the form of oil; Rf(silica, 25% ethyl acetate - hexane) 0,14.

E. [1S-[1 , 2(Z), 3 , 4 ]]-6-[3-[1-[(1,1-dimethylmethoxy)carbonyl]-4,5-dihydro-5-[[2- (trimethylsilyl)ethoxy] carbonyl-1H-them-Gasol-2-yl]-7-oxabicyclo[2.2.1] heptyl-2]-4-hexenoic acid, methyl ester.

Carbon tetrachloride (3,00 ml, and 31.2 mmol) are added to the solution obtained in section D of compound (1,61 g, 2.82 mmol), triphenylphosphine (2,22 is their 4 o'clock The mixture is then diluted with diethyl ether (125 ml), saturated NaCl solution (125 ml) and water (5 ml). Next, the aqueous phase is extracted with simple ether (125 ml). The collected organic layers are dried (Na2SO4) and concentrated in vacuo. The residue is ground to powder in series with simple ether (20, 10 and 7 ml), each time selecting and concentrating the filtrate to the next cycle. The chromatography was carried out (pulse mode, silica, 50 mm diameter, 50% ethyl acetate - hexane) gives 1,09 g (72%) of target compound in the form of oil; Rf(silica, 50% ethyl acetate - hexane) 0,29.

F. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-(5-carboxy-4,5-dihydro-1H-imidazol-2-yl)-7-oxa-bicyclo [2.2.1]heptyl-2]-4-hexenoic acid, hydrochloric acid methyl ester.

To the solution obtained in section E connection (1,09 g, 2.03 mmol) in methylene chloride (2 ml) add TFOC (4 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with toluene (40 ml) and concentrated in vacuo. The residue is transferred into ethyl acetate (60 ml) and washed with saturated solution of NaHCO3(2 times 5 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo, obtaining methyl ether [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-(5-carboxy-4,5-dihydro-1H-imidazol-2-yl)-7-oxabicyclo solid product with chloroform (2 x 15 ml) followed by concentration in vacuo gives the target compound (553 mg, 73%).

G. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[5-[[(4-cyclohexylmethyl)amino] carbonyl] -1H-imida - Zol-2-yl]- 7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

The mixture obtained in section F of acid (516 mg, 1.38 mmol), (4-cyclohexylmethyl)amine in the form of muriate (345 mg, of 1.80 mmol), WSC (345 ml of 1.80 mmol), MBT (243 mg, of 1.80 mmol) and triethylamine (and 0.50 ml, 3.6 mmol) in methylene chloride (15 ml) is stirred for 24 h, the Reaction mixture was diluted with methylene chloride (50 ml) and washed (2 times 10 ml of a saturated solution of NaHCO3), dried (Na2SO4) and concentrated in vacuo, receiving a yellow oil, which is a methyl ester of [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[5-[[(4-cyclohexylmethyl)amino]carbonyl]-4,5-dihyd-ro-1H - imidazol-2-yl]-7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid. The oil obtained is dissolved in chloroform (20 ml). Add active MnO2(Aldrich, 1.0 g). The reaction mixture is stirred for 24 hours Add 0.5 g of MnO2and stirred the mixture for 3 days. Then add 0.5 g of MnO2. After 5 h the reaction mixture was filtered. The filter was washed with chloroform. The collected filtrate was concentrated in vacuo. The chromatography was carried out (pulse mode, silicon dioxide, 25 mm diameter, 2% methanol - PI is oxybutyl)amino] carbonyl] -1H - imidazol-2-yl]- 7-oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid.

To the solution obtained in example 10 of ester in methanol (8 ml) is added 2 n solution of KOH (4 ml). The reaction mixture was stirred at room temperature for 4 h under vacuum to remove methanol. The residue is transferred in methylene chloride (25 ml) and the pH adjusted to 2 by adding 1 n HCl solution. After shaking, the aqueous layer was extracted with methylene chloride (25 ml). The collected organic layers are dried (Na2SO4) and concentrated in vacuo. The residue is transferred in methylene chloride and intensively mixed with an ethereal solution of HCl (4 ml) for 30 C. the Mixture was concentrated in vacuo. Rubbing with 10 ml of ethyl acetate (from boiling to room temperature) gives a white solid which is collected by filtration, washed with ethyl acetate (5 ml) and dried, obtaining the target acid in a solid white color, 126,4 mg (52%); so pl. 168-173aboutC.

1H NMR (tetranitromethane/deuterochloroform, 270 MHz) : with 8.05 (s, 1H), 5,23 and 5.36 (m, 2H), 4,73 (s, 1H), to 4.41 (s, 1H), 3,74 (d, j = 8 Hz, 1H), 3,34-3,37 (m, 2H), 0,84 is 2.44 (m, 28N).

13With NMR (full interchange and 67.8 MHz, tetranitromethane-deuterochloroform) : 175,4, 157,0, 147,8, 130,1, 127,3, 120,7, 80,0, 79,9, 44,9, 39,8, 37,4, 36,9, 33,5, 33,1, 29,1, 28,7, 28,1, 26,5, 26,2, 24,1, 22,6.

IR (KBr): 3427 (m), 3232 (m), 3009 (m), 2923 (s), 2851 (m), 1730 (m), 4 (7), 173 (14), 172 (6), 169 (9), 168 (13), 167 (5), 157 (10), 156 (100), 155 (25), 154 (35), 162 (6).

The elemental composition of

C26H40ClN3O40,25 H2O

Calculated, %: C 63,63; H 8,19; Cl 7,11; N 8,43.

Found, %: C 62,76; 8,30 H; Cl 6,82; N Of 8.37.

P R I m e R 12. [1S-[1 , 2 (Z, 3 , 4 ]]-N-(4-cyclohexylmethyl)-2-[2-[5-(1H-tetrazol-5 - yl)-2-pentenyl] -7 - oxabicyclo[2.2.1]-heptyl-3]-4-oxazolidone.

A. [1S-[1 , 2 (Z), 3 , 4 ]]-2-[5-(1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicyclo[2.2.1] heptane-3-methanol.

To a suspension of 1.0 mmol [4aR (4a , 5 , 8 , 8 (a )] octahydro-5,8-epoxy-1H-2-benzopyran-3-ol, prepared in accordance with U.S. patent N 4143054, and 1.4 mmol of 3-(tetrazol-5-yl)propyltrimethylammonium - bromide in tetrahydrofuran at 0aboutWith added dropwise 1.8 M solution of KOt-Amiata in toluene (2.8 mmol). The obtained mixture is allowed to warm to room temperature over night. The reaction mixture was quenched by addition of acetic acid. The reaction mixture was concentrated in vacuo and purified, chromatographie on silica gel using as eluents mixtures of methanol with methylene chloride.

B. [1S-[1 , 2 (Z), 3 , 4 ]]-2-[5-(1-methoxymethyl-1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicyclo [2.2.1]heptane-3-methanol.

A solution of 1.0 mmol of the obtained above tetrazole at T the th mixture is stirred for 4 h at room temperature and then divided between saturated aqueous NaHCO3and ethyl acetate. An ethyl acetate layer is dried, filtered and concentrated in vacuo, obtaining the target tetrazol.

C. [1S-[1 , 2 (Z), 3 , 4 ]]-N-(4-cyclohexylmethyl)-2-[2-[5-(1-methoxymethyl-1H-tet - razol-5 - yl)-2-pentenyl]-7-oxabicyclo[2.2.1]heptyl-3] -4-oxazolidone.

Synthesis is carried out according to the method of example 1, except that instead of ester section C of example 1 using tetrazol section B of example 12; get the target connection.

D. [1S-[1 , 2 (Z), 3 , 4 ]]-N-(4-cyclohexylmethyl)-2-[2-[5-(1H-tetrazol-5-yl)-2 - pentenyl] - 7-oxabicyclo[2.2.1]heptyl-3]-4-oxazolidone.

To a solution of 1.0 mmol obtained in section C of tetrazole in methanol (25 ml) was added 1 drop of concentrated HCl. The resulting solution was heated (boiled) under reflux for 2 hours After cooling, the reaction mixture was concentrated in vacuo. The crude product was then purified liquid chromatography high-pressure reversed-phase using a mixture of acetonitrile from 0.02% aqueous solution of H3PO4as the mobile phase; get target tetrazol.

Examples of other compounds of this invention, which can be obtained using the methods described in the OPU 2 (Z),3, 4 ]]- 6-[3-[4-[[(6-cyclohexyloxy)-amino] Carbo - Neil]-2-oxazolyl]-7 - oxabicyclo[2.2.1]-heptyl-2-]-4-hexenoic acid, methyl ester.

A. an ester of benzophenone and methanesulfonic acid.

To a solution of 5-phenylpentane-1 (5.0 g, 30.4 mmol) in 20 ml of methylene chloride under stirring in an argon atmosphere at -70aboutTo add the first triethylamine (4.0 g, to 39.5 mmol) and then dropwise methanesulfonanilide and 2.83 ml, 4,18 g of 36.5 mmol).

The reaction mixture is slowly warmed to room temperature, water is added, and the reaction mixture is extracted with methylene chloride (50 ml). The aqueous layer was twice extracted with methylene chloride (25 ml). The organic layers are collected together and washed with brine, then dried over MgSO4and concentrate, receiving 7.30 g (100%) of target compound in the form of a yellow oil; Rf= 0.9 in a mixture of 50% hexane - ethyl acetate (UV, Ce(SO4)2.

B. Benzoylhexanoic.

To the solution obtained in section A of the compound (7.30 g, to 30.1 mmol) in 70 ml of ethanol under stirring at room temperature is added a solution of KCN (9.81 g, to 150.6 mmol) in 29 ml of water. The resulting reaction mixture is stirred for 20 h, then extracted three times with chloroform (50 is the mind, getting a yellow oil containing the target compound and the remains of the compound obtained in section A. This oil is purified by pulsed chromatography (hexane-ethyl acetate composition 95:5); obtain 2.16 g (41%) of the desired product in the form of butter.

13With NMR (CDCl3): 141,8; 128,0; 125,5; 119,5; 35,4; 30,5; 27,9; 24,9; 16,7.

C. Cyclohexanediamine.

To the solution obtained in section B of compound (2.16 g, 12.4 mmol) in 100 ml of acetic acid add PtO2(0,60 g). The resulting mixture was stirred at room temperature in the environment of hydrogen under a pressure of 1 atmosphere. After 20 h, the reaction mixture is filtered and the filter washed twice with ethanol. The filtrate is concentrated to a semi-liquid state. This product is stirred in hexane, and obtain the target product (2.00 g, 95%) after filtration in the form of pujobroto solid white.

D. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[[(6-cyclohexyloxy)amino] carbonyl] -2-OK-sapolil]-7 - oxabicyclo[2.2.1]heptyl-2]-4-hexenoic acid, methyl ester.

Sample oxazolone acid obtained in section G of example 2 (1,61 g, 4.8 mmol), dried by azeotropic distillation in a high vacuum with dry DMF and toluene. The resulting substance (containing residual DMF) p is lillolita (23 mmol). There is a selection of gas. At the bottom of the tank with the reaction mixture formed a dark oil. (This oil is a product of the reaction between DMF and oxalylamino). After 5 min add another 2.9 g of oxalicacid. The mixture is stirred over night. Method TX shows that there is a complete conversion to the acid chloride acid. The supernatant layer is pipetted and transferred into a vessel filled with argon. Place double-mix with new portions of toluene, and select the supernatant layer. United supernatant layers is evaporated with chloroform, getting 1.54 g (yield 91%) of the carboxylic acid, namely, methyl ester [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-(chlorocarbonyl)-2-oxazolyl]-7-oxanilic-lo[2.2.1]heptyl -2]-4-hexenoic acid.

To the solution obtained in section amine (0.55 g, 3.0 mmol) in 5 ml of chloroform at 0aboutWith add triethylamine (0.3 g, 3.0 mmol) and the above acid chloride of acid (about 0.53 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 14 h, then diluted with chloroform and water. Separate the organic layer, the aqueous layer was twice extracted with 20 ml of chloroform. The organic layers were combined, washed with brine, dried over MgSO4and concentrate. Flash chromatography (0 dxun-acetate of structure 1:1 (UV, Ce(SO4)2.

13With NMR (67,8 MHz, CDCl3) : 172,8, 163,5, 160,1, 140,1, 135,8, 129,1, 128,2, 79,2, 51,0, 49,4, 46,3, 38,7, 37,2, 37,0, 33,4, 33,0, 29,4, 29,2, 28,6, 27,5, 26,6, 26,3, 26,1, 22,5.

P R I m e R 31. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[[(6-cyclohexyloxy)-aminocarbonyl)-2-oxazolyl)-7 - oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid.

A solution of 0.49 g (0.97 mmol) of ester obtained according to example 30, in 8 ml of 1 n sodium hydroxide solution and 8 ml of tetrahydrofuran is stirred for 18 h, then concentrated in vacuo to remove tetrahydrofuran and acidified to a pH of 1.5 by 1 N. hydrochloric acid. To the mixture are added ethyl acetate and the separated organic layer. The aqueous layer was twice extracted with 20 ml ethyl acetate. The organic fractions combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo, obtaining the resulting white solid. The specified product is crystallized from hexane and chloroform, getting 0.40 g (84%) of pure product as a white solid.

Rf= 0.36 and 0.1% acetic acid (4% methanol in ethyl acetate). Visualization under UV light: sulfate cerium Ce(SO4)2[ ]Do= = + 30,2, = 0,58 g/100 ml methanol, melting point 32-83aboutC.

P R I m e R 32. M is xenomai acid.

To a solution of 0.49 g (1,40 mmol) of the carboxylic acid obtained as described in example 2 (part 1) and an unknown amount of salt, Vilsmeier in 10 ml of chloroform is added with stirring 0.28 g (2,80 mmol) of triethylamine and 0.38 g (2.1 mmol) of 6-cyclohexylethylamine obtained according to example 30, part C. the Mixture is stirred at room temperature for 10 h, then diluted with ethyl acetate and water. The organic layer is separated and the aqueous layer extracted with two pistons 20 ml of ethyl acetate. The organic fractions combined, washed with brine, dried over magnesium sulfate and concentrated. By chromatography with evaporative (gradient ethyl acetate-hexane, 0 to 100%) to obtain 0.17 g is specified in the header of the product as a clear oil with a yield of 25%. Rf= 0,46 in a mixture of ethyl acetate-hexane 1:1.

P R I m e R 33. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[[(6-cyclohexyl)-amino] carbonyl] -2-OK-sotalol] -7 - oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid.

A solution of 0.17 g (0.33 mmol) of ester according to example 32 in 5 ml of 1 n sodium hydroxide solution and 2 ml of tetrahydrofuran was stirred at room temperature for 10 h, then concentrated in vacuo to remove tetrahed - ROF the practical layer. The aqueous layer was extracted twice with ethyl acetate, combined organic fractions washed them with brine, dried over magnesium sulfate and concentrated in vacuo. In the described operations get a clear oil. It chromatographic using a mixture of ethyl acetate-hexane (1:1) with 0.25% acetic acid, receiving the result of 0.13 g (78%) indicated in the title product as oil (contains 2.5% of the CIS isomer of the compounds according to example 31A). Rf= 0.36 in 4% methanol with 0.1% acetic acid, 95.5% of ethyl acetate (UV visualization using cerium sulfate). []Do= + 55 in methanol at a concentration of 0.50 g/100 ml

P R I m e R 34. Methyl ester (1 , 2 (Z), 3 , 4 (-5-3-[4-1-pyrrolidinylcarbonyl)-2-oxazolyl)-7-oxabicyclo[2.2.1] hept-2-yl]-4-hexenoic acid.

To a solution of 0.18 g (0.50 mmol) of the carboxylic acid obtained according to example 2 (part 1), in 3 ml of chloroform added under stirring in an argon atmosphere at 0aboutWith 0.10 g (1.0 mmol) of triethylamine and 0.07 g (1.0 mmol) of pyrrolidone. The mixture is heated to room temperature and stirred for 10 h, then diluted with ethyl acetate and water. The organic layer is separated and the aqueous layer was twice extracted with 20 ml ethyl acetate. The organic layers about the tion (gradient of ethyl acetate in hexane, from 50 to 100%, then 2% methanol in ethyl acetate) gain of 0.13 g is specified in the header of the product as a clear oil, yield 68%; Rf= 0.6 V mixture of ethyl acetate-methanol 9:1 (UV visualization with cerium sulfate).

These NMR-FROM13(and 67.8 MHz, deuterochloroform), : 172,9, 162,9, 160,0, 141,9, 136,9, 129,0, 128,5, 79,2, 78,9, 51,1, 49,4, 47,9, 46,5, 46,4, 33,5, 29,5, 28,7, 27,6, 26,1, 23,4, 22,5.

P R I m e R 35. (1 , 2 (Z), 3 , 4 ]-6-[ 3-[4-(1-pyrrolidinylcarbonyl)-2-oxazolyl]- 7-oxabicyclo [2.2.1]hept-2-yl]-4-hexenoic acid.

A solution of 0.13 g (0.33 mmol) of the compound according to example 34 in 10 ml of 1 n sodium hydroxide solution and 2 ml of tetrahydrofuran is stirred for 10 h at room temperature, then concentrated in vacuo to remove tetrahydrofuran and acidified to a pH of 1.5 by means of hydrochloric acid. To the mixture are added ethyl acetate and the separated organic layer. The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The result is a transparent oil. It chromatographic using ethyl acetate with 1% of methanol, and 0.25% acetic acid (98,75% ethyl acetate) to give 0.12 g (92%) of pure product in the form of oil; Rf= 0.2 in 1% methanol and 0.5% acetic acid and 98.5% of ethyl acetate, []Doamino)carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1]hept-2-yl]-4-hexenoic acid.

To a solution 0,22 g (3.7 mmol) of Propylamine in 5 ml of chloroform was added when the temperature at 0aboutC in an atmosphere of argon rate £ 0.162 g (0.46 mmol) of the carboxylic acid obtained according to example 2, part I. the Reaction mixture is heated to room temperature and stirred for 14 h, then diluted with chloroform and water. The organic layer is separated and the aqueous layer was extracted with 2 portions of 20 ml of chloroform. The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated. After chromatographic processing fumes (gradient of ethyl acetate in hexane from 0% to 75% ) are obtained 0.15 g specified in the header of the product as a clear oil with a yield of 85% . Rf= 0,29 4% methanol in ethyl acetate (UV visualization, cerium sulfate).

An NMR spectrum WITH13(deuterochloroform), : 173,0, 163,7, 160,4, 140,2, 136,0, 129,2, 128,4, 79,3, 79,2, 51,2, 49,5, 46,5, 40,5, 33,6, 29,6, 28,7, 27,7, 22,7, 22,6, 11,2.

P R I m e R 37. [1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[(propylamino)carbonyl[-2-oxazolyl] 7-oxabicyclo [2.2.1]hept-2-yl]-4-hexenoic acid.

A solution of 0.15 g (0,39 mmol) of ester according to example 36 in 8 ml of 1 n sodium hydroxide solution and 8 ml of tetrahydrofuran is stirred for 18 h, then concentrated in vacuo to walentin and separate the organic layer. The aqueous layer was extracted with 2 portions of ethyl acetate and 20 ml Organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The result is a clear oil, which crystallized from a mixture of hexane and chloroform, getting 0.14 g (yield 100%) of pure product in the form of a solid white; Rf= 0,41 in 0.1% acetic acid, 4% methanol, 95.9% of ethyl acetate (UV visualization, cerium sulfate). Melting point 117-118aboutC []Do= + 42,12 at a concentration of 4.7 g/100 ml methanol.

P R I m e R 38. Methyl ester [1S-[2 , 2 (Z), 3 , 4 ]]-6-[3-[4-[[4-butylphenyl)amino] -carbonyl]-2-oxazolyl]-7 - oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid.

To a solution of 0,189 g (1,27 mmol) 4-butylaniline in 5 ml of chloroform added at 0aboutC in argon atmosphere 0.17 g (0.48 mmol) of the carboxylic acid obtained as described in example 2; part 1, and 0,145 g (1.44 mmol) of triethylamine. The mixture is heated to room temperature and stirred for 14 h, then diluted with chloroform and water. The organic layer is separated and the aqueous layer extracted with 2 portions of 20 ml of chloroform. The organic layers are combined, washed with brine, dried over magnesium sulfate and content 0.16 g of product, specified in the header, in the form of a transparent oil (yield - 69%). Rf= 0.87 in 4% methanol in ethyl acetate (UV graphically, cerium sulfate).

An NMR spectrum WITH13(deuterochloroform) : 173,1, 163,9, 158,2, 141,1, 139,0, 136,2, 129,4, 128,7, 128,4, 119,7, 79,4, 79,3, 51,3, 49,6, 46,6, 34,9, 33,6, 33,5, 29,7, 28,8, 27,8, 22,7, 22,1, 13,8.

P R I m e R 39. [1S-[1 , 2 (Z), 3 , 4 ]]-5-[3-[4-[[(4-butylphenyl)amino] -carbonyl] -2-OK - sapolil]-7 - oxabicyclo[2.2.1]hept-2-yl]4-hexenoic acid.

A solution of 0.16 g (0.34 mmol) of ester according to example 38 1 N. the sodium hydroxide solution and 8 ml of tetrahydrofuran is stirred for 18 h, then concentrated in vacuo to remove tetrahydrofuran and acidified to a pH of 1.5 by 1 N. hydrochloric acid. To the mixture are added ethyl acetate and the separated organic layer. The aqueous layer was extracted twice with 20 ml of ethyl acetate. The organic extracts are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Get a clear oil, which crystallized from a mixture of hexane and chloroform, receiving of 0.13 g (yield 87%) of pure product in the form of a solid yellow color. Rf= 0,47 in 0.1% acetic acid, 4% methanol, 95.9% of ethyl acetate (UV visualization, cerium sulfate). Temperature Plavinas (1S-[ 1], 2 (Z), 3 , 4 [[-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl] -2-oxazolyl] -7 - oxabicyclo-[2.2.1] hept-2-yl]-4-hexenoic acid.

A solution of 0.37 g (0.80 mmol) of ester according to example 40 in 15 ml of 1 n solution of hydroxide of sodium and 15 ml of methanol is stirred for 18 h, then acidified to pH 2 by means of concentrated hydrochloric acid. To the mixture are added ethyl acetate and the separated organic layer. The aqueous layer was extracted twice with 20 ml of ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Receive oil red, which chromatographic using a 0.1% solution of acetic acid in a gradient of ethyl acetate in hexane (0 to 100%), resulting in the 0.25 g (yield 75%) indicated in the title compound in the form of a yellow oil, Rf= 0,29 in 0.1% acetic acid in 50% ethyl acetate in hexane (UV visualization, cerium sulfate). [ ]Do= + 31,2 in methanol at a concentration of 0.48 g/100 ml

P R I m e R 41. [1S-[1 , 2 (Z) 3 , 4 ]]- 6-[3-[4-[[(4-cyclohexylmethyl)amino] Carbo-Neil]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-phenylsulfonyl-4-GE - xenomic.

To a solution of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (102 mg, 0.50 to ol) benzosulfimide and then of 0.14 ml (1.00 mmol) of C2H5O3N finally, 229 mg (0.30 mmol) of the acid obtained as described in example 1. The reaction mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The remainder is redistributed between 25 ml of 1 n hydrochloric acid and ethyl acetate (4 servings 40 ml). The combined extracts in ethyl acetate washed with 30 ml brine, dried over magnesium sulfate. Filtered and concentrated in vacuo. The remainder chromatographic on 30 g of silica gel-60 by Merck, using as eluent 2% methanol in methylene chloride to deliver 250 mg specified in the header sulfonamida. This product is redistributed between 60 ml of ethyl acetate and water (1 portion 20 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, getting 210 mg (yield 70%) indicated in the title compound, as a solid substance. Melting point 154-156aboutWith data thin-layer chromatography on silica gel, 4% methanol - methylene chloride; Rf= 0,45 (cerium sulfate).

An NMR spectrum WITH13specified in the connection header (deuterochloroform, to 67.5 MHz) : 171,1, 170,5, 163,9, 161,1, 140,7, 139,0, 135,9, 133,5, 128,7, 128,2, 79,7, 79,7, 49,5, 46,4, 39,2, 37,4, 37,0, 35,9, 33,3, 33,3, 29,7, 28,8, 27,9, 26,6, 26,3, 26,3, 24,1, 22,3.-oxabicyclo-[2.2.1] hept-2-yl]-4-hexanamide

To a solution of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (102 mg, 0.50 mmol) and 4-dimethylaminopyridine (66,7 mg, 0.50 mmol) in 50 ml of dimethylformamide add 47,6 mg (0.50 mmol) of methanesulfonamide and 0.14 ml (1.00 mmol) of (C2H5)3N, and then 229 mg (0.50 mmol) of the acid according to example 1. The reaction mixture was stirred for 18 h at room temperature and concentrated in vacuo. The remainder is redistributed between 25 1 N. hydrochloric acid and ethyl acetate (4 servings 40 ml). The combined extracts in ethyl acetate washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on 30 g of silica gel-60 by Merck, using as eluent 2% methanol in methylene chloride to deliver 200 mg specified in the header sulfonamida. The resulting product redistribute between 60 ml of ethyl acetate and 20 ml of water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, resulting in the 150 mg (yield 56%) indicated in the title compounds as solids. Melting point 140-142aboutWith the results of thin-layer chromatography (4% methanol - methylene chloride); Rf= 0,40 (cerium sulfate).

Spec is,5, 46,4, 41,3, 39,2, 37,4, 37,0, 36,0, 33,3, 29,7, 28,8, 28,0, 26,6, 26,3, 24,1, 22,3.

P R I m e R 43. Methyl ester [1S-[1 , 2 (Z), 3 , 4 ]]-7-[3-[4-[[(4-cyclohexylmethyl)amino] carbonyl] -2-oxazolyl] -7 - oxabicyclo[2.2.1] hept-2-yl]-5-heptenophos acid.

A. [1S-[1 , 2 (Z), 3 , 4 ]]-7-(3-carboxy)-7-oxabicyclo-[2.2.1] -hept-2-yl)-5-hepta - new acid.

To a solution of methyl ester [1S-[2 , 2 (Z), 3 , 4 ]]-7-(3-oxymethyl)-7-oxabicyclo[2.2.1] hept-2-yl-5-heptenophos acid (1.60 g, 5,79 mmol) in 100 ml of acetone is added under stirring at 0aboutWith manganese sulfate MnSO4treated with Jones reagent (approximately 100 mg manganese sulfate, dissolved in 100 ml of Jones reagent) until red-orange color. The reaction mixture was stirred at 0aboutC for 30 min and at room temperature for 1.5 hours Then the reaction mixture was quenched with isopropyl alcohol and concentrated in vacuo. The remainder is redistributed between 70 ml of a 3M solution of NaHSO3and ethyl acetate (4 portions of 100 ml). The combined extracts in ethyl acetate washed with water (1 portion 70 ml) and brine (1 portion 70 ml). The organic layer is dried over magnesium sulfate and concentrated in vacuo, obtaining of 1.57 g (yield 93%) indicated in the title compound, which was used in the next stage without dopolnitvah cerium).

An NMR spectrum WITH13specified in the connection header (deuterochloroform, to 67.5 MHz) : 176,7, 174,0, 130,5, 128,3, 78,4, 78,2, 51,8, 51,3, 47,8, 33,3, 29,0, 28,7, 27,2, 26,6, 24,6.

B. [2-[(4-cyclohexylmethyl)amino)-1-oxymethyl-2-oxoethyl]-karamanova kislota, 1,1-dimethyl ether.

To a mixture of the hydrochloride of 4-cyclohexylethylamine (19.5 g, 102 mmol), 1-oxibendazole, H2O (16.5 g, 122 mol) and BOC-1-serine (25,0 g, 122 mmol) in 400 ml of dimethylformamide added under stirring at 0aboutC in an atmosphere of argon consistently to 42.5 ml (305 mmol) of (C2H5)3N and 23.4 g (122 mol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture was stirred at 0aboutC for 1 h and at room temperature for 18 hours Then the mixture was concentrated in vacuo and diluted with 800 ml ethyl acetate. The resulting solution was washed with 1 N. hydrochloric acid (3 servings 120 ml) of 0.2 N. the solution of hydrate of sodium oxide (2 servings on 100 ml), a saturated solution of NaHCO3(1 portion 100 ml) and brine (1 portion 150 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, receiving and 39.9 g specified in the title amide in quantitative yield. Thin layer chromatography (silica gel, 4% methanol/methylene chloride):Rf

C. Methyl ester (1S-[1,2 (Z),3 , 4]]-7-[3-[[2-[(4-cyclohexylmethyl)amino] - 1-oxymethyl-2-oxoethyl] amino]carbonyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenophos acid.

To the solution obtained in section B amide (1.90 g, to 5.56 mmol) in 20 ml of methylene chloride added with stirring at 0aboutWith 8 ml triperoxonane acid. The resulting mixture was stirred at 0aboutC for 3 hours the mixture is Then diluted with 50 ml of toluene and concentrated in vacuo, obtaining an amine salt and triperoxonane acid. To a solution of the specified amine salt and triperoxonane acid, acid under section A (1,57 g, to 5.57 mmol) and 1-oxybisethanol H2O (0.75 g, to 5.57 mmol) in 60 ml of dimethylformamide added under stirring at 0aboutC in an atmosphere of argon consistently 3,88 ml (27.8 mmol) of (C2H5)3N and 1.07 g (5,57 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The resulting mixture was then stirred at room temperature for 16 h and concentrated in vacuo. The crude product was diluted with 400 ml ethyl acetate and washed with 1 N. hydrochloric acid (3 portions 70 ml), and 0.2 N. the solution of sodium hydroxide (2 portions of 50 ml) and a saturated solution of NaHCO3(1 parti farout on 70 g of silica gel-60 by Merck, using 2% methanol in methylene chloride as eluent, receiving the result of 1.74 g (yield 42%) specified in the header of alcohol. Thin layer chromatography (silica gel, 2% methanol in methylene chloride): Rf= 0,18 (cerium sulfate).

An NMR spectrum WITH13specified in the header of alcohol deuterochloroform, to 67.5 MHz) : 174,0, 173,2, 170,6, 130,6, 128,5, 79,2, 62,7, 54,4, 53,5, 51,4, 48,0, 39,5, 37,4, 37,0, 33,3, 33,3, 29,6, 28,6, 27,5, 26,6, 26,3, 26,3, 24,7, 24,1.

D. [1S-[1 ,2 (Z),3 , 4 ]]-7-[3-[5-[[(4-cyclohexylmethyl)amino]carbonyl] -4,5 - dihydro-2 - oxazol-2-yl]-7-oxabicyclo-2.2.1]hept-2-yl]-5-geptanona acid, methyl ester.

To a solution of 1.10 g (2,17 mmol) obtained according to the section With alcohol and 0.61 ml (4.35 mmol) of (C2H5)N in 10 ml of dry methylene chloride added with stirring at 0aboutFrom 0.20 ml (2,61 mmol) methanesulfonanilide. The resulting mixture was stirred at 0aboutC in argon atmosphere for 1.5 h and diluted with 200 ml methylene chloride. The reaction mixture was washed with a saturated solution of NaHCO3(1 portion 20 ml) and brine (1 portion 20 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in 20 ml of acetone and added 1.40 g of potassium carbonate K2CO3. The resulting mixture was t through the layer of Celite thickness of 51 mm and washed with acetone (4 portions of 50 ml). The filtrate was concentrated in vacuo. Cleaning produce by chromatography with evaporative 36 g of silica gel firm Merck using as eluent 2% methanol in ethylene chloride, resulting in the 740 mg (yield 70% ) specified in the header oxazoline. Thin layer chromatography (silica gel, 4% methanol in methylene chloride) Rf= 0,48 (cerium sulfate).

An NMR spectrum WITH13specified in the connection header (deuterochloroform, to 67.5 MHz) : 173,7; 171,2; 169,2; 130,5; 128,4; 79,0; 79,0; 69,6; 68,3; 51,3; 48,3; 46,3; 39,0; 37,4; 36,9; 33,3; 33,2; 29,7; 29,6; 28,8; 27,2; 26,6; 26,5; 26,2; 26,2; 24,6; 24,0.

E. Methyl ether [1S-[1 ,2 (Z).3,4 ]]-7-[3-4-[[(4-cyclohexylmethyl)amino] Carbo - Neil]-2-oxazolyl]-7 - oxabicyclo-[2.2.1]hept-2-yl]-5-heptenophos acid.

To the solution obtained according to section D of oxazoline (730 mg, 1.50 mmol) in 15 ml of dry methylene chloride are added during the mixing of 1.10 g of Nickel oxide NiO2. The resulting mixture was stirred at room temperature for 1 h, then add to it 0.74 g NiO2. The mixture is stirred at room temperature for another one hour, and add to it the second portion of 0.74 g NiO2. The resulting mixture was stirred at room temperature for another 1 h, then diluted with 80 ml of EB is rceme ethyl acetate in 120 ml. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on 30 g of silica gel-60 by Merck using 2% methanol in methylene chloride as eluent, to deliver 410 mg (yield 56%) specified in the header oxazole. Thin layer chromatography (silica gel, 2% methanol in methylene chloride): Rf= 0,31 (cerium sulfate).

An NMR spectrum WITH13specified in the connection header (deuterochloroform, to 67.5 MHz) : 173,7; 163,9; 160,5; 140,4; 136,1; 130,5; 128,0; 79,5; 79,3; 51,3; 49,7; 46,6; 39,0; 37,4; 37,0; 33,3; 33,3; 29,8; 28,9; 26,6; 26,3; 24,6; 24,1.

P R I m e R 44. [1S-[1 ,2 (Z),3 , 4]]-7-[3-[4-[[(4-cyclohexylmethyl)-amino] Carbo - Neil] -2-oxazolyl] -7 - oxabicyclo[2.2.1]hept-2-yl]-5-geptanona acid.

To a solution of 410 mg (0.84 mmol) obtained in example 44 oxazole in 20 ml of methanol is added with stirring 5 ml of 1 n sodium hydroxide solution. The resulting mixture was stirred at room temperature for 2.5 h and concentrated in vacuo. This mixture redistribute between 10 ml of 1 n hydrochloric acid, saturated sodium chloride, and ethyl acetate (4 servings 20 ml). Extracts in ethyl acetate is dried over magnesium sulfate, filtered and concentrated in vacuo. The cleaning implement is Nola in methylene chloride with 1% acetic acid for elution, deliver 370 mg (yield 93%) of pure acid specified in the header. The melting point of 123-125aboutC. Thin-layer chromatography: silica gel, 6% methanol in methylene chloride; Rf= 0,22 (cerium sulfate).

An NMR spectrum WITH13specified in the connection header (deuterochloroform, to 67.5 MHz) : 177,8, 164,0, 160,9, 140,9, 135,8, 128,1, 79,4, 79,4, 49,8, 46,7, 39,2, 37,5, 37,0, 33,3, 33,3, 29,8, 27,8, 26,6, 26,5, 26,3, 26,3, 24,4, 24,2.

P R I m e R 45. Methyl ester [1S-[2 , 2(Z),3,4 ]]-6-[3-[4-[[(7,7-di-metroactive)amino] carbonyl]-2-oxazolyl]-7 - oxabicyclo[2.2.1]-hept-2-yl]-4-hexenoic acid.

A. 3,3-Dimethylbutanol.

A solution of 9.4 ml (13,6 g, 107 mmol) oxalicacid in 500 ml of methylene chloride is obtained in the argon atmosphere in the flask to 1000 ml and cool it down to -60aboutTo the solution is added dropwise over 10 min a solution of dimethyl sulfoxide (with 15.4 ml of 18.5 g, 235 mmol) in 25 ml of methylene chloride. The reaction mixture was stirred for 10 min and slowly add 10 g (98 mmol) of 3,3-dimethyl-1-butanol. Stirring is continued for an additional 20 min, then add to the mixture 68,1 ml (49.5 g, 489 mmol) (C2H5)3N and the reaction mixture allowed to warm to room temperature. Then there was added 50 ml of water, the mixture is divided about washed with 1% aqueous solution of hydrochloric acid, water and a saturated solution of NaHCO3again with water and saturated sodium chloride solution and dried over magnesium sulfate. The filtered solution is concentrated using a rotary evaporator, receiving the result of 3.3 g (33%) indicated in the title compound as a yellow oil. The low yield may be due to the high volatility of the product. An NMR spectrum WITH13(deuterochloroform, and 67.8 MHz) : 203,3; 56,4; 31,0; 29,7.

B. (Z)-7,7-dimethyl-4-artenova acid.

To a solution of 13,72 g (31.9 per mmol) 3-carboxypropylbetaine in 60 ml of dry tetrahydrofuran in an argon atmosphere added with stirring at -15aboutWith dropwise within 10 min 1,72 N. To-tert-adalat in toluene (32 ml, to 57.9 mmol). Orange mixture is stirred for half an hour. Then slowly add a 2.00 g (to 19.9 mmol) of the aldehyde under section A in the form of a solution in 5 ml of tetrahydrofuran. The reaction mixture was stirred for 1 h at -15aboutC and at room temperature for 20 hours Then the reaction mixture was quenched with 12 ml of acetic acid are added dropwise, and concentrated in vacuo. The remainder is redistributed between 100 ml ethyl acetate and 100 ml of water. The aqueous layer was extracted twice with 100 ml utility, water, saturated solution of NaHCO3, water and saturated sodium chloride solution, and dried over magnesium sulfate, and then concentrated in vacuo. The remainder chromatographic using elution with 0.3% acetic acid in a gradient of ethyl acetate in hexane (from 1 to 100%), receiving the result of 1.75 g (yield 51%) of the target product, specified in the header.

An NMR spectrum WITH13(deuterochloroform) : 179,8; 128,6; 128,4; 41,0; 34,1; 31,1; 29,2; 22,6.

C. 7,7-Dimethyloctane acid.

To mix the acid solution according to section B (1.2 g,? 7.04 baby mortality mmol) in 8 ml acetic acid is added 0.2 g of platinum oxide. The reaction mixture is stirred for 14 h under hydrogen pressure of 1 ATM (balloon). Then the reaction mixture was filtered through a layer of Celite, and the filtrate was concentrated in vacuo. The residue is diluted with 50 ml of toluene and again concentrated. The process is repeated again, getting in the 1.2 g (yield 100%) specified in the header of the target product in the form of butter.

D. 7,7-Dimethyloctane.

To mix the acid solution according to section (1,21 g, 7,02 mmol) in 50 ml of toluene, add 3 ml of oxalicacid. The resulting reaction mixture is stirred for 1 h at room temperature in Vtoraya to remove traces of oxalicacid. The residue is stirred at room temperature under argon in 5 ml of acetic acid and added to a solution of 1.17 ml (8,43 mmol) C2H5)3N and excess 9M methanolic solution of ammonia (2 ml). After stirring for 16 h the reaction mixture was redistributed between 3 ml of water and 20 ml of ethyl acetate. The aqueous layer was extracted 2 more 20 ml of ethyl acetate. The combined organic layers are washed with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo, receiving semi-solid residue. Specified semi-liquid product is crystallized by trituration with hexane, to deliver 0.5 g (yield 42%) specified in the header of the desired product as a solid substance.

An NMR spectrum WITH13(deuterochloroform) : 176,3; 43,9; 35,9; 30,2; 30,1; 29,3; 25,5; 24,2.

That Is, 7,7-Dimethyloctane.

To the solution obtained according to section D amide (0.45 g, 2,62 mmol) in 50 ml dry ether, stirred in nitrogen atmosphere at 0aboutTo add 0.11 g (2,88 mmol) sociallyengaged; it releases a gas. The reaction mixture was stirred at room temperature for 4 days. Under vigorous stirring, the reaction mixture was quenched by adding to it posle stirring for 0.5 h, a white precipitate of hoteltravel - Ute, and the filtrate was concentrated in vacuo, gaining 0.4 g (yield 89%) indicated in the title compound as a yellow oil. This oil is recrystallized by trituration with hexane and chloroform.

F. Methyl ether [1S-[1 ,2 (Z),3 , 4] ]-6-[3-[4- ]](7,7-dimethyloctyl)amino] carbonyl)- 2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]-4-hexenoic acid.

To a solution of the carboxylic acid obtained according to example 2, part 1 (0,46 g, 1.3 mmol) and an unknown amount of salt, Vilsmeier in 5 ml of chloroform at room temperature in an argon atmosphere add 0.25 ml (0.18 g, 1.8 mmol) (C2H5)3N and 0.24 g (1.5 mmol) of the amine.

That is, the Reaction mixture was stirred at room temperature for 16 h, then diluted with ethyl acetate and water. The organic layer is separated and the aqueous layer is extracted with twice 20 ml of ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate and concentrated. After chromatography was carried out with evaporation (gradient of ethyl acetate in hexane from 0 to 100% ) to obtain 0.20 g (yield 32%) specified in the header of the desired product as oil. Rf= 0.8 V 1% triperoxonane acid, 1% methanol and 98% of ethyl acetate.

7; 27,6; 26,7; 24,1; 22,5.

P R I m e R 46. [1S-1 ,2 (Z),3 ,4 ]]-6-[3-[4-[[(7,7-dimethyloctyl)-amino] carbonyl] -2-oxazolyl-7 - oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid.

A solution of ester obtained according to example 46 (0.20 g, 0.38 mmol) in 10 ml of 1 n sodium hydroxide solution and 10 ml of tetrahydrofuran, representing the reaction mixture was stirred for 13 h, then concentrated in vacuo to remove tetrahydrofuran and acidified to pH = 2 by 1 N. hydrochloric acid. To the mixture are added ethyl acetate and the separated organic layer. The aqueous layer was twice extracted with 20 ml ethyl acetate. The organic layers are combined, washed with brine and concentrated in vacuo, obtaining a clear oil. This oil chromatographic (with 0.1% acetic acid gradient of ethyl acetate in hexane from 0 to 50%), resulting in the 0.12 g (yield 66%) indicated in the title acid as a white solid. The melting point of 68-69aboutC. Rf= 0.18 in a mixture of hexane-ethyl acetate (1:1) from 0.05% acetic acid.

[ ]Do= + 31,1 in methanol C = 0,46 g/100 ml

An NMR spectrum WITH13(deuterochloroform) : 176,8; 163,9; 160,7; 140,8; 135,7; 129,4; 128,4; 79,5; 79,3; 49,6; 46,5; 44,0; 39,1; 33,6; 30,1; 29,6; 29,4; 29,3; 28,8; 27,8; 26,8; 24,3; 22,5.

xenova acid.

A. [1S-[1 , 2 (Z), 3 , 4 ]-7-[3-[[dimethyl-(1,1-dimethylethyl)silyl] oxy] -7-oxabi - cyclo[2.2.1] - hept-2-yl]-5-geptanona acid, methyl ester.

To mix the solution 20,57 g of [1S-[1 , 2 (Z), 3 , 4 ]]-7-[3-oxymethyl-7-oxabicyclo[2.2.1] hept-2-yl] -5-heptenophos acid in the form of methyl ester (obtained as described in U.S. patent N 4143054 method) (with 76.8 mmol) and grade of 5.74 g of imidazole (84,4 mmol, 1.1 EQ.) in 100 ml of methylene chloride in an argon atmosphere at 0aboutTo add a 12.05 g of tert-butyldimethylsilyloxy (79,8 mmol, 1.04 EQ.). This forms a precipitate. The mixture is heated to room temperature and after 10 min, diluted with diethyl ether, washed with water (three times) and brine (once), dried over sodium sulfate and concentrated by evaporation on a rotary evaporator and then under high vacuum. The balance in the number 30,31 g is an almost pure silloway ether specified in the header, and is used without further purification. The output is specified in the header of ester is practically quantitative.

Thin layer chromatography (50% ethyl acetate in hexane - anise aldehyde): the Original product 0,21

Specified in reception - ke ester 0,79

B. [1S-[1 , 2 , 3 , 4 ] ]-3-[[[(1,1-dimethylethyl)dimethylsilane]th ether under section A (with 76.8 mmol) in 200 ml of methylene chloride at -78aboutWith is treated with ozone until a steady blue color within 25 minutes After purging the excess ozone with oxygen added to 48.0 g (770 mmol, 10 EQ. dimethyl sulfide (CH3)2S and heated the reaction mixture to room temperature. After stirring for 1 h at room temperature, the solvent and excess dimethyl sulfide is removed by processing in a rotary evaporator. An NMR spectrum of the N1the crude product indicates incomplete recovery of the derived ozone. So after re-dissolution in methylene chloride at room temperature add to 20.2 g of triphenylphosphine (77 mmol, 1.0 EQ.). The resulting mixture is heated, flowing because the reaction is exothermic. After stirring overnight the solvent most part Argonauts and add to the mixture hexane to precipitate triphenylphosphine oxide and triphenylphosphine. The precipitate is filtered off and the filtrate is concentrated, and then chromatographic (gradient of ethyl acetate in hexane from 5 to 15% ), to deliver to 16.31 g of pure compound indicated in the title, in the form of butter.

Thin layer chromatography (50% ethyl acetate in hexane - anise aldehyde):

Silyl. [1S-( , 2 (E), 3 , 4 )-[4-[3-[[[(1,1-dimethylethyl)-dimethylstyryl)oxy)methyl] -7-OK - sabillo- [2.2.1]hept-2-yl)-2-butenova acid, methyl ester.

The flask containing 3.3 grams, or 37.9 mmol) of lithium bromide, placed under vacuum and heated by means of a fan to remove traces of moisture. After cooling, the flask was rinsed with argon and add 20 ml of methylene chloride. To this mixture is diluted with stirring, a solution 5,44 g (of 29.9 mmol) trimethylphosphate in 30 ml of methylene chloride, and then 4.0 ml (28.7 mmol) of (C2H5)3N. the resulting mixture was stirred for 15 min, then added dropwise within 1 min a solution of 5.4 g (19.0 mmol maximum) of the crude aldehyde in accordance with section B in 35 ml of methylene chloride. The reaction is accompanied by a slight evolution of heat and formation of a crystalline precipitate. The reaction mixture is intensively stirred at room temperature overnight. It is then redistributed between 200 ml of hexane and 100 ml of 0.3 N. hydrochloric acid. The aqueous layer was extracted with 100 ml diethyl ether. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo. Analysis by thin layer chromatography shows that the reaction has not gone to the end (40-50%). the Ospina. This solution was stirred at room temperature for 22 h, then concentrated in vacuo. The residue is triturated with diethyl ether and diluted with an equal solution of hexane. The mixture is cooled in the refrigerator for 2 hours, then separated by filtering the solid residue. The filtrate was concentrated in vacuo. The crude product is purified by chromatographytandem to 167 g of silica gel, using as eluent a mixture of hexane and diethyl ether 4:1, and receiving the result of 5.9 g (yield 91%) specified in the header of ester.

Thin layer chromatography (silica gel, hexane-ether 2:1); Rfor = 0.6 (vanillin).

An NMR spectrum WITH13(and 67.8 MHz, deuterochloroform) : 148,8, 121,8, 79,9, 78,8, 61,9, 51,4, 44,8, 30,7, 29,5, 29,4, 25,9, 18,2, - 5,4.

D. [1S-(1 , 2 (E), 3 , 4 )]-4-[3-[[[(1,1-dimethylethyl)dimethylsilane]oxy]methyl]-7-oxabicyclo [2.2.1](hept-2-yl)-2-butene-1-ol.

A solution of 5.2 g of 15.3 mmol) of ester obtained according to section C in 80 ml of tetrahydrofuran cooled to - 78aboutC. To this solution is added dropwise with stirring to 50.0 ml of a 1.5 M solution of DIBAL-H in toluene for a period of time equal to 20 minutes, the Reaction mixture was stirred for 5 h at - 78aboutC, then the reaction quenched results in the ode (10: 9 by weight). After introducing a few grams of wet silica gel cooling bath removed. The reaction mixture was then diluted with 200 ml of ether. The temperature inside the reaction vessel are carefully monitored, and when it reaches 10aboutWith the flask immersed in a bath of ice. The reaction mixture was stirred for 1 h, after which the silica gel was removed by filtration. The filter cake was washed with 2 portions of 100 ml of ether. The combined filtrates are dried over magnesium sulfate, filtered and concentrated in vacuo, receiving the result of 5.05 g (>100% of theory) of the crude product indicated in the header. Thin layer chromatography (silica gel, hexane-ether 2:1); Rf= 0,1 (vanillin).

An NMR spectrum WITH13(and 67.8 MHz in deuterium chloroform) : 131,6, 130,6, 79,8, 78,8, 63,3, 61,8, 49,3, 45,4, 30,5, 29,5, 29,3, 25,9, 18,2, - 5,4.

E. (1S-(1 , 2 (E), 3 ,4 )]-4-]3-[[[(1,1-dimethylethyl)-dimethylsilane(hydroxy[methyl-7-oxabi - cyclo [2.2.1](hept-2-yl)-2-butene-1-bromide.

Into the flask containing 0,83 g of triphenylphosphine (3,17 mmol, 1.0 EQ.), dissolved in 10 ml of toluene is added in an argon atmosphere at 0aboutWith 0.51 g of bromine (3,17 mmol, 1.0 equiv. ) in one portion. This forms a yellow precipitate and orange retinopathy mass. As a result of processing a spatula resinous is then again cooled to 0aboutC. To it was added dropwise a solution of 1.04 g of the alcohol obtained according to section D (purity 95; 0,99 g, 3,17 mmol) and 0.28 g of pyridine (3,49 mmol, 1.1 EQ.) in 5 ml of toluene (plus 5 ml to rinse). The reaction mixture was stirred at 0aboutC for 30 min, then warmed to room temperature. According to thin-layer chromatography, the reaction does not reach the end. After 4 hours (when the data is thin-layer chromatography not testify about any changes), the reaction mixture was filtered and distilled off from the filtrate the solvent. In the result of the chromatography was carried out with evaporation (gradient of ethyl acetate in hexane (from 3% to 50% ethyl acetate) to obtain 830 mg specified in the header of bromide in the form of oil and 190 mg of unreacted alcohol under part D. the Output is specified in the header bromide equal to 74%.

Thin layer chromatography (25% ethyl acetate in hexane - anise aldehyde):

Alcohol according to the times - the case D 0,21

Specified in the title - lowke bromide 0,75

An NMR spectrum WITH13(and 67.8 MHz, deuterium chloroform) : 135,6, 127,5, 79,8, 78,8, 61,8, 49,4, 45,3, 33,1, 30,5, 29,5, 29,4, 25,9, 18,2, -5,3.

F. [1S-(1 , 2 (E), 3 , 4 )]-6-[3-[[[(1,1-dimethylethyl)-dimethylsilane] oxy]methyl]-7 - oxabicyclo[2.2.1]hept-2-yl)-4-hexenoic acid, 1,1-dimethylether added 1.08 ml of a 2.5 M solution of C4H9Li in hexane to a solution of 303 mg of Diisopropylamine (3.0 mmol, 1,28 EQ.) in 4 ml of dry tetrahydrofuran with stirring in an argon atmosphere at 0aboutC, followed by stirring the mixture for 15 min) is added dropwise with stirring in an argon atmosphere at - 78aboutTo a solution of 348 mg of tert-butyl acetate (3.0 mmol, 1,28 EQ. ) in 3 ml of dry tetrahydrofuran over 15 minutes After stirring for 1 h, to the mixture is added dropwise a solution of 880 mg of the bromide obtained in accordance with section F (2,35 mmol) in 3 ml of tetrahydrofuran at two washes in 2 ml After 8 h of stirring at - 78aboutWith thin-layer chromatography shows the partial reaction, and the reaction mixture is slowly heated (at a rate of approximately 8aboutWith in an hour) to room temperature. Thin layer chromatography shows no further changes, however, the consumption of the bromide is still incomplete. After adding 1 ml of a saturated aqueous solution of ammonium chloride, the mixture is dried over sodium sulfate and the solvent is distilled off. The remainder chromatographic (5% ethyl acetate in hexane), to deliver 550 mg of nearly pure ether complex, specified in the header (with a purity of 97% = 534 mg). Output wisniowa the aldehyde):

Bromide according to the times - business E 0,20

Specified in the title - lowke ester 0,13

An NMR spectrum WITH13(and 67.8 MHz, deuterochloroform) : 172,4, 130,6, 129,6, 80,0, 79,8, 78,8, 61,9, 49,4, 45,8, 35,4, 30,8, 29,6, 29,4, 28,1, 25,9, 18,2, - 5,3.

G. [1S-(1 , 2 (E), 3 , 4 )]-6-[3-(oxymethyl)-7-oxabicyclo[2.2.1] hept-2-yl)-4-GCSE - new acid, methyl ester.

To a solution of 550 mg of nearly pure of ester obtained according to section F (purity 97% = 534 mg, of 1.30 mmol) in 20 ml of methanol is added under stirring at room temperature in an argon atmosphere, 2 ml of a solution of dry HCl in methanol (obtained by adding 2 drops of acetylchloride to 2 ml of methanol at room temperature, followed by curing for 1 min). Thin layer chromatography indicates complete transformation into intermediate for 1 h Specified intermediate then very slowly transforms into the product. Add another 10 ml of HCl in methanol accelerates the reaction. After 14 days add 2 ml (C2H5)3N and the solvent is distilled off from the reaction mixture. The result is 630 mg of the crude alcohol specified in the header.

Thin layer chromatography (50% ethyl acetate in hexane-anise aldehyde):

Ester according to the category of the EPT-2-yl]-4-hexene - Wai acid, methyl ether.

To a solution of 630 mg of the crude alcohol in accordance with section G in 20 ml of acetone are added at 0aboutC in argon atmosphere 4 ml of Jones reagent (2.6 M for CrVI). By the end of the injection of the reagent has seen a steady red color. Formed during the reaction the precipitate was warmed to room temperature for 20 min, then cool and add 2-propanol to absorb the excess reagent. Still at a temperature of 0aboutTo add to the mixture with stirring 3M solution of NaHSO3until then, until all the salt has dissolved. Then add the brine and the mixture is shaken out three times with ethyl acetate. After drying the extracts over sodium sulfate and removal of the solvent the residue chromatographic (silica, gradient in hexane (0.25 to 50%) 5% acetic acid in ethyl acetate) to give after azeotropic distillation of acetic acid with toluene 260 mg indicated in the title acid, which corresponds to a yield of 75% on complex ether obtained according to section F.

Thin layer chromatography (50% (5% acetic acid in ethyl acetate) in hexane-anise aldehyde: Alcohol under section G 0,32

The header acid 0,36

An NMR spectrum WITH13(and 67.8 MHz, deuterochloroform] carbonyl]-2-oxazo-Lil]-7 - oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid.

As described in the example 1 procedure, starting with section E, except for the replacement of the acid according to section D of example 1, the acid according to section H of this example, receive specified in the header connection. Melting point 122-125aboutWith thin-layer chromatography (50%, 5% acetic acid in ethyl acetate in hexane; Rffor the specified header acid 0,33.

An NMR spectrum WITH13(deuterochloroform, and 67.8 MHz), : 176,9; 163,9; 160,7; 140,8; 135,6; 130,0; 128,8; 79,4; 79,0; 49,1; 46,5; 39,1; 37,4; 36,9; 33,7; 33,2; 33,0; 29,7; 29,5; 28,8; 27,5; 26,5; 26,2; 24,0.

P R I m e R 48. [1S-(1 , 2 , 3 , 4 )-3-[4-[[(4-cyclohexylmethyl)aminocarbonyl] -2 - oxazolyl]-7 - oxabicyclo[2.2.1]heptane-2-hexanoic acid.

A solution of 130 mg of the acid according to example 1 in 10 ml of ethyl acetate and 1.0 ml of acetic acid Tegaserod through an iterative process of pumping - etched with argon. To the resulting solution was added 34 mg of 10% palladium on charcoal and replace the atmosphere of hydrogen through two loops vacuum - filling system. Some excess pressure support through the use of a balloon with hydrogen. The mixture is stirred at room temperature for 22,5 h, dilute chloride the stands who headed the remainder of the dilute with toluene and again concentrated. After adding to the residue ethyl acetate, a small amount of gel-like product is not soluble. The solution is decanted and concentrated in vacuo. The crude product is dissolved in a minimum amount of hot ethyl acetate and diluted with about 3 volumes of hexane. After cooling appears solid precipitate, however, after standing at 5aboutWith during the night a white gel-like solid product. It is separated by filtration and dried in vacuum. The resulting white powder is triturated with hexane, filtered and dried in vacuum, obtaining the result 61 mg of pure acid specified in the header. Melting point 97aboutWith (softening).

WITH26H40N2O5.

Calculated, %: C 67,79; H Is 8.75; N Between 6.08.

Found, %: C 67,58; H 8,79; N 5,97.

Thin layer chromatography (silica gel, 4% methanol in methylene chloride): Rf= 0,35 (cerium sulfate).

[ ]D= + 23 (C = 0,68, chloroform).

An NMR spectrum WITH13(deuterochloroform, to 67.5 MHz) : 164,2, 160,8, 140,7, 135,9, 79,5, 79,4, 49,8, 47,2, 39,2, 37,5, 37,1, 33,7, 33,4, 29,9, 29,7, 29,2, 29,0, 28,1, 26,7, 26,4, 24,5, 24,2.

P R I m e R 49. [1S-[1 , 2 (S), 3 , 4 ]]- 6-[3-[4-[[(-4-cyclohexylmethyl)amino)Carbo - Neil)-2-oxazolyl)-7 - oxabicyclo(2.2.1)hept-2-yl)-4-HEXEN is OK - SATELLINE] -1-oxymethyl-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2 - yl]-4-hexenoic acid, methyl ether.

To a stirred mixture of the acid according to example 1, section D (6,70 g of 25.2 mmol), 3,40 g of 25.2 mmol) of 1-oxibendazole and salt triperoxonane acid amine according to example 1, section B (8,97 g, to 25.2 mmol) in 100 ml of dimethylformamide at 0aboutC in argon atmosphere successively added 17.6 ml (126 mmol) (2H5)3N and 4,82 g of 25.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in the form of hydrochloride. The reaction mixture was stirred at 0aboutC for 2 h and then at room temperature for 16 hours the Mixture was concentrated in vacuo and redistribute between 800 ml of ethyl acetate and 1 N. hydrochloric acid (2 servings on 100 ml) of 0.2 N. the solution of sodium hydroxide (2 servings on 100 ml), a saturated solution of NaHCO3(1 portion 100 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The remainder chromatographic on 180 g of silica gel-60 by Merck, using as eluent 2% methanol in methylene chloride, and receiving the result of 4.75 g (yield 39%) indicated in the title amide.

Thin layer chromatography (silica gel, 50% , 5% acetic acid in ethyl acetate in hexane): Rf= 0,22 (anisic aldehyde.

B. (1S-[1 , 2 (Z), 3 (R*), 4 ]]-6-[3-[4-(4-cicli ether.

To a stirred mixture of amide under section A (4,69 g, at 9.53 mmol) in 60 ml of dry methylene chloride added at 0aboutWith the atmosphere consistently: 2.66 ml (19,1 mm) (C2H5)3N and 0.82 ml (10.5 mmol) of methylchloride. The reaction mixture was stirred at 0aboutC for 1 h and diluted with 100 ml methylene chloride, then washed with a saturated solution of sodium bicarbonate NaHCO3(1 x 30 ml) and brine (1 x 30 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo.

The crude mesilate dissolved in 60 ml of acetone and combined with 5.0 g (36,2 mmol) of potassium carbonate (K2CO3). The mixture is heated under reflux for 4.5 hours and cooled to room temperature. The solid residue is filtered off and washed with acetone (4 servings 40 ml). The filtrate was concentrated in vacuo and chromatographic on 120 g of silica gel-60 by Merck, using as eluent 2% methanol in methylene chloride to deliver 3,93 g (yield 86%) specified in the header oxazoline.

Thin layer chromatography (silica gel, 20% acetone in toluene): Rf= 0,29 (anisic aldehyde).

C. (1S-[1 , 2 (Z), 3 , 4 ]]-6-[3-[4-[[(4-cyclohexylmethyl)amino] carbonyl] -2-and oxazoline under section B (3,90 g, 8,23 mmol) in 80 ml of dry methylene chloride is added in an argon atmosphere 6 g of Nickel oxide NiO2. The reaction mixture was stirred at room temperature for 40 minutes, then add 4 g of NiO2. The mixture is stirred for an additional 70 min and again add 2 g NiO2. The mixture is then stirred at room temperature for 2 h and diluted with 120 ml of ethyl acetate, 60 ml of 3 M solution of NaHSO3and 60 ml of 1 M solution of sodium citrate. The aqueous layer was separated and extracted with 4 portions of 150 ml of ethyl acetate. The combined extracts in ethyl acetate, drying over magnesium sulfate, filtered and concentrated in vacuo. Cleaning is performed by the method of chromatography was carried out by evaporation at 120 g of silica gel-60 by Merck, using as eluent 2% methanol in methylene chloride to deliver 1.85 g (yield 48%) specified in the header oxazole.

Thin layer chromatography (silica gel, ethyl acetate): Rf= 0,81 (anisic aldehyde).

7-Examinerlawrence heterocyclic amines of General formula I

< / BR>
where m = 1,2 or 3;

n = 0, 1, 2, 3 or 4;

Z is a group-CH2- CH2- or-CH=CH -, provided that when Z represents - CH=CH-, where n is not 0;

R - UB>2
is phenyl; CONHSO2-benzyl or-CH2- 5-tetrazolyl;

X is 0, S or N;

R1- C1- C16-alkyl which may be substituted WITH3- C8-cycloalkyl or phenyl, which may contain a halogen atom,

WITH3- C8-cycloalkyl, or phenyl which may be substituted with halogen;

R2is hydrogen or C1- C8-alkyl, or R1and R2taken together with the adjacent nitrogen atom form a 5 to 8 membered ring,

or stereoisomer as receptor antagonists of thromboxane.

 

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4 cl, 6 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), halogen atom and oxygen atom (O); R2 is chosen from consisting of H, halogen atom and N=N; R3 is chosen from group consisting of H and halogen atom; R4 is chosen from group consisting of H, halogen atom, amino and N=N; R5 is chosen from group consisting of H, halogen atom, methoxy, methyl and O; or R1 and R2, or R and R5 are joined and form unsaturated carbon ring; R6 is chosen from group consisting of H, (C1-C6)-alkyl, (C2-C6)-alkenyl, 3-phenyl-2-propin-1-yl, benzyl, benzyl substituted with halogen atom, phenyl or methoxy, CH2-cycloalkyl, CH2-2-furan, -(CH2)2SCH3 and -(CH2)2NHBOC; R7 is chosen from group consisting of H, (C1-C6)-alkyl and cycloalkyl; R8 is chosen from group consisting of benzyl and benzyl substituted with OCH2-phenyl; T represents group of the formula or wherein R9 and R10 represent H; or R9 represents H, and R10 are chosen from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, methyl-substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, cycloalkyl, phenyl substituted with (C1-C6)-alkyl, halogen atom, methoxy, -SCH3 or -N(CH3)2, 1-naphthyl and CH2-CH2-1,3-dioxolane; or R9 and R10 are chosen independently from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl, phenyl substituted at position 4 with halogen atom, methoxy, -SCH3 or -N(CH3)2 and 1-naphthyl, or its pharmaceutically acceptable salt, hydrate, or its prodrug as carbamate or ester. Also, invention relates to compounds of the formula (Ia) and the formula (Ib) given in the invention description, and to a method for decreasing levels of beta-amyloid, and to their using and to a method for prophylaxis or treatment of Alzheimer's disease, Down's syndrome. Invention provides preparing novel biologically active compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 17 tbl, 278 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

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