UA75338C2 - Heterocyclic aromatic amides, fungicide composition and a method for control and prevention of invasion - Google Patents

Abstract

Heterocyclic aromatic amides (HAA) according to Formula (I) wherein X1-X4, M, Z, and A are herein defined. The invention also encompasses hydrates, salts and complexes thereof. These compounds are useful as antifun-gal agents. (I)

Description

Description of the invention

This patent application claims priority over prior applications 60/149,977 and 60/150,248, which were 2 filed in the United States Patent Office on August 20, 1999, and August 23, 1999), respectively, the entire content of which is disclosed in the text of this patent application by reference. Previous (patent applications 60/149,977 and 60/150,248)| both claim priority under prior |application 60/144,646, filed June 1999), the entire contents of which are incorporated herein by reference.

This patent application claims priority under |IApplication 09/620,662, filed July 20, 20001, the full content of which is disclosed in the text of this patent application by reference.

This invention relates to fungicidal compounds and methods of their application. More specifically, the present invention relates to new fungicidal heterocyclic aromatic amides, methods, including the use of fungicidally active amounts of such compounds in relation to plant pathogen loci. The present invention also relates to methods of preparation of heterocyclic aromatic amides and their fungicidal compounds. 12 A wide variety of antifungal compounds and methods are well known to those skilled in the art. Antimycin, for example, was identified as a natural substance produced by Zygeriotus spp. and has antibiotic properties

Ivatom. WITH.).; her a). Ootsygpa! piiibioiisv, 1997, 50(9), 729|. These substances have also been found to be effective antifungal agents (Pe MegskK Ipdeh, tuge Eayop, 5. Vidamagi, Ed., MegskK apa So.,

UMUpiepoize Ziayop M.), 1996, p. 1201. In patent application UUO 97/08135) amides of acylaminosalicylic acid are described, which can be effectively used as pesticides. |In the patent application ER-A-0O-661269)| described substituted amides of heterocyclic carboxylic acid that can be effectively used as pharmaceutical agents. The patent application UR-A-7-233165) describes antifungal dilactones from the 3-hydroxypyridinecarboxyl group, which have antifungal properties. Derivatives of isobutyryl, tigloyl, isovaleryl, and 2-methylbutyryl of these compounds were later described in: Geigapedhop 1998, 54, 12745-12774; 9. Apiirioi. 1997, 50(7), 551; 3. p. 29 Apiirioi. 1996, 49(7), 639; 9. Apiirioi. 1996, 49(12), 1226; apa Teiigapeagop GI ek. 1998, 39, 4363-4366). Go)

However, the need for new antifungal agents is still quite high. The present invention represents antifungal agents that have high residual activity, higher activity at lower doses of application, have therapeutic properties, as well as a wider spectrum of effective action.

One aspect of the present invention provides compounds comprising heterocyclic aromatic amides (GAAs) of Formula I:

OM Fo

N yu /2 М-А m. -(, - ху7х 2 1 ши s where Х.-Ху, M, 7 and A are those defined later. The invention also includes hydrates, salts and their :z» compounds.

The present invention also provides antifungal compounds comprising GAA in combination with phytologically acceptable carriers and/or solvents. The method of application of compounds of heterocyclic aromatic amides -1 is disclosed below.

The purpose of this invention is to create GAAs and their compounds that are effective as antifungal agents. 1 Another goal of this invention is to develop a technique for controlling and/or preventing fungal invasion, and this technique will include the use of GAAs and their compounds containing them.

Further objects and advantages of the present invention will be disclosed by the following description of the invention. i95) The present invention relates to a variety of GAA compounds that are active as antifungal agents. The scope of this invention also includes substances that include GAA compounds, as well as methods of using the compounds

GAA. Methods of preparation of GAA compounds are also part of this invention, as well as methods of their preparation and use as antifungal agents.

GAA compounds

The new GAA antifungal compounds of the present invention are described by the following Formula I:

F) name) 60 b5

N

КО ю ху х, where a) represents a 5- or 6-membered heterocyclic aromatic ring, in which le хз, )

Ho t X, (Y) each of X/-Xu is independently O, 5, MK", M, SK" or a bond; (ii) not more than one of X.--Hu is O, 5 or ME; (ii) not more than one of X.4-Hu is a bond; with (im) when any of the H.-Hu is 5, O or ME, one of the adjacent H.-Hu; must be represented by a link; and o (M) at least any of H.-Hu must be O, 5, MK or M; where

K is H, C.4-C3 alkyl, Co-C3 alkenyl, Co-C3 alkynyl, hydroxy, acyloxy, C.-Cv alkoxymethyl, SNE", cyclopropyl or C.4-C. Alkoxy; and K" are independently H, halogen, cyano, hydroxyC4i-C3 alkyl, C41-C3 haloalkyl, cyclopropyl, C41-C3 alkoxy, C--C3 haloalkyl, C4-C3 alkylthio, aryl, C--C3 MHC(O) alkyl , 89

MnNes)n, sS.i-Suz haloalkylthio, So-S; alkenyl, So-C. haloalkenyl, Co-C; alkynyl, Co-C4 haloalkynyl or so nitro, where adjacent substituents K" can form a ring or adjacent substituents K and K" can form a ring; co b) 7 is O, 5 or MORP" in which K" is H or C-C3 alkyl; and c) A represents () C4-C14 alkyl, C0-C14 alkenyl, or C0-C14 alkynyl, any of them can be branched or c. unbranched, unsubstituted or substituted halogen, hydroxy, nitro, aroyl, aryloxy, C--Cv acyloxy,

Ci-Cv alkylthio, arylthio, aryl, heteroaryl, heteroarylthio, heteroaryloxy, Ci-Cv acyl, C4-Cv haloalkyl, C--Cv alkoxy or C.4-Cv haloalkyl, « (iii) C3-C44 cycloalkyl containing 0 -3 heteroatoms and 0-2 unsaturated bonds that can be unsubstituted or substituted by halogen, hydroxy, C-Cv alkyl, C-Cv haloalkyl, cyano, nitro, aroyl, aryloxy, - c heteroaryloxy, C41-Cv alkylthio, arylthio . 4-Ce alkyl groups, (ii) Ce-C.4 bi- or tricyclic ring system containing 0-3 heteroatoms and 0-2 unsaturated bonds, which can be unsubstituted or substituted by halogen, hydroxy, C-Cv alkyl . heteroaryl, C.i-Ce acyl, carboaryloxy, carboheteroaryloxy, C.4-Cv carboalkoxy, as well as amido unsubstituted or substituted by one or two C.4-Cv alkyl groups, o (m) aryl or heteroaryl, which may be unsubstituted or substituted nitro, C-Cv alkyl, C1-Cv o 20 haloalkyl, C3-Cv cycloalkyl, Co-Cv alkenyl, Co-Cv alkynyl, aryl, heteroaryl, halogen, hydroxy, C-Cv alkoxy, C4--Ce haloalkoxy, carboaryloxy , carboheteroaryloxy, C4-Cv carboalkoxy or co amido unsubstituted or substituted by one or two C.i-Cv alkyl groups, C.--Cv alkylthio, C.--Cv alkylsulfonyl, C4-Cv alkylsulfinyl, C4-Cv OS(O) alkyl, OS(O)aryl, C3-Cv OS(O) cycloalkyl, C41-Cv

MHC) alkyl, C3-Cv MHO(O)cycloalkyl, MHC(O)aryl, MHO(O)heteroaryl, C3-Cv cycloalkylthio, C3-Cv 22 cycloalkylsulfonyl, C3-Cv cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio,

Gee! heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)KU, SIMOKUK, in which any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens, and where any aryl or heteroaryl that contains a substituent, may also be unsubstituted or substituted halogen, cyano, nitro, aroyl, aryloxy, aryl, heteroaryl, C 4 -C 60 acyl, C 4 -C 60 haloalkyl, C 4 -C 60 alkoxy, C 4 -C 6 halo alkoxy, C 4 -C 60 carboalkyl or amido, unsubstituted or substituted by one or two C.i.-Cv alkyl groups, where Ku and Ku. are independently H, Ci-Cv alkyl, Co-Cv alkenyl, C3-Cv cycloalkyl, aryl or heteroaryl, and (M) b5

. n "m i, ze a i v! mk, t k, ; E 5 t: v, where 7 is the joining point where 01, 0" is O or 5;

MU is О, СН», СНЕ», or a connection;

Ku is C4-Cv, alkyl, Co-Cv alkenyl, Co-Cv, alkynyl, C3-Cv, cycloalkyl, aryl, or heteroaryl;

E" is H, C4-C3 alkyl, Co-C5 alkenyl or Co-C6 alkynyl;

Ez is H, Ku, OKU, OS (0) Ki, OS(O)OK. or OS(O)MA. CC;

Ku; and Kb are independently H, C-4-Cb alkyl, or C0-Ce alkenyl, provided that the sum of carbons for Ku and Kv is six or less, and further provided that Ku and K5 may be combined in C3z-Sv ring;

Kv and K7 are independently H, C4-C6 alkyl, C3-C8 cycloalkyl, C0-C8 alkenyl, or C0-C8 alkynyl, provided that at least one of Ke and Ku is H; provided that, when y s 29 OM o x MA / so

Zo hu so xx E s iv)

Ye i - ki u n o sn, " ry chn, p s Ne" o a sys. and I g" U yn . 2 Chan shchi o i ni nn a 2 i -I prikdininiya p . 1 1 (95) p. 70 where

КЕ" is H or ОСН", then КО is not isobutyryl, tigloyl, isovaleryl, or 2-methylbutanoyl; 4) M represents

H, BKeVy)Me», Z(RIA)Me», ZIB, Zimez, SIK KZO»Co where Ka is H, C.4-Cv alkyl, Co-Cv alkenyl, Co-Cv 22 alkynyl, C3-Ce cycloalkyl, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl,

HF) alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted arylalkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, C-Cv alkoxy, C3-Cv cycloalkyl, C41-Cv haloalkoxy, Co-Cv alkenyloxy, Co-Cv haloalkenyloxy, Co-Cv alkynyloxy, Co-Cv haloalkynyloxy, C-4-Cv thioalkoxy, substituted and unsubstituted 60 aryloxy, substituted and unsubstituted arylalkenyloxy, substituted and unsubstituted arylalkynyloxy, substituted and unsubstituted aryloxy, substituted and unsubstituted heteroaryloxy, amino unsubstituted or substituted by one or two C.--Cv alkyl groups, and Co is C4-Cv alkyl, Co-Cv alkenyl, C3-Cv alkynyl,

C3-Cv cycloalkyl, aryl, or heteroaryl.

The terms alkyl, alkenyl, alkynyl and the like, as used herein, include both straight and branched groups; for the terms alkenyl, alkenylene, and the like herein include groups containing one or more double bonds; and the terms alkynyl, alkynylene and the like refer to groups containing one or more triple bonds.

Cycloalkyl, as used herein, refers to a C3-C44 cycloalkyl group containing 0-3 heteroatoms and 0-2 unsaturated bonds. Bi- or tricyclic ring systems refer to C 6-C44 aliphatic ring systems containing 0-3

Heteroatoms and 0-2 unsaturated bonds. The terms that will be used later in the text of the application have both replaced and unreplaced forms. Unless otherwise specified, the substituted form refers to substitution with one or more groups selected from halogen, hydroxy, cyano, nitro, aroyl, aryloxy, aryl, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, C--Cv acyl, C--Cv haloalkyl, C-C 6 alkoxy, C 41-C 40 haloalkyl, C 4-C 4 alkylthio, C--C 5 haloalkylthio, carboaryloxy, carboheteroaryloxy, C-C 6 carboalkoxy or /o amido unsubstituted or substituted by one or two C--Cb alkyl groups. All the listed terms and definitions imply that the requirements of the rules of chemical bonds and deformation energy are met.

The term aryl as used herein refers to a substituted phenyl or naphthyl group. The term heteroaryl refers to any 5 or 6 membered ring containing one or more heteroatoms; these heteroaromatic rings can also be combined with other aromatic systems. The terms that will be used in /5 further in the text of the application have both replaced and unreplaced forms. And the substituted form refers to substitution by one or more groups selected from nitro, C.4-Cv alkyl, C4--Cv haloalkyl, C3--Cv cycloalkyl,

Co-Cv alkenyl, Co-Cv alkynyl, aryl, heteroaryl, halogen, hydroxy, C-Cb alkoxy, C-Cb haloalkoxy, C1-Cv alkylthio, C4-Cv alkylsulfonyl, C1-Cv alkylsulfinyl, C--Cv OS(O )alkyl, OS(O) of aryl, C3-Cv OS(O) of cycloalkyl,

C1-Cv MHO(o) alkyl, C3-Cv MHO(O)cycloalkyl, MHC(O)aryl, MHO(O)heteroaryl, C3-Cv cycloalkylthio, C3-Cv cycloalkylsulfonyl, C3-Cv cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio , heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)KU, C(IMOKOK, where

Ku and Ku are independently H, C3-Cv alkyl, C3-Cv alkenyl, C3-Ce cycloalkyl, aryl, or heteroaryl, wherein any alkyl or cycloalkyl containing substituent may be substituted with one or more halogens, and provided , that the requirements of the rules of chemical bonds and deformation energy are met. high school

The terms halogen and halo as used herein include chlorine, bromine, fluorine and iodine. The term haloalkyl and the like refer to groups substituted by one or more halogen atoms. and)

The term Me as used herein refers to a methyl group. The term EE refers to the ethyl group. The term Pg refers to the propyl group. The term V refers to the butyl group. The term RA refers to the phenyl group. The term EUAs refers to ethyl acetate. as used herein, refers to a straight or branched chain alkoxy group. The term haloalkyl refers to an alkyl group substituted with one or more halogen atoms. and,

The term heteroatom, as used here, refers to O, 5 and M. p

Preferred 5- or 6-membered heterocyclic aromatic rings according to the formula

IS) / and -

) x-- "-2 x - - include the corresponding isomers of pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, and?" furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, and thidiazole. The most preferred heterocyclic aromatic rings are pyridine, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, thidiazole, and oxazole. Compositions according to Formula |! are based on 2-amido-3-hydroxypyridine, -I 2-amido-3-hydroxy-4-methoxypyridine, 2-amido-3-hydroxypyrazine, and 4-amido-5-hydroxypyrimidine.

The authors recognize that the preparation of certain combinations of substituent groups of compounds falling within the definitions provided herein may not be possible, for reasons of space or chemistry. Such compounds are not included in the scope of this invention.

Various hydrates, salts and complexes of compounds according to formula 1 can be prepared using conventional methods. For example, salts can be formed by replacing the hydroxyl atom of hydrogen (MAN) with a cation, for example, MNazh, «M(Vy), Ky, Mak, Sa? Hey, Mage, Beh? Si, etc. These derivatives are also useful in connection with the present invention.

In the text of this patent application, all temperatures are presented in degrees Celsius (2C), and all percentages are percentages by weight, unless otherwise indicated. The term ppm means "part per million" (reg tShop). The term rzi means "pounds per square inch" (roshpaz reg zdtsage ipsp). Term t.r. means "dot

IF) melting" (Melting point). The term BR means "boiling point" (Broiipo roipO. ime) Preparation of compounds

The compounds of this invention are prepared using methods well known to specialists in this field. 60 The necessary starting materials are substances that are commercially available or easily synthesized using standard techniques.

PREPARATION OF PYRIDINE-2-CARBOXAMIDES.

The required GAA (2) is prepared by reacting the corresponding ortho-hydroxyheteroaromatic carboxylic acid (1) with an amine in the presence of a binder (phosgene or 1-I3-25 65 dimethylaminopropyl|-3-ethylcarbodiimide hydrochloride (EHSOCI)) and 1-hydroxybenzotriazole (NOV) or 1-hydroxy-7-azabenzotriazole (NOAI) and an acid scavenger, for example, M-methylmethylmorpholine (MMM),

triethylamine, 4-dimethylamino)pyridine (OMAR), or diisopropylethylamine) (Scheme 1). In some cases, acid chlorides with protected hydroxy groups (3) can react with the corresponding amines to form transient amides (4). Removal of the protective group by hydrogenation in the presence of a palladium (Ra) catalyst produces the desired product (2X). The capping of the hydroxyl group of the heterocycle in compound 2 with an acyl, sulfonyl, or silyl group (M) can be accomplished by reacting the corresponding compound 2 with a carboxylic acid chloride, sulfonyl chloride, or silyl chloride (MC) in a suitable solvent, such as, for example, pyridine, with using an acylation catalyst such as OMAR provides the corresponding O-acyl, O-sulfonyl, or O-silyl derivatives (27).

HE oh I N

ORE AMN, MTA hu son SY SYA tTNE EBM / H hota BOS, NEW hm still Z AMN, yati

MM 2 1 | AND

MS

Wow!

OHM

- n s ' -- y o hu x 0: 27 so 7 2u so so

IS)

Me me OMe shcha

BM Nora ROSIN, Ph.D

A OSI 4 i 4 TYA t Ann, | | MNA with MNA SU i z a : M h

Вб мМ у о о - с з» Kk. 4 2

Scheme - I 7 sl.

PREPARATION OF ORTHO-HYDROXYHETEROAROMATIC CARBOXYLIC ACIDS 1. o Preparation of carboxylic acids 1 (X1-M, X»-Xz3-CH, X/- independently of C-Me, C-ZMe, C-CI) is shown in d) 20 Scheme 2. Reaction of 3-hydroxy-2-bromopyridine (5) with 2-(trimethylsilyl) ethoxymethyl chloride (ZEM-CI) using potassium tert-butoxide as a base in a 1:11 mixture of dimethylformamide (OME) - tetrahydrofuran (THE) led to the formation of the necessary of ether 6. Removal of ether b with lithium diisopropylamide (I0A), followed by condensation with an appropriate electrophile (iodomethane, dimethyl disulfide, or hexachloroethane) led to the formation of 4-substituted pyridine 7. 52 Bromine/lithium exchange between pyridine 7 and p-butyllithium (p-Vi!y) followed by carboxylation

F! carbon dioxide (CO,) and acid hydrolysis led to the formation of the necessary 4-substituted-3-hydroxypicolinic acid 1X. ime) 60 b5 de ОН de. Du OSTUOSN, SN, VIMe,

YO - ssnosnusn,imMe, VOK

ZV OMRLNE b ' M Vk. 5 6

Х осн,осн,сН,ВиМе, и 6 (А (2) Evvsigorne s

І МОСВе 7 х on sai .

M; (9 l-Vits and so i 2) so, m7 son (3) Not their sch (8)

Scheme 7 p

Alternatively, 3-hydroxypyridine (8) can condense with BZEM-C1 to form 9 (Scheme 3). Separation of 9 using tert-butylethyl (I-Vy!) followed by condensation with M-fluorobenzenesulfonimide led to the formation of 4-fluoro derivative 10. The condensation of compound 10 with sodium ethylate led to the formation of diester 11.

Separation of 11 E-Viii followed by carboxylation and acid hydrolysis led to the formation of the necessary 4-ethoxypyridine 1X (X-OEV. i - « shi s z -I 1 (95) o 50

IR e)

F) name) 60 b5 od uon den Osn oSsN,SN,ViMe,

S Z BEMSI --- sh

M! Mn 9 8 ! 10.

IS

0 water day in OSN, OSN, SN, ZiMe, 9 - VSH z)2

I am also 40

Oyei dnu OSNITOSN, SN, ZIMe, and

Master of Science

IS ! he ( p. 144 I VSH Oso, | | so (I se m" sso,N so ikh o

IS) | Scheme 3 with

The preparation of acid chloride C is described in Scheme 4. Thus, 3-hydroxypicolinic acid (12) was converted to methyl ester 13 in aqueous methanol using boron trifluoride as a catalyst. Methyl 13 was then brominated using aqueous bromine to give dibromide 14. Benzyl ether 15 was then prepared by compacting compound 14 with benzyl chloride in the presence of sodium hydride. Stepwise methanol from compound 15 in methanol/potassium carbonate led to the formation of the 4-methoxypicolinic acid derivative 16. Conversion of compound 16 to the acid chloride C was carried out using oxalyl chloride using benzene as a solvent and a catalytic amount of OME. - And 1 (95) at 50

IR e)

F) name) 60 b5

Ve - ' 5, ! school

M son MO SSOYUN, you in ssoson, 12 13 14 ni

Vg Me db uOSsNR dnu OSNrA 14 0-3-4 I t--ya- sh- | -n-ya Z ve sm son, in seon 15 16

Scheme 4

PREPARATION OF 4-ETHOXY-3-HYDROXYPICOLINIC ACID (1, H.-M, Ho-Hz-SN, ХА-СОв) (SEE EM

SCHEMES 1 AND 3). at

Her village

A on so s - - m" teo,n s 2 i - a. PREPARATION OF 3-2--TRIMETHYLSILYL)ETHOXYMETHOXY)-PYRIDINE (9).

While stirring, solid potassium tert-butoxide (17.96 g, 0.1 bmol) was added to the solution of OME (100 ml) and TNE (100 ml). After dissolving the solid, the solution was cooled to 59 °C and the solution was immediately added

of 3-hydroxypyridine (14.25 g, 0.15 mol). After stirring for 10 minutes, the mixture was cooled to -10 C with s and ZEM-SI, 25 g, 0.15 mol was added dropwise at such a rate that the internal temperature remained at

From" is equal to "-590. After the end of mixing, the mixture was stirred at 02C for 1 hour, and then for another 2 hours at room temperature. The mixture was poured into water (b00ml) and then extracted with ether (3x150ml). The ether extracts were combined and successively washed with 2M Mahon (100ml), water (50ml), and saturated with Masi-15 solution (100ml), dried (Mo5O)) and concentrated to a brown liquid. The necessary ether 9 was obtained by distillation in the form of a colorless liquid (20.8 g), because 95-999C (F 0.0Zmm Na. 1 b. PREPARATION OF 4-FLUORO-3-(2--TRIMETHYLSILYL) ETHOXYMETHOXY) PYRIDINE (10). While stirring, I-Vi!i (4 ml, 1.5 M pentane solution) was slowly added to a solution of 9 (12.39 g, 0.055 mol) in ether (200 ml) cooled to -709C in an atmosphere of 50 argon. During mixing, the reaction temperature was maintained at -682C. After the end of mixing, the mixture was stirred for an additional 60 minutes at -709С, and then passed through a cannula with stirring to a solution of M-fluorobenzenesulfonimide (18.92g) in dry TNE (200ml), which was also cooled to -702С in an argon atmosphere. After mixing, the cooling bath was removed and the reaction temperature was brought to room temperature. They added

Water (100 mL) and the organic phase were separated, dried (MazO)) and concentrated to form a brown oil.

Chromatography (silica gel, hexane-acetone, 9:11) afforded the desired product 10 as an orange oil (7.5 g) containing approximately 1595 starting material. This crude mixture was used directly in the next reaction. in. PREPARATION OF 4-ETHOXY-3-2--TRIMETHYLSILYLETHOXYMETHOXY)PYRIDINE (11). 10 (1.07g, 4.4mmol) was added to a solution of sodium ethylate (0.9g, 13mmol) in ethanol (10ml) while stirring.

The resulting mixture was stirred at room temperature for 48 hours, and then poured into water (100 ml).

The resulting mixture was extracted with ether (3x50ml). The ether extracts were combined, dried (M95045) and concentrated. The obtained amber oil was chromatographed (silica gel, hexane-acetone, 4:11) to give compound 11 as a yellow oil (O.bg). 65 g. 4-ETHOXY-3-PDROXYPYRIDINE-2-CARBOXYLIC ACID (1, X,-M, X»2-Xz-CH, X.-SOEU.

With stirring, a solution of 11 (2.9 g) in TNE (5 Oml) in an argon atmosphere was cooled to -702С. To it was slowly added E-Vii and (vml, 1.5 M solution of pentane), the reaction temperature was maintained at the level of -6690. After the end of mixing, the mixture was stirred at a temperature of -702C for 45 minutes, and then poured onto a suspension of crushed solid carbon dioxide in ether. The resulting mixture was stirred until reaching room temperature, after which the solvents were evaporated. TNE (25ml) and 4M HC 1 (15ml) were added to the residue and the resulting mixture was stirred at room temperature for two hours. At the end of this period, the insoluble material was filtered off, washed with a small amount of TNE and air dried to give the title compound as a white solid (1.05G).

PREPARATION OF 6-BROMO-3-BENZYLOXY-4-METHOXYPYRIDINE-2-CARBOXYLIC ACID (16) AND ITS 70 ACID CHLORIDE (3) (SEE SCHEME 4). Ev. che sia s s m" so, s: " 16 3 9 a. PREPARATION OF METHYL 4,6-DIBROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (14).

Water (800 ml) and methyl 3-hydroxypyridine-2-carboxylate (15.3 g) were added to a 2-liter flask with necks, a funnel for scaping, and a mechanical stirrer. Bromine (32 g) was slowly added to this solution while stirring. During the course of the reaction, a solid substance was separated from the solution, and the reaction mixture was left to thicken.

After mixing, the mixture was vigorously stirred until the bromine color disappeared. "H-"H-NMR (SOCI3) of a small sample of the crude product showed that the ratio of mono to dibrominated product was 3:1. Sodium carbonate (31.8g) was slowly added to the reaction mixture and additional sobromine (12g) was added dropwise. After the disappearance of the bromine color, the reaction mixture was adjusted to approximately pH5 with concentrated HCl, and the resulting mixture was extracted with CHClCl (3x150ml). The organic extracts were combined, dried (MazO)) and concentrated to form an orange solid (14g). This substance o can be recrystallized from methylcyclohexane (after treatment with charcoal) to give substance 14 as a white solid, e.g. 181-18320. b. PREPARATION OF METHYL 4,6-DIBROMO-3-BENZYLOXYPYRIDINE-2-CARBOXYLATE (15). -

With stirring, solution 14 (7.1 g) was slowly added to a solution of sodium hydride (0.bg) in OME (50 Oml). After mixing, the mixture was stirred at room temperature for 15 minutes, and then benzyl chloride (3.05 g) was added. The mixture was then heated to 902C for six hours, cooled, poured into water (500ml) and extracted with ether (2x200ml). The ether extracts were combined, washed with 2M NaOH (50ml), dried (Ma5O)) and the solvent was evaporated to give compound 15 as a light yellow solid (8.3g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-7696. from 6-BROMO-3-BENZYLOXY-4-METHOXYPYRIDINE-2-CARBOXYLIC ACID (16).

With vigorous stirring, compound 15 (25.5g), potassium carbonate (75g) and methanol (300ml) were heated at reflux for 30 hours. The mixture was cooled, poured into water (80 Oml), and the pH level was adjusted to 2 by -1 addition of concentrated NCI. The resulting mixture was extracted with CH 25СИ (Хх15Омл). The organic extracts were combined, dried (Mo5O)) and the solvent was evaporated to give an almost colorless oil (20.5g), which slowly solidified on standing. it was recrystallized from methanol (125 ml of water (40 ml) to form 2) of the required acid 16 (11.6 bg), m.p. 134-13590. g. PREPARATION OF 6-BROMO-3-BENZYLOXY-4-METHOXYPYRIDINE-2-CARBONYL CHLORIDE (3). Oxalyl chloride (1.90g, 15mmol) was added dropwise to a solution of 16 (2.54g, 7.5mmol) in benzene (30ml) containing OME (Z drops) while stirring. After the end of gas evolution (approximately 45 minutes), the new homogeneous solution was stirred for an additional 15 minutes, after which the solvent was evaporated. 1,2-dichloroethane (3 mL) was added, and the solvent was evaporated again to form a certain amount of substance C as an almost colorless oil. This. the substance was dissolved in CH 2Si" (1Oml) or TNE (1Oml) and used directly in the following combination reactions. iF) 6-BROMO-3-HYDROXYPICOLINIC ACID (17). name) 60 b5

; zn so,n to 17

Bromine (32g) was slowly added to a mechanically stirred solution of methyl Z-hydroxypicolinate (30.bg) in water (80Oml) over 30 minutes. After the addition was complete, stirring was continued for an additional 1 hour. Ether (100 mL) was added with continued stirring until the solids dissolved. t The organic layer was separated and the aqueous phase was extracted with ether (200 ml). The organic phases were combined, dried (M9503) and the solvent was evaporated to give 32.8 g of methyl b-bromo-3-hydroxypicolinate as a yellowish solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117960,

When stirring, a solution of GION HNO (1g) in water (/ml) was added to a solution of this complex ether (2.32g) in TNE (15ml) ZO. The resulting mixture was stirred for 2 hours at room temperature, then poured into water (100 ml). The pH level was adjusted to about 3 1M HCl, after which the mixture was extracted with CH 5Si" (3x100ml).

The organic extract was dried (M9504), filtered and concentrated to give 2.0 g of a white solid whose TN-NMR and MS matched the required acid listed in title 17. 3-BENZYLOXY-6-METHOXYPICHOLINE ACID (18). sch o c) s y so

Meo7 o bm7 "so,n yu i -

A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3-chloroperoxybenzoic acid (5.75 g, 6095 peracid) in SNHSO (100 ml) was stirred at room temperature for 40 hours. The reaction mixture was extracted at 596 V with a solution of sodium bisulfite (10 Oml), and then with a solution of 0.5 M Mahon (15 Oml). After drying (Mo5o/), the solvent was evaporated to form 4.9 g of methyl 3-benzyloxypicolinate-1-oxide in the form of a white solid. Recrystallization from methylcyclohexene/toluene leads to the formation of a crystalline solid, m.p. 104-10690.

A solution of this compound (16.1g) in acetic anhydride (80ml) was stirred and heated in an oil bath at -1252C for 3 hours. Excess acetic anhydride was removed on a rotary evaporator, and the residues were collected in 1 methanol (200 ml). Concentrated sulfuric acid (ml) was added, and the resulting mixture was heated at reflux for 90 minutes. The solvent was evaporated, and saturated sodium bicarbonate was added to the residue. The obtained mixture was extracted with СНоСиИ» (3х100 ml). The organic fractions were combined, dried (Ma5O)) and the solvent was evaporated (95) to give 15.5 g of methyl 3-benzyloxy-6b-hydroxypicolinate as a yellow solid. co Recrystallization from toluene led to the formation of a pale yellow solid, m.p. 91-9296,

With stirring, silver carbonate (16.bg), and then methyl iodide (8.52g) were added to a solution of this compound (10.25g) in toluene (125ml) heated in an oil bath at 602C. The resulting mixture was stirred and heated for 3 hours to 6020. After cooling, the mixture was filtered through Seille? and the solvent was evaporated to form a yellow oil. Silica gel chromatography (4:11 hexane/acetone) gave an almost colorless oil whose TN-NMR and MS data were consistent with methyl 3-benzyloxy-b-methoxypicolinate. Hydrolysis of the ester to the title acid 18 was completed as described above for similar esters. 4-HYDROXYPYRAMIDINE-5-CARBOXYLIC ACID (19). 60 b5 cue i

What the hell

There are 19

Ethyl 4-hydroxypyrimidine-5-carboxylate can be prepared by following the IM procedure. Rezzop ei ai, Eig.

U. Med. Spet.-Spet. Tag; 1974, 9, 585). A solution of this complex ester (500mg, Zmmol) in TNE (1Oml) and meon (ml) was treated with HION.H2O (37Zmg, 8.9mmol) and stirred overnight. The mixture was quenched with concentrated HCl (1 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts were dried (Ma 5 O)) and concentrated to give 26 bO 0 mg of the title compound 19 as an orange solid, m.p. 22090 (day). 4-HYDROXY-2-METHYLPYRIMIDINE-5-CARBOXYLIC ACID (20).

M ON

WITH

M y s so, (o) s

Ethyl 4-hydroxy-2-methylpyrimidine-5-carboxylate was prepared following the procedure |Seiivzzztap ei aiI., 9. Ogd. Spet., 1946, 11, 741). A solution of this ester (75Omg, 4.11mmol) in TNE (1Oml) and Mmeon O (bml) was treated with HyOH.NO (431mg, 10.Zmmol) and stirred overnight. The mixture was quenched with concentrated HCl (1 mL) and extracted with EAs (2x20 mL). The combined organic extract was dried (M950.4) and concentrated to give 155 mg of the title compound 20 as a white solid, m.p. 1802C (December). h- 5,6-DICHLORO-3-HYDROXYPYRAZINE-2-CARBOXYLIC ACID (21). yeah

Y 3 s and V

Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) was stirred in concentrated sulfuric acid (140 mL) and cooled to 02C. Sodium nitrite was added slowly, maintaining the temperature at about 02C.

After an additional 30 minutes at 02C, the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was poured over 500 g of ice, which led to boiling and foam formation. c After 30 minutes, the mixture was extracted three times with EOAc. The combined organic extract was dried (Mo2O), filtered and concentrated. The remaining yellow solid was washed with water and air-dried to obtain 5.0 g of a yellow solid, m.p. 114-116 "S. the 136-NMR spectrum of which coincides with the methyl ester of the compound indicated in the title.

This solid (5.0g) was treated with 1M Mahon (20ml) and the mixture was heated at 902C for 1.5 hours. o After cooling, the mixture was oxidized with concentrated HCl, and then extracted three times with EtOAc. Drying ime) (М95О)), filtration and concentration led to the formation of 0.48 g of a dark yellow solid whose 1C-NMR and MS spectra coincided with the title acid 21. bo 6-CHLORO-3-HYDROXY-B-METHOXYPYRAZINE -2-CARBOXYLIC ACID (22). b5

Mebh M ON 1 2 o " y sy tyu teo, y 22

With stirring, a solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0g, 23mmol) and sodium methylate (3.bg, 67.5mmol) in absolute MeonH (50ml) was heated at reflux for 2 hours, then /5 allowed to cool and oxidized with concentrated NSI. The precipitate was collected by filtration, washed with water and air-dried to form a 3.bg brown solid. Recrystallization from hexane-EOAc (1:1) led to the formation of 2.6 g of a pale yellow solid whose spectra coincided with methyl

C-amino-b6-chloro-5-methoxypyrazine-2-carboxylate.

This compound (1 g, 4 mmol) was collected in concentrated sulfuric acid, cooled to 09C, and slowly treated with sodium nitrite (0.5 g, 6 mmol). After 30 minutes at 02C, the mixture was poured onto 300g of ice/water, resulting in foam formation. Stirring was continued for 30 minutes, after which the solid was collected by filtration and washed with water. The wet solid was taken up in EtOAc, dried (Ma5O), filtered, and concentrated. This led to the formation of 0.95 g of a yellowish solid, tp. 180-1822С, the 1H-NMR spectra of which coincided with methyl c-chloro-3-hydroxy-5-methoxypyrazine-2-carboxylate. (5)

This solid (0.9g, 4.1mmol) was treated with 1M Mahon (bOml), and the mixture was stirred for 1 hour, after which it was oxidized with concentrated HCl. The precipitate was collected by filtration and washed with water and dissolved in EtOAc, dried (Mao 5 O 4 ), filtered and concentrated. This resulted in the formation of 0.62 g of a pale yellow solid, m.p. 25 170-1732С, the spectra of which coincided with acid 22 indicated in (ee) title. c 4-HYDROXYISOTHIAZOLE-3-CARBOXYLIC ACID (23).

This acid was obtained by performing the procedure shown in scheme 5. 2 You. uh-

Ve So, zu ogad -Sh it / , 47 1) he Z s sh NO son Sho , x i 2) NS, no -M 5 -I i-y Scheme 5 o 50

So, when stirring to a solution of solid KOH (8895, 6.98 g, 0.11 mol) in 7 bml of EUN in a flask,

IR e) washed with nitrogen, added thiolacetic acid (8.36 mg, 0.11 mol), washed with 25 ml of EUN. The mixture was stirred under nitrogen for 5 minutes in a sealed flask. To this solution was added 0.1 mol of crude bromine-substituted substance (prepared immediately before this by the method of M. Naiyapak and T. Izpitat, U). Honey. Spet., 1973, 16, 7981). The flask was flushed with nitrogen and sealed. The mixture was stirred in a water bath for 3 hours, after which 30 ml of CHClCl and 1000 ml of water were added. The aqueous layer was extracted four times with 200 ml of CHCl.

The combined organic extracts were washed with 100 ml of cold water, saturated with saline and dried. i.e.) The crude mixture was filtered and concentrated. The resulting oil was chromatographed on silica gel using diethyl ether as eluent to give 13g of a light yellow oil which was allowed to solidify at 60° on settling to a resinous solid. Spectral data coincided with ethyl 2-acetylamino-4-acetylthio-3-oxobutanoate.

With vigorous stirring of a solution of this compound (12.95 g) in 45 x 0 ml of chloroform, cooled in a water bath to a temperature of 52C, bromine (15.8 g, 2 equivalents) was added dropwise in 10 ml of chloroform for 45 minutes. Stirring was continued in an ice bath for another 45 minutes, and then at room temperature. b5 of the environment - for another 30 hours. After that, the mixture was washed with 200 ml of water, after which - another 100 ml of water. The combined washing products were re-extracted with 100 ml of chloroform. The combined chloroform solutions were washed with saturated saline and dried over NaClO). The solution was filtered and concentrated to a crude oil. The latter was chromatographed on silica gel using a serial gradient from petroleum ether -СНоОСИ" (3:11) to СНоОСи" to form the first 0.79 g of ethyl 5-bromo-4-hydroxyisothiazole-3-carboxylate, and then -3.40 g of ethyl 4-hydroxyisothiazole -Z-carboxylate in the form of colorless crystals, etc. 44-72C, which coincided by MS and TN-TN-NMR.

To 710mg of the last complex ester in 30ml of TNE, 370mg of GION.NOO (2.2 equivalents) in 100ml of water was added.

The mixture was stirred for 3 hours at ambient temperature, and then cooled in a refrigerator. The solid substance - the precipitate was collected by filtration to form 71Omg of the dilithium salt of 70 carboxylic acid. This salt was collected in 7 ml of water, cooled in an ice bath, and adjusted to the pH level by adding 2 M CARRIER. The resulting solution was extracted three times with 5 mL EAs. The combined extracts were washed with bml of brine, dried (Ma»5O)), filtered, and the filtrate was left in the refrigerator.

The cooled solution was filtered, and the filtrate was concentrated to give 2300 mg of a colorless solid, m.p. 185-899C, the TN-NMR and 3C-NMR spectra of which coincided with the compound 23 indicated in the title.

3-BENZYLOXY-1-METHYLPYRAZOLE-4-CARBOXYLIC ACID (24) 5-BENZYLOXY-1-METHYLPYRAZOLE-4-CARBOXYLIC ACID (25). 7 NN. o iRY M O.R -h M vi still so, sleep sch o 24 25

A solution of ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate and ethyl 5-hydroxy-1-methylpyrazole-4-carboxylate so 3o (obtained by the process |U. UMapa, ei ai., 7He|)apud bSopdhoeutsap Hierao, 1994, 2, 67 |), were benzened according to the method "9

FROM. Hatatoyo, ei ai)., Japan Patent UR 62148482, 1987), and the mixture was separated by column chromatography, using 31 hexanes: EtOAc as eluents to provide ethyl o

3-benzyloxy-1-methylpyrazole-4-carboxylate and ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate, pure, M) for TN-NMR. M

Ethyl 33-benzyloxy-i-methylpyrazole-4-carboxylate (283mg, 1.08mmol) in TNE (10ml), Meon (2ml), and water (5ml) was treated with HYOH.H2»O (91mg, 2.17mmol) and stirred overnight . The mixture was quenched with concentrated HCl (1 mL) and extracted with E(Ac (2x20 mL). The combined organic layers were dried (NaSO4)) and concentrated to give a white solid (227 mg), m.p. 169-172 oС, the spectra of which coincided (with "

3-benzyloxy-1-methylpyrazole-4-carboxylic acid (24). shsh c Ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) was hydrolyzed in a similar manner with the use of GION.H OO (24 mg, 5.dmol) in TNE (20 ml), Meon (4 ml), and water (1Oml), until the formation of 8mg "" 5-benzyloxy-1-methyl-4-carboxylic acid (25) in the form of a white solid, m.p. 117-12296.

PREPARATION OF OTHER HETEROAROMATIC CARBOXYLIC ACIDS. 4-Hydroxynicotinic acid was prepared (according to the process of M. MiKeirasii ei ai!., Agsy. Rpagt. (Uueippeit, Segtapu) -I 1985, 318, 481-486). 2-Hydroxy-6-methylnicotinic acid can be prepared according to the following method |A

BOogpomu, Spet. Veg 1940, 73, 153). 4,6-Dimethyl-2-hydroxynicotinic acid can be prepared according to the i-th method of K. Magie and E. WeiIspeg, U. At. Spent os, 1951, 73, 2616). 5-Chloro-2-hydroxy-b6-methylnicotinic acid can be prepared according to the process of A. Sae sei. a)., U. Med. Spet., 1989, 32, 2178) 2,5-Dihydroxynicotinic acid can be prepared according to the method of R. Mapika-MatigeKi and A. Kukomuzki,

Mami Speth. Abrvig., 1972, 77, 114205). 3-Hydroxyisonicotinic acid was prepared (according to the method.). Y. Stit and S. N. s Eysiztap, u. Self-employed. Spent 1966, 3, 252-256). 3-Hydroxypyrazine-2-carboxylic acid can be prepd

According to the methodology of R. Kharspo ei ai., u. Selfless. Spent 1997, 34,27). 5,6-Dimethyl-3-hydroxypyrazine-2-carboxylic acid can be prepared by hydrolysis of the corresponding ethyl ester, the synthesis of which is described in 5. I. 7amuaIom and A. G. 7amohip, Igm. Akai. Mak ZBK, 1980, (5), 1067-1070). 4-Hydroxypyridazine-3-carboxylic acid was prepared according to the method of I. Ispitoio, K. Etsia, and S. o Taivyti, Adgis. Vioi Spent 1967, 31, 9791. 3,5-Dihydroxy-1,2,4-triazine-b-carboxylic acid was prepared by the EE method. Baiso, E. Rarra5z, and GG. Niisnipd5, 9. At. Spent Bos, 1956, 78, 1938) 5-Hydroxy-3-methylthio-1,2,4-triazine-6-carboxylic acid was prepared according to the method of K. Vagiozhm and A. Uueisiy, 9. At. because Speth bos, 1956, 78, 12581. Hydroxyisothiazole-, hydroxyisooxazole-, and hydroxypyrazole-carboxylic acids were prepared by Yiza by the TT method. M. MMUyvop ey a), Vioogd. May Spent Hey, 1996, 6, 1043)

3-Hydroxy-1,2,5-thiadiazole-4-carboxylic acid was prepared according to the method.). M. Kozz eyi aYi., U. At. Spent os, 1964, 86, 28611. 3-Hydroxyisooxazole-4-carboxylic acid was obtained according to the method (described by K. Vom/Department of AI, 9U. Spect. bos. (C), 1968, 1721. З3-Hydroxy-1- phenylpyrazole-4-carboxylate was prepared according to the method of MU. 65 Tauyug and KK. T. SooK, Teiapeygop, 1987, 43, 607). 3Z3-Benzyloxyquinoline-2-carboxylic acid was prepared following the procedure (0. I. Vodeg et al.). N. Spep, 9. Ogd. Spent 1995, 60, 7369-73711.

GENERAL PREPARATION OF INTERMEDIATE AMINES AND ANILINES.

The synthesis of cyclic, acyclic and benzylamines was carried out by reduction of the corresponding oximes or by using metal hydrides or metal dissolution reactions (as described by K.O. Niispips and M.K. Niispips ip Sotrgepepzime Ogdapis Zupipeziv; V.M. Tgovi, Ed.; Regdatop Rhevzv: Ohio, 1991; Mo! 8, p. 65; or 0MU.

Nyitap ip Sotrgepepzime Ogdapis Zupipevziv; V.M. Tgovy, Ed.; Regdatop Rgevzv: Ohio, 1991; My! 8, p. 124).

In contrast, these amines can be prepared directly from the required ketones and aldehydes by reaction

Y eisKagi, (as described by K. Sagivop, T. I eiop, T. I opeiiiedi and E. I eSioceges, Asia Spet, Zsapa. 1993, 47, 1046).

Anilines in general were prepared by catalytic reduction of the corresponding nitroaromatics with the use of Pa/o on charcoal or sulphided platinum on charcoal as a catalyst. These procedures are documented, (for example, in K.Y. A!tsdyzviipe, SaiyaMmis Nuaygodepayop, Magse! JuOeskKeg, Ips., Mem

MogK, 1965).

Amines 49, which represent 9-membered dilactone ring systems, were prepared according to the procedure (described

M. Zpitapo, M. Katei, T. Zpiraya, K. Ipodispi, M. Moi, T. Ikagi and N. Bepda, Teigapedgoop, 1998, 54, 12745), or by modifying these procedures. Similar modifications are shown in Scheme 6. Thus, 26 (from the reference above) was reduced with lithium borohydride, and the resulting primary alcohol was capped with triisopropylsilane (TIR5) to form compound 27. The free hydroxyl group of compound 27 reacted with 1-bromo- 2-methyl-2-propene followed by catalytic reduction of the double bond to form substance 28. Selective removal of the para-methoxybenzyl (PMB) blocking group followed by compaction

IU4-BOC-0-benzyl-l-serine led to the formation of substance 29. Removal of the TIRZ group followed by oxidation of the resulting hydroxy group led to the formation of substance 30. This substance (30) was further converted into amine 31 according to the procedures, described in the above references. at

N V, s ay, (5) ni /o 9 M, in: i V, in Nn

And d) ko

Kk, r 49 o iv) in - ovi r 5th vmy i n tmvosuzitotiv RM in tot « ! 1 eny and i I re and 7 o you o Goshe? with . » " 25 p in -And I am a point in both? A

Fo niv sew A AD vo. s 50 typhoid t t on pory rt otu h o iy o o o chi 39 a

Scheme 6

F) eat) In the same way, the synthesis of aminodilactones 38 and 48, with a deficiency of the exocyclic ester functionality, is described in Schemes 7 and 8, respectively. 60 b5

Fn o Shchi n, un, a 8. a yi 5 ı i ne A - it o 1 sha o m Mys tov i Kn nd" Tov o kh p Selkhdzheguyuyutu zi za is. | (M. mo mryi, o o sleep, sleep, o n -ru "and return to study he from him i pen o loto at 12 and from z "bok a z i i vo o o o o sleep, (OSS, DMAR, SNY, (V) SSE, SO tsiv , SNALYCH,O; (F Sg, Aed, Ru KO SE SO in 40) Ayutitmoi 2, Valya RE; 4) 1.0 m lasyu,. bala, SNSM: (d) RU asku, SNION Ha o

Scheme 7! s o o 7 oh RASN, y Rys s R o

Oh would -- vo es pe sha o no sn, sn, sn, yu 39 42 "y -

OomMeo 2. pi . . a, in 9 n, snun ' o ON Suvora « n BOS. Dec -0 VOsMN.

Bach -I 2 pere 1 o sn, sn.RI Sn, SNR nak nm o on and osn. ono kozh s 50 OV o my on o o SNR (Che "5 . Sho mlniznNOas o. miz"zn (a) On 10 ROS, sn,on, NSB (BI rtasi, EM, OMAR, SN.SI; (c) Well. 10 ROS, ED; (4) IVAN,

ECO; (c) 1,3-ryuralao, VRUOEH SNU (P ES, OMAR, OME; (9) (SRSOiRA, SNuSM, NGO; (VU o St, ASON, rug (No RYS, Ed: () BILO, RAV, Vepgale (k) СЕ, СО, Н ho) Scheme 85 60

PREPARATION OF SUBSTANCE 27 (SEE SCHEME 6).

0.1 ml of trimethyl borate was added to a solution of lithium borohydride (2.0 M in TNE, 7.Bml, 15 mmol) in 7.5 ml of dry TNE. This mixture was cooled in a nitrogen atmosphere to -309C. To this solution, a solution of compound 26 (4.58 g, TOmol) in TOml TNE was added dropwise for 10 minutes. The solution was stirred at a temperature of -30 C for 1 hour, and then at a temperature of 09 C for 5 hours. Saturated ammonia solution (1 Oml) was added dropwise, the mixture was stirred for 10 minutes, and the phases were separated. The aqueous phase was extracted with EAs (2x25 ml), and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and evaporated to dryness. The crude product was chromatographed to give 2.1 g of a white solid. The sample was subjected to recrystallization from hexane-EtOAc until the formation of small white crystals, m.p. 91-932C. | |p29--31.92 (С-1.04, SNSIz). This diol (2.04g, 6.22mmol) was dissolved in 4ml of dry OME and imidazole (b8Omg, 1Ommol) was added. The solution was cooled in an ice bath, and then triisopropylchlorosilane (1.39 mL, 6 b.b.mmol) was added over 2 minutes. The mixture was stirred at room temperature for 4 hours, then added to ice water and extracted with 2095 ether in hexane (3 mmol). 70 The combined organic phases were washed with brine, dried, and filtered through a short silica gel filter which was washed with 20 mL of this solvent. The solvent was evaporated until 2.77 g of substance 27 was formed as a pale viscous oil, purified by TN-NMR.

PREPARATION OF COMPOUND 28 (SEE SCHEME 6).

Sodium hydride (6095 oil dispersion, 400mg, TOmmol) was poured into a 50ml flask and washed three times with hexanes. 75 OME (15 ml) was added and the suspension was stirred while adding compound 27 dropwise over 15 minutes (2.53 g, 5.19 mmol) in 5 ml of dry OME. The reaction was stirred for 15 minutes and then cooled to below 109C, and 1-bromo-2-methyl-2-propene (iml, 17 mmol) was added over 5 minutes, followed by stirring for 2 hours at room temperature. The mixture was partitioned between hexanes/ice-cold ammonia solution obtained during the preparation of compound 27, and the crude product was chromatographed to give 2.20 g of a colorless oil, purified by H-NMR and elemental analysis. This substance (2.38 g, 4.4 mmol) was dissolved in bOml E(Ac) in nitrogen in a 100ml Morton flask. 15mg of 5905 RI on carbon was added, and the mixture was stirred under 1 atmosphere of hydrogen for 20 minutes. The catalyst was removed by filtration and the solvent was evaporated to give 2.35g of compound 28 as a colorless oil, which was purified by TN-NMR see

PREPARATION OF COMPOUND 29 (SEE SCHEME 6). at

A solution of ether 28 (2.0 g, 3.6 bvmmol) in 40 ml of SNiCl and 2 ml of water was poured into a 5-ml flask equipped with a magnetic stirrer. This solution was stirred under nitrogen and cooled in an ice bath at a temperature of 1095 with the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0003) (920 mg, 4.005 mmol. The ice bath was removed and the mixture was stirred the mixture for 1 hour at room temperature. The gold suspension was withdrawn by filtration, the crust was washed with 2 x 100 ml of CH»Si, the filtrates were extracted with 0.2 M Mahon (2 x 25 ml). The organic layer was dried and "o concentrated to give a pale oil, which was purified by chromatography to give 1.53 g colorless oil, which was purified by elemental analysis, was dissolved in 25 mL of CH 5Cl3 and stirred in an ice bath under nitrogen, followed by the addition of OMAR (854 mg, 7 mmol), EOSI (1.34 g, 7 mmol), and M--BOC-O- Scheo's benzyl-ii-serine (2.07g, 7mmol). The cooling bath was removed, and the mixture was stirred for 2 hours at room temperature. After that, the solution was poured into a mixture of 300ml of ice-cold 0.5M NSI and 20ml of СНоСИ with intensive stirring ” and continued to stir about for 10 minutes. The phases were separated and the aqueous phase was extracted from them! Oml SNeoSi"; then, the combined organic phases were dried and concentrated to give a pale oil. it was subjected to chromatography to give 2.30 g of compound 29 as an almost colorless heavy oil. TI C and "H-NMR were found to be sufficiently pure. - c PREPARATION OF SPOOKA 30 (SEE SCHEME 6). c The silyl ether of compound 29 was dissolved in 7 ml of dry pyridine and cooled in an ice bath. The HE-pyridine complex ( 4.5 ml), and the solution was stirred at room temperature for 17 hours, after which it was heated to 502C for 4.5 hours, after which the transformation was stopped. The mixture was poured on

Ice water and extracted with 3x5Oml of ether. The combined organic phases were washed with water, 1M MEDIA, then dried and concentrated to yield an oil. The latter was subjected to chromatography to form 1.23 g of the required alcohol in the form of a viscous oil, along with 3.5 mg of the regenerated compound 29. The alcohol (1.14 g, 2.10 mmol) was dissolved in 1 0 mL of OME, and pyridine dichromate (3.76 g, 10 mmol) was added. After 21 hours, the mixture was poured into (95) ice water, 1M NOSI was added until the pH dropped below three, then solid sodium 50% bisulfite was added until an orange color appeared. The aqueous phase was extracted with ether (3 x 5 mL). The organic phases were combined, washed, dried (Ma»5O)), and concentrated. The residue was chromatographed to yield 811 mg of a fairly pure viscous oil. The acid was dissolved in 30 ml of E(As) and 200 mg of the catalyst was added

Perlman. The suspension was shaken at a hydrogen pressure of 500 for 4 hours, 300 mg of fresh catalyst was added, and shaking was continued for another 2 hours. The substance was then filtered and the solvent evaporated to 255 form a viscous gum that was pure enough for further use. about TREONINDITIAN 33 (SEE DIAGRAM 7).

Pentildithian 32 |Nigaii, Ne(egosuYez 1990, 30 (2, res. Ivye), 1101) (20Omg, 0.97/mmol) was dissolved in 100 ml of СНоСі» at room temperature. M-(7)-O-II-Butyl-(I )-threonine (90mg, 2.91mmol) was added followed by

LOBSTER (Zbmg 0.29 mmol). To this mixture was added dropwise a solution of dicyclohexyl carbodiimide (OCS) (IM in bo CHClCl, 2.9 mL, 2.9 mmol) followed by stirring at room temperature overnight. The reaction was eluted with 5 Oml of ether (EBbO), filtered and concentrated. The resulting residue was poured onto a small gravity column (47) and eluted with hexanes/E(Ac 4:11. The eluent was collected from a silica gel column with subsequent purification by radial chromatography using hexanes/EOAc 4:1 as eluents. The fraction products were evaporated and stored in deep vacuum (4522 (F 0.Mtorr) to constant weight to form 500 mg of an almost colorless heavy oil identified as dithiane 33 (TI C B-0.32, "H-NMR).

THREONINECARBOXYLIC ACID 35 (SEE SCHEME 7).

Trionindithiane 33 (500 mg, 1.01 mmol) was dissolved in a 9:21 mixture of 100 ml of CH 33SM/NiO at room temperature.

(|bis(trifluoroacetoxy)iodo|benzene (6b5Omg, 1.5O0mmol) was added, and the reaction mixture was stirred for 10

MINUTES. Saturated Manso" (20ml) was added and E2BO solution (3x20ml) was extracted. The ether layer was dried over

Mao", filtered and concentrated. Aldehyde 34 was pure enough (TI C, GC/MS) for direct use in the next reaction. The crude aldehyde was collected in 15 bml (4.95 mmol) of CgO 3 reagent (prepared from 1 g of CgO 3 , 3 ml of SNUSO»H and 1 ml of pyridine) and stirred at room temperature overnight. The solution was eluted with 30 mL of cold water and extracted with EBO (30 mL). The organic layer was washed with 3 mL of 70 brine, dried (MaSO), filtered, and concentrated. The residues were purified by radial chromatography using 2:1 heptane/EuAc containing 296 CH33CO3H as eluent. Carboxylic acid 35 (120 mg) was sufficiently purified by TIS and H-NMR.

THREONINEHYDROXYCARBOXYLIC ACID 36 (SEE SCHEME 7).

Threonine carboxylic acid 35 (137 mg, 0.324 mmol) was stirred in 3 ml of trifluoroacetic acid for 75 10 minutes and the mixture was concentrated on a rotary evaporator. The residues were dried under high vacuum (0.05 mm) overnight. Hydroxy acid 36 (119 mg) was used directly in the next step.

M-Sr2-THREONINEBISLACTONE 37 (SEE SCHEME 7).

Threonine hydroxycarboxylic acid 36 (119 mg, 0.324 mmol) was dissolved in 1 ml of benzene and added

Alginioitm-2 (85 mg, 0.39 mmol) followed by the addition of triphenylphosphine (0.39 mmol, 101 mg), the reaction mixture was stirred overnight. The crude thioether was eluted with 15 ml of CH ZSM. 1.2 ml (1.1 mmol) of 1.0 M A9dSiO was poured into a separate flask equipped with an irrigation condenser; of a solution in toluene, with the addition of the following 32 ml of CHZSM. This solution was heated under reflux at a rate of 5-10 drops per second (oil bath -1602С). The thioether solution was then added dropwise through an additional funnel at the top of the condenser over 2 hours. The mixture was additionally drained for an additional 30 minutes, cooled and concentrated. The residues were eluted with 1 Oml of 0.5M KSM and extracted with benzene (3x20ml). The benzene layer was combined, washed with 20 ml of water, dried (Mao"), filtered and concentrated. The residue was then taken up in 1 mL of 2:11 pentane/EPO and filtered. The solids were washed with 2:1 pentane/BO and the combined organic solution was concentrated. Radial chromatography (2:11 pentane/Eb2O as eluent) led to the formation of 34 mg of bislactone 37, sufficiently purified TI C (B-0.22) and "H-NMR. with 3-AMINO-4,7,9-TRIMETHYLBISLACTONE 38 (SEE SCHEME 7).

M-Cr2-threonine bislactone 37 (34 mg, 0.097 mmol) was dissolved in 100 ml of methanol in a 500 ml Parr flask and purged with nitrogen. 1 mg of Ra (black) was added to this solution and the mixture was shaken at 45 bar of hydrogen pressure for 1 hour. The catalyst was filtered off and the solvent was evaporated to form free amine 38 (2Omg, 100905). yu

This amine was quite pure ("H-NMR") and was used as such without further purification. 3-BENZYL-4-HYDROXY-5-METHYLBUTYROLACTONE 40 (SEE SCHEME 8).

Pentanoic acid 39 |Zpitapo ei ai., Teiapedgop Gen. 1998, 39, 4363) (1.8 g, 5.23 mmol) was dissolved in

ZOml of methanol in a 500ml Parr bottle and purged with nitrogen. 150 mg of 1095 Ra on carbon was added to this solution, followed by the addition of 6 drops of concentrated NSI. The mixture was shaken at 5 bar of hydrogen pressure for 3 hours. The catalyst was filtered through diatomaceous earth, and the solution was concentrated. The residues were collected in 3 mL of 70 mL of sodium chloride and washed with water (1 x 1 mL). The solution was dried with M9505;, filtered, and concentrated. Crude with 7H-NMR and GC/MS proved purified butyrolactone 40 and 4-methylanisole in a ratio of 4:1 (v/v). This substance (6095 of GC purity) was used directly in the next reaction. 3-BENZYL-B-METHYLBUTENOLYDE 41 (SEE SCHEME 8).

3-Benzyl-4-hydroxy-5-methylbutyrolactone 40 (6095 purity, 1.7g, 8.25mmol) was dissolved in 25ml of CHCl and cooled to 092С. The solution was stirred with the sequential addition of triethylamine (2.3 ml, 16.5 mmol),

LOBSTER (500 mg, 4.13 mmol) and p-toluenesulfonyl chloride (9.0 mmol, 1.7 g). The reaction mixture was warmed to room temperature and stirred for 30 hours. The reaction mixture was eluted with 5 bOml E2O and washed with 595

Ha Manso»z (25 ml). The solution was dried Mo5O), filtered and concentrated. The residue was purified by 5p radial chromatography using 2:1 pentane/ET2O as eluent with a yield of 677 mg of butenolide 41 (29595

Mn purity by GC and "H-NMR). so siv-4-BENZYL-B-METHYLBUTYROLACTONE 42 (SEE SCHEME 8).

3-Benzyl-5-methylbutenolide 41 (677 mg, 3.ppmmol) was dissolved in 30 ml EtOAc in a 50 ml Parr flask and purged with nitrogen. ZOOmg 1095 Pa/C was added to this solution and the mixture was shaken at 45% hydrogen pressure overnight. The catalyst was filtered off and the solvent was evaporated. The residue was purified by radial chromatography using 2:11 pentane/EGD as an eluent to give 484 mg of a colorless oil (7195 yield of pure substance by "H-NMR in SOS" and by GC). 2-BENZYLPENTYLDITHIAN 43 (SEE SCHEME 8 ). siv-3-Benzyl-5-methylbutyrolactone 42 (550mg, 2.89mmol) was dissolved in 15ml of ESB2O and cooled to -78960. 60 Diisobutylaluminum hydride (1.OM in hexane, 3.47mmol, 3.5ml) was added dropwise and the solution was stirred at -182 C for 2 hours. Methanol (3 mL) was added over 15 minutes and the reaction mixture was stirred at -182 C for an additional 30 minutes. Sodium potassium tartrate (1.65 g in 5 mL water) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The layers were separated and the aqueous layer was extracted with EBO (2 x 10 mL). The combined ether layers were washed with sat.

5 ml of СНоСи" and cooled to 02С. 1,3- Propanedithiol (3.4 mmol, 0.35 mL) was added followed by 0.37 mL (2.89 mmol) of boron trifluoro etherate. The reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated Manso 3 was added (20 ml) and the mixture was stirred for 1 hour.

The layers were separated and the aqueous layer was extracted with CH 2Si" (2x1Oml). The combined organic layers were washed with brine (1x20ml), dried over Mad5O5, filtered, and concentrated. The residue was purified by radial chromatography using 3:1 hexane/E(Ac) as eluent to give 5 mg of a yellow oil (6995 yield of pure substance by H-NMR and GC) identified as dithiane.

SERINDITIAN 44 (SEE DIAGRAM 8). 2-Benzylpentyldithiane 43 (5 mg, 1.99 mmol) was dissolved in ml of HOME and cooled to 02С. OM AR (0.29 mmol, Zbmg) was added, followed by the addition of EOSI (0.57 g, 2.98 mmol). After that it was added

M--BOC-O-benzyl-(I)-serine (7bOmg, 2.58mmol) followed by warming to room temperature and stirring at room temperature overnight. The reaction mixture was poured with vigorous stirring into 10 ml of ice-cold 0.5 M NaOH and 20 ml of 2095 ether/hexanes and stirred for 10 minutes. 12 The layers were separated and the aqueous layer was extracted with 2095 ether/hexane (1 x 1 Oml). The combined organic layers were washed with 0.5M HCl (200ml) and brine (2x20ml). The solution was dried with MaZO"), filtered and concentrated.

The resulting residue was kept under high vacuum (452 (F 0.1 torr) to constant weight to yield 1.06 g of an almost colorless heavy oil identified as dithiane 44 (TI C K0.3, 3:1 hexanes/EUAs).

M--VOC-O-BENZYLSERINECARBOXYLIC ACID 45 (SEE SCHEME 8).

Serindithian 44 (1.06 g, 1.90 mmol) was dissolved in 20 ml of a mixture of 9:11 CH with CM/H»O at room temperature. (Bis(trifluoroacetoxy)iodoi|benzene (1.2g, 2.82mmol) was added and the reaction mixture was stirred for 10 minutes. Saturated with Manso, (4Oml) was added and EBO solution (Z X 40ml) was extracted. The ether layer was dried

Ma5O, was filtered and concentrated. The aldehyde was sufficiently pure (TC, GC/MS, "H-NMR) for direct use in the next reaction. The crude aldehyde was collected in 3 mL (3.70 mmol) of the reagent

SgOz (made from gSgO3z, ZOml SNUZUSO»N and 1ml pyridine) and stirred at room temperature (G0) overnight. The solution was eluted with bOml of cold water and EGO was extracted (ZhbOml). Organic layer. washed with 2 x 0 ml of brine, dried at 95°C, filtered and concentrated. The residue was taken up in 100 mL of 2:1 heptane/g(OAc) and evaporated. The residue was purified by radial chromatography using 1.5:1 s 2 heptane/g(OAc containing 295 SNUSO»N as eluent. The carboxylic acid (536 mg) appeared quite pure by

TS and "H-NMR with two I-VOC rotamers clearly expressed in SOSI" but not in acetone-iv. She

M--VOS-SERINBISLACTONE 47 (SEE SCHEME 8). with

M--BOC-O-Benzylserine carboxylic acid 45 (53 mg, 1.11 mmol) was dissolved in 15 ml of EtOAc in 500 Oml

Pratt bottles and purged with nitrogen. 39Omg 1095 Pa/C was added to this solution and the mixture was shaken at 5 Org at

Зз5 pressure of hydrogen by train 17 hours. The catalyst was filtered through diatomaceous earth and the solvent was evaporated to form hydroxy acid 46 (44Omg). Crude hydroxy acid 46 was dissolved in 2 mL of benzene and triphenylphosphine (0.34 g, 1.28 mmol) was added at room temperature. Diisopropylazodicarboxylate (OIAO, 0.25 ml, 1.28 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight.

The solution was concentrated, and the resulting residue was applied to a small (4c) gravity column and eluted with 2:1 hexanes/EuAc. The eluent from the silica gel column was further purified by radial flash chromatography using 2:1 pentane/ether as eluent. Fractions of the product were evaporated to give 132 mg of a yellow oil, which was identified as M-I-BOC-serine bislactone 47 (TI C K.-0.32, quite pure by "H-NMR). ," 3-AMINO-7-BENZYL-9- METHYLBISLACTONE 48 (SEE SCHEME 8).

M--BOC-Serine bislactone 47 (132 mg, 0.35 mmol) was stirred in 3 mL of trifluoroacetic acid for 30

Minutes and concentrated the reaction mixture on a rotary evaporator. The residues were dried under high vacuum (0.OBmm) overnight. The trifluoroacetic acid salt of amine 48 (0.35 mmol) was sufficiently pure by H-NMR and was used as such without further purification.

That's all

Ф) with While stirring, 3-chlorophenol (12.86g) was added to a solution of potassium Y-butoxide (12.3g) in OMBO (100ml).

The resulting solution was stirred for 5 minutes at room temperature, after which 3-fluoronitrobenzene (12.70 g) was added. The resulting dark mixture was heated at 1202 for 12 hours, cooled to room temperature, and then poured into water (/OOml). The obtained mixture was extracted with ether (2 x 200 Oml). The organic fractions were washed with 2M Mahon (100 ml) and then with water (100 ml). After drying (Ma9504), the solvent was evaporated, and the resulting dark oil was distilled to form 3-(3-chlorophenoxy)nitrobenzene in the form of a yellow oil, because 135-1402С at 0.О5mm. 65 A mixture of 3-(3-chlorophenoxy)nitrobenzene (14g) and 595 RI on carbon sulfide (1.25g) in EtOAc (150ml) was pressurized to a hydrogen atmosphere (initial pressure -B5Orzi) on a Parr vibrating mixer. After 4 hours,

the mixture was thoroughly degassed (hydrogen replaced by nitrogen), dried (Mao5O)), and filtered (Whatman paper

Mo50). The solvent was evaporated to give a pale yellow oil (12g) which was 96965 pure by GC. "H-NMR (SOCI3) and GC/MS (t/e-219, 221) were consistent with 3-(3-chlorophenoxy)aniline. 3--4--RITFLUOROMETHYLPHENOXY) ANILINE.

SE, nm o

While stirring, potassium tert-butoxide (7.86 g) was added once to a solution of 3-hydroxyaniline (6.55 g) and 4-fluorobenzofluoride (9.85 g) in HM5O (50 ml). The resulting dark solution was heated for 4 hours at a temperature of 952C, cooled to room temperature, and then poured into water (bObOml). The mixture was extracted with ether (3 x 125 ml). The organic phase was washed with 2M sodium hydroxide (2 x 75 ml) and water (100 ml), dried (M95O)) and the solvent was evaporated to a dark oil. This oil was distilled until the formation of aniline indicated in the title as a colorless oil (8.7 g), 10 t.c. 110-1122C at 0.15mm. 4--4-TRIFLUOROMETHYLPHENYLTHIO) ANILINE. on 5th grade

With Fr

When stirring to a solution of 4-fluorobenzenefluoride (9.85g) 15 and 4-aminothiophenol (7.51) in HOM5O (bOml), cooled in an ice bath, potassium Ebutoxide (6.73g) was added once. The resulting mixture was stirred at 02C for 10 minutes, and then at 602 overnight. After cooling, the mixture was poured into water (bOOml) and the resulting mixture was extracted with ether (2x200ml). The organic phase was washed with 2M sodium Shk hydroxide (5Oml), and then with water (5Oml). After drying (Mao5O4), the solvent was evaporated until a brown solid was formed. Recrystallization from hexane gave the title aniline as a yellow solid, m.p. 97-9990, about 4--3-TRIFLUOROMETHYLBENZYL) ANILINE. -

SEZ

" I do not. I am NOM;" for sq

And Gringard's reagent was prepared by adding a solution of 4-bromo-M,M-bis-(trimethylsilyl) aniline (9.48 g) in dry TNE (75 ml) while stirring to a solution of magnesium shavings (1.09 g) in dry TNE (3 ml). The second solution of the catalyst, HygSysSiH (0.33g), was prepared by adding SiSiO (0.20g) and HiSi (0.13g) to dry TNE (25ml) and stirring until a homogeneous solution was formed. This catalyst solution was added to a solution (95) of 3-trifluoromethylbenzyl bromide (7.17 g) in dry TNE (75 ml). The orange-red solution was cooled in an ice bath (atmosphere M"), and the Gringard solution mentioned above (pre-cooled in an ice bath) was quickly transferred through a cannula into it. After stirring for 15 minutes at 0 2°C, the mixture was stirred overnight at room temperature. The reaction mixture was quenched by adding a saturated solution of MNASI (25 ml). The organic phase was separated, dried (MaSO) and the solvent was evaporated until a dark oil (11 g) was formed. To this oil was added 4M HCl (50ml), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was made a base by careful addition of solid sodium carbonate, after which it was extracted with ether (3x10O0ml). The organic phase was dried (M9505) and the solvent was evaporated. E(OAc) (100 mL) was added and the solution was filtered of any insoluble material. The solvent was evaporated again and the residue was chromatographed (silica gel, 3:11 hexane/E(OAc). The second eluate was collected until an orange oil was formed which darkened rapidly. "H-NMR (SOCIv) and GC/MS (t/e-251) were consistent with the title compound 60. This substance was converted to the HCl salt to give a brown solid. 4-(3-TRIFLUOROMETHYLBENZOYL) ANILINE. b5 o r F ASEZ

With stirring, a solution of 4-bromo-M,M-bis-trimethylsilyl) aniline (9.24 g) in dry TNE (100 ml) was cooled to -782C in an argon atmosphere. A 2.5 M solution of p-butyllithium in hexane (12 ml) was slowly added to it. After mixing, the reaction mixture was stirred at -78 °C for 10 minutes, after which a solution of M-methyl-M-methoxy-3-trifluoromethylbenzamide (6.8 g) in dry TNE (25 ml) was added dropwise. After the end of mixing, the mixture was stirred at -782C for 1 hour, after which the cooling bath was removed and the reaction mixture was allowed to heat up to a temperature of 10 2C. The reaction mixture was quenched by adding a saturated solution of MH SI (5 Oml) and water (1 Oml). The organic phase was separated, dried (MaozO dl) and the solvent was evaporated until a yellow liquid (12g) was formed. it was collected in ether (10 Oml), and 4M NS (100 ml) was added. The resulting mixture was stirred for 30 minutes at room temperature, during which the solid was separated. This solid was filtered, washed with several portions of ether, and then carefully added with stirring to a saturated solution of ManCO3 (100 ml). The resulting mixture was extracted with ether (2 x 100 ml), the organic phase was dried (Mo 5 O;), and the solvent was evaporated until a yellow-white solid (5.7 g) was formed. Recrystallization from methanol/water gave a white solid, m.p. 130-13192С. The spectral data of 29 coincided with the data of the compound indicated in the title. Gee)

ETHYL. 2-AMINO-5--4--RIFTHOROMETHYLPHENOXY)BENZOATE.

EYUOS so - so nom o SE, iy

IS) m.

Hydroxyaminobenzoic acid (10.2g) was added once to a solution of potassium Y-butoxide (15.71g) with mechanical stirring in OM5O (75ml). The mixture was stirred at room temperature under an argon atmosphere for 10 minutes, after which 4-fluorobenzene fluoride (11.16 g) was added, and the resulting mixture was stirred and heated at a temperature of 75-802C overnight. After cooling, the mixture was poured into water (bOOml), and the pH level was adjusted to approximately 2.5. The resulting solid was filtered, washed with several portions of water, and then recrystallized from methanol/water (charcoal) to form a yellow-brown solid (13.5 g), m.p. 165-1672C. This solid was taken up in dehydrated ethanol (250 mL) and concentrated sulfuric acid (15 mL) was added slowly. The resulting mixture was heated at 415 reflux for 24 hours, after which most of the ethanol was evaporated. The residues were slowly added to -1 of melted water (b0Oml), the resulting mixture was made into a base by slowly adding 5095 Masson's solution, and then extracted with ether (2x15O0ml). The organic phase was washed with water (100 ml), after which it was saturated with Mass solution (5 ml). After drying (Mao 5 Z0 4 ), the solvent was evaporated to give a yellow oil with approximately 9895 GC purity. GC/MS indicated the derivative ion t/e-325, which matched the title compound. and 2-AMINOBENZONORBORNANE.

IR f) with |Nam

F) name) 60

When stirring, a 1 M solution of borane in TNE (6.7 ml) was quickly added to a solution of benzoboranene (2.84 g) in dry TNE (ml) cooled to 02С in an argon atmosphere. The solution was stirred for 10 minutes at a temperature of 09C, then - at room temperature for 90 minutes. The reaction mixture was again cooled to 02C and hydroxylamine-O-sulfonic acid (1.58 g) was added once. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. 1M NSII (25ml) was added

and ether (20 mL), and stirring was continued for 10 minutes. The phases were separated and the organic phase was discarded.

The aqueous phase was converted to the base by slow addition of 5095 Mahon solution, and extracted with ether (300 ml). The organic phase was dried (М9590;) and the solvent was evaporated to form a yellow liquid (1.3Bg), which was at 9895 according to GC data. "H-NMR (SOCI3) and GC/MS (t/e-159) coincided with the compound indicated in the title. o : son in Kk snuon y shi y 49 50 81 n.n CE CE 53 52 zv Scheme 9 cm ( 8)

PREPARATION OF A MIXTURE (3--RI?FLUOROMETHYLBEZILOX METHYLINORBONYLAMINE 53.

The preparation of this solution is described in Scheme 9. Thus, a solution of exo- and endo-norbornenecarboxylic acids 49 (ratio -1:4) (7.0g), 2-iodopropane (12.8g) and potassium carbonate (10.47) in ЮМ5БО ( 40ml) was stirred and heated at 559 overnight. After cooling, the mixture was eluted with water (125 mL) and then extracted with pentane. The organic phase was dried (MoSO4) and the solvent was evaporated to form a colorless oil (8.2 g). This oil was added to a solution of sodium 2-propoxide (3.bg) in 2-propanol (10Oml), and the resulting mixture was heated at reflux for 16 hours. Removal of 2-propanol, dilution with water (200 mL), and extraction with pentane gave norbornene isopropyl ester 50 as a 52:48 exo to 20 endo solution. It was separated into pure isomers by chromatography (silica gel, 95:5 hexane/EOAc). Exo isomer 50 (4.0g) was dissolved in ether (HOml), cooled to 02С, and 1M solution of lithium aluminum hydride in ether (14ml) was slowly added. After mixing, the mixture was heated at reflux for 1 hour. "

After cooling, the reaction mixture was quenched by sequential addition of water (0.53 mL), Mahon's 1595 solution (0.5 mL), and then water (1.59 mL). The resulting mixture was dried (MaSO)), filtered, and the solvent was evaporated to form exo-alcohol 51 (2.7 g) as a colorless liquid. GC/MS data (t/e-124) were consistent with the given structure. "" While stirring, a solution of 51 (2.7g) in TNE (10ml) was slowly added to a solution of potassium hydride (1.0g) in dry TNE (25ml). After the end of mixing, the mixture was stirred at room temperature for 30 minutes, and then trifluoromethylbenzyl bromide (5.98 g) was added once (exothermic reaction). The reaction mixture was heated at reflux for 2 hours, cooled, and then poured into water (150 ml). Ether extraction (2 x 75 ml), dried (M9504), and evaporation of the solvent led to the formation of a yellow oil, which was purified

Mn by chromatography (silica gel, 97:3 hexane/acetone) to give pure 52 as a colorless (95) oil (5.2g). "H-NMR (SOSIII) and GU/MS (t/e-282) were consistent with the structure of substance 52.

From this 50, the conversion of substance 52 into the diastereomeric amine solution 53 was carried out by the borane/hydroxylamine-O-sulfonic acid process as described above (yield 20965). c 3-(3-PYRIDYL)-1- PROPANAMIN. | She Mn, o nya yu M 60

This amine was obtained by initial conversion of 3-(3-pyridyl)-1-propanol into the corresponding chloride according to the procedure of V. digvis ei a!I., Zupipevziv, 1988, (11), 868), after which this chloride was converted into an amine according to the procedure 0. U. bitaz ei a!., 9. Ogd. Spet., 1988, 53, 4650). 3-(5-"TRIFLUOROMETHYL)-2-PYRIDYLYOXY|-1- PROPANAMIN. b5

Se, h- " " "t ve l

Mk; Mn, then 2-Fluoro-5-trifluoromethylpyridine (1.831 g, 117 mmol) was dissolved in dehydrated TNE (1 bml) under nitrogen stirring and cooling to 09C in an ice bath. A solution of 3-amino-1-propanol (0.7 bml, 1 mmol) in dehydrated TNE (15 ml) and 1M potassium tert-butoxide in

TNE (1 Oml, 10 mmol). The yellow solution was stirred and allowed to slowly warm to room temperature overnight. The reaction mixture was poured into water (75 mL) and extracted with ether (2 x 5 mL). The organic phase was washed with brine (50 mL), dried (MgSO), filtered, and evaporated in vacuo to a yellow liquid that was nearly pure by H-NMR and MS, and used as such without further purification. (4-TRANS-1 -HYDROXY-2-AMINOCYCLOPENTANE HYDROBROMIDE In C (8) (7u-trans-1-Benzyloxy-2-aminocyclopentane hydrobromide (8.2g, 42.8mmol) was treated with 4095 Ng (bOml).

After stirring for 3 days, the solution was concentrated in a vacuum until 7.09 g (9190) of sodium salt hydrobromide was formed in the form of an orange solid, which was pure by H-NMR (OM50O-yb). 2,3-DIHYDRO-2,2 -DIMETHYL-TN-INDEN-1-AMIN. me) so / IS)

And with me dk. . this is - c This amine was prepared according to the procedure described (in UMO patent application 9927783). " di) » o o "M n p n nn s di

Fi r nn

Phi N | n H o 54 55 vv o 50 so Scheme IO 59 10-AMINO-ENDO-2,5-METHANOBICYCLOY|4.4.0)DEC-3-EME (56).

F! This compound was prepared as shown in Scheme 10. Thus, aluminum chloride (7O0Omg, 5.2 mmol) was added to a solution of 2-10 cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (200 mL). After 40 minutes, freshly filtered ocyclopentadiene (13.7g, 208mmol) was added and heated to 10097 for 2 hours. After cooling, the mixture was diluted with EBO (300 mL) and washed with saturated NaCl (2 x 150 mL) and brine (10 mL). The combined 60 organic layers were dried (M9505), filtered and concentrated. The residues were purified by flash chromatography using 50:1 hexanes:Eb2O as eluent to give the endo (1.74 g) and exo (943 µg) isomers of 2,5-methanobicyclo|4.4.0) dec-3-ep-10-one (54 ), pure according to "H-NMR and GU/MS.

Sodium acetate (1.79g, 21.8mmol) and hydroxylamine hydrochloride (758mg , 10.9 mmol) in methanol (33 mL), and stirred overnight at room temperature. The reaction mixture was quenched with H 20 and extracted with ether (2x5 mL).

The combined organic layers were dried (Mo95O)), filtered and concentrated to give endo-2,5-methanobicyclo(4.4.0|dec-Z-ep-10-one oxime (55) as a viscous residue, pure by "H -NMR and G/MS.

Endo-2,5-Methanobicyclo|4.4.1|)dec-3-ep-10-one oxime (55) (500 mg, 2.7 µmol) was dissolved in EtOAc (25 mL) and 1095 Pa/C (5 µg) was added. After 3 h at H0 (4 Orvz), the suspension was filtered through Seychschete and concentrated.

The suspension was saturated with MNuz and subjected to pressure No (45rvi). After two hours, the suspension was filtered through

Seilleia, diluted with EAs (100 ml), and washed with saturated NaCl (100 ml). The combined organic layers were dried with MaSO»4, filtered and concentrated. "H-NMR and GC/MS showed that amine 56 is a 2:1 mixture of 70 diastereomers (418mgHg).

Sp - SO --e SPA n n n 57 58 53

M Scheme |i 10-AMINO-4-(4-METHYLPENT-3-ENYL)-BICYCLO (4.4.01 DEC-3-EME (59). c

The preparation of this compound was carried out as shown in Scheme 11. Thus, aluminum chloride (7O0Omg, 5.2mmol) was added to a solution of 2-cyclohexen-1-one (2.0g, 20.8mmol) in toluene (10Oml). After 40 minutes, myrcene (17 g, 125 mmol) was added and heated to 1002 for 2 hours. After cooling, the mixture was diluted with ESO (300 ml) and washed with sat. The combined organic layers were dried over Ma 5 O", filtered and concentrated. The residues were purified by flash chromatography using 50:11 hexanes.d 0

With BBO as an eluent to obtain 4-(4'-methylpent-3'-enyl)-bicyclo(4.4.0|dec-3-ep-10-one (57) (2.55g), pure so by "H-NMR and GMOs.

Sodium acetate (1.73 g, 21 mmol) was added portionwise to the solution and 4-(4"-methylpent-3'-enyl)-bicyclo|4.4.0|dec-Z-ep-10-one (57) (2.23 g, 9 mmol) and hydroxylamine hydrochloride (73 mg, 10 mmol) in methanol (32 mL) and stirred overnight at room temperature. The reaction mixture was quenched with NaO and extracted with ether (2 x 5 mL). The combined organic layers were dried over Ma 5 O, filtered - and concentrated. This led to the formation of 4-(4'-methylpent-3'-benyl)-bicyclo(|4.4.0)dec-3-ep-10-one oxime (58) in the form of viscous residues, pure by TN -NMR and GHMS., 4-(4'-Methylpent-3'-enyl)-bicyclo|4.4.0)dec-3-ep-10-one oxime (b0Omg, 2.42 mmol) was dissolved in EOH (25 mL) and CapeuF-Mi (1.09) was poured in. The suspension was saturated with MnCl and pressurized with NO (45 g). After 2 hours, the suspension was filtered through Seille?, diluted with EtOAc (100 ml), and washed with saturated Manso»c (100 ml). The combined organic layers were dried over NaCl, filtered and concentrated. TN-NMR and GC/MS were characteristic of pure of the amine mentioned in the title (550mgHg). 1 o No. pok o: -1 and nan - chn ---- 1 o o o o o o o o o o nya bo v1 62 63 (95) . so | Scheme! 2 o. 2-AMINO-7-FURYL-3-METHYL-4-CHROMANONE HYDROCHLORIDE (63). 25 This amine hydrochloride salt was prepared as shown in Scheme 20 12. Thus,

HF) 7-riffluoromethanesulfonate-3-methyl-4-chromanone (3.0 g, 9.7 mmol), was prepared according to the procedure |K. Kosy, and M. 5. yuyu Viddege, U. Ogu. Spent 1994, 59, 1216) and added 2-(tributylstannyl)furan (3.79g, 10.mmol) to the solution,

RYA(RRIz)4 (223Zmg, 0.19mmol), GIS! (1.23g, 29.00mmol), and two crystals of 25 2,6-dibutyl-4-methylphenol in 1,4-dioxane (50ml), and heated at reflux for 12 hours. After cooling, the mixture was quenched with saturated 60 MNASI (40ml) and extracted with EBO (2x50ml). The combined organic layers were dried over M950, filtered and concentrated. The residue was purified by flash chromatography using 20:1 hexanes:E(OAc) as an eluent to give 7-furyl-3-methyl-4-chromanone (60) (1.78 g) as a yellow solid, m.p. 94-9596 ,.

Sodium acetate (395 mg, 4.82 mmol) was added portionwise to a solution of 7-furyl-3-methyl-4-chromanone (60) (500 mg, b 2.19 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol) in methanol (5 mL), and stirred overnight at room temperature. The reaction mixture was quenched with H2O and extracted with ether (2 x 25 ml). The combined organic layers were dried (MgSO), filtered, and concentrated to give 7-furyl-3-methyl-4-chromanone oxime (61) as a white solid, m.p. 175-17796.

Toluesulfonyl chloride (397mg, 2.08mmol) was added to a solution of 7-furyl-3-methyl-4-chromanone oxime (61) at 02C (461mg, 1.89mmol) and pyridine (0.5ml) in SiO2 (10ml). After 6 hours, the mixture was diluted

SNSI" (ZOml) and washed 595 NS! 15 (20 ml). The organic layer was dried (Mo5O), filtered and concentrated. The residues were purified by flash chromatography using 5:1 hexanes:E(JudAc as eluent to form 7-furyl-3-methyl-4-chromanone O-(toluenesulfonyl)-oxime (62) (429 mg) as a solid, t .p. 163-1642C (deyu).

An ethanolic solution of sodium ethylate (0.3 mL, 2.87 M, 1.0 mmol) was added with stirring to a solution of 7-furyl-3-methyl-4-chromanone-0-(toluenesulfonyl)oxime (62) (410 mg, 1.00 mmol) in benzene (4 ml). After 18 hours, ZM NSI (bml) was added and the layers were separated. The organic phase was further extracted with 3M HCl (2 x 10 mL), and the combined aqueous extracts were concentrated to afford the crude title compound 63 as an orange solid (388 mg), which was used as such without further purification. o nan stump 9 o. oh oh there are also 55

Scheme!3 z - 2- ch 29 2-AMINO-7-(3"-"METHOXYPROPYNYL)-3-METHYL-A-CHROMANONE HYDROCHLORIDE (65). Gee)

This amine hydrochloride was prepared as shown in Scheme 13. Thus, 7-riffluoromethanesulfonate-3-methyl-4-chromanone (3.10 g, TOmmol) was prepared according to procedure |K. Kosi and

M. 5. Viddegv, U. Ogud. Spent 1994, 59, 1216) was added to a solution of methyl propargyl ether (1.05g, 15mmol), (RizR), Ra (21Omg, 0.301Omol), and EBM (bml) in OME (ZOml) and heated at 702 for 1 hour. After cooling, the mixture was quenched. with saturated MNACI (40 ml) and extracted with EBbO (2x5Oml). The combined organic layers (9) were dried with NaOH), filtered and concentrated. The residue was purified by flash chromatography using 9:1 hexanes-ETOAc as eluent to give 7-(3-methoxypropynyl)-3-methyl-4-chromanone (64) (1.40 g) as a white solid, m.p. 60-6320. IF)

The transformation of substance 64 into the compound specified in title 65 was carried out in the same way as described above for 2-amino-7-furyl-3-methyl-4-chromanone hydrochloride. nein,m h s 2» ve - Scheme 14 1 (65) 2-AMINO-A-TETRALON HYDROCHLORIDE (66). 50 This compound was prepared from A-tetralone as shown in Scheme 14 by the same procedure as described above for 2-amino-7-furyl-3-methyl-4-chromanone hydrochloride. M. Y

IR e) o o o n n n n ve m nsini innnvnt shini ya- yam ryn i PI

Ge) n n n Hn their) 67 68. 89 79 605 Scheme 15 2-AMINO-ENDO-6,9-ETHANOBICYCLOY4.4.0)DEC-7-ENONE HYDROCHLORIDE (70).

This amine hydrochloride was prepared as shown in Scheme 15. Thus, aluminum chloride (70 Ω, 5.2 mmol) was added 65 to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (10 Ω). After 40 minutes, cyclohexadiene (8.g, 104 mmol) was added and heated to 1002C for 2 hours. After cooling, the mixture was diluted with EGO (300 mL) and washed with sat. The combined organic layers were dried over Ma 5 O", filtered and concentrated. The residue was purified by flash chromatography using 50:1 hexanes-E2O as eluent to give endo-2,5-ethanobicyclo|4.4.0)dec-7-ep-10-one (67) (2.77g), pure as "H - NMR and GMO.

And a solution of endo-2,5-ethanobicyclo|4.4.O|dec-7-ep-10-one (67) (2.17g, 12.3mmol) in TNE (20ml) was added to a solution of IA (6.7ml, 2.OM in TNE, 13.5 mmol) in TNE (ZOml) at a temperature of -782С. After 45 minutes, trimethylsilyl chloride (2.0 g, 18.5 mmol) was added, and the mixture was slowly heated to 09C. The mixture was diluted with a saturated solution of MansSoO»z (3 ml), extracted with BEBO (2 x 3 ml), dried (M950;) and concentrated. The residues of 70 were dissolved in TNE (bOml), and M-bromosuccinimide (2.6 mg, 14.7 mmol) was added in portions. After 30 minutes, the mixture was diluted with a saturated solution of MNAS! (3 ml) and extracted with E2O (2 x 40 ml). The combined organic layers were dried (MazO)) and concentrated. The residue was purified by flash chromatography using 33:1 hexanes-E2O as eluent to give 2-bromo-endo-b, 9-5 ethanobicyclo|4.4.0|dec-7-epope (68) (1.44g) as a yellow oil , pure by H-NMR and GC/MS. t Sodium azide (280 mg, 4.3 mmol) was added to a solution of 2-bromo-endo-6,9-ethanobicyclo|4.4.0)dec-7-epope (68) (850 mg , Z.ummol) in UOME (20ml). After 2 hours, the mixture was diluted with water (30ml) and extracted with EBO (2x40ml). The combined organic layers were dried (Mao5O)) and concentrated. The residue was purified by flash chromatography using 20: 11 hexanes :EE6E 50 as eluent to form 2-azido-endo-b,3-ethanobicyclo|4.4.0)|dec-7-epope (69) (469mg) as an oil, pure by TN-NMR.

2-azido-endo-6,9-ethanobicyclo|4.4.0|dec-7-epope (69) (31Omg, 1.42mmol) in TNE (1Oml) and water (ml) was added to a solution of triphenylphoephin (486bmg, 1.85mmol) . After stirring for 12 hours, the mixture was diluted with 6M CARRIER (1Oml) and the layers were separated. The organic phase was extracted with 6M 20 HCl (2x5ml), and the combined aqueous layers were concentrated to dryness to form the required compound 70, indicated in the title, in the form of a thick orange oil (500mg), H-NMR data (0M50-a5) which coincided with the given structure

ISOPROPYL ENDO-2-AMINONORBONATE-5-CARBOXYLATE 72). with 7 ni so

Х ХХ y 7 oo oo y. 714 t2 « - s These amines were prepared from isopropyl norbornene-2-epe-5-carboxylate in the same manner as described above (see Scheme 9). "» GENERAL PROCEDURE FOR REFERENCE AMINATION OF KETONES INTO AMINES.

Ketone (1 mmol), ammonium acetate (2 mmol) and ZA molecular weight (2.8 equivalents by weight) were mixed in dehydrated methanol in a dry flask under a nitrogen atmosphere. Sodium cyanoborohydride (4 mmol) was added and the resulting mixture was stirred at room temperature until the disappearance of the initial ketone, which will be confirmed by the analysis of TI C. Methanol was separated from the reaction mixture in a vacuum, and the residues were dissolved in EM NOSI.

After stirring for 15 minutes, non-essential substances were removed by extraction with diethyl ether. (95) The pH of the aqueous phase was slowly raised to −8 using 5095 aqueous Mahon, and the amine was extracted with 50 EtOAc (3 times). The E(Ac) extracts were combined, washed with brine, dried (Ma»5O), filtered, and concentrated to form the corresponding amine. The crude amine was generally pure and used without further purification.

GENERAL PROCEDURE OF VOC-DEPROTECTIZATION OF AMINES.

Triethylsilane (0.5 ml) and trifluoroacetic acid (ml) were added to an ice-cold solution of BOC-protected amine (mmol) in dry CH3O3 (Timl). The course of the reaction was monitored by the disappearance of the starting material (from 5 minutes to 1.5 hours). The reaction mixture was diluted with toluene and concentrated. The residues were dissolved in water (1 ml) and EtOAc (20 ml), the pH level was adjusted to -8 (aqueous Manso's), and the organic phase was separated. The aqueous phase was extracted with E(OAc (2X15 mL). The organic phases were combined, washed with brine, dried (Ma2O)), filtered and concentrated to form the amine. 60 PREPARATION OF AMINES 73 AND 74 b5

PREPARATION OF AMINES 73 AND 74.

I t o; "Other Z nm 2 o .

Oh oh

These amines were prepared from the corresponding known ketodilactones (U. Ogud. Spet. 1998, 63, 9889-94) under standard reductive amination conditions as described above. The spectra of tn, 136 NMR and HC coincided with the spectra of the given structures. o a voschn on s - o) on . 2 p

Susigayuvy | so | | i) o o s vos-ch o n, gas vos-nn o | and - at 78 at 76 | | . -o s o Ge) trip 97, o o I o o - t and i-y Scheme 16 (95) o 50 s PREPARATION OF AMINES 77 AND 78.

The preparation of these amines is shown in Scheme 16. Macrodilactones 75 were prepared according to (procedures U. Ogud. Spet. 1998, 63, 9889-94). Thus, M-A-BOC-aspartic acid (2.33 g) was reacted with 2-chloromethyl-Z-chloropropene (1.25 g) and С82СО»z (7.0 g) in OME (1000 ml) under standard conditions of macrolactonization, as noted above in references, to give 1.12 g (4095 yield) of compound 75 as a glassy solid. The mass spectrum (E1I-) indicated

Ф, IM-1) - at (m/e) 284, when the Н, 7С NMR and УЧ spectra coincided with the structure of compound 75. ко To a solution of alkene 75 (288 mg, 1.01 mmol) in dry EtOAc (bml) was added 1095 Ra /carbon (bOmg). The resulting mixture was purged with nitrogen and stirred under a pressure of 45 bar of Parr hydrogen generator for 2.5 hours. The reaction mixture was purged with nitrogen, filtered and concentrated. The residue, after purification by flash column chromatography (silica gel, 7:3 mixture of hexane- EOAc), obtained 91 mg (32905 yield) of reduced product 76.

The spectra of "H", "3S-NMR and HC coincided with the structure of compound 76.

Removal of the BOC protecting group from compounds 75 and 76, with the following general procedure

BOC deprotection was described earlier for the corresponding amines 77 and 78. The spectra of IN, Zb-NMR, and HC b5 coincided with the given structures.

RE o no nn o

Rugpare

It's okay

OO zh vosnn-4 rMAR vos-chi o "y no sn, 5 Y 75 | RR, TNE "isnu ahodisatbohuiiv o o o nako ---- voszhny o o o o i ve | 8o

Scheme 17 with o

SYNTHESIS OF PHENYL DILACTONE 81.

The preparation of this compound is shown in Scheme 17. To a cold (0 C), well-stirred solution of phenylsuccinic acid (0.923g, 5.2mmol) and OMAR (0.064g, 0.52mmol) in dry SiOCl (55ml) under nitrogen was added dropwise BOS-serinol solution (Zupipeziv 1998, 1113-1118) (1.0 g, 5.2 mmol) for 30 minutes. co

The resulting mixture was slowly heated to room temperature, further stirred for 12 hours, diluted with СНоСи» (40 ml), and extracted with saturated aqueous sodium bicarbonate (3 x 10 ml). The main extracts were combined, carefully oxidized with 2M NOI, and extracted with EtOAc (3x20ml). Combined extract She

EtOAc was washed with brine, dried (Ma»5O)), filtered and concentrated to form a white foam (1.7 g). "H-NMR, indicated as a 1:1 diastereomeric compound of acid 79.

To a well-mixed cold suspension of acids 79 (1.00 g, 2.72 mmol) and triphenylphosphine (78 mg, 3.0 mmol) in dry TNE (122 ml) was added dropwise a solution of diethyl azodicarboxylate (0.52 g, 10 3.0 mmol) in TNE (55 ml) during From hours The resulting mixture was slowly heated to room temperature, further stirred for 5 hours, and concentrated to approximately 5 ml. The residue was diluted with EtOAc (50ml) and water (20ml). The organic phase was separated, washed with aqueous Manso with (10ml), brine (10ml), dried (Ma»zoOd), filtered and concentrated to form fatty Purification by flash chromatography (silica gel, hexanes) led to the formation of 228 mg (22905 yield) of a 1:11 compound of dilactones 80, mp - 161-162 20. with Mass spectrum (EI) noted by M. - at t/e 349.

Removal of the BOC protecting group under standard BOC deprotection conditions was described earlier for amine 81. -I 1 (95) at 50

IR e)

F) name) 60 b5

. o o no svachn Rugidipe o o o vosnn --- Щ VOSNN no o no 2 no o - 8:

RR, TNE

There is dnu atodisnbokuia o o (ev) denunciation 7- L4 2 - vosnny o i TRA, HE O Mnovh sna, o 84 Ra! FIG. 83 about n, wax about

Mn, at 85

Scheme 18 school

AND

(8)

SYNTHESIS OF DILACTONEAMINES 84 and 85.

The preparation of these compounds is shown in Scheme 18. When stirring, to a solution of serinol (3.0 g, 15.7 mmol), pyridine (1.24 g, 0.9 v8 mol) and LAMAR (0.19 g, 1.57 mmol) in dry SNS" (140 ml) was added dropwise solution of

M-SV2 of aspartic anhydride (3.52g, 14.13mmol) in dry TNE (20ml). After stirring for 2 hours at room temperature, the reaction mixture was concentrated to a volume of approximately 100 ml and diluted with EAs and. (100ml) and water (ZOml). The pH level was adjusted to 8.5 (aqueous Manceau)"), and the aqueous phase was separated and oxidized with 2M sodium

NOI to pH 33, and extracted with E(OAc (3x20ml). The combined organic extract was washed with brine, dried (Ma»5O)), filtered and concentrated to give 5.8g of compound 82 as a white foam. i am

H-NMR spectra indicated that this substance was sufficiently pure and contained compounds of diastereomers.

To a solution of triphenylphosphine (3.6 mg, 13.75 mmol) and 1,3Z-diisopropylcarbodiimide (2.80 g, 13.75 mmol) in dry TNE (1.15 L) was added dropwise over 3 hours a solution of acid 82 (5.5 g, 12.5 mmol) in dry TNE ( 100 ml). The resulting mixture was stirred for additional hours, concentrated in vacuo to a volume of approximately 20 ml, and diluted with ether (200 ml) and water (100 ml). The organic phase was separated and washed with 590% aqueous Manso" and brine, dried (Ma»SO)4), filtered and concentrated in vacuo. The fatty residues - c were purified by flash column chromatography until 1.3 g (2395 yield) of the necessary dilactones 83 were formed. and UV spectra coincided with the structure of compound 83. Dilactone 83 was subjected to deprotection under standard BOC deprotection conditions to form amine 84.

1095 Ra/cС (4 Омг) was added to a solution of M-СВ2-protected dilactone 83 (200 mg, 0.47 mmol) in EtOAc (1 Омл).

The resulting mixture was stirred under hydrogen pressure in a cylinder for 12 hours. The reaction mixture was purified by M» - filtered through a metallized glass funnel, and concentrated until the formation of amine 85 (12b6mg). This crude amine was used without further purification.

PREPARATION OF AMINES 86 and 88. (95) syu . oh oh nn

Mn, . h chn, 26 vysatmope 87 | for (F. Kvu: i. MN, BE, TNOCH-RD, 14 tep Mavn, her. Mezmi, sa. Sive TNE name) is Scheme 19 60

The synthesis of 2,6,6-trimethyl-2, 4-cycloheptadienylamine (86) and 2,3,6,6-tetramethyl-3-cycloheptenone (87), which is the precursor of amine 88, is shown in Scheme 19. Thus, eicarvone ISap. in). Spent 1974, 52, 1352| was converted into the corresponding amine 86 using titanium isopropoxide/mvn //Eivm- the intermediate reductive amination procedure (described in Zupieya 1999, 17811. Si (I)-catalyzed Michael addition of trimethylaluminum eicarvone, 65 using the procedure that (|described in Teiapedgoop 1995, 51, 743-754), led to the formation

2,3,5,5-tetramethyl-3-cycloheptenone (87). The latter was converted into 2,3,5,5-tetramethyl-2-cycloheptenylamine (88) according to the general procedure (according to the world patent M/O 99277831).

M-METHYL-M-(2-PHENYLETHYL)-(1,5B5-TRIMETHYL-3-AMINOCYCLOGHEXYL) UREA (89). nm i, and o sho 1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (M. 5. Ledieg and K. M. Negov, U. Ogu. Spet. 1951, 16, 920)| combined with M-Methyl-2-phenylethylamine using standard NOAI, EOSI and

OMAR-intermediate conditions of combination for formation

IM-methyl-M-(2-phenylethyl)|-1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxamide as a pale yellow oil.

The mass spectrum indicated a derivative ion at m/e 301. The IR and 30-NMR spectra were consistent with this structure.

Amine 89 was prepared from this ketone according to the general procedure (UMO World Patent 99277831) by conversion to the corresponding M-hydroxyoxime followed by hydrogenation in the presence of Bapeu? E. "H-NMR of the amine indicated a mixture of 1:diastereomers. 3-(3,3-DIMETHYLBUTOXYCARBONYL)-3,5,5-PHRYMETHYLCYCLOGHEXYLAMINE (90) c (8) and c o c o

And co

IS) with 90% 1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (3.0 g) M. 5. 7edieg and MK. M. Negbozi, 9. Oga. "

Spent 1951, 16, 920) It was treated with 3,3-dimethylpentanol (1.84g), OMAR (2.21g) and 1,3-diisopropylcarbodiimide 400 (2.17) in SNHS. (8 Oml) under standard conditions of combination to form 2.41 g (5595 yield) - with 3-(3,3-dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexanol. The mass spectrum (MS) indicated the derivative ion at m/e a 268. This ketone was converted to the amine indicated in the title amine 90, according to the general procedure (according to "» world patent MO 9927783), by conversion to the corresponding oxime followed by hydrogenation in the presence of Bapeu? Mi. 1'H-NMR of amine 90 indicated a 1:1 solution of diastereomers. -I (9 se, ho SE, t, ov. sg kn. OM

Y, watny he it ZHY. ShK ay (65) al" nov, with c) 70 Sq. 42) 2M 29 NS

And TNE

SE, o SE, o "Ed -- uv ko o sk, o no, 93 vo 92

Scheme 20 0: 4-(4,8-BIS-TRIFLUOROMETHYL-2-PYRIDYLYOXY-3,3,5,l5-TETRAMETHYLCYCLOGHEXYLAMINE (93).

The synthesis of this amine is shown in Scheme 20. Yes, because 4-hydroxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethylene glycol acetal (90mg, 4.2mmol) was dissolved in dry OME

(8.4ml), the mixture was cooled to 09С, and 3595 (m) and a suspension of KN oil (591mg, 5.04mmol) was added. After stirring the mixture for 1 hour, a solution of 2-chloro-4,6-bis-trifluoromethyl-2-pyridine (1.48 g, 6.0 mmol) in OME (2 ml) was added dropwise. The mixture was stirred at 02C for 1 hour, and then at room temperature for 12 hours, and carefully quenched with ammonia.

Diethyl ether (10 Oml) was added, the organic phase was separated, and it was washed with brine, dried (Mo5O), and concentrated to a dark brown solid. Recrystallization from hot hexanes with a yield of 9500 mg (5390 yield) of 4-(4,6-bis-trifluoromethyl-2-pyridyl)oxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethylene glycol acetal (91), 70 t. no.-105-10626.

Acetal 91 (900 mg) was dissolved in a 1:1:1 (3 mL) solution of TNE, dioxane, and 2 M NOI, and the resulting solution was stirred at room temperature for 12 h, after which complete disappearance of the starting material was noted by EX. The mixture was diluted with water and diethyl ether (5 Oml each). The organic phase was separated, washed with brine, dried (Ma».5O)) and concentrated until the formation of fatty residues. These residues 75 were chromatographed on silica gel (hexane-E(OAc, 5:1)) to give 712 mg (9695 yield) of ketone 92 as a colorless oil. The mass spectrum (MS) indicated the derivative ion m/e 383.

The reductive amination of compound 92 to the title amine 93 was performed according to the general procedure

According to the UMO world patent 99277831). (So g o o roms we Ha! o

RYISNYAETSIMSI av a sch

In 5 ozhna nm so z o sho pretn o so s) a 0 chysmen, U s

НН, ОАе с жа 97 96 " o m.

Scheme?! 1 3--2,3-DICHLOROPROPYLOXY)METHYL-3,5,5-TRIMETHYLCYCLOGHEXYLAMINE (97). "

The synthesis of amine 97 is shown in Scheme 21. Dichlorination of alkene 94 according to the Teigapeagop Gay procedure. 1991, -о 70 32, 1831-4), with an acetal yield of 95. The latter (500 mg) was dissolved in a 1:11 solution of TNE and 2M NOI. The resulting solution was stirred at room temperature for 1 hour, when TI C determined the disappearance of the starting material. The mixture was diluted with EtOAc and water (30 ml of each), and the organic phase was separated and washed with brine, dried (Ma»5O)), filtered and concentrated to give 38Zmg of ketone 96 as an oil. TN-YAMe coincided with a diastereomeric mixture of isomers. Reductive amination, as described -1 previously, by standard procedure, led to the formation of the title amine 97. sl : o s SG cm M RN, TNK | : su 2 o pnya c) yann-yayu DfshchD NN zhna o. at

IR f) I i-i 99 100

F) Scheme 22. ime) 3-BENZOYL-3,5,5-TPRIMETHYLCYCLOGHEXYLAMINE (100). bo The preparation of this amine is shown in Scheme 22.

C-cyano-3,5,5-tetramethylcyclohexyl-1,1-ethylene glycol acetal (98) | world patent UUO 99277831), after reaction with phenyllithium followed by acid hydrolysis, led to the formation of diketone 99, which was converted into aminoketone 100, specified in title, according to the procedure described in the above-mentioned patent. b5 o Mo, mo,

Zh ON no sis mo, KE is. 101 102

RE,R otM5 o io om oMme nak party furnaces. . mo, mo, Wepgepa, heyoh

OMG

Ome and zysa che 105 104 105

Scheme 23 58-(2-PHENYLETHYL)-3B-METHOXY-48-METHYL-4-NITRO-CYCLOHEXYLAMINE (105). with

The preparation of amine 105 is shown in Scheme 23. Condensation of nitroethane with dihydrocinnamaldehyde, according to (Procedures ViiY. Spet. bos. dar. 1968, 41, 1441), led to the formation of the corresponding nitro alcohol 101.

Dehydration of compound 101, according to (procedures Bupiipevziz, 1982, 1017), followed by polymer-supported triphenylphosphine-intermediate isomerization. 1998. converted amine 105 according to the standard procedure of p

And the UMO world patent 99277831. And what. « с о Mn, and not - іни нини яни мавн, см в « ю сН.он З с - "» Scheme 24 'p 3-CYANO-3,5, 5-PHRYMETHYLCYCLOGHEXYLAMINE (106). -i This compound was prepared ( Scheme 24) by reductive amination of 3-cyano-3,5,5-trimethylcyclohexanol according to the standard reductive amination procedure described above. The mass spectrum (MS) indicated a derivative ion of t/e 167. (95)

From MN. WITH

Mavnusim 107

Ssn.on

GF) - . Scheme 25 in 3-AMINO-5-PHENYLTHIOPYRAN (107).

This compound was prepared as shown in Scheme 25. Thus, up to 0.96 g (bmmol) of 5-phenyl-3-thiopyranone |P. T. I aperigu, ei aI,, U. At. Spent wasps 1970, 92, 5649) 7.7 g (10 Omol) of ammonium acetate and 6.5 g of ZA molecular seeds were added to 5 mL of anhydride methanol. After stirring for 30 minutes at room temperature, 1.25 g (200 mmol) of sodium cyanoborohydride was added. After stirring for 16 hours, the mixture was subjected to 65 pressureless filtration, and the methanol was evaporated under vacuum. The residue was partitioned between ice/NaCl and ether. The acidic aqueous phase was extracted twice more with ether, then with ice and 5095 water

Mahogany made the base. The mixture was extracted with SiOCl, dried (M95054) and evaporated to give 0.19g (2076) of the title compound. GC/MS showed 10095 purity with molecular

In se, oh se, Mn, works - and - Y no o o . 1 70! 102'. what

Scheme 26 4--4-TRIFLUOROMETHYL) PHENOXYCYCLOHEXYLAMINE (109).

This compound was prepared according to Scheme 26. When stirring, a solution of sodium hydride (1.2 g, 0.05 mol) in 5 Oml

A solution of 1,4-dioxaspiro|4.5|decan-8-ol (7.5g, 0.047mol) in 15ml was added dropwise to OME over 10 minutes.

OME. The mixture was stirred at ambient temperature for 30 minutes. 4-Fluorobenzene fluoride (7.71 g, 0.047 mol) was added and the reaction mixture was stirred at room temperature for 2 hours and then overnight at 702C. The reaction mixture was poured into cold water (70 Oml), and the solution was slightly acidified by adding 1M HCl. The mixture was filtered and the aqueous filtrate was extracted with hexane (2x15Oml). The filtered solid was dissolved in hexane extract and washed with water (5 Oml). The solution was dried over Ma5O, filtered and concentrated to a white solid. This solid was recrystallized from methanol/water to give pure Kemal (8.6bg, 61905).

Silica gel (ZOg) was suspended in 150 ml of CH»oSi». To this suspension, 1295 ml of a solution of NSII in water was added dropwise for 5 minutes. The mixture was vigorously stirred to prevent precipitation. A solution (5) of the above-mentioned ketal (8.0 g, 26.49 mmol) dissolved in 75 ml of CH»oSi» was added, and the reaction mixture was stirred for

From hours After that, the mixture was filtered and washed with a silica gel tablet of 500 ml of CH 2Si. The solvent was evaporated until 5.8 g (8695) of 4-(4-trifluorophenoxy) cyclohexanol (108) was formed.

Reductive amination of ketone 108 by a standard reductive amination procedure as (ee) described above afforded the title compound 109. c co . o Mn, where -- s - o: o yat o inn o no Sg s . c i- 1 | 1 Scheme 27 From p. ;" 4-BENZOYLOXY-3,3,5,5-TETRAMETHYLCYCLOGHEXYLAMINE (111).

This compound was prepared following the procedure of Scheme 27. Upon stirring, a solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro (4.5) decan-8-ol (0.37 g, 1.7 mmol) in bml TNE was cooled to 02 added -I p-Vygy (2.5M in hexanes, 1.73mmol, 0.7ml) 35 dropwise. The reaction mixture was stirred for 10 minutes.

Benzoyl chloride (1.73 mmol, 0.2 mL) was then added, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 50 ml of 0.5 M Mahon and extracted with ether (3 x 20 ml). The ether layer was dried with M95O5, filtered and concentrated. The residues were purified by radial chromatography using 4:1 hexane-E(OAc) as an eluent. Thus, 0.55 g (7100965) of benzoyloxyketal were obtained.

IR e) Silica gel (2.2g) was suspended in 100 ml of SiO2. To this suspension was added dropwise for 5 minutes 0O.Bml 1295 of a solution of NSI in water. The mixture was vigorously stirred to prevent precipitation. A mixture of the above-mentioned benzoyloxy ketal was added, dissolved in 5 ml of CHCl", and the reaction mixture was stirred for 3

HOURS After that, the mixture was filtered and the silica gel tablet was washed with 1000 ml of CH»oSi». The solvent was evaporated until 0.46 g (9095) of benzoyloxycyclohexanol 110 was formed as a clear oil.

IF) While stirring, a solution of hydroxylamine hydrochloride (0.23g, 3.25mmol) and potassium acetate (0.32g, 3.25mmol) in 4ml of water was added to a solution of benzoyloxycyclohexanol 110 (0.46g, 1.6dmol) in 4ml of methanol.

The reaction mixture was stirred at room temperature overnight. Water (20 ml) was added and the resulting mixture was extracted with ether (3x10 ml). The ether extracts were combined, washed, saturated with MnSO3 (1x20ml) and brine (1x1ml). The ether layer was dried with M9504, filtered and concentrated to form the necessary oximes (0.3 g, 80905) in the form of a mixture of E and 7 isomers.

Capeu? Nickel (0.8 g wet weight, AiYidgis Spetisa! So.) in a 500 ml thick-walled Parr bottle was washed with water (3 x 2 O ml), and then with ethanol (3 x 20 O0 ml), the washed solvent was filtered each time. A solution of oxime (0.39g, 1.35mmol) in dehydrated ethanol (30ml) was added to the washed catalyst. Some heating was required to dissolve this mixture. The resulting mixture was saturated with ammonium by bubbling ammonium gas through the solution for 1 minute. This solution was placed under a hydrogen atmosphere (initial hydrogen pressure - BOrvzi) on a Parr mixer, and mixed for 7 hours. The reaction mixture was filtered through a Seille 9 tablet and the solvent was evaporated until an almost colorless liquid was obtained (0.37 g, quantitative yield). Proton "H-NMR and

LC/MS was consistent with a substance that is a diastereomeric (4:1 ratio) mixture of the title amine 111. This substance was used as such without further purification. tsik! мн, зо -- ойования о ати о же хо са 312 Ш 113 і: Scheme 28! 5 4-AMINO-2,2,6,6-TETRAMETHYLCYCLOGHEXYL-6-CHLORO-2-PYRIDINECARBOXYLATE (113).

This compound was synthesized as shown in Scheme 28. When stirred to a solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro I4.5| decane-8-oyl (0.32g, 1.50mmol) in ml of TNE was cooled to 09C, and n-Via (2.5M in hexane, 1.50mmol, 0.bml) was added dropwise. The mixture was stirred for 10 minutes. b-Chloropicolinoyl chloride (1.50 mmol, 0.26 g) was added as a solution in ml of TNE, and the reaction mixture was allowed to warm to room temperature. The solution was left to solidify, and 5 ml of TNE was added, and the reaction mixture was stirred overnight. The reaction mixture was poured into 40 ml of 0.5 M Mahon and extracted with ether (3 x 20 ml). The ether layer was dried over Mo5O, filtered and concentrated. Proton H-NMR showed the expected product together with the starting material in a ratio of 1.6:1.

These compounds could not be separated by silica gel chromatography, so the mixture was kept until the next step and further purified. Silica gel (1.4 g) was suspended in 10 ml of СНоСі". 0.Zml 1295 solution of NOSI in water was added dropwise to this suspension (2.0) within 5 minutes. The mixture was vigorously stirred to prevent co-precipitation. A solution of the above-mentioned compound dissolved in bml of CH»SiO was added and the reaction mixture was stirred for 3 hours. Then the mixture was filtered, and the silica gel tablet was washed with 100 ml of СНоСиИ». The solvent was evaporated until an oil was formed. The precipitation of the necessary picoline ester 112 was influenced by the addition of 1 mL of a 4:1 hexane-EOAc solution.

The solid obtained as a result was filtered and washed with 1 ml of hexane-EOJudAs ratio and - 4:11. The residue from the hexane-E(OAc) wash was combined and evaporated to an oil. The procedure described above was repeated three times until picoline ester 112 was formed as a white solid (214 mg, 4695 over two steps). Proton H-NMR and GC/MS showed the necessary product of 29595 purity.

A solution of this complex ester (200mg, 0.5mmol), titanium (IM) isopropoxide (1.30mmol, 0.3ml), ammonia (1.300mmol, 70mg) and triethylamine (1.30mmol, 0.18ml) in absolute ethanol (5ml) was stirred. in nitrogen with C at ambient temperature for 12 hours. Then sodium borohydride (0.97 mmol, "» 4Omg) was added and the resulting mixture was further stirred for 8 hours at ambient temperature. The reaction mixture was then quenched by pouring into aqueous ammonium solution (2OmL, 2.0M), and the resulting solution was extracted with ether (Zh20Oml). The combined ether extracts were extracted with 2M NOSI (2x20ml) to separate minor materials. The acid solution was washed once with ether (20 ml), and after that

The mixture was treated with aqueous sodium hydroxide (2M) to pH 10-12, and extracted with EtOAc (3x20ml). The combined EtOAc elutions were dried with MazoO, filtered and concentrated to an oil. This c substance coincided with a diastereomeric solution 06b:1 of cyclohexylamine indicated in the title.

Proton H-NMR and GC/MS indicated the required product of 77595 purity. This amine solution was used as (95) without further purification.

IY MN,

F) oZsN, name) 60

This amine was prepared from cyclohexane using the azasulfenylation technology according to |B. M. Tgovi and T. zpivaya, 3. At. 25 Spet. wasps 1982, 104, 3225). b5 piku ndva 9 RYZ | R RY5: 114 115

Scheme 29 9 4-PHENYLTHIOCYCLOGHEXYLAMINE (115).

This substance was prepared following the procedure described in Scheme 29. When mixed into a solution of 4-phenylthiocyclohexanol (M. K. Madam and O. A. Deuaga), U. Ogd. Spent 1998, 63, 3474) (1.20g, 5.83mmol) in 20ml of methanol, a solution of benzyloxyamine hydrochloride (1.80g, 11.22mmol) and potassium acetate 19 (1.10g, 11.22mmol) in 20ml of water were added once. The reaction mixture was stirred at room temperature overnight. Water (bOml) was added, and the resulting mixture was extracted with ether (3x4Oml). The ethereal extracts were combined, washed with saturated sodium chloride (1x5Oml) and brine (1x4Oml). The ether layer was dried (MA 5 O), filtered and concentrated to yield an oil. This substance was purified by radial chromatography (9:1 hexane-EuAc) to give the corresponding O-benzyloxime 114 (1.72 g, 95905) in the form of solution E and 7 isomers.

Lithium aluminum hydride (5.08 mmol, 0.19 g) was suspended in 1 mL of dehydrated ether and cooled to 020.

O-benzyloxime 114 dissolved in 5 mL of ether was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours.

Excess lithium aluminum hydride was destroyed by slowly adding water (0.2 ml) and 1 M Mahon (0.2 ml). The mixture was filtered and the salts were washed with 500 ml of ether. The solvent was evaporated until 0.62 g (9395) of the title amine 115 was formed as an oil. Proton H-NMR and GC/MS confirmed that the product is a diastereomer solution of amines 295905 purity, in a ratio of 1.3:1.

IS) 116 117 m

Scheme 30 3-I3-"TRIFLUOROMETHYL)-2-PYRIDINYLSULFANILUCYCLOGHEXYLAMINE (117). "

This amine was prepared following the procedure shown in Scheme 30. When stirring to a solution of 7 70 2-cyclohexen-1-one (0.44 mL, 4.5 v8 mmol) and 2-mercapto-5-trifluoromethylpyridine (0.82 g, 4.58 mmol) in 20 mL with СНоСИ" at ambient temperature, bismuth trichloride (bOmg, 0.18 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated. The residues were purified by radial chromatography using 4:1 hexane-EUAc as an eluent to give 1.12 g (89965) of the conjugated product 2-(3-oxo-cyclohexylthio)-5-trifluoromethylpyridine (116). 35 p i and 116 (0.26 g, 0.95 mmol) in 3 mL of methanol was added once with stirring to a solution of benzyloxyamine hydrochloride (0.29 g, 1.83 mmol) and potassium acetate (0.18 g, 1.43 mmol) in 3 mL with stirring. water The reaction mixture was stirred at room temperature overnight. Water (10 ml) was added and the resulting mixture was extracted with ether (3x10 ml). The ethereal extracts were combined, washed, saturated with MansSO 3 (1x15ml) and brine (1x15ml). The ether layer was dried (Mo5O), filtered and concentrated to give an oil (95). This substance was purified by radial chromatography (9:1 hexane-EtOAc) until the formation of individual oximes (0.32g, 8996). E-isomer (Ke0.33) and 2-isomer (K0.25) showed east proton NMR and GC/MS spectral characteristics.

Lithium aluminum hydride (1.333mmol, 50mg) was suspended in 3ml of dehydrated ether and cooled to 02C. Combined oximes dissolved in 1ml of ether were added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Excess lithium aluminum hydride was destroyed by slow (F) one-time addition of water (50 pi) and B Mahon (5 Oml). The mixture was filtered and the salts were washed with ether to a total volume of 100 ml. The ether solution was extracted with 2 M MEDIA (2x5 Oml) to separate non-essential substances. The acidic aqueous solution was washed once with ether (5Oml), and then treated with aqueous sodium hydroxide (2M) to pH 10-12, and extracted with ether (3 x 5Oml). The ether layer was dried with Na950O, filtered and concentrated to give 121 mg (5295) of the required amine 117, indicated in the title, as an oil.

Proton -NMR and GC/MS confirmed that the product is a 1.3:1 diastereomeric solution of amines of 295965 purity. b5

. o o o o

Yar R

Be; Chit Ts Mania oi zar

Ra Ra R 118 119 ex

Scheme 31 tennis: 1-35-AMINO-1,3,3-THRYMETHYLCYCLOGHEXYL)-4-PHENYL-1-BUTANONE (120).

The synthesis of this amine was carried out according to the method described in Scheme 31. A suspension of naphthalene (1.23 g, 9.57 mmol) and lithium granules (w/mg, 9.57 mmol) in 10 ml TNE at ambient temperature was stirred overnight under nitrogen. This lithium naphthalide solution was cooled to -602C and phenyl 3-phenylpropyl sulfide (1.1 g, 4.7 mmol) was added. The reaction mixture was heated to -209С to complete the reaction, and then cooled again to -602С7. A solution of 7-cyano-7,9,9-trimethyl-1,4-dioxaspiro|4.5|decane (0.5 g, 2.39 mM MoOl) in bBml TNE was added, and the solution was heated to 02C and stirred for 2 hours at this temperature. The reaction mixture was quenched by adding 1 Oml of saturated ammonia solution, and then treated with 2 M NOSI

VO of pH -4 and stirred at room temperature overnight. The mixture was extracted with ether (3 x 30 ml), dried with Na 5 ZO), filtered and evaporated. The residues were purified by radial chromatography using 6:11 hexane-EtOAc as eluent. Thus, a 1:3 solution of 3-(2-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanol 118 (13 mg, K0.18) was obtained. And its ketal (509mg, K0.33) is a product of unfinished hydrolysis. The total yield of the addition of 1-lithio-3-phenylpropane to the nitrile was calculated to be 85905.

Silica gel (1.82g) was suspended in 100 ml of CHClCl. i) 0.41 ml of 1295 NOI solution in water was added dropwise to this suspension over 5 minutes. The mixture was vigorously stirred to prevent precipitation. A solution of the above-mentioned ketal dissolved in 2 ml of CH»oSi» was added, and the reaction mixture was stirred for 3 hours. After that, the mixture was filtered and the silica gel tablet was washed with 50 ml of СНоСі". The solvent was evaporated to give 9.48 g (10095) of 3-(1-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanol (118) as a clear oil compatible with its NMR and GC/MS properties. and ,

While stirring, a solution of hydroxyl amine hydrochloride (0.16g, 2.28mmol) and sodium acetate (0.25g, 3.0mmol) in 7ml of water was added once to a solution of this bis-ketone (0.62g, 2.17mmol) in 7ml of methanol.

The reaction mixture was stirred at room temperature for 1 hour. Water (20 ml) was added, and the resulting mixture was extracted with ether (3x20 ml). The ether extracts were combined, washed with saturated NaCl (1x2Oml) and brine (1x20ml). The ether layer was dried with M950;, filtered and concentrated to form the required mono-oxime 119 (0.57 g, 87905) in the form of I and 7 isomers. Capeu? Nickel (0.8 g wet weight, Aiagis Spetisa! So.) in a 500 ml thick-walled Parr bottle was washed with water (Z x 20 ml), and then with ethanol (Z 3 x 20 ml), the washed solvent was drained each time. A solution of oxime 119 (0.57g, 1.89mmol) in dehydrated ethanol (40ml) was added to this washed catalyst. The resulting mixture was saturated with ammonium by bubbling ammonium gas through the solution for 1 minute. This solution was placed in an atmosphere of hydrogen (initial pressure of hydrogen - BORG) on a Parr mixer, and stirred for 7 hours. The reaction mixture was filtered through a Seiyet tablet and the solvent was evaporated to yield an oil (0.43 g, 8095). GC/MS analysis showed a 171 diastereomeric mixture of the title amine 120 along with small amounts of undetected side products. This amine solution was used directly as such without further purification. -I sl (v! mon Mn, y Dt i s v ' oz o Ra Ga! Ry Ky Ge) and RA so 121 122 | Scheme 32

F) o 2-BENZYL-6-METHYL-4-PYRANYLAMINE (122).

This amine was prepared according to Scheme 32. 0.22g (3.1mmol) of hydroxylamine was added to 0.37g (1.8mmol) of 2-benzyl-b-methyl-4-pyranone (b. Riapsaiii, ei. ai., 60 Vupipeviv, 1982, 2481) hydrochloride and 0.16 g (2 mmol) of sodium acetate in 100 ml of methanol. After stirring overnight, the mixture was separated into CH 25Si" and water. The organic phase was dried and evaporated. The fatty residues were left to solidify by settling at room temperature to form 0.4 g (9995) of the required oxime 121 as a 1:11 solution of the 2/E isomer in the ratio of GC/MS with molecular ion 219, which was used as such in the subsequent reduction reaction. b5 0.8g (wet weight) was added to 0.4g of 2-benzyl-6-methyl-4-pyranone oxime (121) (1.8mmol) in 5Oml of 9595 ethanol

Capeuf nickel, which was washed three times with water and three times with ethanol. The mixture was placed under 41 g of hydrogen in a mixer

Parra within 32 hours. After ventilation, the mixture was subjected to pressureless filtration and evaporated under vacuum. The residues were separated into CH»oSi» and aqueous sodium carbonate solution. The organic phase was dried and

It was evaporated under vacuum to form 0.19 g of the required solution of amine 122, indicated in the title, plus oxime 121 in a 2:1 ratio by GC/MS analysis. The mixture was used as such without further separation. 1-BENZOYL-4-AMINOPIPERIDINE.

This compound was prepared by the method of Vpayaspgaguua, ei a!., Zupi ei, 1999,11, 17811. ! he he oh Mn,

M M M M

H p 25. (8) 123 124 125 p

Scheme 33 and so with 1-4-METHYLBENZYL)-4-PIPERIDINYLAMINE (125).

The synthesis of this compound was carried out according to Scheme 33. To 5.05g (5Omol) of 4-hydroxypiperidine and 7.08g (5Omol) of

Excess solid potassium carbonate was added to p-methylbenzyl chloride in 25 ml of tert-butanol, and the mixture was heated M. on a steam bath for 3 hours. The mixture was cooled to room temperature and partitioned between ether and water.

The organic phase was extracted with cold dilute HCl, and the acidic aqueous phase was extracted twice with ether. The aqueous phase was made into a base with ice and 5095 aqueous Mahon, and extracted with ether. The ether phase was washed with dilute aqueous sodium bicarbonate solution, brine, dried, and evaporated under vacuum to give 5.Zg (5295) 1-(4-methylbenzyl)-4-hydroxysheridine (123) as an oil. GC/MS showed 100965 purity shsh s with molecular ion 205. . 4.bml (bimmol) OM5O was added to 2.8 ml (32 mmol) of oxalyl chloride in 7 bml of СНоSiO at -7892С. To this "» mixture was added 5.3 g (2 mmol) 1-(4-methylbenzyl)-4-piperidinol 123 in 1 Oml СНоСи», and the cold mixture was stirred for 5 minutes. The mixture was quenched with 18 ml (129 mmol) of triethylamine and left to cool to

At room temperature, and saturated aqueous ammonia was added. The organic phase was washed with water and -I brine, dried, and evaporated to give 4.27 g (81905) of 1-(4-methylbenzyl)-4-piperidinone (124), which was used without further purification. GC/MS showed 100905 the purity of the solution with the molecular ion 203. i-th To 4.25 g (21 mmol) of 1-(4-methylbenzyl)-4-piperidinone 124 in 200 ml of dehydrated methanol was added 32.2 g (420 mmol) of ammonium acetate and 25 g of ZA molecular bran After stirring for 35 minutes, 5.25 g (84 mmol) of sodium cyanoborohydride was added portionwise. After stirring for 16 hours, the mixture was subjected to pressureless filtration and the methanol was evaporated under vacuum. The residues were separated into ether and so ice/NSI. The acidic aqueous layer was extracted twice with ether, basified with 5095 aqueous Mahon and ice, and extracted with SiOCl to give 2.1 g (4890) of the title amine 125 as a viscous oil. GC/MS showed molecular ion 204. This product was used as such without further purification.

F) name) 60 b5 o Mn,

M What did you hear 10 126 127

Scheme 34 15 1--4-TRIFLUOROMETHYLBENZYL)-4-PIPERIDINYLAMINE (127).

It was prepared according to Scheme 34. To 0.8 g (3.1 mmol) of 1-(3-trifluoromethylbenzyl)-4-piperidone (prepared in the same way as 1-(4-methylbenzyl)-4-piperidinone) 123) | 0.22 g (3.1 mmol) of hydroxylamine 20 hydrochloride was added to 7 ml of pyridine, and the solution was stirred overnight. The mixture was evaporated under vacuum, and the residue was partitioned between ether and dilute aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum to give 0.52 g (6290) of the oxime as an oil, which was used as such in the hydrogenation step as described below. GC/MS showed molecular ion 272.

To 0.5 g (2 mmol) of this oxime in 75 ml of ethanol was added 0.5 g (wet weight) of KapeudF nickel, which was previously washed with water and three times with ethanol. Ammonium gas was bubbled into the mixture for several minutes, and the mixture was placed in a Parr mixer under 45 g of hydrogen for 7 hours. The vessel was ventilated and the mixture was subjected to pressureless filtration. The residue was dissolved in ether, filtered, and evaporated to give 0.43 g (8195) of the title amine 127, which was used as such without further purification. GC/MS showed a single peak with molecular ion 258. Yuyu 35 m. 128

Scheme 35 « nnaaaooooooYuoMB CYAT VOLO OO ts siv/rans-2-METHYL-3-TETRAHYDROFURYLAMINE (128). c» This amine was obtained by the method described in Scheme 35. To 1.1 g (1Omol) of 2-methyltetrahydrofuran-3-one oxime (prepared according to a standard procedure from commercially available 2-methyltetrahydrofuran-3-one) in

1 g (wet weight) of CapeuF nickel was added to 1 ml of methanol, which had previously been washed three times with water and three times with ethanol, and placed in a Parr mixer under a hydrogen atmosphere of 44 rz. After 18 hours, the mixture was ventilated. and subjected to pressureless filtration. The methanol was evaporated under vacuum, and the residue was taken up in ether and dried. The ether phase was evaporated under vacuum to give 0.bg (5995) of the title amine 128 as a siv/trans solution. GC/MS showed 4195 with molecular ion 101 and 5995 with molecular o ion 101. This amine solution was used as such without further purification. at 50 p.m. so ve wa . rock - Ah

R RA. OH ry OH yr o kov o vo 130 1m 19 iz ime)

Scheme 36 60 2-BENZYL-2,6-DIMETHYL-4-PYRANYLAMINE (133).

This amine was obtained by the procedure described in Scheme 36. To 4.88 g (19.7 mmol)

2.4 g of 65 (18 mmol) phenylacetone and 1 drop of trimethylsilyl triflate were added to 3-trimethylsilyloxybutyric acid trimethylsilyl ester in 40 ml of CHCl at -782С. The mixture was left to settle in cold water for 2 days, and after that, 0.5 mL of pyridine was quenched and allowed to warm to room temperature.

The organic phase was washed with a diluted aqueous solution of sodium bicarbonate, dried, and evaporated under vacuum. The residues were distilled under vacuum to give 2.89 g (6795) of 2-5 benzyl-2, b-dimethyl-4-methylene-1,3-dioxan-4-one (129), b.p. 125-32 F 0.bmm. GC/MS showed two isomers, each with a single peak at 134 (phenylacetone).

2.9 g (13.9 mmol) of 10 bis-(cyclopentyl)-10 bis-(cyclopentyl)- bis-methyl titanocene in 20 ml of dry TNE. The mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and quenched with excess ether.

The entire solution was filtered through a silica gel pad with ether as eluent. The filtrate was evaporated and chromatographed on 7/0 silica gel with EtOAc and hexane (1:4) containing 0.27% triethylamine. Fractions containing this substance were evaporated and suspended in petroleum ether, and filtered under vacuum to form 1.2 g of a solid substance. GC/MS showed a solution in an approximately 3:1 ratio of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxane (130) with molecular ion 218 and starting material 129. The mixture was used as such in the rearrangement , as described below.

To 1.2 g (5 mmol) of this solution in 5 ml of toluene in nitrogen was added 10.99 ml (11 mmol) of tri-isobutyl aluminum hydride at -782C. The reaction mixture was left to stand cold for 16 hours and then quenched with a few drops of water. The mixture was allowed to warm to room temperature, and an excess solution of aqueous ammonia was added. The mixture was extracted with an excess of CH»-Si» complex separation of the aluminum salt.

The organic layer was dried and evaporated to give 1.1 g (9095) of 2-benzyl-2, 8-dimethyl-4-hydroxypyranol (131) in the form of a 75:25 isomer solution (by GC/MS).

To 1.1 g (bmmol) of compound 131 in 10 ml of CHClCl», 1.6 g (7.bmmol) of pyridinium chlorochromate was added in portions with magnetic stirring. After 1 hour at room temperature, ether was added and the solution was filtered through a silica gel tablet and washed with ether. The filtrate was evaporated to give 0.88 g (80905) of 2-benzyl-2,6-dimethyl-4-pyranone (132). GC/MS showed 9995 purity with base peak 127 (M-benzyl). A solution of the c isomer was used as such in reductive amination as described below.

To 0.88 g (Ammol) of substance 132 in 40 ml of dehydrated methanol was added 6.16 g (VOmmol) of ammonium acetate and about 5 g of ZA molecular seeds. After stirring for 45 minutes at room temperature, 1.02 g (1 mmol) of sodium cyanoborohydride was added in portions with magnetic stirring. The mixture was subjected to pressureless filtration, and the methanol was evaporated under vacuum. The residues were separated into ether and diluted cold NSI. oz 3o The aqueous phase was extracted twice with ether, then a base of ice and 5075 water Mahon was made from it.

The product was extracted with CHCl, dried, and evaporated to give 0.43 g (4990) of a two-component solution of the isomer of the amine 133 indicated in the title. GC/MS showed 5875 with molecular ion 128 and 4296 with 3 "With molecular ion 128.

IS) zv On on o Mn, shcha 03 -03-03-0

M M M M « y - khz Ri RA ra 134 135 136

B Scheme 37 1 (9) 1--3-PHENYLPROPIONYL)-4-AMINOPIPERIDINE (136).

This amine was synthesized according to the method described in Scheme 37. Phenylpropionyl chloride (obtained from bg (4A0mmol) of phenylpropionic acid in excess sothionyl chloride was added to 4g (40mmol) of 4-hydroxypiperidine in 20ml of toluene. An excess of 2M aqueous Mahon was added to the mixture. After stirring for 24 hours, the toluene layer was discarded and the aqueous phase was extracted with СНоСи», then dried and evaporated under vacuum to give 3.6 b3Zg (39905) of 1-(3-phenylpropionyl)-4-hydroxypiperidine (134). GC/MS showed a purity of 10095 with a molecular ion of 233. o To 1.6 bv8ml of oxalyl chloride (19.2 mmol) in Zb5ml of СНоСи»о at -782С was added 2.7Сml (38.5 mmol) of dry OMZO in bml of СНоССи». After mixing, 3.6 mg (15.4 mmol) of 1-(3-phenylpropionyl)-4-hydroxypiperidine 134 in ml (imme) CHClCl was added and the mixture was stirred cold for 5 minutes. 10.7 mL (77 mmol) of triethylamine in 5 mL was added

СНоСИ" and left the mixture to warm to room temperature. The mixture was quenched with a saturated aqueous solution of 60% ammonia. The organic phase was washed twice with water, saturated brine, dried, and evaporated under vacuum to yield 3.2 g (8995) of 1-(3-phenylpropionyl)-4-ketopiperidine (135). GC/MS showed 10095 purity with molecular ion 231.

To 3.2 g (13.8 mmol) of compound 135 in 125 ml of dehydrated methanol was added 21.3 g of ammonium acetate and 20 g of ZA molecular sieves. After stirring for 30 minutes, 3.47 g (55.2 mmol) of sodium 65 cyanoborohydride was added in portions. After 3 hours, the mixture was subjected to pressureless filtration, and the methanol was evaporated under vacuum. The residues were separated into ice/NSI and ether. The acidic aqueous phase was extracted twice with ether. The water phase was made the main one with ice and 50956 water MaonN. The mixture was extracted with CH 5Si", dried, and evaporated under vacuum to give 1.5 g (4795) of amine 136, indicated in the title, GC/MS showed 10090 purity with molecular ion 232. nn chn : i ih tu xx 137 438

Mn, o7o and : o: c o)

RE

! 139

Scheme 38 so so

PREPARATION OF AMINE 139.

The synthesis of this amine is shown in Scheme 38. Compound 137 "U

IM. 5yitagpo ei ai, Teigapedgop, 1998, 54, 12745) (0.80g, 1.21mmol) and bml of pyridine. The solution was cooled to 02С and treated with 1.1 mL of the HE-pyridine complex, and the solution was heated to room temperature with stirring for 17 hours. After that, another 1.1 ml of non-pyridine was added and the reaction mixture was stirred for another 30 hours. This mixture was poured with stirring into a cold solution of 40 ml of 1 M HCl and 20 ml of 1:1 hexane-diethyl ether. The layers were separated and the aqueous layer was extracted 1:1 with hexane-diethyl ether (2x20ml).

The combined organic layers were washed with ice-cold 1M HCl (1x20ml) and brine (1x20ml). The solution was dried

Ma5O,), filtered and concentrated. The crude product was purified by radial chromatography (3:1 hexane-EtOAc) to give 282 mg of hydroxyether (plus minor impurities), which was used in the next step directly. When stirring, isobutyryl chloride (0.2 ml, 1.92 mmol) was added dropwise to a solution of crude hydroxyether (282 mg, 0.4 in 8 mmol) in pyridine cooled to "02С. The cooling bath was removed and the mixture was stirred for 5 hours. Water (2 ml) was added and the mixture was stirred for another 30 minutes. - 45 The solution was extracted with ether (3x1Oml). The ether layer was washed sequentially with ice-cold 1M NOI (2x10ml), saturated Manso (1x10ml) and saline (1x10ml). The solution was dried over NaCl, filtered and concentrated. 1 The crude product was purified by radial chromatography (4:1 hexane-E(OAc) to yield 171 mg of isobutyryl ester 138 (total of 2395 in two steps).

The BOC group of this ester was removed according to standard BOC deprotection conditions as previously described (95) to form the required amine 139.

IR e)

F) name) 60 b5

' tvo o OSNO Tv5O0 o o dn ni eyes

And it tosnRA ot sov

ШЕ: оо: хх вв | RA 140 1: already SNI 142: kan 70 143: KUN, and SNR 144: Kk: As, V x SNR m o o7to o 144, sne sha "re s ShK Ve and Ve ek,

OAs about RN. 145

Scheme 39. and s o

PREPARATION OF AMINE 145.

This amine was prepared as described in Scheme 39. Hydroxyether 140 |M. 5 pitapo ei ai., Tesigapedgop, 1998, 54, 12745) (6.27 mmol) was dissolved in 15 ml of UME and cooled to 02С. To this solution was successively added

LOBSTER (1.53g, 12.53mmol), EOSI (1.8g, 9.40mmol) and M-BOC-O-Bp-(I)-threonine (2.52g, 8.15mmol). The reaction mixture was heated to room temperature and stirred overnight. The solution with vigorous stirring was poured into a mixture of 30 ml of ice-cold 0.5 M HCl and 50 ml of 4:1 hexane-ether. The layers were separated and the aqueous layer was extracted with 4:1 hexane-ether (1 x 30 ml). The combined organic layers were washed with 0.5 M HCl (1x2Oml) and brine (2x20ml). The solution was dried Mo95O), filtered and concentrated. The crude substance was chromatographed on silica gel (150 g) using 1.25 L of 3:11 CH 5 SiO-hexanes to elute anisaldehyde, followed by 65:10:25 CH 2 SiO-ether-hexanes to elute the combined product. 141 (3.95g, 8896).

A mixture of benzyl ether 141 (1.32 g, 1.84 mol) and 200 mg of 1095 Ra/C in 25 ml of EUAs was shaken in a Parr apparatus under hydrogen pressure for 5 hours. Was the mixture filtered through a Seiye tablet? and concentrated until the formation of hydroxy acid 142 (68Omg, 70905), pure enough according to TN-NMR analysis. WITH

Solid sodium bicarbonate (1.2g, 14.27mmol) was added to a solution of hydroxy acid 142 (1.54g, 2.8bmmol) and benzyl bromide (1.5ml, c 12.29mmol) in 7ml of UOME while stirring. The mixture was stirred at room temperature for 24 hours, then divided into 25 ml of water and 1 ml of 4:1 hexane-ether. The layers were separated and the aqueous layer was extracted with 4:1 hexane-ether (2 x 1 ml). The combined organic layers were washed with 0.1M Mahon (1x1Oml) and water (1x1Oml). The solution was dried over MoSSO, filtered and concentrated. The crude -1 75 substance was purified by radial chromatography (4:11 hexane-E(UAs) to form 1.04 g (60905) of hydroxybenzyl ester 143. c When stirring to a solution of ester 143 (840 mg, 1.34 mmol) and acetic anhydride (1 .Oml, with 10.6 dmmol) in 7 ml of pyridine was added OMAR (4Omg, 0.b7mmol). The reaction mixture was stirred at room temperature for 4 hours and diluted with 8Oml of E(OAc. This solution was successively washed with saturated SiSO, (95) 50 (ZxZOml) . using the simple methods described above to form amine 145.

F) name) 60 b5

O.M., On

They are pinnnnn nny

M t" che cha,

Aso Odesa Co "OV

Odessa ov 146 147a: Kene, then 1475: zap: M, 1472: KR, KK: MN, 1474: ve SNR, V x MN, 1416; AC: MN,

Scheme 40 I

PREPARATION OF 2, 3, 4-TRI-O-ALKYL-beta-O-XINOPYRANOSYLAMINE 147c,4,e.

The synthesis of these amines is shown in Scheme 40. During stirring, 1.1 ml (1.0 mmol) of a 1.0 M solution of sodium methylate in methanol was added to a solution of triacetoxy-2-azidoxylopyranosyl azide 146 (Asgoz Spetis! So.) in SNHZON at room temperature. The reaction mixture was stirred overnight and neutralized with 5x8-100 resin acid (-0.6g). The solution was filtered and concentrated. The obtained azidotriol 147a was used directly in the next step. with

Unpurified triol 147a was dissolved in 15 ml of UME and Mann (6095 dispersion, 0.53 g, 13.28 mmol) and added in four portions over 15 minutes. The reaction mixture was stirred for 30 minutes at room temperature, allyl bromide (2.7 mL, 33.20 mmol) was added, and the mixture was stirred overnight. Saturated ammonia (1 Oml) was carefully added, followed by the addition of 5 Oml of water. The aqueous solution was extracted with EtOAc (3 x 30 ml).

The organic layer was successively washed with water (4x3Oml) and brine (2x3Oml). The solution was dried over Mo52, filtered and concentrated, the crude material was purified by radial chromatography (6:1 with hexane-EOAc) to give 753 mg (7790) of tri-Op-allyl-2-azidoxylopyranose 147r.

The resulting azide and allyl components were reduced by mixing with 150 mg of 1095 Ra/C in 40 ml of

EtOAc under 1 atmosphere of hydrogen for 4 hours. The resulting solution was filtered through a Seyjeuv plate and evaporated to give a quantitative yield of the amine indicated in the title 147c.

The preparation of amine 1474 is identical to that described for 147c, except for the use of benzyl bromide in the alkylation stage, followed by reduction of the azide to the amine as described above.

A similar hydrogenation of azide 146 1095 Pa/С in EtOAc under 1 atmosphere of hydrogen led to the formation of amine 147e.

PREPARATION OF 2,3,4-TRI-O-ACETYL-beta-I-FUZUCOPYRANOSYL AMINE (148) « shi s t, o "MH, g" СХ che z |В t 00 Odessa -I zh sl OAs (95) o 50 148 so To a solution of 2,3,4-tri-O-acetyl-beta-b-fucopyranosyl azide (Asgose) (750 mg, 2.3 vmmol) in 40 ml of EtOAc was added 120 mg of 1095 Ra/sС. This solution was stirred in an atmosphere of hydrogen gas (1 atm.) for 3 hours. The mixture was filtered through a SeylephFv pad and washed with EtOAc (25 mL). The solution was evaporated to afford the required amine 148 (688 mg, 10090).

GF) PREPARATION OF 1,3,4,6-TETRA-O-ACETYL-2-AMINO-2-DEOXY-alpha-O-GLUCOPYRANOSE (149). name) 60 b5

OO. Odessa dsOo" "vn 2

OAS

180 mg of 1095 Ra/С was added to a solution of 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-alpha-O-glucopyranose (TCI-O5) (300 mg, 0.800 mmol) in 25 ml of EUAs. This solution was stirred in an atmosphere of hydrogen gas (Tatm.) for 3 hours. Was the mixture filtered through a Seiye tablet? and the tablet was washed with EtOAc (20 ml). The solution was evaporated to form the required amine 149 (282mg, 10090).

PREPARATION OF BENZYL AND METHYL 3-AMINO-TRIDEOXY-I -ARABINO-HEXOPYRANOSIDES 150a and 1505.

These amines were synthesized according to the method of H. Oaieu, ei ai., Zupii. Sottype 1998, 28, 611. o « o and o; I-i - s oche ON ochi vVOoSMN same . pini ini pi kyty chii z o VOSMne Z

РЬ Ra ' o o 1 (95) s 50 .

IR e) o, o o?

N.M tea. oh oh

RA di in; because 153

Scheme 41 b5

PREPARATION OF AMINE 153.

This amine was prepared as shown in Scheme 41. (35.7kK,8K,95)-7-benzyl-8-hydroxy-9-methyl-2,6-dioxo-|1,5)dioxonan-3-yl|-carbamino acid tert-butyl complex ester (151) was prepared (as described by M. Zpitagpo ei ai, Te(ygapedgop, 1998, 54, 1274). When stirring to a solution of this ester (120 Ω, 0.00 mmol) in pyridine (5 ml) slowly methacryoyl chloride (0.100 ml, 1.0 mmol) was added over 5 minutes. The resulting mixture was stirred at room temperature under M2 atmosphere overnight. The reaction mixture was partitioned between E(OAc (75 ml) and IM HCIII (50 ml). The organic layer was washed with water, after saturated mass, dried Mao"), and concentrated to form a clear oil. This crude 7/0 oil was chromatographed on silica gel using 3075 EtOAc in hexane as eluent to give acylated intermediate 152 (138 mg) as a clear glass. The BOC group was removed from of this intermediate as described in reference above to form the title amine 153.

PREPARATION OF ANILINE ANTIMYCIN A"; (154).

Same.

N.M. 8;

M o gch is s o 154 o

When stirring, pyridine (11 L) and PSI5 (27 mg, 0.13 mmol) were added to a solution of antimycin Az (25 mg, 0.048 mmol) in 2.0 ml of CHNOCl cooled to 092°C. The mixture was heated at reflux for 1.5 hours, then cooled to -302C, and methanol (2.5 bml) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The solution was poured into a mixture of 13 ml of CHCl and 13 ml of saturated sodium bicarbonate at a temperature of 0°C. The mixture was shaken in a coupling flask, and the layers were separated. The aqueous layer was extracted with SiOCl (2 x 5 ml) and the combined organic layers were dried (M9505), filtered and

Zo was concentrated until the formation of aniline antimycin Az. -

GENERAL PROCEDURES FOR THE COMBINATION OF AMINES WITH ORTHO-HYDROXYHETEROAROMATICS

WITH CARBOXYLIC ACIDS FOR THE FORMATION OF HETEROCYCLIC AROMATIC AMIDES 2.

COMBINATION PROCEDURE A; COOKING "f

M-(2--4-CHLOROPHENYLETHYL)-3-HYDROXYPYRIDINE-2-CARBOXAMIDE (233). - сон "» и я | n s M - M y o o si ia 233 so A stirred solution of 3-hydroxypyridine-2-carboxylic acid (1.39g, 0.0imole) in dry TNE (bOml) in an argon atmosphere was cooled to - 202C. A 2095 solution of phosgene in toluene (5.1g, 0.01Tmol) was added to it once, and the resulting mixture was stirred for 90 minutes while slowly raising the temperature to 0260. 59 The reaction mixture was then cooled again to -2092C, and a diisopropylethylamine solution was added dropwise

HF) (2.58g, 0.02mol) in TNE (2O0ml) for 30 minutes. After the addition, the mixture was stirred again

HF for 2 hours, then the temperature was slowly brought to 0 2С. Stirring was continued at 02 overnight. 2-(4-chlorophenyl)ethylamine (1.56 g, in 0.001 mol) was added once to this solution while stirring, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with ether (100ml), washed with 1M HCl (100ml), dried (Ma5SO3)) and concentrated to give the title compound as a yellowish solid (1.95g). Mass spectrometry showed the expected 3:1 derivative ion ratio at m/e 276 and 278.

COMBINATION PROCEDURE IN; PREPARATION v5 3-HYDROXY-4-METHOXY-M-(4--4-TRIFLUOROMETHYLPHENOXY)PHENYL)-PYRIDINE-2-CARBOXAMIDE (425).

OMe that | N se Se,

M o "

While stirring, a solution of 4-(4-trifluoromethylphenoxy) aniline (0.20 g, 0.dmol) and OMAR (0.10 g, 0.085 mmol) in CHCl (1 Oml) was added once

3-Benzyloxy-6-bromo-4-methoxypyridine-2-carbonyl chloride (3) (0.29g, 0.mmol) in CHClCl (ml). The resulting mixture was stirred overnight at room temperature, after which it was poured into 2M NOSE (10 ml). The organic layer was separated and the aqueous layer was extracted with СНоСи" (2x10 ml).

The organic layers were combined, dried (M950) and concentrated to form a viscous solid. This solid was collected in E(Ac (20 mL), and triethylamine (0.80 g, 0.vmmol) 596 Pa on (3 carbon (0.10 g) was added. The resulting mixture was placed under a hydrogen atmosphere (initial pressure -5 Org) on a Parr mixer for 30 min. The mixture was filtered, washed with 0.1M HCl (20ml), dried (Mo5O/) and concentrated to afford the title compound as a yellowish solid (0.14Hg), mp -122-1299°C

COMBINATION PROCEDURE p. COOKING "co

M-(4-DICLOHEXYLPHENYL)-3-HYDROXYPYRIDINE-2-CARBOXAMIDE. r where ON oyu | N and - - M

M « o - s. "» On stirring to a solution of 3-hydroxypyridine-2-carboxylic acid (obtained from 16 by catalytic hydrogenation in the presence of Ra/C as described earlier) (0.42g, 3mmol) and 4-cyclohexylaniline (0.35, 2mmol) in dry UOME ( ml) was successively added 1-hydroxybenzotriazole (0.48g), ESOCI (0.65g) and -1M-methylmethylmorpholine (1.41g). An additional amount of OME (bml) was added and the reaction mixture was stirred at room temperature overnight. The solution was poured into water (200ml), followed by extraction with EtOAc (2x75ml). The organic extracts were combined, washed with water (100ml), and saturated with Massey solution (50ml), (95) dried (MasO)) and concentrated. The crude oil, which was left to solidify under settling time 50 Chromatographed on silica gel (4:11 petroleum ether -EHAc) to give the title compound (0.42g) as a yellow-brown solid, mp 91-9390.so CONVERSION OF HETEROCYCLIC AROMATIC AMIDES INTO OTHER HETEROCYCLIC AROMATICS

AMIDES.

PREPARATION OF 4-HYDROXYTHIOPHEN-M-(3,3,5,5-TETRAMETHYLCYCLOGHEXYL)-3-CARBOXAMIDE (554).

F) name) 60 b5

HE in

With H does, 8. 554 4-Methoxythiophenecarboxylic acid and 3,3,5,5-tetramethylcyclohexylamine were coupled by the general coupling procedure as previously described to form 4-methoxythiophene-M-(3,3,5,5-tetramethylcyclohexyl) -3-carboxamide. 5b0Omg of a solution of this methoxythiophenamide in 15 ml of chloroform in a drying tube was stirred in a dry carbon dioxide-acetone bath for 5 minutes. To this solution, 94 mg of a solution of boron tribromide (2 equivalents) in 1 ml of chloroform was added dropwise over 15 minutes. Stirring was continued until the reaction mixture warmed to room temperature, and then overnight. After that, the reaction mixture was placed in a cold water bath, and 15 ml of water was added dropwise. After stirring for 15 minutes, the mixture was diluted with 500 ml of CH»eSi» and the organic layer was separated. The aqueous layer was washed with 5 mL of CH 5 Si. The combined organic extracts were washed with 25 ml of water and saturated saline and dried. The extract was filtered and concentrated. The residues were chromatographed on silica gel using CH 2C12-590

EHUOAc as an eluent for the formation of 310 mg of the title compound in the form of yellow-brown crystals, i) etc. 170-1742С7. The sample was recrystallized from petroleum ether EtOAc until yielding yellow-brown crystals, m.p. 171-17326. p s zo ZO oGrv | oh so g Ge! And 9 he | schu co

I - you - o yu ram ov, and V, o o o her- and Y Z5va: v, KRT, Ku: SNMeSN.RE

NI PA A tBBB:V,: Me, pe: SPK NMkovmegve 1550: A with Me 455: V, I Me, Vu with SM(SNIRNSNOZIMa and Vy « 1664: A, x Me, K. x SNISNIRAYUNON | / with s ze Her .

Y ss ot i m ok -i o) 0 1

Scheme 42 12 (95) o 50

PREPARATION OF COMBINED INTERMEDIATE COMPOUNDS 156a-a. These intermediates were prepared as described in Scheme 42. Upon stirring, to a solution of isopropyl(-)-serine hydrochloride (2.75g) and triethylamine (3.55g) in SNHCl (/5ml) omega was added over five minutes. benzyloxy-6-bromo-4-methoxypyridine-2-carbonyl chloride (3) (5.327) in СНоБСИ» (1B5 ml). The mixture was stirred for 30 minutes at room temperature, then poured into 1M NaCl (75 ml). Separated

GF! the organic layer was washed with water (25 ml), dried (Ma».5O)) and the solvent was evaporated to form a yellow resin (6.7 g). This material was recrystallized from ether/hexane to give 155a as a white solid, m.p. 100-1032C. A similar procedure, starting from the methyl ester of (i)-serine hydrochloride, led to the formation of an intermediate methyl ester. 60 Methylhydrocinnamoyl chloride (0.46g) was added once to a solution of 155a (1.17g), triethylamine (0.31g) and OMAR (0.06g) in SNHSII (25ml) while stirring. The resulting mixture was stirred for 4 hours at room temperature, then poured into 2M NaCl (15 ml). The organic phase was separated, washed with IM Mahon (15 ml), dried (MaSO)) and the solvent was evaporated to form 15ba as a yellow oil (1.45 g). TN-NMR (SOCI,.) was consistent with this oil being a 1:1 mixture of diastereomers. b5 y y y y

A solution of 3-(I-butyldimethylsilyloxy) butyryl chloride (3.55 g) (prepared from the corresponding complex ester of i-butyldimethylsilyl | according to the method of UUizzpeg and S.M. SgidgipzKav, U. Od.Spet., 1978, 43, 39721), in SNSI » (10ml) was quickly added to cold (023), a solution of 1556 (6.bg) and OMAR (0.18g) in dry pyridine (25ml) was stirred. The reaction mixture was stirred for 15 minutes at 02C, and then at room temperature for three hours. After dilution with ether (200 ml), the mixture was extracted with water (2 x 100 ml), dried (M95034) and the solvent was evaporated. Tolusol (25 ml) was added to the residue and the solvent was evaporated again.

The remaining yellow oil was purified by chromatography (silica gel, 7:3 hexane/acetone) to give 1565 as diastereomers. When stirring to a solution of 2-benzyl-3-(i-butyldimethylsilyloxy) propionic acid (7.36g)

IM.R. Reyei, M.G. Hepi2, M.MU. Yutsaiyeu, A.M.H. Odaep, Yu.E. MsSapu, and M.M. CasKe, U. May 30. Spet., 1993, 36, 70 4015), i-butyldimethylsilyl chloride (4.52g), imidazole (4.1g) was added once to OME (20ml), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with water (300 ml), then extracted with pentane (3 x 100 ml). The pentane phase was washed with water, dried (MgSO), and the solvent was evaporated to give a colorless oil (9.5 g). H-NMR (SOCI»z) was consistent with this solution of diastereomers.

This complex ether (4.1 g) was converted into the corresponding acid chloride by the method of M.R. Reege, ei ai., U). Oh 12 Spet., 1978, 43, 3972). This acid chloride was condensed 1555 (4.4g) as described above to give, after silica gel chromatography (4:1 hexane/acetone), the required solution 156c as a solution of diastereomers.

With stirring, concentrated NH (1.5 ml) was added to a solution of 156c (4.5 g) in methanol (35 ml). The resulting mixture was stirred at 452C at room temperature for 30 minutes, diluted with water (200ml), and then extracted with CHClCl (2x1000ml). The organic phase was dried (Ma5O)), and the solvent was evaporated. The residue was purified by silica gel chromatography (7:3 hexane/acetone) to give 1564 as a pale yellow resin (2.8g). "H-NMR (SOCI3) showed it to be a solution of diastereomers. Compounds 15ba-4 were converted into the corresponding deprotected heterocyclic aromatic amide by hydrogenation in the presence of Ra/C as described above. c

ОМе ГГ и омМе / Rv o zi on zi o

H 2 - | M - M - d) zo I: a, Ve m t so c) o so 157 168 syu

Scheme 43

NO

PREPARATION OF INTERMEDIATE 158. The synthesis of this intermediate is shown in Scheme 43. Amide 157 was prepared from 3 c (i)-trans-1-Hydroxy-2-aminocyclopentane hydrobromide (7.09 g, 38.0 mmol) and

of 3-benzyloxy-6-bromo-4,methoxypyridine-2-carbonyl chloride (3) (13.8 g, 38.bmol) in СНоСиИ» (15 Oml), according to the general procedure of coupling B, and was purified by flash chromatography using 1: 1 hexanes-EUAs as an eluent. This led to the formation of compound 157 (13.4 g) as a white solid, m.p. 56-5790.

Dimethyl sulfoxide (7.4 mL, 104.1 mmol) was slowly added at 7892C to a solution of oxalyl chloride (4.54 mL, 52.08 mmol) in СНоСИ» (10 Омл), followed by the addition of a solution of amide 157 (10.46 g, 24.8 mmol) in СНоСИИ» ( 25ml). After 30 minutes, EBM was added and the solution was slowly heated to room temperature. The mixture was poured into saturated NaCl (100 ml) and extracted with CHClCl (2 x 100 ml). The combined 9) organic layers were washed with brine, dried and the solvent was evaporated. The residues were purified by column chromatography, using 1:11 E(ODAs-hexane) as an eluent, to form ketone 158 (9.64 g, 9495), pure according to GC/MS and "H-"H-NMR data.

IR e) Compounds 157 and 158 were converted to the corresponding deprotected heterocyclic aromatic amides by hydrogenation in the presence of Ra/C as described above.

F) name) 60 b5

Ra omu"!

Velgepo 70 ne yav x t Meo OMe she and I. hu ve 9 o : x (o) 1602, y, s, 4 . . . » tlu tyu U - -h chi . -0 to -0 -o0 h 16ba 1605 16os 1604 s 25

Scheme 44 o

PREPARATION OF INTERMEDIATE COMPOUNDS 160a-a. co

These intermediate compounds were prepared as described in Scheme 44. The serinol compound (iz

with 3-benzyloxy-6-bromo-4-methoxypicolinic acid (16) according to the general procedure of coupling C, with (ze) the subsequent formation of 1,3-diol 159 in the form of a colorless oil, pure according to "H, 3C-NMR and UV spectra. so 1,3-diol 159 (1immol) was condensed with the corresponding carbonyl compound (2mmol) or the corresponding dimethyl acetal (2mmol) by irrigation in benzene (200ml/mmol) in a catalytic amount of p-toluenesulfonic acid,

With ACIDS (0.Tmmol) in the Oeap-eiagk installation. them-

Thus, the condensation of compounds 159 and 1,3,3-trimethoxypropane led to the formation of acetal 16b0a in the form of a 2:1 compound of syn and anti diastereomers. The mass spectrum (EM) showed IM in (t/e) 495 and 497. The spectra of "H-, 3S-NMR and HC coincided with compound 160a. "

The condensation of 159 and 2-methyl-3-(4-tert-butyl)phenylpropanone led to the formation of acetal 1606 as a compound of 3:1 syn and anti diastereomers. The mass spectrum (E5) showed (M in (m/e) 597. The spectra of "H, 3C-NMR and HC c coincided with compound 1606. c" Compaction of compound 159 and dihydro-B-ionone led to the formation of acetal 160c in the form of a compound 2:1 syn " and anti diastereomers. The mass spectrum (ET) showed M) in (t/e) 587. The spectra of "H, 3S-NMR and HC coincided with the compound! bos.

Condensation of 159 and 3,3,5,5-tetramethylcyclohexanol led to the formation of acetal 1604, which coincided with - the spectra of "H", "3S-NMR and HC. c Intermediate compounds 1b0a-4 were converted into the corresponding deprotected heterocyclic aromatic amides by hydrogenation in the presence of Pa/C as described above. (95) at 50

IR e)

F) ime) 60 b5 -BO0-

Ome OMme on t on | .- - NO m on nm M b c) y rya chi

OMe he a y

M; a 0 OMa on 281 and n o sm im M y rai bo on « o 162 ss o 280 s

Kou and EOAS, NOAI, OMAR, OM, BA; CI. KMpOZ VES, (SOS y. PASEBA, SNO named after Nz ROS o

Scheme 46 p

PREPARATION OF COMPOUNDS 280 AND 281. so

Scheme 45 describes the preparation of these compounds. Thus, 2,3,6,6-tetramethyl-2-cycloheptenylamine was first combined with 2-hydroxy-3-methoxy-2-picolinic acid using a standard coupling procedure of

C, for the formation of intermediate compound 161. Dichlorination of compound 161 according to the procedure of Teiggapeadgop I! Hey. Yuyu 1991,32, 1831-1834), led to the formation of the dichloro derivative 281. Standard t-SRBA oxidation of 161 in the CH axis" led to the formation of a compound containing M-oxide epoxy - analog 162, which after treatment with H "5 (45 rvi ) - and 10965 Pa/С under standard conditions of catalytic hydrogenation led to the formation of compound 280.

PREPARATION OF trans-4-HYDROXY-3,3,5,5-TETRAMETHYLPICOLINAMIDE (264).

This compound was prepared as shown in Scheme 46. With stirring, sodium borohydride (20 mg, 0.53 mmol) was added to a solution of keto-picolinamide 266 (56 mg, 0.18 mmol) in 2 mL of methanol. The reaction mixture was stirred with t0 for 5 hours and the methanol was evaporated. The crude substance was diluted with 5 ml of water and extracted with EtOAc (3 ml). The organic layer was washed with water (10 mL) and brine (10 mL). The solution was dried, filtered and concentrated. H-NMR and GC analyzes matched the title compound 264 with trans stereochemistry of 9595 purity. -I 1 (95) at 50

IR e)

F) name) 60 b5

Om

M

Х, о Ж, мн, оо ---Щ Ovno0oo

No N t

RASN, O. And y, O soyu RySsN, O o pine of the 00s o -

Ra Ra at 139 ra 163

OMG

AND

The death of the battle of the fire in Jesus Christ

Rv zi

Scheme 47 s (8)

PREPARATION OF COMPOUND 341.

The preparation of this compound is described in Scheme 47. The precursor of benzyl ester 139 (Scheme 38) (ZZmg, 0.04bmmol) was dissolved in 10ml of E(UAs) and 110mg of Perlman's catalyst was added. The mixture was shaken in a Parr apparatus under a pressure of 5Og of hydrogen for 12 hours. The solution was filtered and concentrated. The residue was dissolved in a minimal amount of ether, and petroleum ether was added to form a precipitate. The solid was collected by filtration and dried to afford the title compound 341. c

PREPARATION

M-(3-PYHYDROXY-4-METHOXY-2-PYRIDYLCARBONYL)-2-AMINO-2-DEOXY-alpha-O-GLUCOPYRANOSE (334). Yuyu and - o. ON che u. « I no MO M- Z s on U . "» o

1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-alpha-O-glucopyranose (151) and 3-hydroxy-4-methoxypicolinic acid were combined using standard procedure of coupling C. Lithium hydroxide monohydrate (0.92 mmol, 4OmgH) was added to the resulting solution of picolinamide (0.19g, 0.3vmmol) in one mL of methanol.

Ha 20 The reaction mixture was stirred at room temperature overnight. The solution was neutralized by adding OYUMUEHO 5x8-100 resin acid (0.5g). The mixture was filtered and concentrated to give the title compound (110mg, 88965).

F) name) 60 b5 o me gai, obu on o Z M on 5 . we oh pan ichanrvya i-se h

R v M o RE sho o / . "in

Ome o Oma s») and he and S o uU-ya re: it

M o nni M t o

Gee! Y RI o ti: o 1662: Kz sr 1662: And ERICHN ; T6be: And DR dv Scheme 48 o

GENERAL PREPARATION OF EXOCYCLIC ESTER 16ba, CARBAMATE 1665, AND

CARBONATE 16b6s.

These compounds were generally prepared as described in Scheme 48, starting with amine 164, which was prepared according to (2.0) the procedures of M. Zpitapo, et al., Teganeadgop, 1998, 54, 12745) This amine was coupled (with co

of 3-benzyloxy-6-bromo-4-methoxypicolinic acid 16 by the standard coupling procedure C described earlier, after which the resulting intermediate 165 was reacted with the corresponding carboxylic acid chloride, alkyl isocyanate, or alkyl chloroformate in the presence of a base , to the formation of the necessary protected ester 16ba, carbamate 16660, or carbonate 16bs, respectively. Deprotection of these compounds was carried out according to the procedures described earlier using HO in the presence of Ra/C, which led to the formation of the required ester, carbamate, or carbonate. The steps described above were used to prepare other similar esters, carbamates, and carbonates.

PREPARATION OF THE COMPOUND 166a. "

Cyclopropanecarbonyl chloride (0.45 mL, mmol) was slowly added to a solution of 165 (18O0 mg, 0.29 mmol) in pyridine (1 mL) with stirring over 5 minutes. The mixture was allowed to stir under ts Mo atmosphere at room temperature overnight. The resulting mixture was poured into 1M HCl (30 ml) and extracted with EtOAc (2 x 75 ml). The organic layers were combined and washed with water (25 mL), then saturated with NaCl (25 mL), dried with Moa 5 2 O, and concentrated to give an orange oil. The crude oil was chromatographed on silica gel using a 3095 - 5096 EAs in hexane gradient as eluent for formation of the title compound 16ba (10mg) as a clear oil. - PREPARATION OF COMPOUND 1666. c Triethylamine (2 drops) was added to a stirred solution of 165 (200mg, 0.3mmol) in CHClCl (bml),

LOBSTER (mg), and isopropyl isocyanate (0.2 ml, 2 mmol). The resulting mixture was stirred in a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 1M HCl (25 mL) and extracted with EtOAc

Ha 20 (2xBOml). The organic layers were combined and washed with water, then saturated with Mass, dried with MaZ0O 4 , and concentrated to a pink foam. The crude foam was chromatographed on silica gel using 3096-5096 EtOAc in a hexane gradient as eluent to afford the title compound 166bB (9mg) as a white solid.

PREPARATION OF THE COMPOUND 16b6s. 29 With stirring, a solution of 165 (18Omg, 0.29mmol) in pyridine (5ml) and CHCl (5ml) was cooled to 02С at

HF) in an ice bath in a nitrogen atmosphere. Isopropyl chloroformate (1M toluene, ml) was slowly added to the cooled solution over 1 minute. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was divided into 1 M HCl (25 ml) and EtOAc (75 ml). The organic layer was washed with water, and then saturated with Masi, dried with M950O.4, and concentrated to form a clear oil. Crude 60 odium was chromatographed on silica gel using a 3095-5095 EAs in a hexane gradient as eluent to afford the title compound 16bs (8Omg) as a clear oil. b5 pdutetru" 3

And | - th og - RA o these | Sho o N teh rya M

Ak Du» SR vm Zhute still in M nya o o 168 7 167

Scheme 49; high school

PREPARATION OF INTERMEDIATE COMPOUNDS 167 AND 168. o

The diastereomeric solution of amines 53 obtained as described earlier (Scheme 9) was combined with acid chloride

Following the general coupling procedure of A as previously described (Scheme 49) to form a solution of diastereomers 167 and 168, these were separated by silica gel chromatography (85:15 hexane/acetone) to give pure compounds 167 and 168 in approximately 3595 yields. each they were subjected to Ho deprotection in the presence of Ra/C as previously described. and)

GENERAL PROCEDURES FOR THE CONVERSION OF HETEROCYCLIC AROMATIC AMIDES (2) INTO O-ACYL CO

HETEROCYCLIC AROMATIC AMIDES (2U: MA ACIL), O-SILYL HETEROCYCLIC AROMATIC AMIDES (2U:

M-SILYL) AND O-SULFONYL HETEROCYCLIC AROMATIC AMIDES (2U: M-SULFONYL). that) and - "shi s;" - And 1 (95) at 50

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Scheme 50 points and -

PREPARATION OF COMPOUND 610 0-(3,3-DIMETHYL) BUTANOYL

The preparation of this compound is shown in Scheme 50, starting from compound 169 (prepared by the procedure of M.

Zpitapo, ei aiY, Teigapedgop 1998, 54, 127451). Thus, when stirring a solution of compound 169 (10mg, 0.19mmol) and OMAR (5mg, 0.04mmol) in dehydrated pyridine (3ml), 3,33-dimethylbutanoyl chloride was treated and stirred at ambient temperature for 5.5 hours. After that, it was treated with water (15 ml) and extracted with E(Ac (20 ml). The organic extract was successively washed with water and saturated aqueous Manso with, dried (Ma»5O)), filtered and concentrated. Chromatography on silica gel on preparative plates (thickness 2 mm), eluted with ether, until the formation of the compound indicated in the title in the form of a yellowish solid, m.p. 151-1522S. H-NMR and MS data were consistent with the given structure.

The remaining O-acyl heterocyclic aromatic amides were prepared according to variants of the procedures described above. Such variations included, for example, purification of products by other technologies well known to specialists in this field, such as column chromatography or recrystallization.

PREPARATION OF O-tert-BUTYLDIMETHYLSILYL COMPOUND 720. o The preparation of this compound is shown in Scheme 50. Thus, upon stirring a solution of compound 169 (10 Ω, 2) 20 0L19 mmol) and M-methylmethylmorpholine (0.133 ml, 1.18 mmol) in dehydrated OME (2 ml) was treated with tert-butyldimethylsilyl chloride (57mg, 0.38mmol) and stirred at room temperature for 1 day. The resulting mixture was divided into water (10 ml) and EtOAc (15 ml), and the organic phase was successively washed with saturated aqueous Manso with and brine, dried (Ma»3SO)), filtered and concentrated. The residues were chromatographed on a flash salt gel column eluted with ether to give 25 TAMg of the title compound as a clear fat. The data of the H-NMR spectrum coincided with the given

HF) compound.

PREPARATION OF O-p-TOLUOSULFONYL COMPOUND 722. o The preparation of this compound is shown in Scheme 50. Thus, p-toluenesulfonyl chloride (9mg, 0.46bmmol) was added with stirring to a suspension of compound 169 (200mg, 0.3v88mmol) and potassium carbonate (b5mg, 0.46bmmol ) in 60% dehydrated acetone (Zml). After stirring at ambient temperature for 12 hours, the solution was then diluted with EtOAc (25ml) and washed with H2O (2x10ml). The organic phase was dried (M9503), filtered, and concentrated in vacuo. The residues were purified by flash column chromatography, eluted with hexanes-EHUOAc (1:11), until the formation of 197 mg of a white solid, m.p. 153-155 9C, the data of the TN-NMR spectrum of which coincided with the desired compound indicated in the title.

Table 1 shows additional compounds of Formula 1 prepared from the appropriate starting materials,

according to the procedures described above. The H-NMR spectral data of all these compounds coincided with the data of the specified compounds.

FUNGICIDAL PROPERTIES

The compounds of this invention have been found to be capable of controlling the growth of fungi, particularly plant pathogens and wood rotting fungi. When used to treat plant diseases caused by fungi, the compounds of this invention are applied to the plants in disease-inhibiting amounts and also in amounts that are phytologically acceptable. The compounds can be used both before and after the infection of the plant with fungi. Application can also be carried out by processing plant seeds, soil 70 around the plant, beds for planting seedlings, or water for irrigation. Other applications are possible in the form of wood processing to control the destruction of wood and/or wood.

The term, "in disease-inhibiting amounts and also phytologically acceptable amounts," as used herein, refers to amounts of a compound of the present invention capable of killing or inhibiting plant pathogens and preventing, eradicating, or delaying disease in a plant for which such control is necessary, but is not 75 significantly toxic to the plant: This amount is generally from 1 to 1000 ppm, preferably from 10 to 500 ppm. The exact concentration of the required compound may vary depending on the fungal disease to be controlled, the type of compound used, the method of application, the specific plant species, climatic conditions, and other factors. A suitable dosage is generally considered to be 50 to about 1000 grams per hectare (g/Ha).

The compounds according to the present invention can also be used to protect cereals, during storage, as well as other substances of non-plant origin from fungal infection.

The following experiments were performed in laboratory conditions in order to determine the antifungal effectiveness of the compound according to the present invention.

Biological evaluation of the inhibition of fungal growth by ip migo. Ha

Culture medium: Suspensions of fungal conidia or fungal fragments are prepared in a sterile nutrient medium of potato dextrose (Oiiso) for Madparogiye dgyzea (Rugisciaga ogugae - RUKIOK), i9)

KPigosiopia voYiapi (KNI25BO), Musozrpaegeya dgatipisoia (Zeriogia (gyisi - ZERTTK), Ziadopozroga podopip (Heriozrpaegia podogyt -HERTMO), Ov(Shado tauaiv (0O5TIMA), and in the nutrient medium, rye seeds for

Rpuyurptoga ipteviapz (RNUTIM). The suspensions were introduced with a pipette into sterile 96 microtiter plates, which

Contains samples of experimental fungi dissolved in dimethyl sulfoxide. The concentration of fungicides varies from 0.001 to 100 ppm, with a final solvent concentration not exceeding 1905 agents. at

Fungi were allowed to grow for various lengths of time at 24-302C until the sump became turbid from fungal growth, compared to a control sump containing solvent only. At this point, the growth inhibition is such that it can be determined visually for each isolate, and the percentage of growth can be determined, compared to controls treated with solvent alone. -

In Table II, "-" indicates that the test substance gives at least 8095 growth inhibition and "-" indicates a value of less than 8095 growth inhibition of the target pathogen included in the growth of the carrier at a concentration of 25 ppm. "

A space indicates that the test was not performed.

Biological evaluation of the control of ip mimo fungal infection of the whole plant. - c Preparation of the compound was carried out by diluting technical materials in acetone, followed by sequential dilution in acetone to obtain the required concentration. The final treatment volume was obtained by adding 9 volumes of 0.059565 aqueous Tmeep-20 or 0.019565 Triton X-100, depending on the pathogen.

Initial mold of Grapes (Riazgporaga myisoia - RI ABMI) (daily protective agent): Grape vines (variety - Sagidpape I) were grown from seeds in a peat-based hydroponic mixture ("Meygotih") until the sprouts reach a height of 10-20 cm. After that, such sprouts were sprayed with an excess amount of the tested i-th substance at a dosage of 100 ppm. After 24 hours, the test plant was inoculated by spraying (95) an aqueous solution of a sporangial suspension of Riaztoraga mysoia, IT was kept in a damp room overnight. syu 50 After that, the plants were transplanted to the greenhouse, before the development of the disease on untreated control plants.

IR f) Late blight of tomatoes (Rpuyurpiypoga ipieviiape - RNUTIM) (daily protective agent): tomatoes (variety

Kiidegv) from seeds in a peat-based hydroponic mixture ("Meigotih") until the sprouts reach 10-20 cm in height. After that, such sprouts were sprayed with an excess amount of the tested substance at a dosage of 100 ppm. After 24 hours, the tested plant was inoculated by spraying an aqueous solution of the sporangial suspension of Rpuiorpiyoga ipeziaps, and kept in a damp room overnight. After that, the plants were transplanted to the greenhouse, before the development of the disease on untreated control plants. ko Brown rust of wheat (Rissipia hesopaia - ROSSKT) (daily protective agent); wheat (Mita variety) was grown in a peat-based hydroponic mixture ("Meigotih") until the sprouts reach a height of 10-20 cm. 60 After that, such sprouts were sprayed with an excess amount of the tested substance at a dosage of 100 ppm.

After 24 hours, the tested plant was inoculated by spraying an aqueous solution of the sporangial suspension

Rissipia hesopaia, and kept in a damp room overnight. After that, the plants were transplanted to the greenhouse, before the development of the disease on untreated control plants.

Powdery mildew of wheat (Eguzirpe dgatipiz - EKUZOT) (daily protective agent): wheat (variety Mopop) 65 was grown in a peat-based hydroponic mixture ("Meigotih") until the sprouts reach a height of 10-20 cm.

After that, such sprouts were sprayed with an excess amount of the tested substance at a dosage of 100 ppm. -58c-

After 24 hours, the tested plant was inoculated by dusting with conidia of wheat plants infected with powdery mildew. After that, the plants were transplanted to the greenhouse, before the development of the disease on untreated control plants.

Wheat leaf spots (ZeOogia ipisi - ZERTTEK) (daily protective agent): wheat (Mita variety) was grown in a peat-based hydroponic mixture ("Meygotih") until the sprouts reach a height of 10-20 cm. After that, such sprouts were sprayed with an excess amount of the tested substance at a dosage of 100 ppm. After 24 hours, the tested plant was inoculated by spraying an aqueous suspension of Zeriogia igiisi spores, and kept in a damp room overnight. After that, the plants were transplanted to the greenhouse, before the development of the disease /o on untreated control plants.

Peeling of wheat grains (I eriozrpayegia podogyt - | ERTMO) (daily protective agent): wheat (the Khita variety was grown in a peat-based hydroponic mixture ("Meigotih") until the sprouts reach a height of 10-20 cm.

After that, such sprouts were sprayed with an excess amount of the tested substance at a dosage of 100 ppm.

After 24 hours, the tested plant was inoculated by spraying a water suspension of spores of I eriozrpaegia podogyt, and 7/5 was kept in a wet room overnight. After that, the plants were transplanted to the greenhouse, before the development of the disease on untreated control plants.

In Table II, "her-" indicates that the test substance gave at least 75-10095 control of fungal infection compared to the extent of disease on untreated plants, and "-" indicates that the test substance gave at least 25-7495 control of fungal infection infection, and "-" indicates "2596 control of a fungal infection of the specified pathogen at a concentration of 100 ppm. A space indicates that the test was not performed. 6) (ee) (ze) (ze) iv) - - . and? -and 1 (95) (95)

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