UA77986C2 - Substituted benzopyran derivatives as selective estrogen beta-receptor agonists - Google Patents

Abstract

The present invention relates to substituted benzopyran derivatives, stereoisomers, and pharmaceutical acceptable salts thereof and processes for the preparation of the same. The compounds of the present invention are useful as Estrogen Receptor agonists. Such agonists are useful for the treating Estrogen Receptor mediated diseases such as prostate cancer.

Description

Description of the invention

This invention relates to novel cycloalkylbenzopyrans and their derivatives, pharmaceutical compositions containing these compounds, their use as selective estrogen B-receptor agonists, and their use in the treatment of diseases mediated by estrogen B-receptors, for example, prostate cancer, benign prostatic hyperplasia, cancer testes, ovarian cancer, lung cancer, cardiovascular disease, neurodegenerative diseases, urinary incontinence, central nervous system (CNS) disorders, gastrointestinal (GI) disorders, and osteoporosis. 70 Estrogens play an important role in the development and homeostasis of the reproductive, central nervous, skeletal, and cardiovascular systems in both males and females. The estrogen receptor (ER) is currently the only member of the steroid nuclear receptor subfamily, which has several distinct subtypes. Recently, a new EC isoform, namely EC-B (also known as EC-B1), present in rat prostate and human prostate, was cloned from a rat prostate cDNA library. Accordingly, the previously known EK is now designated as EK-A. 75 EvB-a and EV-B show a high degree of amino acid homology, have similar indicators of binding affinity to 17-B-estradiol (E2) and are able to hetero- or homodimerize with the formation of a signaling complex. See the works of Kiper and others. 138: 863-700 (1997); b. Although E2 activates both EC-A and EC-B, EC-A stimulates transcription and cell proliferation, while EC-B inhibits EC-A activation. It is interesting that 3-B,17-B-androstanediol and 5-A-androstane were proposed as endogenous EC-B ligands by IZ. Weihua and others - 7MUeiptsa ei aI., RMABZ 98:6330-5 (2001)). 3-8,17-B-androstanedial is the main metabolite of dihydrotestosterone (ONT) - an active intracellular androgen in the accessory male genital organs, restored at the 5A position.

EC-B activation also stimulates increased expression of glutathione-5-transferase and quinone reductase. It is shown that these two enzymes have chemoprotective detoxifying properties (V.I. Chang and others - M.M. Spapad ei ai., p.

Rugovaie 40: 115-24 (1999); Montano and others - M.M. Mopiapo ei a)/., 9U.VioY. Spent 273: 25443-9 (1998)). Gee)

Given the recent identification of EC-B and the finding that EC-A and EC-B play different biological roles, EC-selective modulators may also gain great clinical importance. Because EC-B is highly expressed in numerous tissues, including the prostate, bladder, ovaries, testes, lung, small intestine, vascular endothelium, and various parts of the brain, compounds that selectively modulate EC-B could have clinical value in the treatment of various disease states, for example, with prostate cancer, testicular cancer, ovarian cancer, lung cancer, cardiovascular diseases, neurodegenerative diseases, urinary incontinence, CNS disorders, disorders of the gastrointestinal tract and osteoporosis. Such compounds would have minimal effects on EC-A-containing tissues and, therefore, would have different side effect profiles. Thus, EC-B agonists have therapeutic profiles different from those of EC-A antagonists or agonists, and could preferentially affect tissues that depend on EC-B signaling. in

The prostate gland produces substances that are found in semen and blood. Some of them are regulatory peptides. The prostate contains stroma and epithelial cells; the last group consists of columnar secretory cells and basal non-secretory cells. Proliferation of these basal cells, as well as stromal cells, causes benign prostatic hyperplasia (BPH), which is a common prostate disease. BPH is a progressive condition characterized by nodular enlargement of the prostate tissue, which eventually leads to urethral obstruction. This causes an increase in the frequency of urination, nocturnal polyuria, difficulty

And" urination and interruption or delay in the beginning of urination. Possible consequences of VRN include bladder smooth muscle hypertrophy, bladder decompensation, and increased susceptibility to urinary tract infections. The development of VRN is considered an inevitable phenomenon in elderly men. VRN is observed in approximately 7,095 men over the age of 70. In the modern pharmacotherapy of VRN, A-adrenergic and antagonists are used for symptomatic maintenance of the effect of steroid-5-y-reductase inhibitors in order to reduce the volume of - I tissue that has grown. These measures have a limited therapeutic effect. c Mortality from prostate cancer in men with localized tumors tends to be low (9905-1595) when assessed by watchful waiting. These figures, however, refer to patients with (ee) 50 localized disease; they do not necessarily apply to younger people in high-risk groups.

F Younger men with stage TI a tumors have a longer expected risk period than older men with the same stage of disease and are therefore candidates for potentially effective treatment. In watchful waiting studies, high rates of disease progression (3495-8090) suggest that only a small proportion of clinically evident prostate cancers are quiescent. 59 This invention relates to new benzopyran derivatives of formula (1):

Ф) kyu () and 60 Kk e and 2 o in 65 2nd or derivatives of the formula II chu () chE "ka sche ikh to i Kloh where each of B", 2, KZ and K7, regardless of the others, are -H, C.4-Cv-alkyl, -OH, C.-Cv-alkoxy group, halogen, 19 amido group or -CE" group;

B is hydrogen or C-C-C-alkyl; each of U", y2 and UZ, independently of the others, is -H or C.4-Cv-alkyl; and is -Sn-, -Sn-SnNo- or -Sno-CsSnNo-Sn»o-; or their pharmaceutical acceptable salts.

The compounds of this invention include the following compounds, which in no way should be considered as limiting the compounds included in the scope of the invention: a) (-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyl)3,4- dihydro-2H-1-benzopyran, c) (9-2-(4-hydroxyphenyl)-6-trifluoromethyl-cyclopentylis33,4-dihydro-2H-1-benzopyran, c c) (-2-(4-hydroxyphenyl)- 6-methyl-cyclopentylis13,4-dihydro-2H-1-benzopyran, a) (-2-(4-hydroxyphenyl)-6-fluoro-cyclopentyllis3,4-dihydro-2H-1-benzopyran, o e) (-2 -(4-hydroxyphenyl)-5-hydroxy-cyclopentyl)3,4-dihydro-2H-1-benzopyran,

In (9-2-(4-hydroxyphenyl)-7-hydroxy-cyclopentyl-3,4-dihydro-2H-1-benzopyran, a) (-2-(4-hydroxyphenyl)-6-hydroxy-8-methyl-cyclopentyl) |3,4-dihydro-2H-1-benzopyran, so

P) (9-2-(4-hydroxyphenyl)-6-hydroxy-cycloheptyl)|3,4-dihydro-2H-1-benzopyran, Ge) i) (y-2-(4-hydroxyphenyl)-6-hydroxy -8-methoxy-cyclopentylis13,4-dihydro-2H-1-benzopyran,

І) Su-2-(4-hydroxyphenyl)-6-hydroxy-11,11-dimethyl-cyclopentylisi3,4-dihydro-2H-1-benzopyran, F

Yu (9-2-(4-hydroxyphenyl)-6-hydroxy-11,11-diethyl-thiopentylyl-1-3,4-dihydro-2H-1-benzopyran, -

I) (γ-2-(4-hydroxyphenyl)-6-methoxy-cyclopentyliso3,4-dihydro-2H-1-benzopyran, cha t) (-2-(4-hydroxy-3-methylphenyl)-6-hydroxy- cyclopentyl)|3,4-dihydro-2H-1-benzopyran, n) (9-2-(2-methyl-4-hydroxyphenyl)-6-hydroxy-cyclopentylyl3,4-dihydro-2H-1-benzopyran, o) (3-2-(4-Hydroxyphenyl)-cyclopentylyl|3,4-dihydro-2H-1-benzopyran, « p) C9-2-(4-hydroxyphenyl)-6-hydroxy-7-methyl-cyclopentylylyl3,4- dihydro-2H-1-benzopyran, a) (y-2-(4-hydroxyphenyl)-6-hydroxy-cyclohexylis1|Z,4-dihydro-2H-1-benzopyran, - c g) (-2-(4- methoxyphenyl)-6-methoxy-cyclopentylis13,4-dihydro-2H-1-benzopyran,

From» 8) (-2-(4-aminocarbonylphenyl)-6-aminocarbonyl-cyclopentyl)|3,4-dihydro-2H-1-benzopyran, 9 (9-2-(4-aminocarbonylphenyl)-6-hydroxy-cyclopentyl )3,4-dihydro-2H-1-benzopyran, sh) (9-2-(4-hydroxyphenyl)-6-aminocarbonyl-cyclopentylisi3,4-dihydro-2H-1-benzopyran, -I M) (-2- (4-Methoxyphenyl)-6-hydroxy-cyclopentyloxy3,4-dihydro-2H-1-benzopyran, m) (-2-methyl-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyloxy3,4-dihydro-2H- 1-benzopyran, - x) (-2-ethyl-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentylyl3,4-dihydro-2H-1-benzopyran, (Ce) y) (-2-(1-methylethyl )-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentylyl3,4-dihydro-2H-1-benzopyran, or their pharmaceutically acceptable salts or enantiomers.

In a second embodiment, the present invention provides a pharmaceutical composition that contains therapeutically

I) an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides medical methods for the use of compounds of formula (I) as estrogen receptor B agonists ("ERB"), as well as their subsequent use for the treatment of diseases mediated by EC-B, for example, prostate cancer, benign prostatic hyperplasia , testicular cancer,

Ge) cardiovascular diseases, neurodegenerative disorders, urinary incontinence, central nervous system (CNS) disorders, gastrointestinal (GI) tract disorders, and osteoporosis. where As used in this description: a) the term "amido(group)" means aminocarbonyl (С(О)МН»); 60 B) the term "halogen" means an atom of fluorine, chlorine, bromine or iodine;

B) the term "Ci-Cv-alkyl" means an alkyl radical of a branched or normal structure, which contains from 1 to b carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.; c) the term "C.-Cv-Alkoxy (group)" means an alkoxy group of normal or branched structure, which contains from b5 1 atom to b carbon atoms, for example, methoxy group, ethoxy group, "-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, hexyloxy group, etc.;

4) designation ch«-yayute OZInitiates a bond, the stereochemical configuration of which is not specified; f) designation ---- means a connection directed forward from the plane of the page (to the reader);

Her) notation -2.--4ж OZBegins a connection directed back from the plane of the page (from the reader); 9) the terms and abbreviations listed below, used in the descriptions of the preparatory syntheses and in the examples, have the following meanings: nanograms; μg o- micrograms; mg o- milligrams; g o- grams; kg o- kilograms; nmol - nanomoles; mmol - millimoles; mole - moles; μl - microliters; ml - milliliters; l - liters; K; - retention rate; 20.-- degrees Celsius; because - boiling point; mm Hg - pressure in millimeters of mercury column; t.pl. - melting temperature; decl. - schedule; |AI 29 y - specific rotation of the О line of sodium at 202С, obtained in cell 70 with a length of 1 decimeter; c - concentration in g/ml; NM - nanomolar; μM - micromolar; mm - millimolar; M - molar; K, - inhibition constant; Ku - dissociation constant; rvi - pounds per square inch; rpm - revolutions per minute; NRI C - liquid chromatography of high efficiency; NKM5 - high resolution mass spectrum; THF - tetrahydrofuran; roseol - a saturated aqueous solution of sodium chloride; VPV - losses during drying; μKi - microcurie; v.o.c. - intraperitoneally; v.v. - intravenously; and r/min - decays per minute; !) notation not .

In a 1 means that the methyl is attached in the 1-position, and the substituent or substituents designated by K may be attached in any of the 2, 3, 4, 5, or 6 positions;

І) designation c, z se vu (o) and means phenyl or substituted phenyl, while it is understood that any substituent can be attached in any of the positions 1, 2, 3, 4, 5 or 6 It is further understood that when one of the substituents is attached at position 1, the other substituent, designated K, may be attached at any of the c positions 2, 3, 4, 5, or 6; when one of the substituents is attached at the 2-position, the other substituent, designated K, may be attached at any of the 1, 3, 4, 5, or 6 positions; when one of the substituents is attached in the (ee) position

C, then another substituent, denoted by K, may be attached at any of positions 1, 2, 4, 5 or 6; when one Fu of the substituents is attached at the 4-position, the other substituent, designated K, may be attached at any of the 1, 2, 3, 5, or 6 positions; when one of the substituents is attached in position 5, then the other substituent, denoted by K, - can be attached in any of the positions 1, 2, 3, 4 or 6; and when one of the substituents is attached at the M-position 6, the other substituent, designated K, may be attached at any of the 1, 2, 3, 4, or 5 positions;

І) the system of numbering and naming of the tricyclic system of formula (I) and formula (II) correspond to the examples given below: if o is -СН»о-: dihydro-2H-1-benzopyran -1 if о is -СНо-СН»н-: о" -и о) in a

Co.; oo 50 I. ? about her

F cyclohexyl (c) 3,4-dihydro-2H-1-benzopyran if CO is -СНО-СНо-СН»о-: li o) and more with

F) tya 2 1 ime) cycloheptyls|Z,4-dihydro-2H-1-benzopyran

K) the term "enantiomeric excess" or "ee" means the percentage of excess of one of the enantiomers, E1, in a mixture of 60 of two enantiomers, E1-E2, while ХЕ1-Е2)Е1-Е2))Х10О-ее.

The compounds of this invention may have one or more asymmetric centers. Due to the presence of these chiral centers, the compounds of this invention can exist in the form of racemates and individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof are encompassed by this invention. The three main chiral centers, designated 2, C and 4, are shown in formula (I). In the preferred relative stereochemical configuration of the compounds of formula (I), all of the chiral centers 2, 3 and 4 are in the cis configuration, as shown by formulas IV and 1C below:

scha and shk

More games from I and Not I and Y and vne -k shchi and 7. | and - I. . For the purposes of this invention, a compound designated as "racemic IV" or "racemic IS" or its structural formula means the racemic structure of compounds IV and IS. In addition, for the purposes of the present invention, a compound designated as "racemic IO" or "racemic IE" or its structural formula shown below means the racemic structure of compounds IO and IE.

Kk u-e t h- Z ok still t - 2 (io) ey (tv) a

Numerous methods can be used to produce predominantly one optical isomer compared to its enantiomer. For example, it is possible to prepare a mixture of enantiomers with subsequent separation of the two enantiomers.

The method that is usually used for the separation of a racemic mixture is high-performance liquid chromatography on a chiral sorbent. Further details concerning the resolution of mixtures of enantiomers can be found in the monograph "Enantiomers, Racemates and Their Resolution" by Jacques et al. |). dasdtsevz ei ai., o);

Epapithegv, Kasetaijez, apa Kezoishiopz, 19911. The term "pharmaceutically acceptable salt" refers to any salt with an acid or base.

The expression "pharmaceutically acceptable salts with acids" is intended to be used in relation to any non-toxic salt of the compounds of formula (I) of a basic nature with organic or inorganic acids. Examples of inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts with acids, such as sodium monohydrophosphate and potassium dihydrosulfate. Examples of organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, - 35 succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, i-benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acids and sulfonic acids, for example, benzenesulfonic acid, methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in hydrated or practically anhydrous forms. Generally, the acid salts of the above compounds are soluble in water and various hydrophilic organic solvents and have higher melting points than their free bases. sv c The term "pharmaceutically acceptable salts with bases" is intended to be used in relation to any non-toxic! salts of compounds of formula (I) with organic or inorganic bases. Examples of bases that form suitable salts include alkali or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and aliphatic, alicyclic or aromatic organic amines, for example methylamine, dimethylamine, trimethylamine and picoline. It is possible to obtain both mono- and dibasic salts with these -I compounds.

The preferred variants of formula (I) are listed below:

Ш- (1) Compounds in which all chiral centers marked 2, 3 and 4 have a cis-configuration;

Ge) (2) Compounds where O is -CH»-; 50 (3) Compounds where both U? and UZ is -H;

So (4) Compounds where one with VE! and B2 is -OH; 42) (5) Compounds where VZ is -H; (6) Compounds where U! is -H; (7) Compounds where one of B! and B? is -OH and the second is -H.

It is understood that the preferred compounds may be selected according to the requirements of the above compounds

GF) additional variants of compounds that are preferred. For example, constraint (1) can be combined with q constraint (2); constraint (3) can be combined with constraint (4); constraints (1), (2), (3), (5), (6) and (7) can be combined; etc.

Another embodiment of the present invention are compounds of formula II: b5

Kk 2 o on de

Va is - H, -OH or E;

Va is -H, -СНu or -ОСН";

For is -Н or -СНу; is -Сн-, -Сн-СнНо- or -Сно-СсСнНо-Сн»о-; t or their pharmaceutically acceptable salts.

Another embodiment of the present invention are compounds of formula IM:

E (M vk a - 2 what me) uch ka s ko (o) de

B" is an amido group or hydroxyl; K2? is -H or C.--Cv-alkyl; BZ? is -H or C.-Cv-alkyl; B? is an amido group or hydroxyl; and C is -CHo-, - СНо-СНо- or -СНо-СНо-СН»е-; or their pharmaceutically acceptable salts. is),

Illustrative examples of the compounds covered by this invention are racemic mixtures and specific co-enantiomers of the following compounds: (22) o a no o i-on. about t

He; : « racemic mixture racemic mixture 20 . . shv s i" -I -I se) o 50 42)

F) name) 60 b5

- and oh and. and I about ; b S y oy shy dk vd i

Same in: BUT sia and:

I ol ren sei t, y y schi A: heat: so is 40 racemic-sumiy VadeDeNYa um no)

Ku rea: )» rokta. wav Ki A rn and herself vh ie! hence what - Bena "was

F o" fe I, year

F ko bo b5

Carrier No yno from TS, and kshch t. ' - В - КИ vvi y . Also - p o racemic stv freshchemichna sum i zv

And their rations » ЖЖ збета 7 ней " ши я и "SN; t | ay s K

N SEE Щ I и ш - ТЯ

Kn and 4. pc sleep sit down -Vadi sleep 4 with si. oh yang SHY. i i- ik shE m

What: What is she?

ЦО: i y y v, Х х о Neck A KZ a y a | dk no |: me? and I am it is in: i ; come on and;

Schemes of reactions

Compounds of formula (I) and their intermediates can be prepared as illustrated below in Reaction Schemes A-O.

All substitutes, unless otherwise specified, are as defined above. Reagents and starting materials are easily available to a specialist. b5

Yekema and what KK I uk with,

SE LO a B na. sh-y es you Shik kt B dra pra I

But 2 dk shi he. se m 'I . gi; same g. De yu 70 : 1 i m le s s "v: reg, ".

V sti Zhov vad not vuz ih ve A . I call and ride! in Minutes You: In How: . no: in oz and ksn, sepia: iz gai skh y

Sh with the same ; Tya 51 Iv v venikv vin

TYA m: y : e z

KO s : From vu | Article C 6) of the National Register of Citizens of Ukraine

And there are other things. y yy What and . p Gu 7 chai ziv hi u i ay "ehvdia bi racakhikoya suhe Z o - ih i DN ka M I . l - dyin a dyin z VA: I nev - | chu zo YOU OB schu I i - seg SHE CHA Yo

I. "x si, MT y" VypemIchna S

In the meaning used in this scheme, the symbols B, K2, BZ and U! correspond to substitutes, respectively B", 22, VZ and

U, except when the substituents B, B2 and BZ are hydroxyls, and the substituent U! is -H (thus, the group -O-U! is a hydroxyl). In such cases, the corresponding hydroxyl group is protected with an alkoxymethyl ester radical, for example, methoxymethyl ("MOM") or methoxyethoxymethyl ("MEM"). -I In Scheme A, step Ta, the hydroxyl groups of the phenol of formula (2) are protected with suitable protecting groups to give the protected phenol of formula (4) using methods and procedures well known to those skilled in the art. For example, phenol of formula (2) is mixed with a suspension containing a suitable anhydrous solvent,

Go! 20, for example, anhydrous dimethylformamide (DMF) and a suitable strong base, for example, a metal hydride, preferably sodium hydride. Alkoxymethyl ether chloride, preferably MOM-CI, is added to this suspension in an amount corresponding to an approximately equimolar amount, depending on the number of hydroxyls to be protected, in the phenol of formula (2). The reaction can be carried out at room temperature for a time ranging from about ЗОхв. up to about 2 days. Then, water and a suitable ether are added to the reaction mass, for example, 22 diethyl ether or EUDS, and the organic layer is washed with a suitable base, for example, sodium hydroxide or

GF) Manso", and brine. The protected phenol of formula (4) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization. wherein According to Scheme A, step 16, the 2-oxocycloalkane carboxylate of formula (3) is activated with triflate (trifluoromethanesulfonate) to give the activated cycloalkane carboxylate of formula (5) using 60 methods and procedures well known in the art; see Crisp and others (OT Stgivr eyi ai., U. Ogd. Spet. 57, 6972-6975, 1992). For example, methyl-2-oxocycloalkane carboxylate of formula (3) is dissolved under anhydrous conditions in a suitable solvent, for example, in tetrahydrofuran, dichloromethane, acetone, ethyl acetate, toluene or diethyl ether and brought into contact with a suitable activating agent, for example, trifluoromethanesulfonic anhydride. The reaction is carried out in the presence of a base, for example, M-methylmorpholine, sodium carbonate, triethylamine, M,M-diisopropylethylamine, potassium carbonate, sodium bicarbonate, pyridine or

2,6-di-tert-butyl-4-methylpyridine. The reaction is carried out, as a rule, at temperatures from -782C to ambient temperature. The duration of the reaction is, as a rule, from an hour to 24 hours. Then the reaction mixture can be quenched. The product of formula (5) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

According to Scheme A, stage 2, the protected phenol of the formula (4) is combined with the activated cycloalkane carboxylate of the formula (5) to obtain the product of the combination of the formula (6). For example, the coupling reaction is carried out in the presence of butyllithium, zinc chloride and a palladium compound. The reaction is preferably carried out in a suitable solvent, for example in tetrahydrofuran (THF), and can be carried out initially in anhydrous conditions. 70 In a preferred embodiment, the protected phenol of formula (4) is dissolved in a suitable solvent, such as THF, treated with butyllithium at reduced temperature, then zinc chloride in the solvent is added and the mixture is allowed to warm to ambient temperature. However, a palladium compound such as tetrakis(triphenylphosphine Pa(0)) is added together with the activated cycloalkane carboxylate of formula (5) and the temperature, in a preferred embodiment, is raised to the boiling point of the solvent for a period of time ranging from about 75 Bh to 24h The coupling product of formula (b) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In Scheme A, step 3, the coupling product of formula (6) is reduced with a suitable reducing agent to give the reduced product of formula (7) using methods and procedures well known in the art. For example, the coupling product of formula (6) is contacted with a suitable reducing agent, for example a palladium compound, preferably 595 or 1095 palladium on carbon, in a suitable solvent or solvent mixture, for example methanol. The reaction is preferably carried out in the presence of a suitable base, for example trialkylamine, more preferably triethylamine. Then the reaction mixture is heated to a temperature ranging from 302C to the boiling point for a period of time ranging from approximately 2h. up to 24 hours The reduced product of formula (7) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.

According to Scheme A, step 4, the reduced product of formula (7) can be converted to the Weinreb amide of formula (8). This transformation can be accomplished using a reaction of the type described by Williams et al. |9U.M. UMPatptzg ei ai., (Se) Teiapedgop Ietsege 36, 5461-5464, 1995). For example, the reduced product of formula (7) is mixed with M,O-dimethylhydroxylamine hydrochloride in a suitable aprotic solvent, e.g., U09 tetrahydrofuran, preferably under anhydrous conditions, and cooled to a temperature (He) ranging from about 02C to about -302C, in a more preferred embodiment, to about -1020.

A suitable Grignard reagent is then added, preferably isopropylmagnesium chloride, in a molar ratio of about 1.5, and the reaction mixture is stirred for about 15 min. up to 2 hours Then - the reaction is quenched with a source of protons, for example, a saturated solution of ammonium chloride. Weinreb amide of formula (8) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization. "

According to Scheme A, stage 5, the Weinreb amide of formula (8) is combined with an aryllithium of formula (9), and a ketone of formula (10) is obtained. For example, an aryllithium of formula (9) is added to a solution of a Weinreb amide of formula (8) in a suitable aprotic solvent, such as anhydrous tetrahydrofuran, cooled to a temperature ranging from about -202C to about 52C, preferably to about 02C, and stirred the reaction mixture during a period of approximately 15 minutes. to Agreement Then the reaction is quenched with a source of protons, for example, a saturated solution of sodium bicarbonate. The ketone of formula (10) can be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization. - According to Scheme A, stage ba or br, the ketone of formula (10) is subjected to cyclization in the presence of an acidic -I catalyst with subsequent reduction of the obtained hemiketal to obtain the compound of formula (IA or IA"), which is a racemic mixture of the compound of formula (I). For example, in stage b, p-toluenesulfonic acid (re) is added in an approximately equimolar ratio to the ketone of formula (10) in a suitable alcoholic solvent, eg, anhydrous methanol. The mixture is then heated to a temperature in the range of 402C to 609C, alternatively, which is preferred, to 50 °C, for a time period of 12 hours to 24 hours, in the preferred embodiment, 18 hours. The mixture is cooled to ambient temperature and a suitable reducing agent, e.g. sodium cyanoborohydride, is added, together with a suitable indicator, for example, bromocresol green, according to a method similar to that described by Srikrishna and others (A. Zgikgiznpa ei ai., 52 Teigapedgop, moi.51, po.11, yr.3339-3344 , 1995). Then slowly add methanol, saturated with hydrogen chloride, to

HF) obtaining a stable yellow color of the mixture. After reaching the final color change, the mixture is stirred for about 1-2 hours. Then the reaction is quenched with a suitable proton acceptor, for example, a saturated solution of sodium bicarbonate. With such a combination of reaction conditions, the cis-configuration of chiral centers (that is, such centers in compounds IV or IS) is obtained. Using Kz5ZIN/TRA (trialkylsilane and 60 trifluoroacetic acid) in stage 65, the trans-configuration of chiral centers (that is, such centers in compounds I or IE) is obtained. The product of formula (IA) or (IA) can then be isolated and purified by methods well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, the coupling product of formula (b) may be synthesized as shown in reaction scheme B. All substituents, unless otherwise specified, are as defined above. Reagents and starting materials are readily available to one skilled in the art.

Scheme B is com ma z sv v z BUS Other stage 1 aa and i, i stage 2 (a

Ge

According to Scheme B, step 1, the hydroxyl groups of the bromophenol of formula (11) are protected with suitable protecting groups to give the protected bromophenol of formula (12) using the methods and procedures described in Scheme A, step 75 and.

According to Scheme B, stage 2, the protected bromophenol of formula (12) is coupled with an activated cycloalkane carboxylate of formula (5) to give the coupling product of formula (6), using the methods and procedures described in Scheme A, stage 2.

An alternative method of obtaining specific bromine-substituted intermediates is shown in Scheme C 70 Scheme C

BUT or V nanny m yani A mom t Vg sch ono ven, Vg y rishi oh a osn, (5)

Go and Ch

In addition, specific compounds of formula (I) where Y is methyl can be prepared according to Scheme 0.

Scheme of sulfuric acid! about trifluoroacetate

E | acid i- on ---- in sn, oo and - «

INV. had no s » ! in racemic sum n, - i - hydrogen 4 (Se) vas Kk Z i so ri s k- 7 rapemic mixture Z i) racemic mixture . In addition, the amide-containing compounds of formula (I) represented by formulas (16) and (17) can be synthesized as described in Scheme E. All substituents, unless otherwise indicated, are as defined above. 60 b5

RYN, sa,

I.pennndnyanya o i i zhi

There racemic mixture racemic mixture rapemic mixture I

Rona ia2 | RR then | new steel? From the language "

In paragraph 7. racemic mixture racemic "mixture

The reagents and starting materials are readily available to one skilled in the art. According to Scheme EE, step 1, the dihydroxy compound of formula (13) can be converted into a mixture of the monotriflate of formula (14) and the ditriflate of formula (153. The resulting mixture can be separated using conventional chromatography. According to Scheme E, stage 2, monotriflate of formula (14) and ditriflate of formula (15) are combined with 1,1,1,3,3,3-hexamethyldisilazane under carbonylation conditions with a palladium catalyst and carboxamides of formulas (16) and (17) are obtained.

In addition, amide-containing compounds of formula (19) can be synthesized as described in Scheme PE. All substituents, unless otherwise specified, are as defined above. high school

Scheme E o

And RT, and everyone else, tsdyso on . tank, floor o stage 1 t stage 7 (ee) az B F racemic mixture racemic mixture cha

Y o o o ) o p o n ch r a p s i c sum m o n t h o s Reagents and starting materials are readily available to one of ordinary skill in the art According to Scheme B, step 1, a dihydroxy compound of formula (13) can be selectively converted to a benzyl ether of formula (18). According to )» Scheme P, stage 2, the remaining phenolic group is treated with triflate, followed by co-coupling under conditions identical to those of Scheme E, stage 2. Finally, the benzyl group is removed, and after purification of NRI C, a carboxamide of the formula is obtained ( 19). -and In addition, compounds where B is C.1-Cv-alkyl can be obtained as described in Scheme 0. - scheme 0 (Ce) and in, m be 70 '

F but Kk as me Leona

M ny mn nnnnnnnnnn-chnnnnnnnn fran ah m a kE E 52 peru Kk iya va M iF) so) b. yuyu ramemic sumint so) racemic sad

According to Scheme 0, the ketone of formula (10) is reacted with an alkyl-containing organometallic reagent, for example, with methyllithium or ethylmagnesium bromide, and tertiary alcohols of formula (20) are obtained. Under the acidic conditions described in Scheme A, stage va, benzopyrans of formula (21) are obtained from these tertiary alcohols. b5

0.0

Well

A suspension of sodium hydride (6095 in mineral oil, 3.81g, 9545mmol) in anhydrous DMF (5Oml) is stirred under a nitrogen atmosphere at 02C, and a solution of hydroquinone (5.00g, 45.45mmol) in 70% anhydrous DMF (5Oml) is added dropwise. ). Methoxymethyl chloride (7.2 mL, 95.45 mmol) was added drop by drop to this suspension, while additional gas evolution was observed. Allow the reaction mixture to warm to ambient temperature and stir for an hour. Quench the reaction with water and diethyl ether.

The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 20905 ethyl acetate in hexane to give Intermediate 1 (5.64 g, 6395) as a clear oil. "H NMR (SOCI3): 6.97 (in, 4H), 5.11 (5, 4H), 3.47 (in, 6H).

IS

A suspension of sodium hydride (6095 in mineral oil, 0.67g, 16.67mmol) in anhydrous DMF (25ml) with 29 is stirred in a nitrogen atmosphere at 02С and a solution of A,A,A-trifluoromethyl-p-creosol (U (2.50g, 15.15mmol) in anhydrous DMF (25ml). To this suspension was added dropwise methoxymethyl chloride (1.3ml, 16.67mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1h. The reaction was quenched with water and diethyl ether. The organic layer was washed with 1 N sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 2 (2.50 g, 8090) in :FO in the form of a transparent oil. IN NMR (SOSI»z): 7.25 (a, U-8.6Hz, 2H), 6.83 (a, 9U-8.3Hz, 2H), 4.93 (in, 2H), 3.19 (in, ЗН). F

Preparatory sonIez Z shcha "a m. be what | | | "

A suspension of sodium hydride (6095 in mineral oil, 0.89g, 22.17mmol) in anhydrous DMF (25ml) is stirred under a nitrogen atmosphere at 02С, and a solution of guaiacol (2.50g, 20.1bmmol) in anhydrous C is added dropwise. DMF (25 ml). Methoxymethyl chloride (1.7 mL, 22.17 mmol) was added dropwise to this suspension. y" Allow the reaction mixture to warm to ambient temperature, and stir for an hour.

Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate C (2.22 g, 6696) as a clear oil. IN NMR (SOSI"): 6.97-6.89 (t, 4H), 5.01 (5, 2H), 3.89 (8, ZN), 3.22 (v, ZN). 7" Shshpoorchy synthesis 4 se) tv, and Go 42) no

A suspension of sodium hydride (6095 in mineral oil, 0.41g, 10.30mmol) in anhydrous DMF (25ml) is stirred under a nitrogen atmosphere at 02C, and a solution of 2-bromo-4-methylphenol (2.50g, 14 o'clock) is added dropwise .71 mmol) in anhydrous DMF (25 ml). Methoxymethyl chloride (0.7 ml, 10.300 mmol) was added drop by drop to this suspension. Allow the reaction mixture to warm to room temperature and stir for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 4 (2.45 g, 7290) as a clear oil. b5

Preparatory synthesis 5 nak

And 0.0

A suspension of sodium hydride (6095 in mineral oil, 0.58g, 14.4Omol) in anhydrous DMF (25ml) is stirred in a nitrogen atmosphere at 02С, and a solution of 2-bromo-4-fluorophenol (2.50g, 70 13) is added dropwise .09 mmol) in anhydrous DMF (25 mL). Methoxymethyl chloride (1.1 mL, 14.40 mmol) was added dropwise to this suspension. Allow the reaction mixture to warm to room temperature and stir for an hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine.

The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 5 (2.71 g, 8895) as a clear /5 Oil. "YAN YMR (SOSI"): 7.40-7.35 (t, 1H), 7.01-6.89 (t, 1H), 6.85-6.79 (t, 1H), 4.99 (in, 2H), 3.87 (in, ЗН) and yours

A suspension of sodium hydride (6095 in mineral oil, 1.90g, 47.68mmol) in anhydrous DMF (25ml) is stirred under a nitrogen atmosphere at 02C, and a solution of resorcinol (2.50g, 22.70mmol) in anhydrous DMF is added dropwise. (25ml). Methoxymethyl chloride (3.3 bml, 47.68 mmol) was added drop by drop to this suspension, while additional gas evolution was observed. Allow the reaction mixture to warm to ambient temperature and stir for an hour. Quench the reaction with water and diethyl ether.

The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo. It was purified by flash chromatography eluting with 20905 ethyl acetate in hexane, n.s.) to give Intermediate 6 (2.49 g, 5596) as a clear oil. "H NMR (SOCIz): 7.20 (i, 9-8.2 Hz, Sh), so 6.74-6.68 (t, ZN), 5.16 (z, AN), 3.48 (85 , 6H). M5 (mass spectrum) calculated 198.2; M5 (Mn) 199.0.

Pishgotovchii synthesis 7 Ф сн, и о. Sn, - o "

A suspension of sodium hydride (6095 in mineral oil, 1.11 g, 27.78 mmol) in anhydrous DMF (25 ml) is stirred in a nitrogen atmosphere at 092 C, and a solution of 4-bromoresorcinol (2.50 g, in» 13, is added drop by drop 22 mmol) in anhydrous DMF (25 ml). Methoxymethyl chloride (2.1 mL, 27.78 mmol) was added drop by drop to this suspension, while additional gas evolution was observed. Allow the reaction mixture to warm to ambient temperature and stir for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2090 ethyl acetate in -1 hexane to give Intermediate 7 (2.46 g, 6795) as a clear oil. "H NMR (SOSIz): 7.40 (a,

U-7.8Hz, 7), 6.87 (a, 0-2.7, 1H), 6.63 (aa, 9-2.7Hz, 7.8Hz, 71H), 5.22 (v, 2H ), 5.14 (in, 2H), 3.51 (in, ЗН), ик 3.46 (85, ЗН). M5 calculated 277.12; M5 (M--1) 277.2, 279.2. se 72 o i le sn, u ag z y ime)

A suspension of sodium hydride (6095 in mineral oil, 1.58g, 39.21mmol) in anhydrous DMF (5Oml) 60 is stirred under a nitrogen atmosphere at 09С, and a solution of 2,6-dibromohydroquinone (5.00Hg, 18.67mmol) is added dropwise ) in anhydrous DMF (5 Oml). Methoxymethyl chloride (3.0 mL, 39.21 mmol) was added dropwise to this suspension, and additional gas evolution was observed. Allow the reaction mixture to warm to ambient temperature and stir for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 20905 ethyl acetate in hexane to give Intermediate 8 (3.49g, 5395) as a clear oil. "H NMR (SOCI3): 7.23 (in, 2H),

5.10 (in, 4H), 3.46 (in, 6H).

Production synthesis From blow and more

A suspension of sodium hydride (6095 in mineral oil, 3.00g, 74.92mmol) in anhydrous DMF (50ml) is stirred under a nitrogen atmosphere at 09C, and a solution of methoxyhydroquinone (5.00g, 35.67mmol) in anhydrous DMF ( 5 Oml). Methoxymethyl chloride (5.2 mL, 12 74.92 mmol) was added drop by drop to this suspension, while additional gas evolution was observed. Allow the reaction mixture to warm to ambient temperature and stir for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2090 ethyl acetate in hexane to give Intermediate 9 (5.84g, 7295) as a clear oil. "H NMR (SOSIz): 7.05 (a,

U-8.6Hz, 1H), 6.63 (a, 9-2.7Hz, 1H), 6.55 (aa, 9-9.0Hz, 2.7Hz, 71H), 5.14 (v, 2H ), 5.12 (in, 2H), 3.86 (in, ЗН), 3.51 (in, ЗН), 3.47 (in, ЗН).

HPi-titoid synthesis of 10 sv) with water and water; oh saint

A suspension of sodium hydride (6095 in mineral oil, 3.54g, 88.61mmol) in anhydrous DMF (100ml) is stirred under nitrogen at 09C, and a solution of 4-methoxyphenol (10.000OHg, 80.55mmol) in anhydrous DMF (5 Oml). Methoxymethyl chloride (b.7 ml, 09 88.61 mmol) is added drop by drop to this suspension. Allow the reaction mixture to warm to ambient temperature, and stir the FU for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 10 (11.55 g, 8590) M as a clear oil.

PSishotovchii synthesis 11 « o. there is one dream, From the village

I" To a suspension of hexane-washed sodium hydride (6095 in mineral oil, 1.64g, 68.2mmol) in anhydrous

A solution of 4-bromo-2-cresol (10.6g, 56.8mmol) and methoxymethyl bromide (5.bml, 68.2mmol) in anhydrous THF (30ml) was added dropwise to THF (70ml) under a nitrogen atmosphere at room temperature. After stirring for 18 hours. the mixture is partitioned between dilute aqueous sodium bicarbonate and diethyl ether. -i The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give Intermediate 11 (12.74g, 97905) as a clear oil.

Preparatory synthesis 12 se) at 50 M,

That's me in

F sv, t Vg and o n

A solution of Intermediate 8 (1.00g, 2.81mmol) is cooled to -782C and t-butyllithium (1.3M solution in cyclohexane, 2.1Oml, 2.81mmol) is added dropwise to it. Stir the mixture for 15 min, then add methyl iodide (0.18 mL, 2.81 mmol) and stir overnight, allowing the mixture to warm to ambient temperature of 60 °C. The reaction is quenched with saturated sodium bicarbonate solution and ethyl acetate is added.

Wash with brine, dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 1095 ethyl acetate in hexane to give Intermediate 12 (0.66g, 8195) as a clear oil. IN nMR (SOCI3): 7.12 (a, 3-2.9Hz, 1), 6.83 (a, 9-2.9Hz, 1), 5.10 (c, 2H), 5.04 (85 , 2H), 3.63 (in, ЗН), 3.48 (in, ЗН), 2.30 (85, ЗН). M5 calculated 291.1; M5 (Mt) 291.2, 293.2. b5

Cho lo v. This synthesis is carried out as described in u. Oh Spent 57, 1992, 6972-6975). Diisopropylethylamine (61.5 ml, 352.1 mmol) and trifluoromethanesulfonic anhydride (14.2 ml, 84.51 mmol) were added to a solution of methyl-2-oxocyclopentanecarboxylate (10.0 g, 70.42 mmol) in anhydrous dichloromethane (30 Oml), cooled to -182C. ). The reaction mixture is stirred for 16 hours, allowing it to heat up to a temperature of about 5 degrees Celsius. The reaction is quenched with water, and the mixture is washed with 1095 citric acid and then with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 13 (12.0 g, 6390) as a dark oil, which was used without further purification. IN NMR (SOSI): 3.79 (v, ZN), 2.75-2.68 (t, 4H), 2.03-1.98 (p, 2H).

Eh and oh with 4 sleep, o

It is carried out according to a procedure similar to that described for the synthesis of Intermediate 13, with the exception that methyl 2-oxo-1-cycloheptanecarboxylate (5.00 g, 29.37 mmol) is used, and Intermediate 14 (4.34 g, 4995) is obtained in the form dark oil (Se)

From Shgotochy synthesis 15 so vi F

ET

E - oh and -

To a solution of methyl-2-oxo-5,5-dimethyl-cyclopentanecarboxylate |U. Spent Zos. 1996, 1539-15401 (0.85 g, 5.000 mmol) in anhydrous dichloromethane (1 bml), cooled to -7892С, isopropylethylamine (4.4 ml, 25.00 mmol) and trifluoromethanesulfonic anhydride (1.00 ml, 6.0O0mmol). Stir the reaction mixture for 16 hours, allowing it to warm to ambient temperature. The reaction is quenched with water, and the mixture is washed with 1095 citric acid and then with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 15 (1.16 g, 7790) as a dark oil, which was used without further purification. (SOSI"): 3.78 (in, ZN), 2.64 (5 9-7.1Gu, 2H), 1.83 (5. 9-7.1Gu, 2H), 1.18 (z, 6H ). 2.94g, gF) 14.85mmol) in anhydrous dichloromethane (100ml) cooled to -782С, add with stirring diisopropylethylamine (13.0ml, 74.25mmol) and trifluoromethanesulfonic anhydride (3.0ml, 17.82mMmol).

Stir the reaction mixture for 16 hours, allowing it to warm to ambient temperature. The reaction is quenched with water, and the mixture is washed with 1095 citric acid and then with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 1590 ethyl acetate in hexane to give Intermediate 16 (3.96 bg, 8290) as a dark oil which was used without further purification. IN NMR (SOSIz): 3.78 (in, ZN), 2.60 (i, 9-7.4Hz, 7.8Hz, 2H), 1.83 (6 9-7.8Hz, 7.1Hz, 2H ), 1.46 (a, 9-7.4Hz, 7.4Gu, 7.4Gu, 4H), 0.91 (5, 9-7.4Hz, 7.4Hz, 6H). b5

Field preparation synthesis 17

N,

Liquid 70 A solution of Intermediate 1 (0.95g, 4.81mmol) in anhydrous THF (25ml) is cooled to -782C, and tert-butyllithium (1.7M solution in pentane, 2.8ml, 4.81mmol) is added to it ). The mixture is stirred for 15 minutes, after which it is heated to 02C. A solution of zinc chloride (1.0M in diethyl ether, 4.vml, 4.8mmol) is added dropwise, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (0.88g, 3.21mmol) and 75 tetrakis-(triphenylphosphine)Ra(0) (0.37g, 0.32mmol) in anhydrous THF (25ml), and the resulting mixture is heated solution at 502 for 1 hour. The reaction mixture is cooled to ambient temperature and quenched with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 30905 ethyl acetate in hexane to give Intermediate 17 (0.56g, 5595) as a clear oil. IN nMR (SOCI3): 7.04 (a, yu-9.0hu, 1), 6.90 (aa, 9-3Ihu, 9.0Hz, 1H), 6.81 (a,

UZ 1HC, 1), 5.10 (5, 2H), 5.02 (v, 2H), 3.56 (v, ZN), 3.46 (v, ZN), 3.42 (v, ZN) , 2.80 (and 9-8.6Hz, 8.2Hz,

AN), 2.05-1.95 (t, 2H). M5 calculated 322.2; M5 (M.n1) 323.1.

Preparatory synthesis 18 s tya o) o ! and o

E (Se) 30.

ET co

A solution of Intermediate 2 (2.50g, 12.14mmol) in anhydrous THF (40ml) is cooled to -782С, and tert-butyllithium (1.7M solution in pentane, 7.00ml, 13.35mmol) is added 9) to it. The mixture is stirred for 15 minutes, after which it is heated to 02. A solution of zinc chloride (1.0M in diethyl ether, 12.Tml,

of 12.14 mmol), and allow the resulting solution to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (3.32 g, 12.14 mmol) and tetrakis-(triphenylphosphine Ra(O) (0.70 g, 0.61 mmol) in anhydrous THF (4 Oml), and the resulting solution is heated at 502C for 16 hours. Cool the reaction mixture to ambient temperature and quench water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and C 70 brine. Dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 18 (2.87g, 7295) as 1% clear oil. IN nMR (SOCI3): 7.49 (aa, 0-1.9Hz, 82Hz, 1), 7.37 (a, 9U-2.3Hz, 1), 7.20 (a, 3U-8.6Hz, 71Н), 5.16 (v, 2Н), 3.55 (85, ЗН), 3.43 (в, ЗН), 2.80 (5 9У-7.4Hz, 7.8Hz, 4Н), 2, 06-1.98 (t, 2H). M5 415 calculated 330.1; M5 (Mt) 331.1. - Preparatory synthesis 19 -I se)

Pho oo and and more

A solution of Intermediate 6 (2.49g, 12.57mmol) in anhydrous THF (25ml) is cooled to -782C and added

HF) to it tert-butyllithium (1.7M solution in pentane, 7.4ml, 12.57mmol). The mixture is stirred for 15 min., after which it is heated to 02. A solution of zinc chloride (1.0 M in diethyl ether, 12.bml, about 12.57 mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (2.30 g, 8.38 mmol) and 60 tetrakis-(triphenylphosphine)Ra(0) (0.48 g, O0.41 mmol) in anhydrous THF (25 mL), and the resulting mixture is heated solution at 502 for 16 hours. The reaction mixture is cooled to ambient temperature and quenched with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 19 (1.70 g, 4195) as a colorless oil. IN NMR (SOCI3): 7.15 (5 9U-8.2Hz, 8.6Hz, 1), 6.78 (a, 9-8.2Hz, 2H), 5.09 (Bv,

AN), 3.52 (v, ZN), 3.42 (v, 6H), 2.83-2.77 (t, 4H), 2.04-1.99 (t, 2H). M5 calculated 322.1; M5 (Mt) 323.1.

Preparatory synthesis of the 20th century to the 70th

A solution of Intermediate 1 (2.00g, 10.133mmol) in anhydrous THF (25ml) is cooled to -782C, and tert-butyllithium (1.7M solution in pentane, 5.9ml, 10.133mmol) is added to it. The mixture is stirred for 15 minutes, after which it is heated to 02C. A solution of zinc chloride (1.0M in diethyl ether, 10.Tml, 10.13mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 14 (2.04 g, 6.7 mmol) and tetrakis-(triphenylphosphine Ra(O) (0.40 g, 0.34 mmol) in anhydrous THF (25 mL), and the resulting solution is heated at 502 for 1 hour Cool the reaction mixture to ambient temperature and quench with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 20 (2.13g, 9095) as a colorless oil. IN nMR (SOSIz): 6.98 (a, yu-90ogu, yin, 6.85 (aa, U-3.1 Hz, 9.0 Hz, 1H), 6.65 (a,

ChZ HC, 1H), 5.10 (in, 4H), 3.45 (in, ZN), 3.44 (in, ZN), 3.38 (in, ZN), 2.56-2.50 ( t, 4H), 1.84-1.80 (t, 2), CSE 1.65-1.60 (t, 4H). M5 calculated 350.1; M5 (M.-1) 351.1. at

Preparatory synthesis 21. t» o

From g, so o.,0

NS dich F sn, and -

A solution of Intermediate 9 (2.18g, 9.5bmmol) in anhydrous THF (40ml) is cooled to -782C, and tert-butyllithium (1.7M solution in pentane, b.2ml, 10.52mmol) is added to it. The mixture is stirred for 15 minutes, after which it is heated to 02C. A solution of zinc chloride (1.0M in diethyl ether, 9.bml, « 9.5bmmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (2.627, 9.5 mmol) and tetrakis-(triphenylphosphine Ra(O)) (0.55 g, 0.4 v8 mmol) in anhydrous THF (4 Oml), and the resulting solution is heated at in" 502 for 16 hours. The reaction mixture is cooled to ambient temperature and quenched with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 21 (0.62g, 1895) in this. in the form of colorless oil. IN nMR (SOCI3): 6.57 (a, 9-2.7Hz, 1H), 6.40 (a, 9-2.7Hz, 1H), 5.11 (c, 2H), 4.89 (5, 2H), 3.81 (in, ZN), 3.58 (85, ZN), 3.47, (8, ZN), 3.44 (in, ZN), 2.83-2.77 (t, 4H), 2.03-1.96 (t, 2H). M5 calculated 352.1; M5 (M'-1) 353.1. o Pishotovchi synthesis 22 o 50 sm, 4) sm, sm, ts p. A solution of Intermediate 1 (1.13g, 5.71mmol) in anhydrous THF (40ml) is cooled to -782C, and tert-butyllithium (1.7M solution in pentane, 34ml, 5 .71 mmol). The mixture is stirred for 15 minutes, after which it is heated to 02. A solution of zinc chloride (1.0 M in diethyl ether, 5.7 ml, 5.71 mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 15 (1.15 g, 3338 mmol) and tetrakis-(triphenylphosphine Ra(O) (0.55 g, 0.48 mmol) in anhydrous THF (40 mmol), and the resulting solution is heated at 502 for 4:00 p.m. Cool the reaction mixture to ambient temperature and quench with water. 65 Ethyl acetate is added and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine.

The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 22 (0.42g, 3290) as a colorless oil. "YAN YMR (SOSI5): 7.05 (a, 9U-9.0Hz, 1), 6.92 (da, 9-3.1GHz, 9.0Hz, 1), 6.62 (a, 9-3 ... . (M-1) 351.1.

Infantry syngyez 25 and 0. .and tk ste and 0 o

A solution of Intermediate 1 (3.64g, 18.3v8mmol) in anhydrous THF (50ml) is cooled to -782С, and 75% tert-butyllithium (1.7M solution in pentane, 3.4ml, 5.71mmol) is added to it. The mixture is stirred for 15 minutes, after which it is heated to 02. A zinc chloride solution (1.0M in diethyl ether, 10.v8ml, 18.3v8mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 16 (3.96g, 12.25mmol) and tetrakis-(triphenylphosphine Ra(O) (0.71g, 0.61mmol) in anhydrous THF (50ml), and the resulting solution is heated at 502C for 1 hour Cool the reaction mixture to ambient temperature and quench with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 23 (3.30 g, 8495) as a colorless oil. IN NMR (SOSI3): 7.05 (a, 9-9.0Hu, tn), 6.89 (aa, 9U-3.1Hz, 9.0Hz, tn), 6.62 (a, p 29 )- 9.7Hz, 1H), 5.11 (in, 2H), 5.00 (in, 2H), 3.49 (in, ЗН), 3.46 (in, ЗН), 3.40 (in, ЗН ), 2.65 (B, 9U-7.8Hz, 7.0Hz, Ge) 2H), 1.87 (5 9-7.8Gu, 7.4Hz, 2H), 1.45-1.38 (t , 4H), 0.90-0.82 (t, 6H). M5 calculated 378.1; M5 (Mt) 379.1.

Preparatory synthesis 24 hours, Ф со н, - ! ! and -

A solution of Intermediate 4 (2.43g, 10.51mmol) in anhydrous THF (25ml) is cooled to -782C, and t-butyllithium (1.3M solution in cyclohexane, 8.9ml, 11.5bmmol) is added to it. The mixture is stirred for 15 minutes, after which it is heated to 092C. A solution of zinc chloride (1.0M in diethyl ether, 10.51ml, 10.51mmol) was added dropwise and the resulting solution was allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (2.88 g, 10.5 mmol) and 73 g of tetrakis-(triphenylphosphine)Ra(0) (0.60 g, 0.52 mmol) in THF (25 mL) and heated the resulting solution at 502C for 1 hour. The reaction mixture is cooled to ambient temperature and quenched with water. )» Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 24 (1.07g, 2695) as a light yellow oil. -1 TN o NMR (SOCIz): 7.05 (p85, 2H), 6.95 (rev, 1H), 5.10 (v, 2H), 3.59 (v, ZN), 348 (v, ZN ), 2.85 (i

U7,OGu, 7.0Gu, 4H), 2.32 (v, ЗН), 2.06-1.99 (t, 2H). M5 calculated 276.1; M5 (M.n1) 277.1. o Preparatory synthesis 25 o 50 credits, 42) no credits,

A solution of Intermediate 5 (2.60g, 11.0bmmol) in anhydrous THF (25ml) is cooled to -782C, and t-butyllithium (1.3M solution in cyclohexane, 9.3ml, 12.1bmmol) is added to it. . The mixture is stirred for 15 minutes, after which it is heated to 092C. A solution of zinc chloride (1.0 M in diethyl ether, 60 11.0 ml, 11.0 mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (3.03 g, 11.0 mmol) and tetrakis-(triphenylphosphine)Ra(0) (0.63 g, 0.500 mmol) in THF (25 mL), and the resulting solution is heated at 502C for 1 day. The reaction mixture is cooled to ambient temperature and quenched with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 25 (1.49g, 4895) as a light yellow oil. IN nMR (SOCI3): 7.07-7.04 (t, 1H), 6.93-6.90 (t, 1H), 6.82 (aa,

U-31Hz, 9.0Hz, 1), 5.05 (v, 2H), 3.56 (z, ZN), 3.42 (v, ZN), 2.82-2.78 (t, 4H) , 2.03-1.96 (t, 2H). M5 calculated 280.1; M5 (M-n1) 281.1.

Preparatory synthesis 20 0» o

Ri

It's not

A solution of Intermediate 7 (2.46g, 8.8vmmol) in anhydrous THF (25ml) is cooled to -782C, and sec-butyllithium (1.3M solution in cyclohexane, b.8ml, 8.88mmol) is added to it. The mixture is stirred for 15 minutes, after which it is heated to 02C. A solution of zinc chloride (1.0M in diethyl ether, 8.9ml, 8.88mmol) was added dropwise, and the resulting solution was allowed to warm to ambient temperature. Using a cannula, this solution was added to a solution of Intermediate 13 (1.60 g, 5.8 mmol) and tetrakis-(triphenylphosphine)Ra(0) (0.51 g, 044 mmol) in THF (25 mL), and the resulting solution was heated at 502С for 1 day The reaction mixture is cooled to ambient temperature and quenched with water. Ha

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 26 (1.20 g, 4295) as a colorless oil. IN nMR (SOS3): 7.05 (a, 9U-8.6Hz, 1H), 6.81 (a, 9-2.0Hz, 1H), 6.69 (aa, 9U-2.3Hz, 8, 6HC, 71Н), 5.15 (in, 2Н), 5.09 (in, 2Н), 3.58 (in, ЗН), 348 (з, ЗН), 3.43 (в, ЗН), 2, 79 (5 9-7.0Hz, 74GHz6,

AN), 2.04-1.95 (t, 2H). M5 calculated 322.2; M5 (M-n1) 323.1. co

Preparatory synthesis 27 (22) o--sn, m

But that's the game

A solution of Intermediate 12 (1.24g, 4.2bmmol) in anhydrous THF (20ml) is cooled to -782C, and t0 is added to it with t0-butyllithium (1.3M solution in cyclohexane, 3.3ml, 4.2bmmol). The mixture is stirred for 15 minutes, after which it is heated to 02C. A solution of zinc chloride (1.0M in diethyl ether, 4.3ml, 1" 4.2bmmol) is added dropwise, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (1.17 g, 4.2 mmol) and 15 tetrakis-(triphenylphosph1H)RY(0) (0.24 g, 0.21 mmol) in THF (20 mL), and the resulting solution is heated at 502C -1 for 1 hour. The reaction mixture is cooled to ambient temperature and quenched with water.

Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. Dry the organic layer over sodium sulfate, concentrate in vacuo and purify by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 27 (0.54g, 3895) as a colorless oil. IN NMR (SOCIz): 6.80 (a, 9-2.4 Hz, 1), 6.61 (a, 9-2.3 Hz, 1), 5.09 (v, 2H), 4.79 so ( 5, 2H), 3.57 (8, ЗН), 3.48 (in, ЗН), 3.46 (in, ЗН), 2.83-2.76 (t, 4Н), 2.29 (in , ZN), 2.02-1.96 (t, 2H). M5

Ф is calculated as 336.2; M5 (M.n1) 337.2.

Pideotov synthesis 28 o--70-sn,

F) Neo name) pe 6o oo

A solution of Intermediate 10 (2.00g, 11.p90mmol) in anhydrous THF (20ml) is cooled to -782C, and t-butyllithium (1.3M solution in cyclohexane, 7.7ml, 13.09mmol) is added to it. The mixture is stirred for 15 min., after which it is heated to 02. A solution of zinc chloride (1.0 M in diethyl ether, 11.9 ml, 11.90 mmol) is added drop by drop, and the resulting solution is allowed to warm to ambient temperature. Using a cannula, this solution is added to a solution of Intermediate 13 (3.26 g, 11.00 mmol) and tetrakis-(triphenylphosphine)Ra(o) (0.69 g, 0.58 mmol) in THF (20 mL) and the resulting solution is heated at 502 during

4 p.m. The reaction mixture is cooled to ambient temperature and quenched with water. Ethyl acetate is added, and the resulting organic layer is washed with saturated sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 20906 ethyl acetate in hexane to give the title compound (1.28g, 38905) as a colorless oil, which, according to NMR, is a mixture of regioisomers. M5 calculated 292.1; M5 (M.--1) 293.1. un o o g p zn, ee) t racemic mixture

A solution of Intermediate 17 (0.27g, 0.4mmol) in methanol (10ml) is added to a suspension of 590 palladium on charcoal (0.27g) in methanol (10ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402 for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3095 ethyl acetate in hexane to give Intermediate 29 (0.20 g, 7596) as a clear oil. "H NMR (SOSIz): 6.98 (4,

U-8.6Hz, yin), 6.86 (a, 9-3Hz, 1), 6.81 (aa, 9-31Hz, 9.0Hz, 71), 5.1 (v, 2H), 5, 08 (in, 2H), 3.64-3.59 (t, 1H), 3.50 (85, ЗН), 3.45 (in, ЗН), 3.39-3.30 (t, 7Н) , 3.19 (v, ZN), 2.12-1.98 (t, 4H), 1.93-1.82 (t, 1H), 1.72-1.63 (t, 1H). M5 calculated 324.2; M5 (M.n1) 325.2. s g Shagotochy synthesis 30 re 7 o rn, y (Se) 30 " 0-0

E (ee)

E. (22) . - raci and cha 35 A solution of Intermediate 18 (1.51g, 4.58mmol) in methanol (10ml) is added to a suspension of palladium on charcoal (0.19g) 595 in a mixture of methanol (50ml) and triethylamine (1.00ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3095 ethyl acetate in hexane to give Intermediate 30 (0.95 g, 63905) as a clear oil. with TN NMR (SOSIz): 7.42 (t, 2H), 7.15 (0.9-9.0 Hz, 1H), 5.26 (v, 2H), 3.65-3.62 (t , 1H), 3.51 (in, ЗН), 3.35-3.31 (t, 1Н), 3.15 (in, ЗН), 2.16-2.00 (t, 4Н), 1, 90-1.86 (t, 1H), 1.70-1.68 (t, 1H). M5 calculated 332.1; and" M8 (Ma) 333.1.

Preparatory synthesis of Zi - and -I (Se) o (ee) non-GI racemic mixture

A solution of Intermediate 24 (1.07 g, 3.8 mmol) in methanol (1 Oml) was added to a suspension of 595 palladium on charcoal (0.13 g) in a mixture of methanol (5 Oml) and triethylamine (1.00 ml). The mixture is kept with shaking in

GF) in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3095 ethyl acetate in hexane to give Intermediate 31 (0.72 g, 6790) as a clear oil. "H NMR (SOSI»v): 6.96-6.93 (t, ЗН), 5.17 (v, 2H), 3.67-3.60 (t, 1H), 3.50 (z, ЗН), 3.34-3.28 (t, 1Н), 60 3.15 (8, ЗН), 2.25 (в, ЗН), 2.15-1.99 (t, 4Н), 1, 90-1.83 (t, 1H), 1.70-1.63 (t, 1H). M5 calculated 294.1; M5 (Mat) 295.1. b5

Preparatory synthesis of the 32nd rapemic mixture

A solution of Intermediate 25 (1.31g, 4.6v8mmol) in methanol (10ml) was added to a suspension of 595 palladium on charcoal (0.24g) in a mixture of methanol (50ml) and triethylamine (1.00ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3095 ethyl acetate in hexane to give Intermediate 32 (1.01 g, 7790) as a clear oil. M5 calculated 282.1; M5 (M-n1) 283.1.

Mid-preparatory synthesis 33 hours of sleep, more than 0.0 hours of sleep - (o) rhytemic sumshie

A solution of Intermediate 19 (1.70g, 5.28mmol) in methanol (10ml) was added to a suspension of 590 palladium on charcoal (0.34g) in methanol (100ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 4023 for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3095 ethyl acetate in hexane to give Intermediate 33 (0.99g, 5896) as a clear oil. "H NMR (SOSIz): 7.05 (and,

U-8.6Hz, 8.2Hz, 1), 6.78 (a, 9-8.2Hz, 2H), 5.11 (aa, 9-6.6Hz, 18.4Hz, 4H), 4Д8-4ДИ (t, 1H), 3.49 (5, 6H), Ф 3.21 (v, ЗН), 3.15-3.08 (t, 1H), 2.28-2.19 (t, 2H) , 2.03-1.89 (t, ZN), 1.62-1.50 (t, 1H). M5 calculated 324.2; m

M5 (M-1) 325.2. zo Cidgotochy synthesis 34 t o , sn, "o,o no s i" b. - sn, - raisemic mixture (Te) To a suspension of palladium 590 on charcoal (0.60 g) in methanol (25 ml) add a solution of Intermediate 26 (120 g, 3.7 mmol) in methanol (1 ml). The mixture is kept with shaking in a Parr apparatus under hydrogen pressure (60 psig, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through 4) a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 34 (0.82g, 6895) as a clear oil. "H NMR (SOSIz): 7.06 (a,

U-8.6Hz, 1), 6.77 (a, 9-2.3Hz, 71H), 6.60 (aa, 9-24Hz, 8.6Hz, 71H), 5.20 (v, 2H), 5.14 (aa, 2-6.6Hz, 9.7Hz, 2H), 3.61-3.54 (t, 1H), 3.50 (v, 6H), 3.45 (v, ЗН), 3.31-3.26 (t, 1H), 2.16-1.94 (t, 4H), 1.86-1.80 (t, 1H), about 1.71-1.60 (t, 1H). M5 calculated 324.2; M5 (M-n1) 325.2. name) 60 b5 so sn, tyu sV, sv?

Annual meeting

A solution of Intermediate 27 (0.54g, 1.61mmol) in methanol (1Oml) is added to a suspension of 590 palladium on charcoal (0.25g) in methanol (25ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60-72 psig, 414kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 35 (0.49g, 8996) as a clear oil. "H NMR (SOSIz): 6.69 (a,

U-2.8Hz, 7), 6.65 (a, 9-3IHz, 1), 5.04 (t, 2H), 4.93 (da, 9-5.9Hz, 16.0Hz, 2H), 3.73-3.67 (t, 1H), 3.57 (5, ЗН), 3.42 (8, ЗН), 3.25-3.19 (t, 4Н), 2.25 (in, ЗН), 2.17-2.12 (t, 71Н), 2.05-1.85 (t, 4Н), 1.70-1.60 (t, 70 1nu M8 calculated 338.2; M (М --1) 339.2. s o not. sh ee: (Se) that sn, so

Bi ( (22) raecemic mixture k

A solution of Intermediate 20 is added to a suspension of 590 palladium on charcoal (0.38g) in methanol (35ml)

Zo (0.75g, 2.14mmol) in methanol (1Oml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 - psi, 414 kPa) at 402 for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 36 (0.63g, 8496) as a clear oil. "H NMR (SOCIz): 6.95 (4, « 5-9.0 Hz, 1), 685 (a, 9-31 Hz, MH), 6.79 (aa, O-31 Hz, 9.0 Hz, 1 H) , 5.15 (in, 2H), 5.13-505 (t, 2H), sho 70 3.56-3.51 (t, 1H), 3.50 (5, ZN), 3.45 (85 , ZN), 3.30 (85, ZN), 3.08-3.04 (t, 1H), 2.23-2.17 (t, 1H), 2.04-1.80 s (t, 6H), 1.55-1.40 (t, ZN). M5 calculated 352.2; M5 (M-41) 353.2. )" Preparatory synthesis 37 v. ha: on - o. t se ned o be 72 9

F sn, racemic mixture

To a suspension of 595 palladium on charcoal (0.08g) in a mixture of methanol (50ml) and triethylamine (1.00ml) was added a solution of Intermediate 21 (0.62g, 1/bmol) in methanol (10ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 2095 ethyl acetate in hexane to give Intermediate 37 (0.50 g, 8195) as a clear oil. "H NMR (SOCIv8): 6.50 (a, 9-2.7Hz, 1H), 6.44 (4, 9-2.7Hz, 1H), 5.14-5.05 (t, 4H), 3.80 (t, 4H), 3.58 (5, ЗН), 3.46 (в, ЗН), 3.25 (t, 4Н), 2.15-2.09 (t, 1Н), 2 .07-1.90 (t, 4H), 1.72-1.64 (t, 1H). M5 calculated 354.1; M5 (Mt) 3551. b5

Preparatory synthesis 38

SN - There is a SN, UN, 70 racemic sumini

A solution of Intermediate 22 (0.42g, 1.19mmol) in methanol (10ml) was added to a suspension of 595 palladium on charcoal (0.05g) in a mixture of methanol (50ml) and triethylamine (1.00ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo and purified by flash chromatography 712 eluting with 2096 ethyl acetate in hexane to give Intermediate 38 (0.16 g, 38905) as a clear oil. "H NMR (SOCIz): 7.00 (y, 9-8.2Hz, 0.5), 6.94 (4, 9-7.8Hz, 0.5H), 6.84-6.75 (t , 1.5H), 6.67 (4,

ultrasound, 0.5H), 5.12-5.01 (t, 4H), 3.77 (a, 9-9.0Hz, 0.5H), 3.64 (a, 9-11.3Hz, 0 .5H), 3.52 (8, 1.5H), 3.49 (5, 1.5H), 3.48-3.43 (in, 4.5H), 3.35 (8, 1.5H ), 2.55-2.42 (t, 0.5Н), 2.17-2.02 (t, 1Н), 1.95-1.88 (t, 0.5Н), 1.81-1 .75 (t, 1H), 1.69-1.60 (t, O,BN), 1.55-1.50 (t, 0.5H), 1.15 (in, 1.5H), 1 .01 (in, 1.5Н), 0.78 (in, ЗН). M 720 is calculated as 352.2; MH (M-n1) 353.2.

Piltotov synthesis 39 o s i io) ne "ov, tych oo (Se) racemic sumi so

A solution of Intermediate 23 (1.25g, 33.89mmol) in methanol (10ml) was added to a suspension of 595 palladium on charcoal (0.58g) in a mixture of methanol (50ml) and triethylamine (1.00ml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. The reaction mixture is purged with nitrogen and filtered through a layer of celite. The filtrate is concentrated in a vacuum and purified by flash chromatography! PI! and - eluting with 1595 ethyl acetate in hexane to give Intermediate 39 (0.89g, 7290) as a clear oil. M5 calculated 380.2; M5 (M-n1) 381.2.

Infantry synthesis of the 40s, "dya no s sn, i" oo i. -I and racemic mixture of a suspension of 596 palladium on charcoal (0.15 g) in a mixture of methanol ml) with triethylamine (1.0 ml) are added to it 595 i illy (0.15 g) ishi (5 Oml) and i (1, Oml) with a 50% solution of Intermediate 28 (0.58g, 1.80mmol) in methanol (LOml). The mixture is kept under shaking in a Parr apparatus under hydrogen pressure (60 psi, 414 kPa) at 402C for 12 hours. They blow out the reactionary; the mixture with nitrogen and filtered through a pad of celite. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 1595 ethyl acetate in hexane to give Intermediate 40 (0.25 g, 43905) as a clear oil. M5 calculated 294.1; M5 (M-n1) 295.1.

Shotov synthesis 4 is. well, name) . -sh-B8- tu rn,

Well, here is 65 racemic sumini

This synthesis is carried out according to the method described in Teigapedgop I eige 36, 31, 1995, 5461-5464). Suspension

Intermediate 29 (0.50g, 1.54mmol) and M,O-dimethylhydroxylamine hydrochloride (0.23g, 2.31mmol) in anhydrous THF (25ml) are cooled to -102C in a bath (dry ice with acetone), isopropylmagnesium chloride ( 2.0M, 2.3ml, 4.62mmol), and stir the reaction mass for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 41 (0.49g, 9095) as a clear oil, which was used without further identification. "Kk shi okt rn, sla

IS

IS

It is a racemic mixture

A suspension of Intermediate ZO (0.95g, 2.86bmmol) and M,O-dimethylhydroxylamine hydrochloride (0.42g, i. 4.29mmol) in anhydrous THF (40ml) is cooled to -1092C in a bath (dry ice with acetone) , add isopropylmagnesium chloride (2.0M, 4.3ml, 8.58mmol), and stir the reaction mass for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 s about ethyl acetate in hexane to give Intermediate 42 (0.86 bg, 8395) as a clear oil, which was used without further identification. io) n.s. U " F 30 rn, so o "a F , - 35 t s. in rapemic university

A suspension of Intermediate 31 (0.71g, 2.55mmol) and M,O-dimethylhydroxylamine hydrochloride (0.37tg, 3.83mmol) in anhydrous THF (40ml) is cooled to -102C in a bath (dry ice with acetone), isopropylmagnesium is added -chloride (2.0M, 2.5ml, 5.1Omol), and stir the reaction mass for 30 minutes. Quench the reaction with 40% saturated ammonium chloride solution. Ethyl acetate is added, and the organic layer is washed with brine. The organic (73) layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 43 (0.36 bg, 4695) as a clear oil, which was used without further identification. 45th No TV,

Hn shchi Ts - sun, so o o o 50

Pho racemic mixture

A suspension of Intermediate 32 (0.98g, 3.48mmol) and M,O-dimethylhydroxylamine hydrochloride (0.51g, 5.22mmol) in anhydrous THF (40ml) is cooled to -102C in a bath (dry ice with acetone), isopropylmagnesium is added -chloride (2.0M, 5.2ml, 10.42mmol), and stir the reaction mass for 30 minutes. The reaction is quenched with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 44 (0.61 g, 5695) as a clear oil, which was used without further identification. b5

Нн и ух не охо 70 racemic mixture

A suspension of Intermediate 33 (0.97g, 2.99mmol) and M,O-dimethylhydroxylamine hydrochloride (0.44g, 4.49mmol) in anhydrous THF (40ml) is cooled to -102C in a bath (dry ice with acetone), isopropylmagnesium chloride (2.0M, 4.5ml, 9.000mmol) is added, and the reaction mass is stirred for 30h. The reaction is quenched with saturated ammonium chloride solution. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 45 (0.71g, 6795) as a clear oil, which was used without further identification.

H not and whether - 9.0.0 s 25. io) not Te) - se racemic sum g o

A suspension of Intermediate 34 (0.82g, 2.53mmol) and M,O-dimethylhydroxylamine hydrochloride (0.37, Fd) 3.8O0mmol) in anhydrous THF (30ml) is cooled to -102С in a bath (dry ice with acetone), add isopropylmagnesium chloride (2.0M, C3, vml, 7.bOmmol), and stir the reaction mass for 30 minutes. The reaction is quenched with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 46 (0.80 g, 9095) as a clear oil, which was used without further identification. "no s H, 1" vol y . WHERE am I? -I o o -I sp. se) with a racemic mixture

A suspension of Intermediate 35 (0.48g, 1.42mmol) and M,O-dimethylhydroxylamine hydrochloride (0.21g, 4) 2.13mmol) in anhydrous THF (20ml) is cooled to -1092C in a bath (dry ice with acetone), add isopropylmagnesium chloride (2.0M, 2.1ml, 4.20mmol) and stir the reaction mass for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 5095 ethyl acetate in hexane to give Intermediate 47 (0.46 bg, 8895) as a clear oil which

F) used without additional identification. name) 60 b5

Preparatory synthesis 48 o two oo o. sn, and in, racemic mixture

A suspension of Intermediate 36 (0.63g, 2.53mmol) and M,O-dimethylhydroxylamine hydrochloride (0.26g, 75 2.68mmol) in anhydrous THF (30ml) is cooled to -109C in a bath (dry ice with acetone), added isopropylmagnesium chloride (2.0M, 2.7ml, 5.4O0mmol), and stir the reaction mass for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Add ethyl acetate and wash the organic layer with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 48 (0.54g, 7695) as a clear oil, which was used without further identification.

ON the village

O.A. tn sv, shchi oo o (Se)

Y m o (22) racemic mixture t-

A suspension of Intermediate 37 (0.50g, 1.41mmol) and M,O-dimethylhydroxylamine hydrochloride (0.24g, ra 2.12mmol) in anhydrous THF (30ml) is cooled to -1092C in a bath (dry ice with acetone), added isopropylmagnesium chloride (2.0M, 2.1ml, 4.20mmol), and stir the reaction mass for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 49 (0.31g, 5790) as a clear oil, which was used without further identification. and" no. t, sn, o m sn, -i 0,0 -i ne sia, o so U bo 0 racemic mixture

A suspension of Intermediate 38 (0.16g, 0.45mmol) and M,O-dimethylhydroxylamine hydrochloride (0.07tg, 42) and i.

0.bdmmol) in anhydrous THF (1Oml) is cooled to -102С in a bath (dry ice with acetone), isopropylmagnesium chloride (2.0M, 0.7ml, 1.4O0mmol) is added, and the reaction mass is stirred for 30 min. The reaction is quenched with an aqueous solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 (F) ethyl acetate in hexane to give Intermediate 50 (0.15 g, 8795) as a clear oil, which was used without further identification. 60 b5

BUT sleep, oh and

Not pcs, but 10. . racemic mixture

A suspension of Intermediate 39 (0.25g, 0.77mmol) and M,O-dimethylhydroxylamine hydrochloride (0.11g, 1.1bmmol) in anhydrous THF (20ml) is cooled to -1092C in a bath (dry ice with acetone), isopropylmagnesium is added -chloride (2.0M, 1.2ml, 2.40mmol), and stir the reaction mass for 30 minutes. Quench the reaction 72 with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 ethyl acetate in hexane to give Intermediate 51 (0.20g, 7495) as a clear oil, which was used without further identification. sv, o, um 0. s n, "sn, (o) racemic mixture

A suspension of Intermediate 40 (0.91g, 3.07mmol) and M,O-dimethylhydroxylamine hydrochloride (0.45g, 4.04mmol) in anhydrous THF (20ml) is cooled to -1092C in a bath (dry ice with acetone), isopropylmagnesium chloride (2.0M, 3.Tml, 6.20mmol) is added, and the reaction mass is stirred for 30 minutes. Quench the reaction with a saturated solution of ammonium chloride. Ethyl acetate is added, and the organic layer is washed with brine. The organic (9) layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 50905 mg of ethyl acetate in hexane to give Intermediate 52 (0.36 bg, 3695) as a clear oil which

Zo is used without additional identification. in. suspension of sodium hydride (6095 in mineral oil, 2.54g, 63.58mmol) in anhydrous DMF (5Oml) is cooled in a nitrogen atmosphere to 02С and a solution of 4-bromophenol (10, O00OHg, )» 57.80mmol) in anhydrous DMF (5Oml). Methoxymethyl chloride (4.8 ml, 63.58 mmol) was added drop by drop to the resulting suspension. Heat the reaction mixture to ambient temperature and stir for 1 hour. Quench the reaction with water and diethyl ether. The organic layer is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 1095 ethyl acetate in hexane to give Intermediate 53 (10.42 g, 8390)-I as a clear oil. IN NMR (SOSI»z): 7.38 (a, 9-8.8Hz, 2H), 6.93 (a, 9-8.7Hz, 2H), 5.14 (c, 2H), 3.43 (in, ZN). that Shphotochy synthesis 54

F K.

A solution of Intermediate 53 (3.03g, 14.00mmol) in anhydrous THF (40ml) is cooled to -782C in a nitrogen atmosphere and t-butyllithium (1.3M in cyclohexane, 10.7ml, 14000mmol) is added dropwise to it ). The solution is stirred at -782C for 30 minutes, and a solution with a concentration of 0.40M is obtained.

Use immediately, maintaining a temperature of -7826. name) 60 b5

Multi-subtle synthesis 55

WITH

Her identity is "Me;

Intermediate 54 (0.40M, 42.5ml, 17.00mmol) was added at 02C to a solution of Intermediate 41 (6.00g, 17.00mmol) in anhydrous THF (50ml), and the resulting solution was stirred for 30 minutes. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 ethyl acetate in hexane to give Intermediate 55 (7.11 g, 9796) as a colorless foam. "H NMR (SOCI3): 7.61 (a, O-86Hz, 2H), 6.83 (a, O-8.6Hz, 2H), 6.76 (a, 9-2.7Hz, 1), 6.71 (a, yu-8.7Hz, 1H), 6.60 (aa,

U-2.7Hz, 8.6Hz, 1), 5.18 (v, 2H), 5.08-4.95 (t, 4H), 4.27-4.23 (t, 1H), 3, 83-3.79 (t, 1H), 3.43 (in, ЗН), 3.40 (in, ЗН), 3.39 (in, ЗН), 2.25-1.93 (t, 5Н) , 1.79-1.70 (t, 1H). s yan, y o

WITH

(Se) to sn, so oo F

IS

IS -

It is a racemic mixture

Intermediate 54 (0.40M, 8.9ml, 3.57mmol) was added at 02C to a solution of Intermediate 42 (0.86Hg, 2.3mmol) in anhydrous THF (50ml), and the resulting solution was stirred for 30 minutes. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 2090 g of ethyl acetate in hexane to give Intermediate 56 (1.03 g, 9995) as a clear oil. yen, - o

WITH

-i o se) at 50

Fo "ten, a racemic mixture

HF) Intermediate 54 (0.40M, 6b.1ml, 2.34mmol) was added at 02С to a solution of Intermediate 43 (0.36Hg, q 1.17mmol) in anhydrous THF (20ml), and the resulting solution was stirred for 3h. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 60 . DI. 1 of ethyl acetate in hexane to give Intermediate 57 (0.41 g, 9290) as a clear oil. "NN NMR (SOSI3U 7.61 (a, 0-y4hz, 2H), 6.92-6.81 (t, ZN), 6.76-6.65 (t, 2H), 5.15 (v, 2H), 4.93 (t, 2H), 4.29-4.23 (t, 1H), 3.82-3.76 (t, 1H), 3.45 (z, ЗН), 3.40 (in, ZN), 2.23-1.92 (t, 8H), 1.80-1.69 (t, 1H). b5 sho; o

Y. | oh hey

E racemic mixture t Intermediate 54 (0.40M, 9.vml, 3.92mmol) was added at 02C to a solution of Intermediate 44 (0.61g, 1.9bmmol) in anhydrous THF (20ml), and the resulting solution was stirred for 3h . at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 ethyl acetate in hexane to give Intermediate 58 (0.59g, 92965) as a clear oil. BUT yaYAMme (SOSIZU 7.61 (a, 9-74hz, 2H), 6.92-6.80 (t, ZN), 6.78-6.72 (t, 1H), 6.63-6.59 (t, 1H), 5.17 (aa, U-6.6Gu, 9.4Hz, 2H), 4.90 (aa, 9-4.5Hz, 6.6Hz, 2H), 4.30-4, 26 (t, 1H), 3.80-3.75 (t, 1H), 3.43 (in, ЗН), 3.39 (in, ЗН), 2.20-1.91 (t, 5Н) , 1.80-1.70 (t, 1H).

Preparatory synthesis of 59 compounds of 3 F

Intermediate 54 (0.40 M, 7.5 mL, 3.0 mmol) was added at 02C to a solution of Intermediate 45 (0.7 1 g, 20 2.01 mmol) in anhydrous THF (20 mL), and the resulting solution was stirred for 3 h. at 02C. Extinguish the reaction! with saturated sodium bicarbonate solution. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 g of ethyl acetate in hexane to give Intermediate 59 (0.80 g, 9395) as a clear oil. "H NMR (SOSIZU 7.55 (a, 9-7.0 Hz, 2H), 6.80-6.75 (t, ZN), 6.48 (9, 9U-8.2 Hz, 2H), 5, 15-5.06 (t, 2H), 4.96 (v, 4H), 4.39-4.31 (t, 1H), 3.80-3.76 (t, 1H), 3.46 ( 85, 6H), 3.40 (8, ZN), 2.55-2.45 (t, 1H), 2.30-2.20 (t, 1H), -I 2.15-2.05 ( t, 1H), 1.96-1.85 (t, 2H), 1.70-1.60 (t, 1H). M5 calculated 430.2; M5 (M.-1) 431.2. - Preparatory synthesis 5)

F Ki vo 0 o 42) o

F) where) H o 60 is not a racemic mixture

Intermediate 54 (0.40M, 8.5ml, 3.40mmol) was added at 02C to a solution of Intermediate 46 (0.80Hg, 2.26mmol) in anhydrous THF (20ml), and the resulting solution was stirred for 3h. at 02C. Quench the reaction with 65% saturated sodium bicarbonate solution. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 ethyl acetate in hexane to give Intermediate 60 (0.87g, 9095) as a clear oil. "NN NMR (SOSISU 7.61 (a, 9-8.6GHz, 2H), 6.99-6.96 (t, 71H), 6.86 (9, uU-8, IHz, 2H), 6, 50-6.46 (t, 2H), 5.15 (5, 2H), 5.40-4.97 (t, 2H), 4.92 (v, 2H), 4.26-4.21 ( t, 1H), 3.80-3.74 (t, 1H), 3.44 (in, ЗН), 3.40 (85, ЗН), 3.938 (in,

ZN), 2.24-1.90 (t, 5H), 1.79-1.71 (t, 1H). M5 calculated 430.2; M5 (M.-1) 431.2.

Infantry synthesis 61

And I'm sorry

Fo tia and. that 20 . racemic mixture

Intermediate 54 (0.40M, 4.7ml, 1.8v8mmol) was added at 02C to a solution of Intermediate 47 (0.46Hg, 1.25mmol) in anhydrous THF (20ml), and the resulting solution was stirred for 3h. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 g of ethyl acetate in hexane to give Intermediate 61 (0.43 g, 7795) as a clear oil. "H NMR (SOSI3U 7.61 (a, O-v6hz, 2H), 6.80 (a, 9-90gu, 2H), 6.51 (a, 9n2,yIgz, 1H), 6.41 (a, 9-2, IHz, 1), 513 (8, 2H), 4.97-4.85 (t, 4H), 4.26-4.21 (t, 1H), 3.85-3.80 ( t, 7Н), 3.61 (v, ЗН), 342 (8, ЗН), 3.37 (8, ЗН), «о зо 233-222 (t, 1Н), 2.15-1.89 ( t, 7H), 1.80-1.69 (t, 1H). M5 calculated 444.2; M5 (M-n1) 445.2.

Ilgotochy synthesis of 62 cents

Ha - sh 5 i - ne tu I s 5 o 5 s iy 1» sn. rapemic sumipi 75 Intermediate 54 (0.40M, 6b,vml, 2.74mmol) is added at 02C to a solution of Intermediate 48 (0.54g, -i i - . . . 1.37mmol) in anhydrous THF (20ml), and the resulting solution is stirred for ЗОхв. at 02C. Quench the reaction with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 5p ethyl acetate in hexane to give Intermediate 62 (0.25g, 4095) as a clear oil. TN nMR bo (SOSIZU 7.55 (9.9-8.6GHz, 2H), 683 (a, 9U-9.0Gu, 1H), 6.76-6.72 (t, ЗН), 6.57 ( aa, uU-3.2Hz, 9.0Hz, 1H), b 5.14 (in, 2H), 5.00-4.92 (t, 4H), 4.10-4.03 (t, 71H) , 3.70-3.63 (t, 1H), 3.45 (85, ЗН), 3.43 (85, ЗН), 3.938 (in,

ZN), 2.38-2.30 (t, 1H), 2.10-1.82 (t, 8H), 1.55-1.45 (t, 1H).

F) name) 60 b5

Preparatory synthesis 63 sm, at 0.0. sleep, o and 5

Not a racemic mixture

Intermediate 54 (0.40M, 4.0ml, 1.62mmol) is added at 02C to a solution of Intermediate 49 (0.31g, 0.8mmol) in anhydrous THF (10ml), and the resulting solution is stirred for 3h . at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 ethyl acetate in hexane to give Intermediate 63 (0.12g, 3295) as a clear oil. "H NMR s (SOSIS): 7.65 (a, 9U-8.0Gu, 2H), 6.99-6.96 (t, 1H), 6.80 (a, 9U-8.0Hz, 2H) , 6.29 (a, 9U-2.7Hz, 1H), 6.23 (a, o

U-2.7HZ, 71H), 5.13 (v, 2H), 5.02-4.89 (t, 4H), 4.24-4.19 (t, 1H), 3.94-3, 89 (t, 1H), 3.67 (in, ЗН), 3.60 (in,

ZN), 3.44 (5, ZN), 3.39 (in, ZN), 2.30-2.27 (t, 1H), 2.13-2.02 (t, 1H), 1.99 -1.90 (t, 2H), 1.80-1.74 (t, 1H).

Powder-refined synthesis 64 t)

Sn, d) o 3 F en, t n, i - z ry sh us. sn, at « i Y y - s ryaepemic sum

Intermediate 54 (0.40M, 1.5ml, 0.59mmol) was added at 02C to a solution of Intermediate 50 (0.15g, 0.39mmol) in anhydrous THF (10ml), and the resulting solution was stirred for 30 minutes. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 - ethyl acetate in hexane to give Intermediate 64 (5mg, 2895) as a clear oil. another 50 t sleep,

GF) oo su,

But breath

Heh) "that's racemic - uMmIsh

Intermediate 54 (0.40M, 2.1ml, 0.85mmol) was added at 02C to a solution of Intermediate 51 (0.20Hg, 0.57mmol) in anhydrous THF (10ml), and the resulting solution was stirred for 30 minutes. at 02C. The reaction is quenched with a saturated solution of sodium bicarbonate. Add ethyl acetate and wash with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 3090 mL of ethyl acetate in hexane to give Intermediate 65 (0.21 g, 8695) as a clear oil.

Preparatory synthesis of 66 units, y; oh oh ben, a racemic mixture

Intermediate 54 (0.40M, 5.5ml, 2.22mmol) is added at 02C to a solution of Intermediate 52 (0.36Hg, 1.11mmol) in anhydrous THF (20ml), and the resulting solution is stirred for 30 minutes at 02C. Quench reaction with saturated sodium bicarbonate solution. Ethyl acetate was added and washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography eluting with 5090 ethyl acetate in hexane to give Intermediate 66 (0.41g, 9295) as a clear oil . but n, sch io) sn, ne Te zo ote . c racemic mixture o

To a solution of 0.92 g (2.8 mmol) of Intermediate 11 in 1 mL of THF, 3.4 mL (5.5 mmol) of a 1.7 M solution of tert-butyllithium is added at -782C. The resulting mixture was added via a cannula at -782C to a solution of 0.7g (2.0mmol) of Intermediate 41 in 10ml of anhydrous THF with magnetic stirring, and the mixture was allowed to warm to room temperature. After 5 hours the mixture is distributed between diethyl ether and a saturated aqueous solution of sodium bicarbonate. The organic layer is washed with water and brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel eluting with 1095 ethyl acetate in hexane, obtaining "

Intermediate 67 (0.51g, 5796). The "H-NMR spectrum of the product (in SOCI3) contains an arylmethyl singlet signal at 2.1 ppm", and the product is used without further processing. no s Pishotovchii synthesis 68 )» Red -I -I (se) N a ke o 50

F ps that's it

To a solution of 0.70 g (3.00 mmol) of 4-bromo-O-methoxymethyl-m-cresol in 1 ml of THF, 3.0 ml (6 g.1 mmol) of 1.7 M solution of tert-butyllithium is added at -789C. The resulting mixture is added to the solution using a cannula at -782C

F, 0.98g (2.77mmol) of Intermediate 41 in 10ml of anhydrous THF under magnetic stirring, and the mixture is allowed to warm to room temperature. After 5 hours the mixture is distributed between diethyl ether and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel eluting with 1095 ethyl acetate in hexane with 0.195 triethylamine admixture to give Intermediate 68 (0.31g, 2596). "H NMR (SOCIz5): 7.39 (a, 35-9.5Hz, 71H), 6.83 (c, 1H), 6.70 (aa, 9-9.5Hz, 2.5Hz, 1H), 6.68 (in, 1H), 6.61 (a, 9-2.5Hz, 1H), 5.15-4.98 (t, 4H), 4.76 (a, 9-6.3Hz, 1H ), 4.65 (a, 9-64 Hz, 1), 4.24 (t, 1H), 3.68 (t, 1H), 3.47 (t, 1H), 3.44 (c, ЗН) . 65 Example 1

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyliso3,4-dihydro-2H-1-benzopyran

SH

Ge) racemic mixture

To a solution of Intermediate 55 (7.10 g, 16.51 mmol) in anhydrous methanol (200 ml) add 70 g of p-toluenesulfonic acid (1.04 g, 16.5 mmol), and heat the resulting solution at 509C for 18 hours.

Cool the reaction mixture to ambient temperature and add bromocresol green (1mg) and sodium cyanoborohydride (5.18g, 82.55mmol). Methanol, saturated with NH (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another 1 hour. The reaction is quenched with saturated sodium bicarbonate solution, 75% ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 1095 diethyl ether in dichloromethane. The obtained product was re-dissolved in diethyl ether (approximately 2 ml), precipitated with dichloromethane and filtered, obtaining the compound of Example 1 (2.10 g, 4595) as a light purple oil. "H NMR (45-OM30): 9.28 (in, 1H), 8.80 (in, 1H), 7.20 (4, U-8.6Hz, 2H), 6.73 (a, 9- 8.6Hz, 2H), 6.61 (a, 0-8.7Hz, yin), 6.53 (9, 9-2.7Hz, 1H), 645 (aa, 9-2.7Hz, 8.5Hz , 1H), 4.92 (a, 9-2.0Hz, 1H), 3.38-3.32 (t, 1H), 2.53-2.47 (t, 1H), 2.07-2 .02 (t, 1H), 1.65-1.59 (t, 1H), 1.45-1.22 (t, 4H). M5 calculated 282.1; M5 (M-1) 281.1.

Example 1A Preparation of (2K,3H,4K)-(4-hydroxyphenyl)-6-hydroxy-cyclopentylyl3,4-dihydro-2H-1-benzopyran and (25,35,45)-(4-hydroxyphenyl)-6-hydroxy -cyclopentyliso3,4-dihydro-2H-1-benzopyran

E s ra . And about

Fo (fi z on zon shchi; s (25, ZK, 45) (ik, ZB.)

Using standard NRIS equipment, the product according to Example 1 is chromatographed (3.51 g, Me) SpigairakaO column 8x32 cm, eluent 80905 heptane in isopropyl alcohol, 35 Oml/min, detection at a wavelength of 252 nm). After concentration of the pure fractions, the isomers (5,5,5) (1.67g, ee 99.995, retention time 325 b, Ohv.) and (K,K,E) (1.7 1g, ee 98.99, retention time 9.3 min.) in the form of white foam. -

Example 2

Preparation of ()-2-(4-hydroxyphenyl)-6-trifluoromethyl-cyclopentyl)3,4-dihydro-2H-1-benzopyran

IS "

E no s )» On u5 Watercemic mixture -1 To a solution of Intermediate 56 (1.03g, 2.3B5mmol) in anhydrous methanol (40ml) is added p-toluenesulfonic acid (0.11g, 1.7bmmol), and the resulting solution is heated at 502C for 18 hours. The reaction mixture is cooled to ambient temperature, and bromocresol green (1mg) and sodium cyanoborohydride (0.74g, 11.75mmol) are added to it. Methanol, saturated with NOSI (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with a saturated solution of sodium bicarbonate, ethyl acetate is added to the mixture and

F wash the organic layer with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 2095 ethyl acetate in hexane to give the compound of Example 2 (0.38 g, 4895) as a light pink oil. "H NMR (d6-OM50): vv 9.37 (8, 1H), 7.54 (a, 9-1.9Hz, 1H), 7.40 (aa, U-1.9Gu, 8, bGu, 1), 7.24 (a, uU-82Hz, 2H), 7.00 (a, U-8.6Gu, 1), 6.74 (a, 0-82Hz, 2), 5.17 (a, 9-2.0Hz, 1), 3.53 (5 9-7.4Gu, 6.6bHzc, 1H), 2.65-2.62 (t, 1H), 2.18-2.10 iF) ( t, 1H), 1.78-1.72 (t, 1H), 1.46-1.29 (t, 4H). M5 calculated 334.1; M5 (M-1) 333.1. ko Example C

Preparation of ()-2-(4-hydroxyphenyl)-6-methyl-cyclopentyliso3,4-dihydro-2H-1-benzopyran 60 b5

! I'm those on

And their GU

70. p-toluenesulfonic acid (0.05g, 0.78mmol) is added to a solution of Intermediate 57 (0.40g, 1.04mmol) in anhydrous methanol (50ml), and the resulting solution is heated at 502C for 18 hours. Cool the reaction mixture to ambient temperature, and add bromocresol green (1mg) and sodium cyanoborohydride (0.33g, 5.20mmol). Methanol, saturated with NSII (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 2095 ethyl acetate in hexane to give the compound of Example C (0.21 g, 7295) as a light purple solid. "H NMR (SOCIz): 7.33 (a, 9-9Hz, 2), 7.00 (a, 9-1.2Hz, 1), 6.92 (aa, 9U-2.0Hz, 82Hz, 1H ), 6.87-6.81 (t, ZN), 5.44 (in, 1), 5.09 (y, 9-2.0HZ, 1), 3.50-3.46 (t, 1H ), 2.61-2.54 (t, 1H), 2.30 (v, ЗН), 2.20-2.10 (t, МН), 1.90-1.82 (t, 1H), 1.71-1.60 (t, 1H), 1.57-1.36 (t, ЗН). M5 calculated 280.1; M5 (M-1) 279.1.

Example 4

Preparation of (x)-2-(4-hydroxyphenyl)-6-fluoro-cyclopentylyl-3,4-dihydro-2H-1-benzopyran and its derivatives

On - - (Se) racemic suMmsh so

p-toluenesulfonic acid (0.07g, 1.14mmol) was added to a solution of Intermediate 58 (0.59g, 1.52mmol) in anhydrous methanol (30ml), and the resulting solution was heated at 502C for 18h. Cool the F) reaction mixture to ambient temperature, and add bromocresol green (1mg) and M sodium cyanoborohydride (0.48g, 7.6bmmol). Methanol, saturated with NSII (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred again - for an hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 2095 ethyl acetate in hexane to give the compound of Example 4 (0.34 g, 7996) as a light purple solid. "H NMR (SOCI5): 7.33 (a, 0-8.6Hz, 2H), 6.88-6.76 (t, 5H), 5.13 (v, 1H), 5.08 (y, 9-2.3Hz, 1H), 3.49-3.45 (t, 1H), - s 2.62-2.55 (t, 1H), 2.20-2.11 (t, 1H), 1.83-1.75 (t, 1H), 1.67-1.58 (t, 1H), 1.56-1.39 (t, ZH). M5 calculated at" 284.1; M5 (M -1) 283.1.

Example 5

Preparation of ()-2-(4-hydroxyphenyl)-5-hydroxy-cyclopentylisi3,4-dihydro-2H-1-benzopyran nn -I -I so 0 on so - y

F rapemic mixture

p-toluenesulfonic acid (0.09g, 1.40mmol) was added to a solution of Intermediate 59 (0.80g, 1.8bmmol) in anhydrous methanol (30ml), and the resulting solution was heated at 502С for 18h. The reaction mixture is cooled to ambient temperature, and bromocresol green (1mg) and sodium cyanoborohydride (0.58g, 9.300mmol) are added to it. Add drop by drop methanol, saturated with HCIII (gaseous), until iF) obtaining a stable yellow color of the mixture. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 575 diethyl ether in dichloromethane, obtaining the compound of Example 5 (0.41 g, 7890) as a light pink solid. "H NMR (a6-OM50O): 9.31 (in, 1H), 9.30 (in, 1H), 7.20 (y, 9-8.2 Hz, 2H), 6.83 (5 9-7 ,4Hz, 10.0Hz, 1H), 6.75 (a, yuu-8.6Hz, 2H), 6.39 (a, 9-7.9Hz, 71), 6.28 (a, 9-7, 9Hz, 1), 4.87 (a, 9-IOHC, LN), 3.46-3.41 (t, 1H), 2.60-2.56 (t, 1H), 2.14-2, 09 (t, 1H), 1.62-1.56 (t, 1H), 1.51-1.29 (t, 4H). M5 calculated 282.1; M5 (M-1) 281.1. 65 Example 6

Preparation of ()-2-(4-hydroxyphenyl)-7-hydroxy-cyclopentyliso3,4-dihydro-2H-1-benzopyran

"It is a racemic mixture

To a solution of Intermediate 60 (0.8 mg, 2.00 mmol) in anhydrous methanol (5 Oml) add 70 g of p-toluenesulfonic acid (94 mg, 1.50 mmol), and heat the resulting solution at 502C for 18 hours. The reaction mixture is cooled to ambient temperature, and bromocresol green (1mg) and sodium cyanoborohydride (0.63g, 10.000mmol) are added to it. Methanol, saturated with NOSI (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 5905 diethyl ether in dichloromethane, obtaining the compound of Example b (0.32 g, 5790) as a light yellow solid. "H NMR (d5-OM80): 9.31 (in, 1H), 9.30 (in, 1H), 7.21 (a, 9-8.6 Hz, 2H), 6.84-6.80 ( t, 1H), 6.73 (a,

U-8.6Hz, 2H), 6.38 (a, 9-7.8Hz, 1), 6.29 (0, 9-82Hz, 1H), 4.87 (8, 1H), 3.45- 3.41 (t, 1H), 2.62-2.58 (t, 1H), 2.18-2.09 (t, 1H), 1.61-1.54 (t, 1H), 1, 50-1.22 (t, 4H). M5 calculated 282.1; M5 (M-1) 281.1.

Example 7

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-8-methyl-cyclopentyl)3,4-dihydro-2H-1-benzopyran no s o io) sn, on racemic mixture o

To a solution of Intermediate 61 (0.15 g, 2.00 mmol) in anhydrous methanol (30 mL) add 0 p-toluenesulfonic acid (45 mg, 0.7 mmol), and heat the resulting solution at 502C for 18 hours. Cool the reaction mixture to ambient temperature, and add bromocresol green (1mg) and sodium cyanoborohydride (0.29g, 4.65mmol). Methanol, saturated with NSI (gaseous), is added drop by drop to it to obtain a stable yellow color of the mixture. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 5905 of diethyl ether in dichloromethane, obtaining the compound of Example 7 (0.15 g, 5490) as a light yellow solid. TN nMR (a5-0OM50): 9.29 (in, IN), 8.66 (in, 1H), 7.24 (4, U-8.6Hz, 2H), 6.65 (a, 9U-8 ... 07-2.00 (t, 1H), 1.62-1.59 (t, 1H), 1.42-1.21 (t,

BN). M5 calculated 296.1; M5 (M-1) 295.1.

And" Example 8

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-cycloheptyls|3,4-dihydro-2H-1-benzopyran and dood -I o se) o 50 | , he

Rademic mixture

To a solution of Intermediate 62 (0.25g, 0.54mmol) in anhydrous methanol (20ml) is added p-toluenesulfonic acid (25mg, 0.41mmol), and the resulting solution is heated at 502C for 18 hours. The reaction mixture is cooled to ambient temperature, and bromocresol green (1Omg) and sodium cyanoborohydride (0.17g, 2.7Omol) are added to it. Add drop by drop methanol, saturated with HCIII (gaseous), until iF) obtaining a stable yellow color of the mixture. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography with elution of 575 diethyl ether in dichloromethane and chromatographed with NRI C (column UMO 005-A, 0.46X5 cm, gradient 5-9595 0.196 TEA/water and 0.190

TEA/acetonitrile, 3.Oml/min., detection at a wavelength of 214nm), obtaining the compound of Example 8 (35mg, 2195) as a light pink solid. "H NMR (as-YOM50): 9.31 (b, 1H), 8.77 (b, 1H), 7.21 (a, o-8.6Hz, 2H), 6.75 (a, 9U- 8.6Hz, 2H), 6.49-6.46 (t, 2H), 6.47 (aa, 0-2.4Hz, 8.7Hz, 7H), 4.93 (v, 1H), 65 3 ,40-3 32 (t, 1H), 2.45-2.37 (t, 1H), 2.19-2.14 (t, 1H), 1.78-1.40 (t, 5H), 1.35-1.26 (ip, 1H), 1.20-1-07 (t, 1H), 1.02-0.83 (t, 2H). M5 calculated 310.2; M5 (M-1 ) 309.2.

Example 9

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-8-methoxy-cyclopentyl 3,4-dihydro-2H-1-benzopyran

BUT this is "sn, it is 2 racemic compounds

To a solution of Intermediate 63 (0.12g, 0.2bmmol) in anhydrous methanol (15ml) is added p-toluenesulfonic acid (12mg, 0.20mmol), and the resulting solution is heated at 502C for 18 hours. Cool the reaction mixture to ambient temperature, and add bromocresol green (1mg) and 75% sodium cyanoborohydride (0.08g, 1.30mmol). Methanol, saturated with NSII (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 4095 ethyl acetate in hexane to give the compound of Example 9 (37 mg, 4695) as a light yellow solid. "H NMR ad-acetone): 8.25 (p5, 1H), 7.90 (rev, 71H), 7.32 (4, 9-8.3Hz, 2H), 6.85 (a, 9-2 , IHz, 2H), 6.30 (a, y-2.7Gu, 1), 6.24 (a, 0-24Hz, 7H), 4.94 (a, 0-2.3Hz, 1H), 3 .74 (in, ZN), 344-340 (t, 1H), 2.69-2.62 (t, 1H), 2.18-2.10 (t, 1H), 1.85-1.69 (t, 1H), 1.59-1.55 (t, 1H), 1.49-1.41 (t, 2H), 1.39-1.33 (t, 1H). M5 calculated 312.2 ; M5 (M-1) 311.2. p

Example 10 Fr

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-11,11-dimethyl-cyclopentylisi3,4-dihydro-2H-1-benzopyran ne yl (Se) o s on F . . - racemic sum

To a solution of Intermediate 64 (40mg, 0.09mmol) in anhydrous methanol (10ml), p-toluenesulfonic acid (45mg, 0.7mmol) is added, and the resulting solution is heated at 502C for 18 hours. The reaction mixture is cooled to ambient temperature, and bromocresol green (1mg) and sodium cyanoborohydride (27mg, 0.4 mmol) are added to it. Methanol, saturated with NOSI (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After the final color change is achieved, the mixture is stirred again

Ghana within an hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and chromatographed using a chromatotron (1 mm plate) eluting with 3090 ethyl acetate in hexane to give the compound of Example 10 (1 mg, 5990) as a light pink solid. IN NMR avd-acetone): 8.20 (85, 71Н), 7.80 (в, 1), 7.28 (а, 9-8.2Hz, 2Н), 6.84 (а, -И У- 8.6Hz, 2H), 6.72 (a, 92-8.6Hz, 71H), 6.64 (a, 0-32Hz, 1H), 6.60 (aa, 9-3Hz, 8.bHz, 1H ), 4.73 (a, 9-2.7Hz, 1H), 3.04-2.98 (t, 2H), 1.64-1.59 (t, 1H), 1.43-1.37 (t, 2H), 1.25-1.20 (t, 1H), 1.19 (in, ЗН), 0.53 (in, ЗН). - M5 is calculated as 310.2; M5 (M-1) 309.2.

Te) Example 11 with 50 Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-11.11-diethyl-cyclopentylisi3,4-dihydro-2H-1-benzopyran nn sn,

F.

Gu iv; o o ih) yu . racemic mixture bo To a solution of Intermediate 65 (0.21g, 0.57mmol) in anhydrous methanol (10ml) add p-toluenesulfonic acid (31mg, 0.48mmol), and heat the resulting solution at 502C for 18 hours. The reaction mixture is cooled to ambient temperature, and bromocresol green (1mg) and sodium cyanoborohydride (15mg, 2.400mmol) are added to it. Methanol, saturated with NSII (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and chromatographed using a chromatotron (plate 2 mm) eluting with 3090 ethyl acetate in hexane to give the compound of Example 11 (5mg, 2690) as a light pink solid. IN NMR (meOb): 7.20 (a, 2-8.2Hz, 2), 6.75 (a, 9-8.2Hz, 2H), 6.70 (a, 20-8.2Hz, 1) . 9-10.5Hz, 1), 2.92-2.83 (t, 1H), 1.61-1.53 (t, 2H), 1.49-1.20 (t, 5H), 1, 05-0.95 (t, 4H), 0.50 (th O-8.8Hz, ZN). M5 calculated 338.2; M5 (M-1) 337.2.

Example 12

Preparation of ()-2-(4-hydroxyphenyl)-6-methoxy-cyclopentylisi3,4-dihydro-2H-1-benzopyran o i? io racemic mixture

p-toluenesulfonic acid (47mg, 0.75mmol) was added to a solution of Intermediate 6b (0.40g, 1.00mmol) in anhydrous methanol (20ml), and the resulting solution was heated at 502С for 18h. Cool the reaction mixture to ambient temperature, and add bromocresol green (1mg) and sodium cyanoborohydride (0.31g, 5.000mmol). Methanol, saturated with NSII (gaseous), is added drop by drop until a stable yellow color of the mixture is obtained. After reaching the final color change, the mixture is stirred for another hour. The reaction is quenched with saturated sodium bicarbonate solution, ethyl acetate is added to the mixture, and the organic layer is washed with sodium bicarbonate solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 4095 ethyl acetate in hexane, obtaining the compound of Example 12 (0.15 g, 5195) as a light purple solid. "H NMR and 9) (SOCI3): 7.33 (a, 9-8.2 Hz, 2H), 6.85-6.82 (t, 3H), 6.72-6.66 (t, 2H), 5.27 (in, 1), 5.05 (4, 9-2.0 Hz, 1H), 3.79 (8, ЗН), 3.50-3.45 (t, 1H), 2.58- 2.54 (t, 1H), 2.19-2.11 (t, 1H), 1.84-1.79 (t, 2H), 1.67-1.58 (t, 1H), 1, 55-1.68 (t, 2H). M5 calculated 296.1; M5 (M-1) 295.1. He)

Example 13

Preparation of ()-2-(4-hydroxy-3-methylphenyl)-6-hydroxy-cyclopentyl)3,4-dihydro-2H-1-benzopyran sono F cha on riacemic mixture

To a solution of Intermediate 67 (0.51g, 1.10mmol) in anhydrous methanol (15ml) while bubbling with gaseous nitrogen in order to remove oxygen, toluenesulfonic acid (0.17g, 0.8bmmol) is added. solution at 502 for 18 hours under a nitrogen atmosphere. Bromocresol green (approximately mg) and sodium cyanoborohydride (0.35 g, 5.500 mmol) are added to the reaction mixture at ambient temperature. Methanol saturated with HCI (gaseous) is added in portions, during which time so as to maintain the yellow color of the mixture. After cessation of the spontaneous color change to blue, the mixture is partitioned between diethyl ether and saturated aqueous sodium potassium tartrate solution. The organic layer is dried over - sodium sulfate, concentrated in vacuo and subjected to flash chromatography on silica gel with elution 390 -I of diethyl ether in methylene chloride, obtaining 0.11 g (3495) of a mixture of cis- and trans-stereoisomers (3:2).

By reverse-phase chromatography on a C18 column with gradient elution with acetonitrile and water with an admixture of 0.196 TEA, 10 mg (395) of the cis-condensed compound according to Example 13 were obtained. ), 8.81 (in, 1H), 7.10 (in, 1H), 7.03 (a, 9U-8.2Hu, 1H), 6.74 (a, 9-82Hutz, 1H), 6, 63 (a,

U-8.2Hz, 1H), 6.55 (a, 9-2.8Hz, 1H), 6.47 (aa, 9-2.7Hz, 8.2Hz, 1H), 4.95 (v, 1H ), 3.37 (t, 1H), 2.55 (t, 1H), s 2.12 (v, ЗН), 2.02 (t, 1H), 1.65-1.24 (t, 5H ). M5 calculated 296.3; M5 (M-1) 295.1.

Example 14 cv Preparation of ()-2-(4-hydroxy-3-methylphenyl)-6-hydroxy-cyclopentyl)3,4-dihydro-2H-1-benzopyran

GF! no t o sia, 60 on racemic mixture

The fraction containing the trans-condensed product is subjected to repeated reversed-phase chromatography on a C18 column eluting with a mixture of acetonitrile and water (40:60) and 8.2 mg (2965) 65 of the trans-condensed compound according to Example 14 are obtained. -ав): 9.05 (85, 1Н), 7.10 (в, 1Н), 7.03 (а,

U-8.2Hz, 1), 6.74 (a, 0-8.2Hz, 1H), 6.62-6.55 (t, 2H), 6.47 (aa, 9-2.7Hz, 8 ,2Hz, 1), 4.13 (a, 9-11.0Hz,

1H), 2.95 (t, 1H), 2.43 (t, 1H), 2.20 (t, 1H), 2.12 (v, ZH), 1.70-1.40 (t, 4H ), 1.17 (t, 1H).

Example 15

Preparation of ()-2-(2-methyl-4-hydroxyphenyl)-6-hydroxy-cyclopentyl)3,4-dihydro-2H-1-benzopyran by

It is a racemic mixture

To a solution of Intermediate 68 (0.31g, 0.70mmol) in anhydrous methanol (15ml) while bubbling with gaseous nitrogen to remove oxygen, p-toluenesulfonic acid (0.10g, 0.52mmol) was added. The bubbling is stopped, and the resulting solution is heated at 502C for 18 hours in a nitrogen atmosphere. Bromocresol green (approximately mg) and sodium cyanoborohydride (0.22g, C, 5mmol) were added to reaction mixture 75 at ambient temperature. Methanol saturated with NH (gaseous) is added in portions over a period of time so as to maintain the yellow color of the mixture. After stopping the spontaneous color change to blue, the mixture is partitioned between diethyl ether and water. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography on silica gel eluting with 395 diethyl ether in methylene chloride, obtaining 0.07 g of crude product. By reverse-phase chromatography on a C18 column with gradient elution with acetonitrile and water with an admixture of 0.195 TPA followed by lyophilization, 17 mg (8905) of the compound according to Example 15 was obtained in the form of a red gummy substance. "H NMR (0OM5O-dv): 9.21 (c, 1H), 8.83 (8, 1H), 7.26 (a, U-8.0Hz, 1), 6.60 (a, 9- 7.6HzC, 2H), 6.56 (v, 2H), 6.47 (aa, 9-7.6Hz, 2.8Hz, 2H), 5.04 (85, 1H), 3.42 (t, 1H), 2.50 (t, 1H), 2.19 (v, ЗН), 2.07 (t, 1H), 1.64-1.18 (t, 5H). Gee!

Preparatory synthesis 69 o so; oh so

The synthesis is carried out (as described in Teiggapeadgop, 53, 39, 1997, pp. 13329-13338). A solution of 4-methoxyphenol (7.5 g, 60.67 mmol) in sulfuric acid (12 mL, 121.3 mmol) and TEA (9.0 mL, 121.3 mmol) is cooled to 02C and methyl 2-oxocyclopentane carboxylate (17, 25g, 121.3mmol). The mixture is stirred at ambient temperature for 48 hours. The mixture is poured into a saturated solution of sodium bicarbonate, ensuring the final M main reaction of the mixture, then ethyl acetate is added, and the mixture is washed with 1-n. sodium hydroxide solution and brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 10095 dichloromethane. The resulting crude product was precipitated from a mixture of dichloromethane and hexane to give Intermediate 69 (1.84 g, 1795) as a light yellow solid. "H" 20 NMR (SOSIZU 725 (a, 9-7.3Gu, 1H), 7.03 (aa, 9-2.9Gu, 8.8Gu, 1H), 6.82 (94, 9-2.9Hz . ), 2.23-2.15 (t, 2H). M5 calculated 216.1; M5 (M-n1) 217.1.

Preparative synthesis of 70 and their oto - I A solution of phenol (5.0 g, 53.1 mmol) in 80905 sulfuric acid (bOml) is cooled to 09C and methyl 2-oxocyclopentane carboxylate (18.88 g, 133.97 mmol) is added. Stir the mixture at ambient temperature for 48 hours. The mixture is poured into a saturated solution of sodium bicarbonate, ensuring the final (ee) 50 main reaction of the mixture, then ethyl acetate is added, and the mixture is washed with 1-n. sodium hydroxide solution and

F brine. The organic layer is dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 10095 dichloromethane. The resulting crude product was precipitated from a mixture of dichloromethane and hexane to give Intermediate 70 (1.32 g, 1395) as a white solid. "H NMR (SOCI3): 7.46-7.40 (t, 2H), 7.35-7.32 (t, 1H), 7.26-7.22 (t, 1H), 3.09- 3.4 (t, 2H), 2.93-2.88 (t, 2H), 2.24-2.18 (t, 2H). M5 calculated 186.1; M5 (M.-1) 1871. o Preparatory synthesis 71 names) povi 60 no o

A solution of methylhydroquinone (4.09g, 33.00mmol) in 80905 sulfuric acid (4AOml) is cooled to 09 and methyl 2-oxocyclopentane carboxylate (11.70g, 82.50mmol) is added. Stir the mixture at ambient temperature for 48 hours. The mixture is poured into a saturated solution of sodium bicarbonate, ensuring the final basic reaction of the mixture, then ethyl acetate is added, and the mixture is washed with 1-n. sodium hydroxide solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude solid product is dissolved in 1-n. Mason, washed with diethyl ether and precipitated from the aqueous layer of 1-n. NSI The mixture was filtered to give Intermediate 71 (3.10 g, 4395) as a yellowish-brown solid. "H NMR (d6-0M50): 9.61 (in, 1H), 7.11 (5, 1H), 6.78 (in, 1H), 2.67 (5 9U-64Hz, 7.93Hz, 4H ), 2.15 (v, ZN), 2.08-2.01 (t, 2H). M5 calculated 216.1; M5 (M.n1) 2171.

Preparatory synthesis 72 sho oo

A solution of hydroquinone (3.10g, 28.17mmol) in 8095 sulfuric acid (4AOml) is cooled to 09C, and methyl 2-oxocyclopentane carboxylate (10.00g, 70.42mmol) is added. Stir the mixture at ambient temperature /5 Environment for 9 days. The mixture is poured into ice water and filtered. The solid product is dissolved in methanol and concentrated in vacuo. The solid product is dissolved in chloroform, filtered while hot and concentrated in vacuo. The filtrate is chromatographed with elution of 490 methanol in chloroform, and obtained

Intermediate 72 (1.10g, 1995) as a light yellow solid compound. "H NMR (d6-OM50): 9.67 (in, 1U, 7.23 (a, o-8.8Hz, 1), 6.95 (da, 9-2.9Gu, 8.8Hz, 1) , 6.84 (a, 0-24Hz, tn), 2.98 (5 9U-6.8Hz, 8.3Hz, 20. 2H), 2.71 (6 9-7.3Hz, 7.3Hz, 2H ), 2.10-2.02 (t, 2H). M5 calculated 202.2; M5 (M-n1) 203.2.

Pshpotovchii synthesis 73

RK is not about sch

X s si o n, sn, -

A solution of 4-bromophenol (25.00 g, 144.5 mmol), tert-butyldimethylsilyl chloride (23.96 g, 158.95 mmol) and imidazole (10.82 g, 158.95 mmol) in anhydrous DMF (200 ml) was stirred for 18 h. Add diethyl ether, wash with water and brine, and dry the organic layer over sodium sulfate. Concentrate in vacuo and ee, subject to flash chromatography eluting with 1095 ethyl acetate in hexane, obtaining Intermediate 73 ee) (40.98g, 9995) as a clear oil. IN NMR (SOSIz): 7.24 (a, o-8.8GHz, 2), 6.73 (a, uU-8.8Hz, 2H), 0.99 o (5, 9H), 0.20 ( in, 6H).

Preparatory synthesis 74 i- ne ma i -

Solution of Intermediate 71 (2.20g, 10.19mmol), tert-butyldimethylsilyl chloride (2.30g, 15.28mmol) and imidazole (1.04g, 15.28mmol) ) in anhydrous DMF (200 ml) is stirred for 18 hours. Add diethyl ether, wash with water and brine, and dry the organic layer over sodium sulfate. Concentrate in vacuo and flash chromatograph eluting with 2095 ethyl acetate in hexane to give Intermediate 74 (3.33g, 9995) in this. in the form of a white solid. IN nMR (SOCI3): 7.16 (v, 1H), 6.75 (85, 1H), 3.04-3.00 (t, 2H), 2.98-2.90 (t, -i 2H ), 2.29 (in, ЗН), 2.25-2.20 (t, 2Н), 1.04 (in, 9Н), 0.24 (in, 6Н). c Shotovchii synthesis 75 tone oi I

Phew

A solution of Intermediate 73 (2.04g, 7.11mmol) in anhydrous THF (25ml) is cooled to -782C, and t-butyllithium (1.3M in cyclohexane, 5.5ml, 7.11mmol) is added dropwise. . Stir the solution at -182C for 15 minutes, and use it without additional purification. dk Preparatory synthesis 76 bo 3-3 em,

To a solution of Intermediate 72 (0.90g, 4.45mmol) and imidazole (0.45g, 6.6mmol) in anhydrous DMF

(15ml) is added with stirring tert-butyldimethylsilyl chloride (1.00g, 6.6vmmol). The resulting solution is stirred for 48 hours, then quenched with a saturated solution of sodium bicarbonate. Add diethyl ether, wash with brine, dry the organic layer over sodium sulfate and concentrate in vacuo. The resulting crude product was chromatographed eluting with 1095 ethyl acetate in hexane to give Intermediate 76 (1.01 g, 7295) as a white solid. "IN YaYaMeR (SOSIz): 7.24 (a, yu-44gu, tn), 6.96 (aa, 9-2.9Hz, 9.3Gu, 1H), 6.82 (a, 9-2.5Hzu , 1H), 3.03 (t, 2H), 2.93 (t, 2H), 2.20 (t, 2H). M5 calculated 314; M5 (M-n1) 315. nor sn, ' sn,

A solution of Intermediate 76 (0.50 g, 1.58 mmol) in anhydrous dichloromethane (30 mL) is cooled to -789C, isobutylaluminum hydride (1.0 M in toluene, 1.8 mL, 1.8 mmol) is added and stirred for 1 h. The mixture is quenched with methanol (5.00 ml) and heated to ambient temperature. Ethyl acetate is added to the mixture, and washed with bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting foam is dissolved in anhydrous THF (10 ml) and cooled to -782C. They add

Intermediate 75 (0.21M, 22.5ml, 4.74mmol) and stirred for 1h. Add 1-n. NSI (5 Oml), heated to ambient temperature and stirred for ЗОхв. Ethyl acetate is added to the mixture, and it is washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford Intermediate 77 (0.81 g, 10095) as a red oil. This product is used at the next stage without further purification.

Example 16

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentylisi3,4-dihydro-2H-1-benzopyran (Ce) pso ce Ge)one y- racemic sumiyn y-

A solution of Intermediate 77 (0.81g, 1.58mmol) and tetrabutylammonium fluoride (10M in THF, 6b,3ml, 6.32mmol) in THF (20ml) was stirred at ambient temperature for 30min, then 1-n was added. NSI (7ml), and stir for 5 minutes. Ethyl acetate is added to the mixture, it is washed with a saturated solution of /-"F bicarbonate and brine, the organic layer is dried over sodium sulfate and concentrated in vacuo. The crude C product is subjected to flash chromatography eluting with 595 methanol in dichloromethane. The obtained product c is dissolved in methanol (1Oml), 595 palladium on carbon (bOmg) and ammonia solution (2.0M in methanol,

I" 0.25 mmol, 0.1 ml), set an elastic chamber with hydrogen on the reaction vessel, and stir the mixture at ambient temperature overnight. The mixture is filtered through a layer of celite, concentrated in vacuo and subjected to flash chromatography eluting with 1095 of diethyl ether in dichloromethane, obtaining compound -1 79 of Example 16 (4Omg, 1095) as a light pink solid. "H NMR (MeOb): 7.19 (a,

U-8.8Hz, 2H), 6.75 (a, 9-8.3Hz, 2H), 6.62 (t, 2H), 6.47 (aa, 9-2.9Hz, 8.8HzC, 1H ), 4.14 (a, 9-11.3 Hz, 1H), 3.00 -I (t, 1H), 2.48 (t, 1H), 2.28 (t, 1H), 1.70 ( po, 2H), 1.56 (t, 2H), 1.28 (t, 1H). M5 calculated 282; M5 (M.-1) 283. so Preparatory synthesis 75

Fo 22 and 42) and) o

F) sn, racemic mixture in Solution of Intermediate 69 (0.76g, 3.52mmol) in anhydrous dichloromethane (bOml) is cooled to -789С, diisobutylaluminum hydride (1.0M in toluene, Z, Uml, 3.87mmol) is added , and stir for 2 hours. The mixture is quenched with methanol and heated to ambient temperature. Ethyl acetate is added to the mixture, and washed with bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting foam is dissolved in anhydrous THF (1 Oml) and cooled to 02. Add magnesium aromatic 65 reagent (0.51 M, 3.bml, 1.84 mmol) and stir for 100 min. Add 1-n. NSI (5 Oml), heated to ambient temperature and stirred for 30 min. Ethyl acetate is added to the mixture, and it is washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography eluting with 5095 dichloromethane in hexane to give Intermediate 78 (0.33g, 3090) as a red oil. IN nMR (SOCI3): 7.33 (a, 9-8.3Hz, 2H), 6.89 (a, o-8.8Hz, 2H), 6.80 (a, 8.8Hz, 1H), 6.68 -6.63 (t, 2H), 5.04 (4, 9-2.5HZ, 1H), 3.80 (in, ЗН), 3.75 (in, ЗН), 3.47-3.43 (t, 1H), 2.60-2.54 (t, 1H), 2.14-2.09 (t, 1H), 1.82-1.76 (t, 1H), 1.67-1 .57 (t, 1H), 1.50-1.30 (t, ZN). p

S schi and

A solution of Intermediate 70 (0.44g, 2.37mmol) in anhydrous dichloromethane (40ml) is cooled to -789C, diisobutylaluminum hydride (1.0M in toluene, 2.8ml, 2.84mmol) is added and stirred for 2 hours. The mixture is quenched with methanol and heated to ambient temperature. Ethyl acetate is added to the mixture, and washed with bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting foam is dissolved in anhydrous THF (1 Oml) and cooled to -782C. Add Intermediate 75 (0.21M, C35.5ml, 7.11mmol) and stir for 10 minutes. Add 1-n. NSI (5 Oml), heated to room temperature and stirred for ЗОхв. Ethyl acetate is added to the mixture, and it is washed with brine. The organic layer is dried over sodium sulfate and concentrated in vacuo to give (o)

Intermediate 79 (0.40g, 4395). This product is used at the next stage without additional purification. "H NMR (MeOb): 7.25-7.18 (t, 2H), 7.1-7.08 (t, 2H), 6.91-6.83 (t, 2H), 6.80- 6.75 (t, 2H), 4.90 (t, 2H), 3.35-3.31 (t, 1H), 2.81-2.60 (t, ZN), 2.28-2, 17 (t, 1H), 1.98-1.90 (t, 2H), 1.00 (v, 9H), 0.24 (v, 6H). "o zo M5 calculated 396.2; M5 (M -1) 395.4.

Preparatory synthesis of 80 sos, Ф cha ох сн, а - not o 2 сн, он re « no З s A solution of Intermediate product 74 (1.00g, 3.0Zmmol) in anhydrous dichloromethane (bOml) is cooled to -789С, in» add isobutylaluminum hydride (1.0 M in toluene, 3.5 mL, 3.6 mmol), and stir for 2 hours. The mixture is quenched with methanol and heated to ambient temperature. Ethyl acetate is added to the mixture, and washed with bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting foam is dissolved in anhydrous THF (1 Oml) and cooled to -78 C. Intermediate and product 75 (0.21 M, 45.4 ml, 9.09 mmol) are added and stirred for 10 min. Add 1-n. NSI (5 Oml), heated to -1 ambient temperature and stirred for 30 min. Ethyl acetate is added to the mixture, and it is washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give intermediate 80 (0.51 g, 99905) as a red oil. This product is used on the following

Go) 20 stages without additional cleaning. IN NMR (SOCIz): 7.30 (a, u-8.2Hz, 2H), 6.87 (a, 9-8.6Hz, 2H), 6.70 (v, 1H), 6.60 (85 , 1H), 5.50 (85, 1H), 4.99 (in, 2H), 2.93-2.69 (t, 4H), 2.38-2.32 (t, 1H), 2, 28 (in, ZN), 2.09-1.95 sh (t, 2H), 1.09 (in, 9H), 1.08 (in, 9H), 0.32 (in, 6H), 0, 22 (8, 6H). M5 calculated 540.3; M5 (M-1) 5391. vol

F) ime) 60 9 rapemic mixture b5 o. at 70 pm, racemic mixture

A solution of Intermediate 78 (0.33g, 1.07mmol) and palladium on carbon 596 (333mg) in methanol (50ml) is shaken in a Parr apparatus under hydrogen pressure (60 psig, 414kPa) at ambient temperature of 72 overnight. The reaction mixture is purged with nitrogen, filtered through a layer of Celite and concentrated in vacuo. The resulting oil was subjected to flash chromatography eluting with 6096 dichloromethane in hexane to give Intermediate 81 (9Omg, 27965) and Intermediate 82 (5Omg, 1595) as pale pink solids.

Intermediate product 81 - "H NMR (SOCIz5): 7.35 (4, 9U-8.6Hz, 2H), 6.90 (4, uU-8.6Hz, 2H), 6.81 (a, uU-8 ... ), 3.47-3.43 (t, 1H), 2.58-2.52 (t, 1H), 2.17-2.08 (t, 1H), 1.83-1.76 (t , 1H), 1.69-1.58 (t, 1H), 1.52-1.35 (t, ЗН). M5 calculated 310.2; M5 (M.-1) 311.2.

Intermediate product 82 - "H NMR (SOSIv): 7.31 (4, 9-8.6Hz, 2H), 6.90 (a, 9U-8.7Hz, 2H), 6.82 (4, 9-8 ... 8HZ, yin), 3.80 (5, ZN), 3.75 (v,

ZN), 3.12-3.06 (t, 1H), 2.58-2.50 (t, 1H), 2.37-2.28 (t, 1H), 1.78-1.70 ( t, 2H), 1.63-1.55 (t, 2H), 1.34-1.23 sch (t, 1H). M5 calculated 310.2; M5 (M'1) 311.2. heh)

Example 17

Preparation of ()-2-(4-hydroxyphenyl)-cyclopentyl)3,4-dihydro-2H-1-benzopyran (Se) so o (22) racemic mixture

Example 18

Preparation of ()-2-(4-hydroxyphenyl)-cyclopentyl)3,4-dihydro-2H-1-benzopyran, a racemic mixture

A solution of Intermediate 79 (0.40g, 1.01mmol) and tetrabutylammonium fluoride (10M in THF, 1.1Tml, and 1.1O0mmol) in THF (5ml) is stirred at ambient temperature for 30 minutes, then - 1 -N. NS (5 ml) and stir for 5 min. Ethyl acetate is added to the mixture, it is washed with saturated bicarbonate solution and brine, the organic layer is dried over sodium sulfate and concentrated in vacuo. The crude (Ce) product is dissolved in methanol (1Oml) and ammonia solution (2.0M in methanol, 0.2bml, 0.52mmol) is added. Add 590 bo 50 palladium on carbon (ZOmg), install an elastic chamber with hydrogen on the reaction vessel, and stir the mixture at ambient temperature overnight. The mixture is filtered through a layer of celite, concentrated in 4) vacuum and subjected to flash chromatography with elution of 295 diethyl ether in dichloromethane, obtaining compounds according to Examples 17 and 18 in the form of foamed substances of light pink color.

Example 17 - "H NMR (d5-0OM50): 9.41 (in, 1H), 7.24 (a, U-8.6Hz, 2H), 7.10 (a, 9-7.5Hz, 1H) , 7.02-6.99 (t, 1H), 6.87-6.80 (t, 2H), 6.73 (a, 9-8.6Hz, 2H), 5.02 (8, 1H) , 3.42-3.38 (t, 1H), 2.55 (t, 1H), 2.11-2.01 (t,

He) 1H), 1.79-1.71 (t, 1H), 1.58-1.49 (t, 1H), 1.42-1.25 (t, ЗН). M5 calculated 266.2; M5 (M-1) 265.2.

Example 18 - "H NMR (0d5--OM50): 9.42 (in, 1H), 7.22 (a, 9-7.0Hz, ЗН), 7.04 (5 9-7.4Hz, 7, 9Hz, 1H, 6.86 o (6 9-7.4Hz, 7.4Hz, 1H), 6.76-6.73 (t, ZN), 4.25 (a, I-11.00Hz, 71H) , 3.05-2.98 (t, 1H), 2.48-2.41 (t, 1H), 2.35-2.22 (t, 1H), 1.68-1.22 (t, 2H), 1.56-1.48 (t, 1H), 1.21-1.13 (t, 1H). M5 calculated 266.2; M5 (M-1) 265.2. 6o Example 19

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-7-methyl-cyclopentyliso3,4-dihydro-2H-1-benzopyran b5

It is a rapemic mixture

Example 20

Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-7-methyl-cyclopentyl)3,4-dihydro-2H-1-benzopyran and its racemic sum

A solution of Intermediate 80 (0.42g, 0.78mmol) and tetrabutylammonium fluoride (10M in THF, 1.bml, 1.63mmol) in THF (20ml) is stirred at ambient temperature for 30 minutes, then 1-N, NS (7 ml), and stir for 5 min. Ethyl acetate is added to the mixture, it is washed with saturated bicarbonate solution and brine, the organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product was subjected to flash chromatography eluting with 6095 ethyl acetate in hexane. The obtained product is dissolved in methanol (1Oml), 595 palladium on carbon (bOmg) is added, an elastic chamber with hydrogen is installed on the reaction vessel, and the mixture is stirred at ambient temperature overnight. The mixture is filtered through a layer of Celite, concentrated in vacuo and subjected to flash chromatography eluting with 395 g of methanol in (He) dichloromethane, obtaining the compounds of Examples 19 and 20 as light pink solids.

Example 19 - "H NMR (MeOb): 7.24 (a, 9-9.0Hz, 2H), 6.77 (a, 9-9.3Hz, 2H), 6.56 (c, 1H), 6 .54 (in, 1H), 4.92 (a, 9-1.6Hz, 1H), 3.39-3.31 (t, 1H), 2.58-2.49 (t, 1H), 2 ,15-2.03 (t, 4H), 1.79-1.71 (t, 1H), 1.63-1.52 (t, 1H), 1.49-1.28 (t, ЗН) M5 is calculated as 296.1, M5 (M-1) is 295.1, etc.

Example 20 - "H NMR (MeO0b): 7.22 (a, U-8.6Hz, 2H), 6.78 (a, 9-8.7Hz, 2H), 6.59 (c, 1H), 6 .52 (in, 1), 00 4.17, (10.95 1), 3.01-2.92 (t, 1H), 2.56-1.45 (t, 1H), 2.31- 2.22 (t, 1H), 2.10 (v, ЗН), 1.78-1.62 (t, 2H), 1.59-1.50 (t, 2H), 1.33-1, 25 (t, 1H). M5 calculated 296.1; M5 (M-1) 295.1. F

Preparatory synthesis 53 - i - oo « du A solution of hydroquinone (6b.0g, 54.4Ommol) in 8095 sulfuric acid (2O0ml) is cooled to 09 and ethyl 2-oxocyclohexane carboxylate (19.48g, 114.4Ommol) is added. Stir the mixture at ambient temperature for 24 hours. The mixture is poured into ice water, and the solid phase is separated by filtration under 1" vacuum. The separated solid product is washed with a large amount of water. The solid product is dissolved in a mixture of 496 methanol and chloroform and subjected to flash chromatography (silica gel, elution with a gradient of 2-5906 MeonN in

СНоСИ»), obtaining Intermediate 83 (3.40 g, 2995) as a yellowish amorphous solid. TN NMR -I (y6-0M5O): 9.59 (v, 1H), 7.13 (arr 4, 9-9.7Hz, 1H), 6.89-6.92 (t, 2H), 2, 62-2.65 (t, 2H), 2.33-2.36 (t, 2H), 1.64-1.74 (t, 4H); M5 (IZ) t/e 217 (M.n1). 7 Preparatory synthesis of А4 se) оо, and З со not CH

F d o

A solution of Intermediate 83 (2.82g, 13.0bmmol), tert-butyldimethylsilyl chloride (2.95g, 19.58mmol), o-imidazole (1.78g, 26.11mmol) and 4-(dimethylamino)pyridine (0, 32 g, 2.61 mmol) in anhydrous DMF (75 ml) is stirred at ambient temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate is added and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine, dried (sodium sulfate) and evaporated to give a light yellow solid. The resulting product was purified by flash chromatography (silica gel, eluting with a gradient of 10-2095 diethyl ether in hexane) to give Intermediate 84 (3.80 g, 8890) as a white solid. "H NMR (SOCIz): 7.35 (a, 9-2.93Hz, 1H), 7.06 (a, 9U-8.80Hz, 1), 6.90 (da, 4-9.29Hz, 2 .94Hz, 1), 2.44 (5 2-6.36Hz, 2H), 2.36 (i 9U-6.36Hz, 2H), 1.62-1.66 (t, 2H), 1.52 -1.57 (t, 2H), 0.78 (c, b5 9H), 0.00 (c, 6H); M5 (IB) t/e 331 (M--1).

t- sn, kaoveo

I AN, b "on on; lion, not sleep,

A solution of Intermediate 84 (1.00 g, C, 0 Mmol) in anhydrous tetrahydrofuran (C5 mL) is cooled to -7182C, and a 1.0 M solution of diisobutylaluminum hydride in toluene (3.48 mL, 3.48 mmol) is added dropwise so that the mass temperature did not exceed -652C. Stir the mixture at -782C for 3.5 hours. Quench the mixture 12 with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium-potassium tartrate, and then heat the resulting mixture to ambient temperature. The obtained aqueous mixture is extracted with ethyl acetate. The combined extracts are washed with a saturated aqueous solution of sodium-potassium tartrate and brine, dried (sodium sulfate) and concentrated in vacuo. The obtained white crystalline substance is dissolved in anhydrous

THF (ZOml). The solution is added drop by drop with stirring during ЗОхв. to a solution of Intermediate 75 (8.91 mmol) in anhydrous THF (18 ml) cooled to -782C. Stir the mixture at -782C for 1.5 hours. Add water (50 ml) and a saturated aqueous solution of sodium bicarbonate (50 ml), then heat the mixture to ambient temperature and stir for 30 minutes. The obtained aqueous mixture is extracted with diethyl ether and then with ethyl acetate. The combined extracts are washed with a saturated aqueous solution of sodium-potassium tartrate, water and brine, dried (sodium sulfate) and concentrated in vacuo. The product obtained from 29 was purified by flash chromatography (silica gel, elution with a gradient of 25-6095 ethyl acetate in hexane), and he) obtained Intermediate 85 (1.10 g, 6795) as a yellowish foamy solid. M5 (IZ) t/e 539 (M-1).

Preparatory synthesis 86 so so (22) o ! them he and -

Racemic mixture

A solution of Intermediate 85 (0.89g, 1.65mmol) and tetrabutylammonium fluoride (1.0M in THF, 3.46bml,

34bmmol) in THF (25ml) is stirred at ambient temperature for 1 hour, then TEA (0.65ml, 8.2mmol) is added and stirred for 4h. The reaction mixture is poured into a cooled container with a saturated aqueous solution of sodium bicarbonate. The obtained aqueous mixture is extracted with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Unrefined product

And" are subjected to flash chromatography (silica gel, elution with a gradient of 25-5095 ethyl acetate in hexane), and obtain

Intermediate 86 (410mg, 8595). Me(I5) t/e 295 (M'-1).

Example 21 -I Preparation of ()-2-(4-hydroxyphenyl)-6-hydroxy-cyclohexylis)3,4-dihydro-2H-1-benzopyran -I se) o 50 o on m, i rapemic mixture

Dissolve Intermediate 86 (38Omg, 1.30 mmol) in methanol (17 mL), add 2.0 M ammonia in methanol (0.32 mL, 0.65 mmol) and 5905 palladium on carbon (225 mg). An elastic chamber with hydrogen is placed on the reaction vessel, and the mixture is stirred at ambient temperature overnight. The mixture is filtered through a layer of Celite, concentrated in vacuo and subjected to flash chromatography (silica gel; elution with a gradient of 25-4595 ethyl acetate in hexane) to obtain the compound of Example 21 (190 mg, 5095) as a light pink solid foam. 60 Example 21 - "H NMR (OM5O-yv): 9.30 (b, 1H), 8.77 (b, 1H), 7.16 (a, 9-8.60 Hz, 2H), 6.73 ( a, 9-8.60Gu, 2H), 6.67 (arr 4, 9-2.35Hz, 1H), 6.63 (a, 9U-8.60Hzc, 1H), 6.49 (arr aa, 92 -9.00Hz, 2.74Hz, 1H), 4.99 (v, 1H), 3.29-3.34 (t, 1H), 2.24-2.28 (t, 1H), 1.89 -1.94 (t, 1H), 1.59-1.65 (t, 1H), 1.47-1.56 (t, 1H), 1.33-1.39 (t, 1H), 0 ,90-1,12 (to, 4H). M5 (IZ) t/e 295 (M-1).

Example 22 b5 Preparation of ()-2-(4-methoxyphenyl)-6-methoxy-cyclopentyl)|3,4-dihydro-2H-1-benzopyran -BO0-

oz z rhecemic mixture

See Preparatory synthesis 81.

Example 23

Preparation of ()-2-(4-methoxyphenyl)-6-methoxy-cyclopentyl)|3,4-dihydro-2H-1-benzopyran n, o yin, racemic mixture

See Preparatory synthesis 82. sch

Preparatory synthesis 87 ": ге) что (Се) х че ; Е со

Ge; Te (22) racemic mixture; - more Shdgotovchky synthesis 85 te

E Yi

2

Fuck them

Generation of racemic mixtures - 15 A solution of the compound according to Example 1 (0.100g, 0.354mmol) and cesium carbonate (0.287g, 0.8v8mmol) in DMF (5ml) is stirred for 5 minutes. M-phenyltriflamamide (0.136 g, O0.2 mmol) is added in one portion, and the mixture is kept under stirring for 1 hour. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid. The obtained (ee) solid product is purified by flash chromatography (silica gel, eluting with a gradient of 0-10-2595 ethyl acetate in

F hexanes), and give Intermediate 88 (0.038g, 20905) and then Intermediate 87 (0.052g, 3690) separately as white solids.

NR NMR of Intermediate 88 (SOCI3): 7.54 (a, U-8.4Hz, 2H), 7.32 (a, 9-84Hz, 2), 7.11 (a, y-2.8Hz, 1 ), 7.02 (aa, 0-2.8Hz, 9.0Hz, 1), 6.96 (a, 9-9.0Hz, 1), 5.22 (a, 9-2.0Hz, 1) , 3.57 (a 9-2.8Hz, 7.8Hz, 1H), 2.65 (t, 1H), 2.22 (t, 1H), 1.82 (t, 1H), 1.55 ( t, ЗН), 1.38 (t, 1Н).

F) NMR of Intermediate 87 (SOCIz): 7.54 (a, 9-8.0Hz, 2H), 7.29 (a, 9-8.0Hz, 2H), 6.79 (a, uU-8 ... ... ), 2.16 (t, 1H), 1.80 (ho, 1H), 1.53 (t, ЗН), 1.31 (t, 1H). in Example 24

Preparation of ()-2-(4-aminocarbonylphenyl)-6-aminocarbonyl-cyclopentylis1Z3,4-dihydro-2H-1-benzopyran b5

OO chn, racemic mixture

A solution of Intermediate 88 (0.038g, 0.07mmol) and bis(triphenylphosphine)palladium(!!) dichloride (0.003g, 0.0035mmol) in DMSO (ml) and hexamethyldisilazane (0.25ml) was stirred. An atmosphere of carbon monoxide is created in the reaction vessel, and the reaction mixture is heated at 809C for 16 hours. Allow the mixture to cool to room temperature. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water 19 (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid.

The obtained solid product is purified by flash chromatography (silica gel, elution with a gradient of 0-50-8095 ethyl acetate in hexane), and the compound of Example 24 (0.011 g, 4790) is obtained as a white solid.

NR NMR of the compound according to Example 24 (SOCI3): 7.85 (a, 9-8.4Hz, 2H), 7.54 (a, 9-8.4Hz, 2H), 7.10 (a, 9-2, 8Hz, 1), 7.03 (aa, 0-2.8Gu, 8.0Hz, 1), 6.97 (a, 9-8.0HzC, 1), 6.10 (rg 8, 2H), 5.80 (rg 8, 2H), 5.24 (a,

U-1.6Gu, 1H), 3.57 (hy, 9U-7.8Hz, 1H), 2.68 (t, 1H), 2.21 (t, 1H), 1.80 (t, 1H) , 1.53 (t, ZN), 1.34 (t, 1H).

Example 25

Preparation of ()-2-(4-aminocarbonylphenyl)-6-hydroxy-cyclopentylisocyanate, 4-dihydro-2H-1-benzopyran and its io) rt. (Se) 30 . , a chemical mixture

A solution of Intermediate 87 (0.052g, 0.12bmmol) and bis(triphenylphosphine)palladium dichloride!) (0.005Hg, Me)

0.00bmmol) in DMSO (ml) and hexamethyldisilazane (0.25ml) are stirred. An atmosphere of carbon monoxide is created in the reaction vessel, and the reaction mixture is heated at 809C for 16 hours. Allow the mixture to cool to room temperature. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid.

The obtained solid product is purified by flash chromatography (silica gel, elution with a gradient of 0-50-8095 "ethyl acetate in hexane), and the compound of Example 25 (0.022g, 4790) is obtained as a white solid. From 10 IN NMR of the compound according to Example 25 (SOCI3): 7.83 (a, 9-8.2 Hz, 2H), 7.54 (a, 9-8.2 Hz, 2H), 6.79 (a, U- 8.4Hz, c 1), 6.66 (a, 9-2.8Hz, 1), 6.60 (aa, 0-2.8Hz, 8.4Hz, 1H), 5.-6.2 (rg a, 2H), 5.16 (a, 9-2.0HZ, MH), 3.49

Iz" (ab 9-2, oGu, 7.8Hz, 1H), 2.62 (da, 9U-2.0Gu, 8.0Hz, 1H), 2.15 (t, 1H), 1.81 (ip , 1H), 1.42-1.65 (t, ЗН), 1.29 (t, 1H).

Preparatory synthesis 89 no -I x -I

It's 50

F racemic mixture

A solution of the compound according to Example 1 (0.100g, O0.354mmol) and cesium carbonate (0.287g, 0.8v8mmol) in DMF (4ml) was stirred for 5 minutes. Add benzyl chloride (0.045 ml, 0.39 mmol), and keep the mixture under stirring for 4 hours. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate.

The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid. The resulting solid product is purified by flash chromatography (silica gel, elution with a gradient of 0-15-3090 ethyl acetate in hexane), and an inseparable mixture (2:1) of two intermediate monobenzyl ethers is obtained. for TN NMR of the predominant benzyl ether - a component of Intermediate 89: (SOZO0): 7.46 (t, 2), 7.38 (a, 9-8.0 Hz, 2), 7.28-7.41 (t , ZN), 7.01 (a, o-8.0Hz, 2H), 6.72 (a, 9-8.8Hz, tn), 6.64 (a, -2.8Hz, 1), 6, 56 (aa, 9U-2.8Gu, 8.8Гц, 1Н), 5.11 (в, 2Н), 5.02 (а, 9-2.2Гц, 1), 3.47 (i, 9-8 ,4HzC, 1H), 2.63 (t, 1H), 2.16 (t, 1H), 1.81 (go, 1H), 1.62 (ip, 1H), 1.51 (t, 2H) , 1.37 (t, 1H).

Example 26 65 Preparation of ()-2-(4-hydroxyphenyl)-6-aminocarbonyl-cyclopentyliso3,4-dihydro-2H-1-benzopyran and its racemic mixture

A solution of intermediate benzyl ethers obtained by Preparative synthesis 89 (0.062 g, 0.16 mmol) and cesium carbonate 70 (0.108 g, 0.3 mmol) in DMF (4 ml) was stirred for 5 min. M-phenyltriflamamide (0.089 g, 0.249 mmol) was added, and the mixture was kept under stirring for 4 h. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid. The obtained solid product is purified by flash chromatography (silica gel, 72 elution with a gradient of 0-10-2095 ethyl acetate in hexane), and an inseparable mixture (2:1) of two intermediate triflates (0.070g, 8495) is obtained. A solution of the obtained triflamides and bis(triphenylphosphine)palladium dichloride) (0.003 g, 0.0035 mmol) in DMF (0.42 ml) and hexamethyddisilazane (0.12 ml) is stirred. An atmosphere of carbon monoxide is created in the reaction vessel, and the reaction mixture is heated at 802C for 16 hours. Allow the mixture to cool to room temperature. A saturated aqueous solution of sodium bicarbonate is added, and the mixture is extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water (twice) and brine, dried (sodium sulfate) and evaporated to give a yellow solid. The obtained solid product was purified by flash chromatography (silica gel, eluting with a gradient of 0-50-8095 ethyl acetate in hexane) to give an inseparable mixture (2:1) of carboxamides (0.021g, 3790) as a white solid.

A solution of carboxamides (0.021 g, 0.051 mmol) and 1095 palladium on carbon (0.005 g) in THF (4 mL) and meon c (1 O mL) was stirred under hydrogen pressure (40 psig, 276 kPa) for 4 h. The mixture is purged with nitrogen and filtered, (9) obtaining a mixture of the target compound according to Example 26 and the compound according to Example 25, which are separated by NRI C.

Example 27

Preparation of ()-2-(4-methoxyphenyl)-6-hydroxy-cyclopentyliso3,4-dihydro-2H-1-benzopyran (22) diim racemic mixture

A solution of the compound according to Example 1 (0.060g, 0.21mmol) and diisopropylethylamine (0.044ml, O0.25mmol) in Meon (0.Tml) and acetonitrile (ml) is stirred for 5 minutes. A solution of trimethylsilyldiazomethane (0.105 ml, 2.0 M in hexane, 0.21 mmol) is added, and the reaction mixture is kept under stirring for 1 hour. The mixture is concentrated, and a light yellow solid is obtained. The obtained solid product is purified (73 s by flash chromatography (silica gel, elution with a gradient of 0-10-2095 ethyl acetate in hexane), and the compound of Example 22 (0.009g, 1495), the compound of Example 27 (0.021g, 33905) is obtained in the form white solid, )" compound of Example 7 (0.008g, 995) and starting material (0.018g, 30905).

IR NMR of the compound according to Example 27 (SOCI3): 7.38 (a, 9-8.2Hz, 2H), 6.92 (a, 9-8.2Hz, 2H), 6.79 (a, U-8, 4Hz, 1H), 6.66 (a, 9-32Hz, 1), 6.59 (da, 9-3.2Hz, 8.4Hz, 1), 5.06 (a, 9-18Hz, 1), 3.83 (in, ZN), 3.46 (a, -i 42.4 I c, 8.0Gu, 1H), 2.58 (t, 1H), 2.13 (t, 1H), 1, 81 (t, 1H), 1.36-1.70 (t, 4H). M5 calculated 296.2; M5 (M-1) 295.1. - PSHishotovchni synthesis 0 o

Te) oo; o 50 42) o we Y

A mixture of Intermediate 55 (150mg, 0.3bmmol) with THF (4ml) is cooled to 02С. Methyllithium (1.6 M in EBO, 0.31 ml) is added drop by drop). Stir the reaction mixture for 30 minutes, and quench it with a saturated solution of MNASI. The mixture is extracted with EtOAc (twice), the extracts are dried (Ma»5O)), filtered and concentrated in vacuo. Intermediate 90 is pure and is used in the next step without further purification. because NEMZ5 calculated 469.2202; found (electrospray, M--Ma) 469.2205.

Example 28

Preparation of ()-2-methyl-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyl)3,4-dihydro-2H-1-benzopyran b5 no on

To a solution of Intermediate 90 (bOmg, 0.1Zmmol) in anhydrous methanol (bml) is added p-toluenesulfonic acid (25mg, 0.1Zmmol), and the resulting solution is heated at 5023 for 18 hours in an atmosphere of )/0 B3otU. The reaction mixture is cooled to ambient temperature, concentrated in vacuo and purified by flash chromatography (10g 5iO", 4Oml/min, 25-5095 ethyl acetate in hexane for 25 min.), obtaining the compound of Example 28 (ZOmg, 0.Tmmol, 70905) in the form of a yellow solid. NKM5 calculated 296.1412; found (EI) 296.1436.

Final synthesis 91

Shake

Run away

A mixture of Intermediate 55 (115mg, 0.27mmol) with THF (4ml) is cooled to 02C. EIMOSI (2.0 M in THF, 0.27 ml) is added drop by drop. Stir the reaction mixture for ЗОхв. and extinguish it with a saturated solution of MNASI. The mixture is extracted with EtOAc (twice), the extracts are dried (Ma»5O)), filtered and concentrated in CM vacuum. The product is purified by flash chromatography (10g 5iO", 4Oml/min, 0-3095 ethyl acetate in hexane for He) for 25min. and 3095 ethyl acetate for 7 min.), to give Intermediate 91 (95 mg, 77905) as a light yellow oil. NKM5 calculated 483.2359; found (electrospray, M--Ma) 483.2325.

Example 29

Preparation of ()-2-ethyl-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyliso3,4-dihydro-2H-1-benzopyran

p-toluenesulfonic acid (29mg, 0.15mmol) was added to a solution of Intermediate 91 (7mg, 0.1bmmol) in anhydrous methanol (bml), and the resulting solution was heated at 502C for 18 hours. in a nitrogen atmosphere. Cool the reaction mixture to ambient temperature, concentrate in vacuo and "purify by flash chromatography (10g 5iO", 40ml/min., 10-4095 ethyl acetate in hexane for 25min.), obtaining the compound according to Example 29 (40Omg, 0.1Zmmol, 8790) in the form of a pink solid substance. NKM5 calculated - with 310.1569; found (Ex) 310.1578. in" Nidgotochii synthesis 92

SA

- And - oh, that's it) because

A mixture of Intermediate 55 (115mg, 0.27mmol) with THF (4ml) is cooled to 02C. Add iI-RIMOSI (2.0M in THF, 0.27ml) drop by 4) drop. Allow the reaction mixture to warm to room temperature and stir overnight. The mixture is quenched with a saturated solution of MH Si, extracted with EtOAc (twice), the extracts are dried (Ma»5O)), filtered and concentrated in a vacuum. The product was purified by flash chromatography (10g 500, 4Oml/min, 0-3095 ethyl acetate in hexane for 25 min and 3096 ethyl acetate for 7 min) to give Intermediate 92 (7Omg, 5590) as a light yellow oil. NKM5 calculated 497.2515; found (electrospray, and) MaMa) 497.2500. name) Example 30

Preparation of ()-2-(1-methylethyl)-2-(4-hydroxyphenyl)-6-hydroxy-cyclopentyliso3.4-dihydro-2H-1-benzopyran 60 8 no I sn. b5 St, , ,

-B4- is added to a solution of Intermediate 92 (bOmg, 0.1Zmmol) in anhydrous methanol (bml)

p-toluenesulfonic acid (25 mg, 0.1 mmol), and the resulting solution is heated at 502C for 18 hours. in a nitrogen atmosphere. The reaction mixture is cooled to ambient temperature, concentrated in vacuo and purified by flash chromatography (10 g 5iO, 40 ml/min, 10-4095 ethyl acetate in hexane for 25 min.), obtaining the compound according to Example 3 (32 mg, 0.1 mmol, 78905 ) in the form of a pink solid. M5 calculated 323.16; found (electrospray, M-1) 323.1.

Test methods

EC binding test

EC competitive binding tests were performed in a buffer solution containing 50 mM 70. M-(2-hydroxyethyl|piperazine-M'-2-ethanesulfonic acid (HERE5), pH 7.5, 1.5 mM EDTA, 150 mM Mass, 1095 glycerol , 1 mg/ml of egg albumin, zMM OTT, 0.025 μCi per well of ZN-estradiol (MEM YAMET517, 118Ci/mmol, 1 mCi/ml) and 1 ng per well of the EK-A or EK-B receptor (Rapmega). Competitive compounds were added in 10 different concentrations.

Non-specific binding was determined in the presence of ImKM E2 (17-B-estradiol, Zidt company, 5. I otsiv, Moscow).

The reaction mixture for the binding test (14 Ωcl) was incubated for 4 hours. at room temperature, 75 then added to each sample 7 µl of cooled buffer with activated carbon coated with dextran (OCS) (OCS buffer is prepared by adding 0.75 g of activated carbon (Zidt company) and 0.25 g of dextran (the company

Riagtasia) to XHOml of buffer solution for testing). The incubation tablets were shaken for 8 min. on an orbital shaker at 42C, and then centrifuged at 300 rpm. within 1 Okhv. at 49C.

An aliquot of the mixture with a volume of 120 μl was transferred to another 96-well tablet with a white flat bottom (Soviag company) and 175 μl of scintillation liquid Oriirpaze Nizais Z from the U/aPas company was added to each well. Tablets were hermetically sealed and intensively shaken on an orbital shaker. After incubation for 2.5 hours. radioactivity was measured using a Mishoreb counter of the U/aIas company. The ISvo and percentage of inhibition at a concentration of 10 μM were calculated. The value of K for ZN-estradiol was determined by binding saturation with KE-A and KE-B receptors. ICso values for compounds were converted into K values; using the Cheng-Prusoff (Spepo-Rgizoii) equation and determined the value of Ku by binding saturation. The compounds of Examples 1-30 show activity in the described test. The compounds listed in Table 1 bind to the receptor

KE-V with K; less than 100nM. Preferred compounds bind to the KE-B receptor with K; less than 2OnM. The most preferred compounds bind to the KE-B receptor with K; less than 1NM. Compounds that selectively bind to the KE-B receptor compared to the KE-A receptor bind to the KE-B receptor d) at lower K values; compared to K values; for the KE-A receptor. Selective relative to KE-B compounds, which are preferred, bind to the KE-B receptor at a ratio of K; (NM) (KE-AUK; (NM) (KE-B) is more than 4, as can be seen from table 1. b» cha z» c c « 7 Z -

I" in vv 7 811118

V. s 7 s ov o 516 yu vo

A sample with a xenograft of human RSa type I MSar

KE-B agonists were evaluated for their effect on the growth of xenografts of androgen-sensitive prostate cancer 65 (PSa) human type IMsar, which grew in intact sexually mature (age 5-6 weeks) male mice of the Nga:Atutis line

Myde-pi (Atutis Myde). 2.0x109 tumor cells and MSarg were injected into the pretracheal area of a testicularly healthy male mouse by bilateral subcutaneous injection. Mice assigned to the positive control group were castrated through the scrotum. The test compounds were administered to mice bearing xenografts once a day by subcutaneous injection or feeding at various dosage levels in a volume of 0.2 ml, starting the day after tumor injection. Doses of the test compounds were adjusted weekly taking into account the average body weight of the animals within the group. The carrier in these experiments was a 195 solution of carboxymethylcellulose (CMC) with an admixture of 0.2595 Tween-80 (Tmeep 80). Body weight and tumor size were recorded weekly and entered directly from an electronic calibration device into an MRTM spreadsheet (ZA5; Sagu, MS). In MR, the tumor volume in mm was calculated using the formula I xMUxHx0O,5236. Tumor response and body weight for 70 individual mice were recorded weekly. When I MSaR tumor volumes reached the logarithmic phase of propagation, lesions were measured every 3-4 days. The value of the growth rate was determined by linear modeling of the logarithm of tumor characteristics, and the time to the cessation of the therapeutic effect (tumor volume 1300-1500 mm3) was determined using a linear extrapolation model (ZA5; Sagu, MS). For reasons of humane treatment of animals, mice were euthanized , when the volume of the tumor approached 1200-1400 mm H. During the necropsy, the final volume of the tumor and body weight were recorded, a whole blood sample was taken by cardiac puncture and allowed to clot on ice. The plasma was transferred into appropriately marked Eppendorf microtubes with a capacity of 0.5 ml and stored at -802C for biomarker determination.

General method of training rats

Female Sprague-Dawley (Zrgadoe-Oamieu) rats aged (unless otherwise specified) 75 days (body weight range 200-225 g) were obtained from Charles River (Spapez Kimeg I arv., Rogiade, MI). Animals were subjected to either bilateral ovariectomy (0OMH) or Sham surgery (pat) at Charles River and sent to the customer a week later. Upon arrival, animals were housed in metal hanging cages in groups of 3-4 animals per cage and provided with free access to food (calcium content approximately 0.595) and water for one week. The temperature of the room was maintained in the range of 22.2 - 1.72C with a minimum relative humidity of 4095. The light regime corresponded to 12 hours. lighting and 12h. of darkness (at)

Dosing regimen and tissue sampling: After a 1-week acclimatization period (ie, 2 weeks after OMH), daily administration of compounds of formula (I) ("P-I") was started. 17a-ethynylestradiol or B-| administered orally (unless otherwise indicated) in the form of a suspension in a 195% solution of carboxymethylcellulose or a solution in 2090% cyclodextrin. Animals received compounds daily for 4 days. After the dosing period, the animals were weighed, anesthetized with a mixture of ketamine and xylazine (2:11 by volume), and blood samples were taken by (ee) cardiac puncture. Then the animals were killed by asphyxia using CO 5, the uterus was removed through an incision b along the middle line, and the weight of the undried uterus was determined. 17A-ethinyl estradiol was obtained from bZidta

Snetis! So., 5. I otsiv, MO. uh-

Cardiovascular disease. Hyperlipidemia and | | m

The aforementioned blood samples were left to clot at room temperature for 2 hours, and plasma was obtained by centrifugation for 7 hours. at 33000 rpm. Cholesterol was determined in plasma using a highly effective cholesterol test from the company "Behringer Mannheim" (Woengipdeg Mappeit Oiadpowiisv). According to this technique, cholesterol is oxidized to cholest-4-en-3-one, while hydrogen peroxide is formed. Hydrogen peroxide is then reacted with phenol and 4-aminophenazone in the presence of peroxidase, and a p-quinoneimine dye is obtained, which is quantitatively determined by the spectrophotometric method at a wavelength of 50 nm. Cholesterol concentration c is then calculated using a standard curve. The entire analysis is performed automatically with the use of the "Biomek" automatic stand system (Viotek Aciotaiiea Uuogkzgiaiop).

Test for uterine eosinophil peroxidase (ERO)

The above-mentioned uteri are kept at 42C until enzyme analysis. Then the uteri are homogenized in 50 to 75 volumes of 5 OMM Tris buffer (pHv,0) with an admixture of 0.00595 Triton X-100. After adding 0.0195 hydrogen peroxide and 10 mM o-phenylenediamine (final concentrations in Tris-buffer), the increase in absorption at a wavelength of 450 nm is monitored for 1 h. The presence of eosinophils in the uterus is an indicator of the estrogenic activity of the compound. o The maximum speed for a 15-second interval is determined from the initial linear section of the reaction curve.

Test Method for Inhibition of Bone Loss (Osteoporosis) (ee) After preparation according to the general method described above, rats were administered the test compounds for

F 35 days (by animals in the experimental group) and on the 36th day they were killed by asphyxiation using CO 5.

A 5-day period is sufficient to provide a maximal decrease in bone density, measured as described below. After killing the rats, the uteri were removed, separated from extraneous tissues, and before determination of the wet weight of the uterus, the fluid contained in them was removed to confirm estrogen deficiency associated with total ovariectomy. The response to ovariectomy is usually a reduction in uterine mass of approximately (F) 7595. The uteri were then stored in 1095 buffer-neutralized formalin for subsequent histological analysis.

GI In each animal, the right thigh was separated, digitized radiographs of the peripheral metaphysis were obtained, and they were analyzed using the image analysis program (MIN etade). The proximal appearance of the femur in these animals was also studied by quantitative computer tomography. According to the above methods, PE-I or ethinyl estradiol (EE) in 2090 hydroxypropyl-p-cyclodextrin was orally administered to the studied animals.

Therapeutic methods of application and dosage

The various diseases and conditions mentioned herein as treatable are well known and understood by those skilled in the art. It is also known that a person skilled in the art can affect relevant diseases and pathological conditions by treating with a therapeutically effective amount of compounds -58c-

of formula (I) to a patient currently suffering from such a disease or pathological condition, or by prophylactically administering a therapeutically effective amount of a compound of formula (I) to a patient suffering from such a disease or pathological condition.

As used herein, the term "patient" refers to a warm-blooded animal, such as a mammal, suffering from a particular disease mediated by the B-estrogen receptor. It is intended that examples of living creatures covered by said term include guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans.

The term "therapeutically effective amount" of a compound of formula (I) as used herein refers to an amount that is effective in affecting diseases and pathological conditions associated with diseases mediated by the estrogen receptor B, such as cancer. prostate, benign prostatic hyperplasia, testicular cancer, cardiovascular diseases, neurodegenerative disorders, urinary incontinence, CNS disorders, gastrointestinal tract disorders, and osteoporosis. The term "effect" is intended to indicate all processes, including slowing down, interrupting, delaying or stopping the development /5 of the mentioned diseases and pathological conditions, but does not necessarily indicate the complete exclusion of all symptoms of diseases and pathological conditions, but covers the prevention of diseases and pathological conditions associated with estrogen receptor B-mediated diseases, such as prostate cancer, benign prostatic hyperplasia, testicular cancer, cardiovascular disease, neurodegenerative disorders, urinary incontinence, CNS disorders, gastrointestinal tract disorders, and osteoporosis.

A therapeutically effective amount can be readily determined by a physician skilled in the art using conventional methods and by observing the results obtained in similar cases. When determining the therapeutically effective amount and dose, the attending physician takes into account various factors, including (but not limited to) the type of mammal, its body weight, age and general health; a specific disease to be treated; degree of damage or severity of the disease; individual reaction of the patient; the specific content of the applied compound; method of introduction into the body; bioavailability characteristics of the used drug; the selected dosing regimen; use of concomitant therapy; and other relevant circumstances. io)

It can be expected that a therapeutically effective amount of a compound of formula (I) varies from approx

0.001mg per kilogram of body weight per day (mgokg day 7) to about 10Omg.kg' day". Preferred amounts can be determined by one skilled in the art. (Se)

In the treatment of a patient suffering from the aforementioned diseases or pathological conditions, the compound of formula (I) can be administered to the body in any form and by any method that ensures the bioavailability of said compound in a therapeutically effective amount, including oral , by inhalation and (Ge) parenteral ways. For example, compounds of formula (I) can be administered to the patient orally, by inhalation of an aerosol or dry powder, subcutaneously, intramuscularly, intravenously, -

Transdermal, nasal, rectal, local methods, etc. Oral or inhalation administration is usually preferred in the treatment of respiratory diseases, for example, asthma. A specialist in the field of preparation of dosage forms can easily choose the appropriate form and method of administration of the mentioned compounds, taking into account the specific characteristics of the selected compound, the disease or pathological condition to be treated, the stage of development of the disease or pathological condition and other relevant circumstances. See the monograph "Betipdiop'v Rnaptaseciisa!" the content and nature of which is determined by the solubility and chemical properties of the selected compound selected by the route of administration and standard pharmaceutical practice.Compounds of the present invention, effective per se, may be formulated and administered in the form of pharmaceutically acceptable salts thereof, e.g., acid salts - or salts with bases, for reasons of stability, ease of crystallization, increased solubility, etc. -1 In another embodiment, the present invention provides pharmaceutical compositions which contain a therapeutically effective amount of a compound of formula (I) mixed or otherwise combined with one or more is), pharmaceutically acceptable carriers or fillers. so 50 The mentioned pharmaceutical comp zitions are made by methods well known in the field of pharmacy. Said carrier or filler can be a solid, semi-solid or liquid material that can act as a carrier 4) or medium for the active ingredient. Suitable carriers or excipients are well known in the art.

Said pharmaceutical composition can be adapted for oral, inhalation, parenteral or local use and can be introduced into the patient's body in the form of tablets, capsules, aerosols, inhalation mixtures, suppositories, solutions, suspensions, etc. o The compounds of this invention can be administered orally, for example, with an inert diluent or with an edible carrier. they can be placed in gelatin capsules or pressed into tablets. For oral and therapeutic use, the mentioned compounds can be combined with fillers and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gums, etc. These dosage forms 60 should contain at least 495 compounds of the present invention as an active ingredient; its content, however, can vary depending on the particular dosage form and, in a preferred embodiment, is from 490 to about 7095 by weight of the dosage unit. The amount of the compound in the composition should ensure its suitable dose.

Preferred compositions and dosage forms of the present invention can be determined by one skilled in the art.

Said tablets, pills, capsules, lozenges, etc. may also contain one or more of the following 65 auxiliary substances: binders, for example, microcrystalline cellulose, tragacanth or gelatin; fillers, for example, starch or lactose; disintegrators, for example, alginic acid, Primogel (Rgitodei),

corn starch, etc.; lubricating agents, for example, magnesium stearate or Sterotex (Ziegoiech); sliding agents, for example, colloidal silicon dioxide; and sweeteners, such as sucrose or saccharin, or flavorings, such as mint, methyl salicylate, or orange flavor. If the dosage unit is a capsule, it may contain, in addition to materials of the aforementioned types, a liquid carrier such as polyethylene glycol or fatty oil. Other unit dosage forms may contain a variety of other materials that modify the physical form of the dosage unit, such as a coating. Yes, tablets or pills can be coated with sugar, shellac, or other enteric coating materials. The syrup may contain, in addition to the compounds of this invention, sucrose as a sweetener and certain preservatives, dyes and pigments and 7/0 bmacoaromatic impurities. The materials used to make these various compositions must be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic use, the compounds of the present invention can be incorporated into solutions or suspensions. These dosage forms should contain at least 0.195% of the compound of this invention as active ingredient; its content, however, can vary and be from 0.195 to about 5095 by weight of the composition. 7/5 The amount of the compound of formula (I) in the composition should ensure its suitable dose. Preferred compositions and dosage forms of the present invention can be determined by one skilled in the art.

The compounds of this invention can also be administered by inhalation, for example, in the form of an aerosol or dry powder. Administration may be accomplished by means of a liquefied or compressed gas or a suitable pumping system that provides for the delivery of the compounds of the present invention or dosage forms thereof. Medicinal

Forms for inhalation of the compounds of formula (I) can be produced in the form of single-phase, two-phase or three-phase systems. Various systems are known for introducing aerosols of compounds of formula (I) into the body.

Dosage forms based on dry powders are made either by granulating or grinding the compounds of formula (I) to obtain particles of the appropriate size, or by mixing the granulated or ground compounds of formula (I) with a suitable carrier, for example, with lactose and the like. Administration by inhalation involves the use of appropriate containers, activators, valves, auxiliary containers, etc. Aerosol and dry powder dosage forms for inhalation use, which are preferred, can be determined by a specialist in o); this field.

The compounds of this invention can also be administered topically, in which case the carrier may contain a solution, ointment or gel base. Said base, for example, may contain one or more of the following substances: petroleum jelly, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, as well as emulsifiers and stabilizers. contain the compounds of formula (I) or their pharmaceutical salts in a concentration of from about 0.195 to about b 1095 mass per unit volume.

Solutions or suspensions may also contain one or more of the following auxiliary substances: i- sterile diluents, for example, water for injections, saline solution, non-volatile oils, polyethylene glycols, i- glycerin, propylene glycol or other synthetic solvents; antimicrobial agents, for example, benzyl alcohol or methylparaben; antioxidants, for example, ascorbic acid or sodium bisulfite; chelating agents, for example, ethylenediaminetetraacetic acid; buffer compounds such as acetates, citrates or phosphates, and tonicity agents such as sodium chloride or dextrose. Parenteral drugs can be placed in ampoules, disposable syringes or multi-dose vials made of glass or 7-3 c plastic. and"

Claims (20)

The formula of the invention -I 1. The compound of the formula y U se) t u is o 50 v ee 4 Z vo Her t SHE o sia o ko o A. 0-x vo 0) where each of B", B2 and B3, independently of the others, is -H, C1-C8-alkyl, -OH, C1-C8-alkyl, halogen or a group -CE6; 65 B is hydrogen or C-C-C-alkyl; each of U", y2 and UZ, independently of the others, is -H or C.4-Cv-alkyl; and C is -CH»o-, -"СНо-СНо- or -СНо-СНо-СН»; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, where C is -СН»о-. 3. Compound according to claim 1, where both groups U2 and UZ are -H. 4. The compound according to claim 1, where at least one of the groups B and B? is -OH. 5. The compound according to claim 1, where VZ is -Н. 6. Compound zap. 1, where U! is -N. 7. The compound according to claim 2, where one of the groups B and B is -OH, and the other is -H. 8. The compound according to claim 1, which has the formula II with 1a k for She 4 with | r 2 o | te a ry 2 sn "MI where VZ is -H, -OH or E; 2 is -H, -CH3 or -OSN"; s va is -Н or -СНУ; o is -Sn-, -Sn-SnNo- or -Sno-SsSnNo-Sn»o-; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, which has the formula IV, IS, IO or IE: Z and U2 Fo! b Ф Х х- ise 5 і- 4 that in Z Я 2, pcs Z o | - no s Ж 0--o3 I» « (IV) chZ - h: - di o se) to (ee) in Kk) ee 42) 2 nn ш Zh. iF) pa-- t PO) bo b5 chZ shchi 1-8 Shk ; K 4 Still in Her Mo 2 70th Zh. 0О0-- ' (I du Z h: schi v She 4 vo Her Me s schu 07 o r 0-kh F zo « ME) so or its pharmaceutically acceptable salt. Gee! 10. The compound according to claim 1, which has the formula: cha i - no Sh-- « s a She no - )» r On ' -I or its pharmaceutically acceptable salt. -1 11. The compound according to claim 10, which is the (25,3K,45)-enantiomer of the formula se) doyu HO, i Ф ше o: (Ф) р ruyu On vo or its pharmaceutically acceptable salt. 12. The compound according to claim 10, which is the (21,35,4K)-enantiomer of the formula b5 no | : What! po o pa | Zhican or its pharmaceutically acceptable salt. 13. Compound according to claim 1, which has the formula: но Ш-- ше о шчи | o r s 7 on o or its pharmaceutically acceptable salt. 14. The compound according to claim 1, which has the formula: Ге со (22) dО | m I - Ek « on ' no s or 1" yav z - i 07 zh F o 50 Shi F an o no ime) | y: 6o an o | she Shi on b5 or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 1, which has the formula: на а ШЕ ne о Х ШЕ он : но » нд то Не шт он: сч о ех (ге) | so Shin no o XX F i- Shi z on. and, on them and but with | and )"! She oh nya | re -And - sleep щ Z on: (Te) On o 50 sho a | Shk F) Po) SHE on. 60 b5 N y | SN, page 70 she on: N SCHI dosh o same ve on: s o E sho so | so ich- dk - On .: Her : Z s o sh-x )» sh 45 th: 7a | ee - SHO so On: bo 20 4) N, with oo ko slya in On .: 65 E E | She and shle about and Shock | nt He .: z» no che sne, | about | and Shin On: sch 5) no She (Se) , sho o | - to her about Shi - ON Ten, - Sn, " AD 2 s u» on | - - s still be 0 On ' 4) no dO (F) z, sn ko o a i She Z 60 Shin On : b5 sn. But no che | sh o se in On ' . with a SHE about | in sch shu o | o Ф сн, со сн, Ф h- | - And "nie I with I" to Fr V. sn, -I so in 7 BUT a o sn yuyu me a-І37З7- Z bo 65 no : щ SHE I o: y: He or and A na - she ns sho. Z On s Z o no ne Shk ny so E : o: a F zv sn. he m or its pharmaceutically acceptable salt. 16. The compound of the formula ІІ "s no s ve )" pi y 3 -Kryn 5 y - o ee sh v ry (Se) e- so ЧО 4) where B" is an amido group or hydroxyl; 225 is -H or C .-Cv-alkyl; BZ is -H or C.-Cv-alkyl; 29 B is an amido group or hydroxyl; and hF) is -Sn-, -Sn-SnNo- or -Sno-Csno-Sn»o-; or a pharmaceutically acceptable salt thereof. 17. Compound according to claim 16, which has the formula: bo b5 -v6- o : Nm | z o - 70 рн МН 2 з ' or new sh- o y: сч МН рн 2 (о) о (Се) о ' со Ге) eco і- nm m. sht o te « r on Z s sh . . or a pharmaceutically acceptable salt thereof. )" 18. A compound selected from the group consisting of: a) (-2-(4-hydroxyphenyl)-6-hydroxycyclopentyl 3,4-dihydro-2H-1-benzopyran, c) (9-2-(4-hydroxyphenyl)- 6-trifluoromethylcyclopentyl 3,4-dihydro-2H-1-benzopyran, -1 c) (-2-(4-hydroxyphenyl)-6-methylcyclopentyl 3,4-dihydro-2H-1-benzopyran, -1 a) (- 2-(4-hydroxyphenyl)-6-fluorocyclopentyl)|3,4-dihydro-2H-1-benzopyran, e) (-2-(4-hydroxyphenyl)-5-hydroxycyclopentyl)3,4-dihydro-2H-1-benzopyran , ise) U (9-2-(4-hydroxyphenyl)-7-hydroxycyclopentyl)|3,4-dihydro-2H-1-benzopyran, Ge | 20 a) (-2-(4-hydroxyphenyl)-6-hydroxy-8-methylcyclopentylyl3,4-dihydro-2H-1-benzopyran, FR) -dihydro-2H-1-benzopyran, y) (y-2-(4-hydroxyphenyl)-6-hydroxy-8-methoxycyclopentyliso3,4-dihydro-2H-1-benzopyran, y) su-2-(4-hydroxyphenyl )-6-hydroxy-11,11-dimethylcyclopentyl 13,4-dihydro-2H-1-benzopyran, Y (9-2-(4-hydroxyphenyl)-6-hydroxy-11,11-diethylcyclopentyl 3,4-dihydro-2H- 1-benzopyran, I) (y-2-(4-hydroxyphenyl)-6-methoxycyclopentyl 33,4-dihydro-2H-1-benzopyran, o t) (-2-(4-hydroxy-3-methylphenyl)-6- hydroxycyclopentyl 3,4-dihydro-2H-1-benzopyran, imo) n) (9-2-(2-methyl-4-hydroxyphenyl)-6-hydroxycyclopentyl 3,4-dihydro-2H-1-benzopyran, o) (3- 2-(4-hydroxyphenyl)cyclopentyl-13,4-dihydro-2H-1-benzopyran, 60 g) C9-2-(4-hydroxyphenyl)-6-hydroxy-7-methylcyclopentyl-3,4-dihydro-2H-1-benzopyran, a) (y-2-(4-hydroxyphenyl)-6-hydroxycyclohexylis33,4-dihydro-2H-1-benzopyran, C (-2-(4-methoxyphenyl)-6-methoxycyclopentyls13,4-dihydro o-2H-1-benzopyran, 8) (-2-(4-aminocarbonylphenyl)-6-aminocarbonylcyclopentylyl) 4-dihydro-2H-1-benzopyran, w) (-2-(4-hydroxyphenyl)-6-aminocarbonylcyclopentylisi|3,4-dihydro-2H-1-benzopyran, m) (-2-(4-methoxyphenyl)-6-hydroxycyclopentylyl33,4-dihydro-2H-1-benzopyran, m) (-2-methyl-2-(4-hydroxyphenyl)-6-hydroxycyclopentylyl33,4-dihydro- 2H-1-benzopyran, x) (-2-ethyl-2-(4-hydroxyphenyl)-6-hydroxycyclopentyliso3,4-dihydro-2H-1-benzopyran and y) (-2-(1-methylethyl)-2- (4-Hydroxyphenyl)-6-hydroxycyclopentylyl3,4-dihydro-2H-1-benzopyran, and pharmaceutically acceptable salts of these compounds. 19. A pharmaceutical composition comprising a compound according to any one of claims 1-18 and a pharmaceutically acceptable carrier. 20. Use of a compound according to any of claims 1-18 for the manufacture of a medicinal product for the treatment of prostate cancer 70, benign prostatic hyperplasia or a disease state mediated by B-estrogen receptors. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated 7/5 Microcircuits", 2007, M 2, 15.02.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s io) (Se) so (22) cha i - "no s i" -I -I se) o 50 42) F) ime) 60 b5