KR100720766B1 - Fungicidal heterocyclic aromatic amides and their compositions, methods of use and preparation - Google Patents

Abstract

Heterocyclic aromatic amides (HAA) are provided by the following formula (I). This invention includes its hydrates, salts and complexes.

These compounds are useful as fungicides.

[Equation 1]

Provided that X ₁ -X ₄ , M, Z and A are defined.

Fungicides, Heterocyclic Aromatic Amides

Description

Fungicidal Heterocyclic Aromatic Amides and Compositions, Uses and Preparations of the Invention {FUNGICIDAL HETEROCYCLIC AROMATIC AMIDES AND THEIR COMPOSITIONS, METHODS OF USE AND PREPARATION}

FIELD OF THE INVENTION The present invention relates to sterilization compositions and methods of sterilization, and more particularly to sterilization methods comprising the application of new bactericidal heterocyclic aromatic amide compounds and such compounds to the habitat of plant pathogens in bactericidal effective amounts.

The present invention also relates to a process for preparing heterocyclic aromatic amides and their sterilizing compositions.

Various antimicrobial compositions and antimicrobial methods are known in the art. For example, antimycin is recognized as a naturally occurring substance produced by Streptomyces ssp and has antimicrobial activity (Barrow, C. J; et al., Journal of Antibiotics, 1997, 50 (9). , 729). These substances have also been found to be effective fungicides (The Merck Index, Twelfth Edition, S. Budavari, Ed., Merck and Co., Whitehouse Station, N.J., 1996, p.120).

WO97 / 08135 describes acylamino salicylic acid amides useful as insecticides (pesticides).                 

EP-A-O-661269 discloses substituted heterocyclic carboxylic acid amides useful as pharmaceuticals.

JP-A-7-233165 discloses an antimicrobial dilactone having a 3-hydroxypyridinecarboxyl group with antifungal activity.

The following data describe iso-butyryl, ticroyl, iso-valeryl and 2-methylbutyryl derivatives of the compounds;

Tetrahedron 1998, 54, 12745-12774; J. Antibiot. 1997, 50 (7), 551; J. Antibiot. 1996, 49 (7), 639; J.Antibiot. 1996, 49 (12), 1226; And Tetrahedron Lett. 1998, 39, 4363-4366.

But new fungicides are still needed. The present invention provides fungicides having high residual activity, high activity at low application rates, therapeutic activity and broader efficacy.

According to one aspect of the invention there is provided a compound comprising a heterocyclic aromatic amides of the formula (I) (hereinafter also referred to as "HAA").

[Equation 1]

In the above formula, X ₁ -X ₄ , M, Z and A are as described later.

The invention also includes hydrates, salts and complexes of the compounds.

The present invention also provides a sterile composition comprising HAA with a botanically acceptable carrier and / or diluent.

Also disclosed are heterocyclic aromatic amide compounds and methods of using the compositions.

It is an object of the present invention to provide HAA and compositions thereof useful as fungicides.

Another object of the present invention is to provide a method for controlling and / or preventing fungal infection, comprising applying HAA and a composition containing the same.

Other objects and advantages of the present invention will be apparent from the following description.

Hereinafter, the present invention will be described in detail.

The present invention relates to various HAA compounds active as antibacterial agents. Also included are formulations containing HAA compounds and methods of use thereof.

Also disclosed are methods of making HAA compounds, and also use as bactericides.                 

HAA Compound

The novel bactericidal HAA compounds of the present invention are described by the following formula (I).

[Equation 1]

In the above formula

은 5-혹은 6-멤버 헤테로사이클릭 방향족링을 나타내는 것으로서,a)

Is a 5- or 6-membered heterocyclic aromatic ring,

(Iii) each of X _{1 to} X ₄ independently represents O, S, NR ′, N, CR ″ or bond;

       ;

(Ii) at least one of X _{1 to} X ₄ is O, S or NR ′;

(Iii) at least one of X _{1 to} X ₄ is a bond;

(Iii) when any one of X _{1 to} X ₄ is S, O, or NR ′, one of adjacent X ₁ to X ₄ is

       Must represent a bond;

(Iii) at least one of X _{1 to} X ₄ is O, S, NR ′ or N;

Wherein R ′ is H, C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, hydroxy, acyloxy,

C ₁ -C ₆ alkoxymethyl, CHF ₂ , cyclopropyl or C ₁ -C ₄ alkoxy;

R ″ is independently H, halogen, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl,

Cyclopropyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkylthio, aryl,

C ₁ -C ₃ NHC (O) alkyl, NHC (O) H, C ₁ -C ₃ haloalkylthio, C ₂ -C ₄ alkenyl,

C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl,

C ₂ -C ₄ haloalkynyl, or nitro, adjacent R ″ substituents form a ring or

Or adjacent R ′ and R ″ substituents may form a ring.

b) Z is O, S or NOR ₂ and R _z is H or C ₁ -C ₃ alkyl;

c) A represents

  (Iii) all are branched or unbranched, unsubstituted,

Allogenes, hydroxy, nitro, aroyl, aryloxy, C ₁ -C ₈ acyloxy,

C ₁ -C ₆ alkylthio, arylthio, aryl, heteroaryl, hetero arylthio,

Heteroaryloxy, C ₁ -C ₆ acyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or

C ₁ -C ₆ haloalkoxy group which can be substituted, C ₁ -C ₁₄ alkyl, C ₂ -C ₁₄ alkenyl or

C ₂ -C ₁₄ alkynyl

(Ii) unsubstituted, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl,

Cyano, nitro, aroyl, aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio,

Arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy,

C ₁ -C ₈ acyloxy, aryl, heteroaryl, C ₁ -C ₆ acyl, carboaryloxy,

Carboheteroaryloxy, C ₁ -C ₆ carboalkoxy also is unsubstituted or 1 or

It may be substituted with an amido substituted with a C ₁ -C ₆ alkyl group of 2, 0 to 3 heteroatoms

And C ₃ -C ₁₄ cycloalkyl containing 0 to 2 unsaturated groups

(Iii) unsubstituted, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl,

Cyano, nitro, aroyl, aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio,

Arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy,

C ₁ -C ₈ acyloxy, aryl, heteroaryl, C ₁ -C ₆ acyl, carboaryloxy,

Carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or unsubstituted or 1 or

0 to 3 heteroatoms, which may be substituted with an amido substituted with a C ₁ -C ₆ alkyl group of 2

And a C ₆ -C ₁₄ 2 (bi) or 3 (tri) -cycling system, containing 0-2 unsaturated groups,

(Iii) unsubstituted or nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl,

C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl, hetero aryl,

Halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, carboaryloxy,

Carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or unsubstituted or 1 or

C ₁ -C ₆ alkyl group of 2, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl,

C ₁ -C ₆ OC (O) alkyl, OC (O) aryl, C ₃ -C ₆ NHC (O) cycloalkyl, C ₁ -C ₆ NHC (O) alkyl,

C ₃ -C ₆ NHC (O) cycloalkyl, NHC (O) aryl, NHC (O) heteroaryl,

C ₃ -C ₆ cycloalkylthio, C ₃ -C ₆ cycloalkylsulfonyl,

C ₃ -C ₆ cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio,

    Heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl,

Arylsulfonyl, C (O) R _Y , Amido substituted with C (NOR _X ) R _Y , and

    The alkyl or cycloalkyl-containing substituent is substituted with one or more halogens

    Can be,

    The aryl or heteroaryl containing substituents are also unsubstituted,

    Halogen, cyano, nitro, aroyl, aryloxy, aryl, heteroaryl,

C ₁ -C ₆ acyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ carboalkoxy

Or unsubstituted or substituted with amido substituted with 1 or 2 C ₁ -C ₆ alkyl groups

Can and

R _Y and R _X are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl,

Aryl or heteroaryl,

Aryl or heteroaryl

단, 상기 식에서 *는 부착점이며,(Ⅴ)

Where * is the attachment point,

Q ₁ , Q ₂ is O or S;

W is O, CH ₂ , CHR ₆ , or a bond;

R ₁ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, aryl or

Heteroaryl;

R ₂ is H, C ₁ -C ₃ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl;

R ₃ is H, R ₁ , OR ₁ , OC (O) R ₂ , OC (O) OR ₁ or CO (O) NR ₁ R ₆ ;

R ₄ and R ₅ are independently H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl, but the total of R ₄ and R ₅

The number of carbon atoms is 6 or less, and R ₄ and R ₅ may be combined to form a C ₃ -C ₆ ring.

R ₆ and R ₇ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C ₂ -C ₅ alkenyl or

C ₂ -C ₅ alkynyl or at least one of R ₆ and R ₇ is H.

가

일때, And

end

when,

(Where R ″ is H or OCH ₃ )

R ₁ is not asobutyryl, tigroyl, isovaleryl or 2-methylbutanoyl.

(d) M represents H, Si (t-Bn) Me ₂ , Si (Ph) Me ₂ , SiEt ₃ , SiMe ₃ , C (Z) R ₈ , SO ₂ R ₉ ,

Wherein R ₈ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, alkoxyalkyl, haloalkyl, alkoxyalkenyl, haloalkenyl , Alkoxyalkynyl, haloalkynyl, substituted and unsubstituted arylalkyl, substituted and unsubstituted arylalkenyl, substituted and unsubstituted arylalkynyl, substituted and unsubstituted aryl, substituted and substituted Unsubstituted heteroaryl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyloxy, C ₂ -C ₆ haloalkenyloxy, C _2- C ₆ alkynyloxy, C ₂ -C ₆ haloalkynyloxy, C ₁ -C ₆ thioalkoxy, substituted and unsubstituted arylalkoxy, substituted and unsubstituted arylalkenyloxy, substituted and unsubstituted Arylalkynyloxy, substituted and unsubstituted aryloxy, substituted and unsubstituted heteroaryloxy, And also substituted amino not ring, or one or more C ₁ -C ₆ alkyl group,

R ₉ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, aryl or heteroaryl.

As used herein, the terms alkyl, alkenyl, alkynyl and the like are to be interpreted to include both straight and branched groups falling within the scope; The terms alkenyl, alkenylene, and the like include groups having one or more double bonds; The terms alkynyl, alkynylene and the like are to be understood to include groups having one or more triple bonds.

The term cycloalkyl means a C ₃ -C ₁₄ cycloalkyl group having 0-3 heteroatoms and 0-2 unsaturated groups.

2 (Bi)-or 3 (tri) -cyclic ring system means a C ₆ -C ₁₄ aliphatic ring system having 0-3 heteroatoms and 0-2 unsaturated groups.

The term further refers to both substituted and unsubstituted.

Unless defined otherwise, substituted are halogen, hydroxy, cyano, nitro, aroyl, aryloxy, aryl, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, C ₁ -C ₈ acyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio, carboaryloxy, carboheteroaryloxy, C _1- Substituted with C ₆ carboalkoxy or those selected from the group consisting of unsubstituted or amido substituted with 1 or 2 C ₁ -C ₆ alkyl groups.

The term aryl, as used herein, means a substituted phenyl or naphthyl group.

The term heteroaryl means a 5 or 6 membered aromatic ring having one or more heteroatoms, which heteroaromatic rings may be conjugated to other aromatic systems.

The terms further include substituted or unsubstituted forms. Substituted forms include nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl, heteroaryl, Halogen, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxysulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ OC (O) alkyl, OC (O) aryl, C ₃ -C ₆ OC (O) cycloalkyl, C ₁ -C ₆ NHC (O) alkyl, C ₃ -C ₆ NHC (O) cycloalkyl, NHC ( O) aryl, NHC (O) heteroaryl, C ₃ -C ₆ cycloalkylthio, C ₃ -C ₆ cycloalkylsulfonyl, C ₃ -C ₆ cycloalkylsulfinyl, aryloxy, heteroaryloxy, heteroarylthio , Heteroarylsulfinyl, heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C (O) R _Y , C (NOR _X ) R _{Y It} is substituted with at least one group selected from,

Wherein R _Y and R _X are independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, aryl or heteroaryl, wherein the alkyl or cycloalkyl containing substituent is one It can be substituted with the above halogen, the chemical bond and strain energy law is satisfied.

As used herein, the terms halogen and halo include chlorine, bromine, fluorine and iodine. The term haloalkyl and the like means a group substituted with one or more halogen atoms.

The term Me refers to a methyl group and Et refers to an ethyl group. Pr means a propyl group, Bu means a butyl group. Ph refers to a phenyl group and EtOAc refers to ethyl acetate.

The term alkoxy means a straight or branched chain alkoxy group and haloalkoxy means an alkoxy group substituted with one or more halogen atoms.

The term heteroatom means O, S and N.

을 갖는 바람직한 5- 또는 6-멤버 헤테로사이클릭 방향족링은 피리딘, 피리다진, 피리미딘, 피라진, 피롤, 피라졸, 이미다졸, 퓨란, 티오펜, 옥사졸, 이소옥사졸, 티아졸, 이소티아졸 및 티아디아졸의 적절한 이성체를 포함한다. 가장 바람직한 헤테로사이클릭 방향족링은 피리딘, 피리미딘, 피라진, 피리다진, 티아졸, 이소티아졸, 티아디아롤 및 옥사졸이다.

Preferred 5- or 6-membered heterocyclic aromatic rings having pyridine, pyridazine, pyrimidine, pyrazine, pyrrole, pyrazole, imidazole, furan, thiophene, oxazole, isoxazole, thiazole, isothia Suitable isomers of sol and thiadiazole. Most preferred heterocyclic aromatic rings are pyridine, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, thiadirol and oxazole.

Particularly preferred compounds of formula I are 2-amido-3-hydroxypyridine, 2-amido-3-hydroxy-4-methoxypyridine, 2-amido-3-hydroxypyrazine and 4-amido- Based on 5-hydroxypyrimidine.

It is understood that certain combinations of substituents for compounds falling within the scope defined herein cannot be prepared for steric and / or chemical reasons, and such compounds are not within the scope of the present invention.

Various hydrates, salts and complexes of the compounds of formula I can be prepared according to conventional methods.

,등과 같은 양이온과 교체 시킴으로써 형성될 수 있다. 이들 유도체 역시 본 발명에 따라 유용하다.
For example, salts may represent hydroxyl hydrogen atoms (M = H) with NH ₄ ⁺ , ⁺ N (Bi) ₄ ,

It can be formed by replacing with a cation such as. These derivatives are also useful according to the invention.

Throughout this specification, unless stated otherwise, all temperatures refer to degrees Celsius (Celsius) and all percentages are by weight.

The term ppm refers to parts / million (parts per million), and, psi; means pounds / inch ^{2 (pounds per square inch),} mp is melting point, and bp means boiling point, respectively.

Preparation of the compound

Compounds of the present invention are prepared using known chemical processes. The required starting materials are either commercially available or can be readily formed using standard procedures.

(General method of pyridine-2-carboxamides)

The required HAAs (2) are selected from a suitable ortho-hydroxyheteroaromatic carboxylic acid (1) as coupling agent (phosgene or 1- [3-dimethylaminopropyl] -3-ethylcarbodiimide hydrochloride (EDCI)) + 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) and acid scavengers such as N-methylmorpholine (NMM), triethylamine, 4- ( Prepared by reaction with an amine in the presence of dimethylamino) pyridine (DMAP) or diisopropylethylamine (method 1).

In some cases, the intermediate amide (4) can be prepared by reacting an acid chloride having a protected hydroxy group as in (3) with a suitable amine. Removal of the protecting group through hydrogenation in the presence of a palladium (Pd) catalyst yields the required product (2x).

Capping a heterocycle hydroxyl group in compound 2 with an acyl, sulfonyl, or silin group (M) is appropriate for (2) carboxylic acid in a suitable solvent such as pyridine, using an acylation catalyst such as DMAP. It can be readily accomplished by reacting with chloride, sulfonylchloride or silylchloride (MCl) to provide the corresponding 0-acyl, 0-sulfonyl, or 0-silyl derivatives (2Y).

(Preparation of ortho-hydroxy heteroaromatic carboxylic acid 1)

독립적으로 C-Me, C-SMe, C-Cl)의 제조방법이 방법2에 도시되어 있다.
Carboxylic acid 1

Independently, a process for preparing C-Me, C-SMe, C-Cl) is shown in Method 2.

3-hydroxy-2-bromopyridine (5) and 2- (trimethylsilyl) using potassium tert-butoxide as a base in a 1: 1 mixture of dimethylformamide (DMF) -tetrahydrofuran (THF) Ethoxymethylchloride (SEM-Cl) was reacted to give the required ether 6.

Deprotonated 6 with lithium diisopropylamide (LDA) and then condensed with an appropriate electrophile (iodinemethane, dimityldisulfide, or hexachloroethane) to give 4-substituted pyridine 7.

After bromine / lithium exchange between 4-substituted pyridine 7 and n-butyllithium (n-BuLi), carboxylation with carbon dioxide (CO ₂ ) and acid hydrolysis to remove 1 × of the required 4-substituted-3-hydroxypicolinic acid. Got it.

Optionally, 9 can be obtained by condensation of 3-hydroxypyridine (8) with SEM-Cl (method 3).

Dequantization of 9 with tert-butyllithium (t-BuLi) followed by condensation with N-fluorobenzenesulfonimide gave 4-fluoro derivative 10.

10 was condensed with sodium ethoxide to give dieter 11.

Deether 11 was deprotonated with t-BuLi, followed by carboxylation and acid hydrolysis to afford the required 4-ethoxypyridine 1 × (X-OEt).

The preparation of acid chloride 3 is briefly shown in process 4.

Thus, 3-hydroxy picolinic acid (12) was converted to methyl ester 13 in reflux methanol using boron trifluoride as a catalyst and then brominated with bromine in a basic aqueous solution to obtain dibromide 14. Dibromide 14 was then condensed with benzylchloride in the presence of sodium hydride to produce benzylether 15.

Benzyl ether 15 was carefully methanololyzed in methanol / potassium carbonate to give 4-methoxy picolinic acid derivative 16.

The conversion of compound 16 to acid chlorite was achieved as oxalylchloride using benzene and catalytic amounts of DMF as solvent.

의 제조 (방법 1 및 3 참조)> <4-ethoxy-3-hydroxypicolinic acid

Preparation (see methods 1 and 3)>

a. Preparation of 3- (2- (trimethylsilyl) ethoxymethoxy) -pyridine (9)

To a stirred mixture of DMF (100 mL) and THF (100 mL) was added solid potassium tert-butoxide (17.96 g, 0.16 mol).

After all the solids had dissolved, the solution was cooled down to 5 ° C. and 3-hydroxypyridine (14.25 g, 0.15 mol) was added all at once. After stirring for 10 minutes, the mixture was cooled to −10 ° C. and SEM-Cl (25 g, 0.15 mol) was appropriately added while maintaining the internal temperature at −5 ° C. or lower.                 

After addition, the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The mixture was added to 60 mL of water and then extracted with ether (3 × 150 mL).

The ether extracts were combined, washed sequentially with 2N NaOH (100 mL), water (50 mL) and saturated NaCl solution (100 mL), dried (MgSO ₄ ) and concentrated to give a brown liquid. Distillation gave the desired ether 9 which was a colorless liquid and was bp 95-99 占 폚 (0.3 mmHg).

b. Preparation of 4-fluoro-3- (2- (trimethylsilyl) ethoxymethoxy) pyridine (10)

T-BuLi (40 mL, 1.5 M pentane solution) was slowly added to the stirred solution in which Compound 9 (12.39 g, 0.055 mol) was dissolved in ether (200 mL) cooled to -70 ° C or lower under an argon atmosphere.

The reaction temperature was kept below -68 ° C during the addition.

After the addition was complete the mixture was stirred for a further 60 min at -70 ° C or less and then via cannula, N-fluorobenzenesulfonimide (18.92 g) in dry THF (200 mL), also cooled to -70 ° C under argon. It was transferred to the stirred solution in which it was dissolved.

After the addition was completed the cooling bath was removed and the reaction mixture was allowed to rise to room temperature.

Water (100 mL) was added and the organic phase was separated, dried (MgSO ₄ ) and concentrated to give a brown oil.

Chromatography (silica gel, hexane-acetone, 9: 1) gave the desired product 10, such as an orange oil containing 15% starting material. This crude mixture was used directly in the next reaction.

c. Preparation of 4-ethoxy-3- (2- (trimethylsilyl) ethoxymethoxy) pyridine (11)

Compound 10 (1.07 g, 4.4 mmol) was added all at once to a stirring solution in which sodium ethoxide (0.9 g, 13 mmol) was dissolved in ethanol (10 mL). The resulting mixture was stirred for 48 hours at room temperature and then transferred to water (100 mL).

The resulting mixture was extracted with ether (3 × 50 mL). The ether extracts were combined, dried (MgSO ₄ ) and concentrated. The resulting amber oil was chromatographed (silica gel, hexane-acetone 4: 1) to give compound 11 (0.6 g) as a yellow oil.

d. 4-ethoxy-3-hydroxypyridine-2-carboxylic acid

The stirred solution of Compound 11 (2.9 g) dissolved in THF (50 mL) was cooled to -70 ° C or lower under argon atmosphere.

T-BuLi (8 mL, 1.5 M pentane solution) was slowly added thereto while maintaining the reaction temperature at -66 ° C or lower.

After completion of the reaction, the mixture was stirred for 45 minutes at -70 DEG C or lower, and then poured into a slurry containing flake dry ice in ether. As a result, the mixture was stirred until reaching room temperature and the solvent was evaporated.                 

THF (25 mL) and 4NHCl (15 mL) were added to the residue and the resulting mixture was stirred at room temperature for 2 hours,

At the end of this period the insoluble material was filtered off, washed with a small amount of THF and air dried to afford the above compound (1.05 g) as a white solid.

<Preparation of 6-bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic acid (16) and its acid chloride (3)> (see method 4)

a. Preparation of Methyl 4,6-dibromo-3-hydroxy pyridine-2-carboxylate (14)

To a 2L 3-necked flask with a titration pinnel and a mechanical stirrer was added water (800 mL) and methyl3-hydroxypyridine-2-carboxylate (15.3 g). Bromine (32 g) was slowly added to this stirred solution.

As the reaction developed, the solids and reaction mixture separated from the solution became difficult to stir.

After the addition was completed, the mixture was stirred vigorously until the bromine color disappeared.

¹ H-NMR (CDCl ₃ ) on small amounts of crude product samples showed a 3: 1 mixture of mono: dibrominated products.

Sodium carbonate (31.8 g) was carefully added to the reaction mixture, followed by titration of additional bromine (12 g).

After the bromine disappeared, the pH of the reaction mixture was adjusted to pH 5 with concentrated HCl, and the mixture was extracted as CH ₂ Cl ₂ (3 × 150 mL). The organic extracts were combined, dried (MgSO ₄ ) and concentrated to give an orange solid (14 g). This material was recrystallized from methylcyclohexane (after charcoal treatment) to give compound 14 as a white solid at mp 181 to 183 ° C. have.

b. Preparation of Methyl 4,6-dibromo-3-benzyloxypyridine-2-carboxylate (15)

Compound 14 (7.1 g) was added to the stirred mixture in which sodium hydride (0.6 g) was dissolved in DMF (50 mL). After the addition was completed, the mixture was stirred at room temperature for 15 minutes, and then benzyl chloride (3.05 g) was added at once.

The mixture was then heated to 90 ° C. for 6 hours, then cooled, poured into water (500 mL) and extracted with ether (2 × 200 mL).

The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO ₄ ) and the solvent was evaporated to afford compound 15 as a pale yellow solid (8.3 g).

Recrystallization from a small amount of methanol yielded an analytical sample with mp 75-76 ° C.

c. 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic acid (16)

A vigorously stirred mixture of compound 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated to reflux for 30 minutes.

The mixture was cooled, poured into water (800 ml) and the pH was adjusted to 2 by addition of concentrated HCl. The resulting mixture was extracted as CH ₂ Cl ₂ (3 × 150 mL).

The organic extracts were combined, dried (MgSO ₄ ) and the solvent was evaporated to yield an almost colorless oil (20.5 g) that solidified slowly upon standing.

This was recrystallized from methanol (125 mL) / water (40 mL) to give the required acid 16 (11.6 g) with mp 134-135 ° C.

d. Preparation of 6-bromo-3-benzyloxy-4-methoxypyridine-2-carbonylchloride (3)

Oxalyl chloride (1.90 g, 15 mmol) was added to a stirred solution in which compound 16 (2.54 g, 7.5 mmol) was dissolved in benzene (30 mL) containing DMF (3 drops).

After the gas volatilization was stopped (about 45 minutes), the now homogeneous solution was further stirred for 15 minutes before the solvent was evaporated.

1,2-dichloroethane (30 mL) was added and the solvent was evaporated again to afford compound 3, which was an almost colorless oil.

The foreign material was dissolved in CH ₂ Cl ₂ (10 mL) or THF (10 mL) and used directly for the next coupling reaction.

6-bromo-3-hydroxy picolinic acid (17)

Bromine (32 g) was slowly added over 30 minutes to a mechanically stirred solution in which methyl 3-hydroxypicolinate (30.6 g) was dissolved in water (800 mL). After the addition was completed, the mixture was stirred for 1 hour.

Ether (300 mL) was added and stirring continued until all solids dissolved. The organic layer was separated and the aqueous phase was extracted with ether (200 mL). The organic phases were combined, dried (MgSO ₄ ) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as off-white solid. Recrystallization from methanol / water gave an analytical sample of mp 115-117 ° C.

To a stirring solution of this ester (2.32 g) dissolved in THF (15 mL) was added a solution in which LiOH.H ₂ O (1 g) was dissolved in water (7 mL) at once.

The resulting mixture was stirred at room temperature for 2 hours and then poured into water (100 mL). The pH was adjusted to about 3 with 1N HCl and the mixture was extracted with CH ₂ Cl ₂ (3 × 100 mL).

The organic extract was dried (MgSO ₄ ), filtered and concentrated to yield 2.0 g of white solid, which was consistent with the required acid 17 by ¹ H-NMR and MS testing.

<3-benzyloxy-6-methoxypicolinic acid (18)>

A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3-chloroperoxybenzoic acid (5.75 g, 60% peracid) in CN ₂ Cl ₂ (100 mL) was stirred at room temperature for 40 hours.

The reaction mixture was extracted with 5% sodium bisulfite solution (100 mL) and then with 0.5N NaOH solution (150 mL).

After drying (MgSO ₄ ), the solvent was evaporated to afford 4.9 g of methyl 3-benzyloxy picolinate-1-oxide as a white solid. Recrystallization from methylcyclohexane / toluene yielded a crystalline solid with mp 104-106 ° C.

The solution of this compound (16.1 g) dissolved in acetic anhydride (80 mL) was stirred and heated in an oil bath at 120 ° C. for 3 hours.

Excess acetic anhydride was removed on the rotary evaporator and the residue was collected in methanol (200 mL).

Concentrated sulfuric acid (1 mL) was added and the resulting mixture was heated to reflux over 90 minutes.

The solvent was then evaporated and sodium bicarbonate was added to the residue. The resulting mixture was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic fractions were combined, dried (MgSO ₄ ) and then solvent evaporated to afford 15.5 g of methyl 3-benzyloxy-6-hydroxypicolinate as a yellow solid.

Recrystallization from toluene gave a pale yellow solid with m.p 91-92 ° C.

The compound (10.25 g) was dissolved in toluene (125 mL), and silver carbonate (16.6 g) was added to a stirred solution warmed to 60 ° C. in an oil bath, followed by methyl iodide (8.52 g). The resulting mixture was heated at 60 ° C. for 3 hours.

를 통해 여과하고 용매 증발후 황색오일을 얻었다.After cooling, the mixture was cooled to Celite.

Filtration through and evaporation of the solvent gave a yellow oil.

Silicagel chromatography (4: 1 hexanes / acetone) gave an almost colorless oil, with 'H-NMR and MS data consistent with methyl 3-benzyloxy-6-methoxypicolinate.

Hydrolysis of this ester to acid 18 was accomplished with LiOH.H ₂ O as described previously for the relevant ester.

<4-hydroxypyrimidine-5-carboxylic acid (19)>

Ethyl 4-hydroxypyrimidine-5-carboxylate can be prepared as described in M. Pesson et al., Eur. J. Med. Chem. Chem. Ther. 1974, 9, 585.

The solution (500 mg, 3 mmol) dissolved in THF (10 mL) and MeOH (5 mL) was treated with LiOH.H ₂ O (373 mg, 8.9 mmol) and stirred overnight.

The mixture was quenched with concentrated HCl (1 mL) and extracted as EtOAc (2 × 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give 260 mg of compound 19 as an orange solid with mP 220 ° C. (dec.).

<4-hydroxy-2-methylpyrimidine-5-carboxylic acid (20)>

Ethyl-4-hydroxy-2-methylpyrimidine-5-carboxylate is prepared by Geissman et al., J. Org. Prepared according to the procedure of Chem., 1946, 11, 741.

The solution of this ester (750 mg, 4.11 mmol) dissolved in THF (10 mL) and MeOH (5 mL) was treated with LiOH.H ₂ O (431 mg, 10.3 mmol) and stirred overnight.

This mixture was quenched with concentrated HCl (1 mL) and extracted as EtOAc (2 × 20 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated to give 150 mg of a white solid compound 20 which was mp 180 ° C. (dec).

<5,6-dichloro-3-hydroxypyrazine-2-carboxylic acid (21)>

Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) was stirred in concentrated sulfuric acid (140 moL) and cooled to 0 ° C. Sodium nitrite was added slowly while maintaining the temperature near 0 ° C. After 30 minutes of addition at 0 ° C. the mixture was brought to ambient temperature and stirred for 3 hours. The mixture was poured into 500 g of ice, which resulted in bubbles.

After 30 minutes, the mixture was extracted three times with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated. The remaining yellow solid was washed with water and air dried to give 5.0 g of a yellow solid at mp 114-116 ° C., which was in agreement with the methyl ester of the main compound of the ¹³ C-NMR spectrum.

This solid (5.0 g) was treated with 1N NaOH (20 mL) and the mixture was heated at 90 ° C for 1.5 h. After allowing to cool, the mixture was acidified with concentrated HCl and extracted three times with EtOAc.

Drying (MgSO ₄ ), filtration and concentration yielded 0.48 g of a dark yellow solid, which was consistent with acid 21 by ¹ H-NMR and MS spectrum analysis.

<6-Chloro-3-hydroxy-5-methoxypyrazine-2-carboxylic acid (22)>

Pure MeOH (50 mL) was stirred under reflux with a stirring mixture containing methyl-3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) and sodium methoxide (3.6 g, 67.5 mmol) for 2 hours. After heating it was left to cool and acidified with concentrated HCl.

The precipitate was collected by filtration, washed with water and air dried to yield 3.6 g of a brown solid.

Recrystallization from hexane-EtOAc (1: 1) yielded 2.6 g of a pale yellow solid, and the spectrum was consistent with methyl-3-amino-6-chloro-5-methoxypyrazine-2-carboxylate. The compound (1 g, 4.6 mmol) was collected in concentrated sulfuric acid and cooled slowly at 0 ° C. and then slowly treated with sodium nitrite (0.5 g, 6.9 mmol). After 30 minutes at 0 ° C., the mixture was poured into 300 g ice / water and bubbled. After stirring for 30 minutes, the solid was collected by filtration and washed with water.

The wet solid was collected in EtOAc, dried (MgSO ₄ ), filtered and concentrated.

0.95 g of an ivory solid with a m.p of 180-182 ° C. was obtained, which was consistent with methyl 6-chloro-3-hydroxy-5-methoxypyrazine-2-carboxylate by NMR spectrum analysis.

This solid (0.9 g, 4.1 mmol) was treated with 1N NaOH (60 mL) and the mixture was stirred for 1 hour and acidified with concentrated HCl. The precipitate was collected by filtration, washed with water, dissolved in EtOAc, dried (MgSO ₄ ), filtered and concentrated. 0.62 g of a pale yellow solid with mp 170-173 ° C. was obtained, which was consistent with the desired acid 22 by spectral analysis.

<4-hydroxyisothiazole-3-carboxylic acid (23)>

This acid was obtained in the order shown in Method 5.

Thus, thiol acetic acid (8.36 g, 0.11 mol) washed with 25 mL of EtOH was added to a stirred solution in which solid KOH (88%, 6.98 g, 0.11 mol) was dissolved in 75 mL of EtOH in a nitrogen-scraped flask. The mixture was stirred for 5 minutes under nitrogen.

0.1 mol of a crude bromine compound (prepared according to M. Hatanaka and T. Ishimaru, J. Med. Chem., 1973, 16, 798) was added thereto.

The flask was nitrogen cleaned and clogged. The mixture was placed in a water bath at ambient temperature, stirred for 3 hours, and poured into 300 mL CH ₂ Cl ₂ and 1000 mL water.

The aqueous layer was extracted four times with 200 mL of CH ₂ Cl ₂ . The combined organic extracts were washed with 100 mL of cold water and saturated brine and dried.

The crude compound was filtered and concentrated. The resulting oil was chromatographed on silica gel using diethyl ether as eluent to obtain 13 g of a pale yellow oil which solidified when left to become a gum-like solid. Spectral analysis was consistent with ethyl-2-acetylamino-4-acetylthio-3-oxobutanoimide.

The compound (12.95 g) was rapidly stirred in 450 mL chloroform and a solution in which bromine (15.8 g, 2 equivalents) was dissolved in 50 mL of chloroform was added to the stirred solution cooled in an ice bath to 5 ° C. or lower, over 45 minutes. The mixture was stirred for 45 minutes in an ice bath and then stirred for 30 hours at ambient temperature.

The mixture was then washed with 200 mL water and then again with 100 mL water.

The combined wash water was extracted with 100 mL chloroform. The combined aqueous chloroform solution was washed with saturated brine and dried using MgSO ₄ .

The solution was filtered and concentrated to give crude oil.

This was chromatographed on silica gel using a serial gradient from petroleum ether-CH ₂ Cl ₂ (3: 1) to CH ₂ Cl ₂ to initially ethyl 5-bromo-4-hydroxyisothiazole-3-carboxylate. 0.79 g and then 3.4 g of ethyl-4-hydroxyisothiazole-3-carboxylate as colorless crystals were obtained, these mps being 44-7 ° C. and consistent with MS and ¹ H-NMR.

710 mg of the latter ester was added to 30 mL of THF, and 370 mg of LiOH.H ₂ O (2.2 equivalents) dissolved in 10 mL of water was added thereto. The mixture was stirred at ambient temperature for 3 hours and then cooled in a refrigerator. The precipitated solid was collected by filtration to give 710 mg of the dilithium salt of carboxylic acid. The salt was added to 7 mL of water, cooled in an ice bath and adjusted to pH 1 by addition of 2N HCl.

The resulting solution was extracted three times with 50 mL of EtOAc. The combined extracts were washed with 5 mL brine, dried (Na ₂ SO ₄ ), filtered and the filtrate was stored in the refrigerator. The cooled solution was refiltered and the filtrate was concentrated to give 230 mg of a colorless solid, mp 185-189 ° C., with ¹ H-NMR and ¹³ C-NMR spectra consistent with compound 23.

<3-benzyloxy-1-methylpyrazole-4-carboxylic acid (24) and 5-benzyloxy-1-methylpyrazole-4-carboxylic acid (25)>

Ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate and ethyl 5-hydroxy-1-methylpyrazole-4-carboxylate (Y. Wang, et al., Zhejiang Gongxueyuan Xuebao, 1994, 2, Obtained according to the procedure of 67) was benzylated as disclosed in S.Yamamoto, et al., Japanese Patent JP62148482, 1987, and the mixture was separated by column chromatography using 3: 1 hexanes: EtOAc as eluent. To ethyl 3-benzyloxy-1-methylpyrazole-4-carbonylate and ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate, which were pure by ¹ H-NMR.

Ethyl 3-benzyloxy-1-methylpyrazole-4-carboxylate (238 mg, 1.08 mmol) dissolved in TNF (10 mL), MeOH (2 mL) and water (5 mL) was dissolved in LiOH.H ₂ O (91 mg, 2.17 mmol). ) And stirred overnight. The mixture was cooled with concentrated HCl (1 mL) and extracted as EtOAc (2 × 20 mL).

The combined organic layers were dried (MgSO ₄ ) and concentrated to give a white solid (227 mg) with mp 169-172 ° C., the spectra consistent with 3-benzyloxy-1-methylpyrazole-4-carboxylic acid (24).

In the same manner, ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) was added to LiOH.H ₂ O (243 mg) in THF (20 mL), MeOH (4 mL), and water (10 mL). , 5.8 mmol) to give 608 mg of 5-benzyloxy-1-methyl-4-carboxylic acid (25) having a mp 117 to 122 ° C as a white solid.

<Production of Other Heteroaromatic Carboxylic Acids>

M. Mittelbach et al., Arch. 4-hydroxynicotinic acid was prepared according to the procedure of Pharm (Weinheim, Germany) 1985, 318, 481-486. 2-hydroxy-6-methylnicotinic acid is described in A. Dornow, Chem. Ber. 1940, 73, 153, and 4,6-dimethyl-2-hydroxynicotinic acid can be prepared by R. Mariella and E Belcher, J. Am. Chem. Soc., 1951, 73, 2616.

5-Chloro-2-hydroxy-6-methylnicotinic acid is described in A. Cale et.al., J. Med. Chem., 1989, 32, 2178, wherein 2,5-dihydroxynicotinic acid is described by P. Nantka Namirski and A Rykowski, Chem. Abstr., 1972, 77, 114205.

3-hydroxyisonicotinic acid is described in J. D. Crum and C. H. Fuchsman, J. Heterocycl. Chem. It was prepared according to the method of 1966, 3, 252-256.

3-hydroxypyrazine-2-carboxylic acid is described in A. P. Krapcho et al., J. Heterocycl. Chem. It can be prepared according to the method of 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 S.I.Zavyalov and A.G.Zavozin, Izv. Akad. Nauk SSSR, 1980, (5), 1067-1070.

4-hydroxypyridazine-3-carboxylic acids are described in I. Ichimoto, K. Fujii and C. Tatsumi, Agric. Biol. Chem. 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid was prepared according to the methods of 1967, 31, 979. E.Falco, E.Pappas, and G.Hitchings, J. Am. Chem. Soc., 1956, 78, 1938.

5-hydroxy-3-methylthio-1,2,4-triazine-6-carboxylic acid is described by R. Barlow and A. Welch, J. Am. Chem. Soc., 1956., 78, 1258, wherein hydroxyisothiazol-hydroxyisoxazole-, and hydroxypyrazole-carboxylic acids are described in T.M. Willson et al., Bioorg. Med. Chem. Lett., 1996, 6, 1043.

3-hydroxy-1,2,5-thiadiazole-4-carboxylic acid is described in J. M. Ross et al., J. Am. Chem. Soc., 1964, 86, 2861, and 3-hydroxyisoxazole-4-carboxylic acid is described in K. Bowdem et al., J. Chem. Obtained according to the methods described in Soc. (C), 1968, 172.

3-hydroxy-1-phenylpyrazole-4-carboxylate was produced according to the methods of AWTaylor and RTCook, Tetrahedron, 1987, 43, 607, and 3-benzyloxyquinoline-2-carboxylic acid was found in DLBoger and JHChem, J. Org. Chem. 1995, 60, 7369-7371.

General Formulation of Intermediate Amine and Aniline

Synthesis of cyclic, acyl and benzylamines is described by RO Hutchins and MK Hutchins in Comprehensive Organic Synthesis; BM Trost, Ed .; Pergamon Press: Oxford, 1991; Vol 8, p. 65; Or JW Huffman in Comprehensive Organic Synthesis; BM Trost, Ed .; Pergamon Press: Oxford, 1991; Vol 8, p. As illustrated at 124, this was done either by dissolving the metal reactant or by reducing the corresponding oxime using a metal hydride.

Optionally, these amines are described in R. Carlson, T. Lejon, T. Lunstedt and E. LeClouerec, Acta Chem. Scand. It can also be prepared directly from the ketones and aldehydes required via the Lenckart reaction as illustrated in 1993, 47, 1046.

Aniline is generally prepared by catalytic reduction of the corresponding nitro aromatic compound using Pd on charcoal or sulfide on platinum on charcoal. Such procedures are well described, for example, in RL Augustine, Catalytic Hydrogenation, Marcel Decker, Inc., New York, 1965.

Amine 19, a 9-membered dilactone ring system, was prepared according to the procedures of M.Simano, N.Kamei, T.Shibata, K.Inoguchi, N.Itoh, T.Ikari and H.Senda, Tetrachedron, 1998, 54, 12745 Or it can be manufactured by modifying the procedure. Such modifications are shown in Method 6 below.

As such, 26 is reduced to lithium borohydride and the resulting primary alcohol is capped with triisopropylsilane (TIPS) to provide 27.

The free hydroxyl group of 27 catalyzed the double bond after reaction with 1-bromo-2-methyl-2-propene to give 28.

The para-methoxybenzyl (PMB) breaking group is deselected and then condensed with N-t-BOC-O-benzyl-L-serine to provide 29.

Removal of the TIPS group results in oxidation of the hydroxy group to give 30. This material 30 is then converted to amine 31 using the method described in the above reference.

Similarly the synthesis of aminodilactones 38 and 48 without exocyclic ester-capable groups is disclosed in methods 7 and 8 below.

<Preparation of 27 (refer to method 6)>                 

0.1 mL trimethyl borate was added to a solution of lithium borohydride (2.0 M in THF, 7.5 mL, 15 mmol) in 7.5 mL dry THF. The mixture was cooled to −30 ° C. under a nitrogen atmosphere. To this solution was added a solution of Compound 26 (4.58 g, 10 mmol) dissolved in 10 mL THF over 10 minutes. The solution was stirred at −30 ° C. for 1 hour and then at 0 ° C. for 5 hours. Saturated ammonium chloride solution (10 mL) was added and stirred for 10 minutes before phase separation.

The aqueous phase was extracted with EtOAc (2 × 25 mL) and the combined organic phases were washed with saturated brine, dried over sodium sulphate and evaporated to dryness. The crude product was chromatographed to give 2.1 g white solid.

Recrystallized from hexane-EtOAc showed a white needle, m.p 91 ~ 93 ℃,

[] _D ²⁵ = + 31.9 ° (C = 1.04, CHCl ₃ ).

This diol (2.04 g, 6.22 mmol) was dissolved in 4 mL of anhydrous DMF and imidazole (680 mg, 10 mmol) was added. The solution was cooled in an ice bath and then triisopropylchlorosilane (1.39 mL, 6.5 mmol) was added over 2 minutes.

The mixture was stirred at rt for 4 h and then poured into ice-water and 20% ether was also extracted in hexane (3 x 15 mL). The combined organic phases were washed with brine, dried and filtered through a short flop of silica gel and washed with 20 mL of uniform solvent. Evaporation of the solvent gave 2.77 g of compound 27 as pale colloidal oil, which was pure by ¹ H-NMR.

Preparation of 28 (See Method 6)

Sodium hydride (60% oil dispersion, 400 mg, 10 mmol) was charged to a 50 mL flask and washed three times with hexane.

DMF (15 mL) was added and stirred with addition of Compound 27 (2.53 g, 5.19 mmol) dissolved in 5 mL anhydrous DMF. The reaction was stirred for 15 minutes, then cooled to below 10 ° C. and 1-bromo-2-methyl-2-propene (1 mL, 10 mmol) was added over 5 minutes and then stirred at room temperature for 2 hours. The mixture was partitioned between hexane / ice cooled ammonium chromide solution and treated as in the preparation of compound 27 and the crude product was chromatographed to give 2.2 g of colorless oil which was pure by ¹ H-NMR and elemental analysis. This material (2.38 g, 4.4 mmol) was dissolved in 50 mL EtOAc under nitrogen in a 100 mL Morton flask. 150 mg of 5% Pt supported on carbon was added and the mixture was stirred for 20 minutes under a 1 atmosphere of hydrogen. The catalyst was removed by filtration and the solvent was evaporated to yield 2.35 g of compound 28 as a colorless oil, which was purified by ¹ H-NMR.

Preparation of 29 (see Method 6)

In a 50 mL flask equipped with a magnetic stirrer, 40 mL CH ₂ Cl ₂ and an ether (2.0 g, 3.68 mmol) solution dissolved in ₂ mL water were charged.

2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDR) (920 mg, 4.05 mmol) was added under stirring with nitrogen and cooled to 10 ° C. or less in an ice bath.

The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The gold suspension was stirred for 1 hour, washed with 2 × 10 mL CH ₂ Cl ₂ with cake and the filtrate was extracted with 0.2N NaOH (2 × 25 mL).

The organic layer was dried and concentrated to obtain a pale oil, which was purified by chromatography to give 1.53 g of colorless oil.

It was dissolved in 25 mL CH ₂ Cl ₂ and under nitrogen while slowly adding DMAP (854 mg, 7 mmol), EDCI (1.34 mg, 7 mmol), and Nt-BOC-O-benzyl-L-serine (2.07 g, 7 mmol) sequentially. Stir in an ice bath.

The cooling bath was removed, the mixture was stirred at room temperature for 2 hours, and then poured into a mixture of 50 mL of ice-cooled 0.5N HCl and 20 mL of CH ₂ Cl _{2 which} was stirred rapidly and cooled for 10 minutes.

The phases were separated and the aqueous phase was extracted with 1 × 10 mL CH ₂ Cl ₂ , then the combined organic phases were dried and concentrated to give a pale oil. This was chromatographed to give 2.3 g of a compound 29, like a colorless dark oil. TLC and ¹ H-NMR results were very pure.

<Preparation of 30 (see Method 6)>

Cyryl ether 29 was dissolved in 7 mL anhydrous pyridine and cooled in an ice bath. HF-pyridine complex (4.5 mL) was added over 1 minute and the solution was stirred at room temperature for 17 hours and then heated to 50 ° C. for 4.5 hours, at which time the conversion was stopped.

The mixture was poured into ice-water and extracted with 3 x 50 mL ether. The combined organic phases were washed with water, 1N HCl, dried and concentrated to give an oil.

This was chromatographed to give 1.23 g of alcohol required as a colloidal oil and 365 mg recovered 29.

Alcohol (1.14 g, 2.10 mmol) was dissolved in 10 mL DMF and pyridinium dichromate (3.76 g, 10 mmol) was added.

After 21 hours, the mixture was poured into ice-water and 1N HCl was added until the pH was below 3 and solid sodium bisulfite was added until the orange was decolorized.

The aqueous phase was extracted with ether (3 x 50 mL). The organic phases were combined, concentrated after washing and drying (NaSO ₄ ). The residue was chromatographed to give 811 mg of pure colloidal oil. The acid was dissolved in 30 mL EtOAc and 200 mg of Pearlman's Catalyst was added.

The slurry was shaken under 50 psi hydrogen pressure for 4 hours, 300 mg fresh catalyst was added, and shaken for another 2 hours.

It was then filtered and solvent evaporated to give pure Collagen Gum 30.

<Threoninedithiane 33 (see Method 7)>

Pentyldithiane 32 (Hirai, Heterocyles 1990, 30 (2, Spec. Issue), 1101) (200 mg, 0.97 mmol) was dissolved in 10 mL of CH ₂ Cl ₂ at room temperature. N- (Z) -Ot-butyl- (L) -threonine (900 mg, 2.91 mmol) was added followed by DMAP (36 mg, 0.29 mmol). A solution of dicyclohexyl carbodiimide (DCC) (1M, 2.9 mL, 209 mmol) in CH ₂ Cl ₂ was added to the mixture, followed by stirring at room temperature overnight.

The reaction was diluted with 50 mL of ether (Et ₂ O), filtered and concentrated. As a result, the residue was applied to a small (4 ″) silica gel gravity column and eluted with 4: 1 hex / EtOAc.

The eluate collected from the silica gel column was again purified by radial chromatography using 4: 1 hexanes / EtOAc as eluent.

The product was evaporated and maintained at high vacuum (45 ° C. 0.1 torr) at a constant weight to yield 500 mg of a nearly colorless dark oil, identified as Ditian 33 (TLC R ₅ = 0.32, ¹ H-NMR).

<Threonine Carboxylic Acid 35 (See Method 7)>

Threonintian 33 (500 mg, 1.01 mmol) was dissolved in 10 mL of 9: 1 CH ₃ CN / H ₂ O compound at room temperature. [Bis (trifluoroacetoxy) iodo] Benzene (650 mg, 1.50 mmol) was added and stirred for 10 minutes.

Saturated NaHCO ₃ (20 ml) was added and the solution was extracted as Et ₂ O (3 × 20 mL).

The ether layer was dried over MgSO ₄ , filtered and concentrated. Aldehyde 34 is pure enough (TLC, GC / MS) and can be used directly for the next reaction. 15 mL crude aldehyde CrO ₃ reagent (prepared with 1 g CrO ₃ , 30 mL CH ₃ CO ₂ H and 1 mL pyridine) was added and stirred overnight at room temperature.

The solution was diluted with 30 mL cold water and extracted with Et ₂ O (3 × 30 mL). The organic layer was washed with 30 mL brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by radial chromatography using 2: 1 heptanes / EtOAc containing 2% CH ₃ CO ₂ H as eluent.

Carboxylic acid 35 (12 mg) was very pure by TLC and ¹ H-NMR.

<Threonine Hydroxycarboxylic Acid 36 (See Method 7)>

Threoninecarboxylic acid 35 (137 mg, 0.324 mmol) was stirred in 3 mL of trifluoroacetic acid for 10 minutes and the mixture was concentrated on a rotary evaporator.

The residue was dried overnight under high pressure (0.05 mm). The hydroxy acid 36 (119 mg) was used directly in the next step.

<N-Cbz-threoninebislactone 37 (see Method 7)>

-2를 첨가(85mg, 0.39mmol)한 후 트리페닐포스핀(0.39mmol, 101mg)을 첨가하고 밤새 교반하였다. 그 조질 티오에스테르를 CH₃CN 15mL로 희석하였다. 환류 컨덴서가 달린 별도의 플라스크에 AgClO₄ 1.0M 1.2mL(1.16mmol)을 톨루엔에 용해시킨 용액을 장입한후, CH₃CN 32mL를 장입하였다.Threoninehydroxy carboxylic acid 36 (119 mg, 0.324 mmol) was dissolved in 1 mL benzene and Aldrithiol

-2 was added (85 mg, 0.39 mmol) followed by triphenylphosphine (0.39 mmol, 101 mg) and stirred overnight. The crude thioester was diluted with 15 mL of CH ₃ CN. To a separate flask with a reflux condenser was charged with a solution of 1.2 mL (1.16 mmol) of AgClO ₄ 1.0M in toluene, followed by charging 32 mL of CH ₃ CN.

The solution was heated at 5 to 10 drops / sec reflux rate (oil bath to 160 ° C.). The thioester solution was then titrated over 2 hours via an addition funnel at the top of the condenser. The mixture was further refluxed for 30 minutes, cooled and concentrated. The residue was diluted with 10 mL 0.5 M KCN and extracted with benzene (3 x 20 mL).

The benzene layers were combined, washed with 20 mL water, dried over MgSO ₄ , filtered and concentrated. The residue was then taken up in 10 mL of 2: 1 pentane / Et ₂ O and filtered. The solid was washed with 2: 1 pentane / Et ₂ O and the combined organic solutions were concentrated. Radial chromatography (2: 1 pentane / Et ₂ O as eluent) gave 34 mg of bislactone 37, which was very pure by TLC (R ₅ = 0.22) and ¹ H-NMR.

<3-amino-4,7,9-trimethylbislactone 38 (see Method 7)>

N-Cbz-threoninebislactone 37 (34 mg, 0.097 mmol) was dissolved in 10 mL of methanol in a 500 mL Parr container and nitrogen-swept. To this solution was added 10 mg of Pd (black) and the mixture was shaken at 45 psi hydrogen pressure for 1 hour.

The catalyst was filtered off and the solvent was evaporated to give oily amine 38 (20 mg, 100%). This amine was pure ( ¹ H-NMR) and used as such without further purification.

<3-benzyl-4-hydroxy-5-methylbutyrolactone 40 (see method 8)>

Pentanic acid 39 (Shimono et al., Tetrahedron Lett. 1998, 39, 4363) (1.8 g, 5.23 mmol) was dissolved in 30 mL of methanol in a 500 mL Parr vessel and nitrogen was used.

To this solution was added 150 mg of 10% Pd supported on carbon followed by the addition of 6 drops of concentrated HCl.

The mixture was shaken for 3 hours at 50 psi hydrogen pressure. The catalyst was filtered through diatomaceous earth and the solution was concentrated. The residue was taken up in 30 mL CH ₂ Cl ₂ and washed with water (1 × 10 mL). This solution was dried over MgSO ₄ , filtered and concentrated. ¹ H-NMR and GC / MS showed butyrolactone 40 and 4-methylanisole in a 4: 1 ratio (v / v). This material (60% pure by GC) was used directly in the next reaction.

<3-benzyl-5-methylbutenode 41 (see method 8)>

3-benzyl-4-hydroxy-5-methylbutyrolactone 40 (60% purity, 1.7 g, 8.25 mmol) was dissolved in 25 mL CH ₂ Cl ₂ and cooled to 0 ° C.

The solution was stirred with triethylamine (2.3 mL, 16.5 mmol), DMAP (500 mg, 4.13 mmol) and p-toluenesulfonyl chloride (9.0 mmol, 1.7 g) sequentially.

The reaction was brought to room temperature and stirred for 30 hours. The reaction was diluted with 50 mL Et ₂ O and washed with 5% NaHCO ₃ (25 mL). The solution was dried over MgSO ₄ , filtered and concentrated. The residue was purified by radial chromatography using 2: 1 pentane / Et ₂ O as eluent to give 677 mg of butenolide 41 (more than 95% purity, GC and ¹ H-NMR).

<Cis-3-benzyl-5-methylbutyrolactone 42 (see Method 8)>

3-benzyl-5-methylbutenode 41 (677 mg, 3.60 mmol) was dissolved in 30 mL of EtOAc in a 500 mL Parr vessel and purged with nitrogen. 300 mg of 10% Pd / c was added to the solution and the mixture was shaken at 45 psi hydrogen pressure overnight.

The catalyst was filtered off and the solvent was evaporated. The residue was purified by radial chromatography using 2: 1 pentane / Et ₂ O as the eluent to give 484 mg of colorless oil (71% yield of pure material by ¹ H-NMR and GC in CDCl ₃ ).

<2-benzylpentylthiane 43 (see Method 8)>

Cis-3-benzyl-5-methylbutyrolactone 42 (550 mg, 2.89 mmole) was dissolved in 15 mL of Et ₂ O and cooled to -78 ° C.

Diisobutyl aluminum hydride (1.0 M in hexane, 3.47 mmol, 3.5 mL) was added directly and stirred at −78 ° C. for 2 hours. Methanol (3.3 mL) was added over 15 minutes and the reaction stirred for 30 minutes at -78 ° C. Sodium potassile tartrate (1.65 g in 5 mL of water) was added and the reaction was allowed to warm to room temperature and stirred overnight.

The layers were separated and the aqueous layer was extracted with Et ₂ O (2 × 10 mL). The combined ether layer was washed with saturated NaHCO ₃ and brine (1 × 10 mL). The solution was dried over MgSO ₄ , filtered and concentrated. Crude lactol (555 mg) was dissolved in 5 mL of CH ₂ Cl ₂ and cooled to 0 ° C.

1,3-propanedithiol (3.46 mmol, 0.35 mL) was added followed by 0.37 mL (2.89 mmol) boron trifluoride etherate. The reaction was allowed to warm up to room temperature and then stirred overnight. Saturated NaHCO ₃ was added (20 mL) and the mixture was stirred for 1 h. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 mL).

The combined organic layer was washed with brine (1 × 20 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified by radial chromatography using 3: 1 hexanes / EtOAc as eluent to give 560 mg of yellow oil (69% yield for pure material by ¹ H-NMR and GC).

<Seridian 44 (See Method 8)>

2-benzylphenyldithiane 43 (560 mg, 1.99 mmol) was dissolved in 5 mL of DMF and cooled to 0 ° C. DMAP (0.29 mmol, 36 mg) was added followed by EDCI (0.57 g, 2.98 mmol). N-t-BOC-O-benzyl- (L) -serine (760 mg, 2.58 mmol) was then added and then warmed to room temperature and stirred overnight.

The reaction was poured into a mixture of 10 mL of ice cold 0.5N HCl and 20 mL of 20% ether / hexane, which was stirred rapidly and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with 20% ether / hexanes (1 × 10 mL). The combined organic layer was washed with 0.5N HCl (20 mL) and brine (2 × 20 mL). The solution was dried over MgSO _4, filtered and concentrated. The resulting residue was subjected to high vacuum (45 ° C ⓐ 0.1 torr) and left to constant weight to give 1.06 g of a substantially colorless heavy oil, identified as Ditian 44 (TLC R ₅ = 0.3, 3: 1 hexanes / EtOAc). .

<N-t-BOC-O-benzylserinecarboxylic acid 45 (see Method 8)>

Serindian 44 (1.06 g, 1.90 mmol) was dissolved in 20 mL of a 9: 1 CH ₃ CN / H ₂ O mixture at room temperature.

[Bis (trifluoroacetoxy) iodo] Benzene (1.2 g, 2.82 mmol) was added and stirred for 10 minutes. Saturated NaHCO ₃ was added (40 mL) and the solution extracted with Et ₂ O (3 × 40 mL).

The ether layer was dried over MgSO ₄ , filtered and concentrated. This aldehyde was sufficiently pure (TLC, GS / Ms, ¹ H-NMR) and could be used directly for the next reaction.

Crude aldehyde was treated with 30 mL (9.70 mmol) of CrO ₃ reagent (prepared with 1 g CrO ₃ , 30 mL CH ₃ CO ₂ H and 1 mL pyridine) and stirred overnight at room temperature.

The solution was diluted with 6 mL of cold water and extracted with Et ₂ O (3 × 60 mL). The organic layer was washed with 2 x 60 mL brine, dried over MgSO ₄ , filtered and concentrated. The residue was taken up in 2: 1 heptane / EtOAc and evaporated. Purification by radial chromatography using 1.5: 1 heptane / EtOAc containing 2% CH ₃ CO ₂ H as eluent. The carbonic acid (536 mg) appeared to be very pure by TLC and ¹ H-NMR and two t-BOC rotamers were apparent in CDCl ₃ but not in acetone-d ₆ .

<N-t-BOC-serinebislactone 47 (see Method 8)>

N-t-BOC-O-benzylserinecarboxylic acid 45 (536 mg, 1.11 mmol) was dissolved in 15 mL of EtOAc in a 500 mL Parr vessel and purged with nitrogen. 390 mg of 10% Pd / c was added to this solution and the mixture was shaken at 50 psi hydrogen pressure for 17 hours.

The catalyst was filtered through diatomaceous earth and the solvent was evaporated to give hydroxy acid 46 (440 mg). Crude hydroxy acid 46 was dissolved in 23 L of benzene and triphenylphosphine (0.34 g, 1.28 mmol) was added at room temperature. Diisopropylazodicarboxylate (DIAD, 0.25 mL, 1.28 mmol) was titrated and the reaction stirred overnight at room temperature.

The solution was concentrated and the resulting residue was applied to a small (4 ″) gravity column and eluted with 2: 1 hexanes / EtOAc. The eluate from the silica gel column was purified by radial chromatography using 2: 1 pentane / ether as eluent. The product was evaporated to give 132 mg of yellow oil, identified as Nt-BOC-serinebislactone (TLC R _f = 0.32, pure by ¹ H-NMR).

<3-amino-7-benzyl-9-methylbislactone 48 (see Method 8)>

Nt-BOC-serinebislactone 47 (132 mg, 0.35 mmol) was stirred in 3 mL of trifluoroacetic acid for 30 minutes and the reaction was concentrated on a rotary evaporator. The residue was dried under high vacuum (0.05 mm) overnight. Trifluoroacetic acid salt of amine 48 (0.35 mmol) was very pure by ¹ H-NMR and used without further purification.

<3- (3-chlorophenoxy) aniline>

3-chlorophenol (12.86 g) was added all at once to a stirring solution in which potassium t-butoxide (12.3 g) was dissolved in DMSO (100 mL). The resulting solution was stirred for 5 minutes at room temperature and then 3-fluoronitrobenzene (12.70 g) was added in one portion.

The resulting dark mixture was heated to 120 ° C. for 12 hours, cooled to room temperature and poured into water (700 mL). As a result, the mixture was extracted with ether (2 × 200 mL).

The organics were washed with 2N NaOH (100 mL) and then with water (100 mL). After drying (MgSO ₄ ), the solvent was evaporated and the resulting dark oil was distilled to give 3- (3-chlorophenoxy) nitrobenzene as a yellow oil, bp 135-140 ° C. at 0.05 mm.

A mixture of 3- (3-chlorophenoxy) nitrobenzene (14 g) and 5% Pt supported on carbon sulfide in EtOAc (150 mL) was subjected to hydrogen atmosphere (initial pressure = 50 psi) on a Parr shaker.

After 4 hours, the mixture was thoroughly degassed (replace hydrogen with nitrogen), dried (MgSO ₄ ) and filtered (# 50 Whatman paper). The solvent was evaporated to give a pale yellow (12 g), which was more than 60% pure by GC. ¹ H-NMR (CDCl ₃ ) and GC / MS (m / e = 219, 221) were consistent with 3- (3-chlorophenoxy) aniline.

<3- (4-trifluoromethylphenoxy) aniline>

Potassium tert-butoxide (7.86 g) was added at once to a stirring solution in which 3-hydroxyaniline (6.55 g) and 4-fluoro benzotrifluoride (9.85 g) were dissolved in DMSO (50 mL). The resulting dark solution was heated at 95 ° C. for 4 hours, cooled to room temperature and poured into water (600 mL). The mixture was extracted with ether (3 x 125 mL). The organic phase was washed with 2N sodium hydroxide (2 × 75 mL) and water (100 mL), dried (MgSO ₄ ) and the solvent was evaporated to give a dark oil. This oil was distilled off to obtain the desired aniline as a colorless oil (8.7 g), at bp 110-112 ° C. at 0.15 mm.

<4- (4-trifluoromethylphenylthio) anneal>

4-fluorobenzotrifluoride (9.85 g) and 4-aminothiophenol (7.51 g) were dissolved in DMSO (60 mL) and potassium t-butoxide (6.73 g) was added all at once to a stirred solution cooled in an ice bath. It was.

The resulting mixture was stirred at 0 ° C. for 10 minutes and then stirred at 60 ° C. overnight. After cooling, the mixture was poured into water (600 mL) and the resulting mixture was extracted with ether (2 x 200 mL). The organic phase was washed with 2N sodium hydroxide (50 mL) and then with water (50 mL). After drying (MgSO ₄ ), the solvent was evaporated to give a brown solid. Recrystallization from hexane gave the desired anneal, which was mp 97-99 ° C. as a yellow solid.

<4- (3-trifluoromethylbenzyl) anneal>

To a stirred mixture of magnesium turning (1.09 g) in anhydrous THF (10 mL) was dissolved a solution of 4-bromo-N, N-bis- (trimethylsilyl) aniline (9.48 g) in anhydrous THF (75 mL). Grinard reagent was prepared by addition.

CuCl ₂ (0.20 g) and LiCl (0.13 g) were added to anhydrous THF (25 mL) and stirred until a homogeneous solution was obtained to prepare a second solution of catalyst Li ₂ CuCl ₄ (0.33 g).

This catalyst solution was then added to a solution of 3-trifluoromethylbenzyl bromide (7.17 g) dissolved in anhydrous THF (75 mL). The orange-red color solution was cooled in an ice bath (N ₂ atmosphere) (previously cooled in an ice bath) and the Grignard reagent was fed through a tube.

After 15 min stirring at 0 ° C. the mixture was stirred overnight at room temperature. The reaction mixture was quenched by addition of NH ₄ Cl solution (25 mL).

The orange phase was separated, dried (MgSO ₄ ) and the solvent was evaporated to give a dark oil (11 g).

4N HCl (50 mL) was added to the oil, and the mixture was stirred at room temperature for 3 hours. This mixture was extracted with ether (3 × 100 mL) after careful addition of solid sodium carbonate.                 

The organic phase was dried (MgSO ₄ ) and the solvent was evaporated. EtOAc (100 mL) was added and the solution was withdrawn from insoluble material.

The solvent was evaporated again and the residue was chromatographed (silica gel, 3: 1 hexanes / EtOAc). The second eluate was collected to give an orange oil which quickly turned dark. NMR (CDCl ₃ ) and GC / MS (m / e-251) matched the desired compound. This material was converted to HCl salt to give a brown solid.

<4- (3-trifluoromethylbenzoyl) aniline>

The stirred solution in which 4-bromo-N and N-bis- (trimethylsilyl) aniline (9.24 g) was dissolved in anhydrous THF (100 mL) was cooled to -78 ° C under an argon atmosphere.

To this slowly added n-butyllithium 2.5M solution dissolved in hexane (12 mL). After the addition was completed, the reaction mixture was stirred at −78 ° C. for 10 minutes, and a solution in which N-methyl-N-methoxy-3-trifluoromethylbenzamide (6.8 g) was dissolved in anhydrous THF (25 mL) was added directly. .

After the addition was completed, the mixture was stirred at -78 ° C for 1 hour, then the cooling bath was removed and the reaction temperature was raised to 10 ° C. The reaction was quenched by addition of saturated NH ₄ Cl solution (50 mL) and then water (10 mL). The organic phase was separated, dried (MgSO ₄ ) and the solvent was evaporated to give a yellow liquid (12 g).

It was taken up in ether (100 mL) and 4N HCl (100 mL) was added.

As a result, the mixture was stirred at room temperature for 30 minutes, during which the solids were separated. This solid was filtered off, washed with ether several times and then carefully added to a stirred, saturated NaHCO ₃ solution (100 mL). The resulting mixture was extracted with ether (2 × 100 mL), the organic phase was dried (MgSO ₄ ) and the solvent was evaporated to yield an off white solid (5.7 g).

Recrystallization from methanol / water gave a white solid with mp 130-131 ° C. Spectral data were consistent with the desired compound.

<Ethyl 2-amino-5- (4-trifluoromethylphenoxy) benzoate>

To the mechanically stirred solution of potassium t-butoxide (15.71 g) in DMSO (75 mL) was added 5-hydroxyanthranilic acid (10.2 g). The mixture was stirred at room temperature under argon for 10 minutes, after which 4-fluorobenzotrifluoride (11.16 g) was added, as a result of stirring the mixture and heating at 75-80 ° C. overnight.

After cooling, the mixture was attached to water (600 mL) and the pH adjusted to about 2.5. The resulting solid was filtered, washed several times with water and recrystallized with methanol / water (charcoal) to give a tan solid (13.5 g), m.p 165-167 ° C.

This solid was taken up in anhydrous ethanol (250 mL) and concentrated sulfuric acid (15 mL) was carefully added.

As a result, the mixture was heated to reflux for 24 hours and then most of the ethanol was evaporated. The residue was carefully added to ice water (600 mL), and the resulting mixture was made basic by slowly adding 50% NaOH solution and extracted with ether (2 × 150 mL). The organic phase was washed with water (100 mL) and then with saturated NaCl solution (50 mL).

After drying (MgSO ₄ ), the solvent was evaporated to give a yellow oil with 98% GC purity. GC / MS showed ionic m / e = 325 consistent with the desired compound.

<2-aminobenzonobonan>

To an agitated solution in which benzonorbornene (2.84 g) was dissolved in anhydrous THF (8 mL), cooled to 0 ° C. under argon atmosphere, a Bonan 1 M solution dissolved in THF (6.7 mL) was added quickly.

The solution was stirred at 0 ° C. for 10 minutes and then at room temperature for 90 minutes. The reaction mixture was cooled back to 0 ° C. and hydroxyamine-0-sulfonic acid (1.58 g) was added in one portion. The ice bath was removed and the reaction mixture was stirred for 2 hours at room temperature. 1N HCl (25 mL) and ether (20 mL) were added and further stirred for 10 minutes. Phase separated and the organic phase was discarded. The aqueous phase was made basic by carefully adding 50% NaOH solution and then extracted with ether (3 × 30 mL).

The organic phase was dried (MgSO ₄ ) and the solvent was evaporated to give a yellow liquid (1.35 g) having a purity of 98% as measured by GC. NMR (CDCl ₃ ) and GC / MS (m / e = 159) results were consistent with the desired compound.

<Preparation of a mixture of (3-trifluoromethylbenzyloxymethyl) norbornylamine 53>

The preparation of this mixture is shown in Method 9 above. Exo- and endo-norbornenecarboxylic acids 49 (-1: 4 ratio) (0.7 g), 2-iodine propane (12.8 g) and potassium carbonate (10.4 g) were mixed in DMSO (40 mL). One mixture was stirred and heated at 55 ° C. overnight. After cooling the mixture was diluted with water (125 mL) and extracted with pentane.

The organic phase was dried (MgSO ₄ ) and the solvent was evaporated to give a colorless oil (8.2 g).

This oil was added to a solution of sodium 2-pooxide (3.9 g) dissolved in 2-propane (100 mL), and the resulting mixture was heated to reflux for 16 hours. 2-propane was removed, diluted with water (200 mL), and pentane was extracted to obtain norbornene isopropyl ester 50 having an exo: ento ratio of 52:48.

It was isolated as pure isomer via chromatography (silica gel, 95: 5 hexanes / EtOAc). The exo isomer 50 (4.0 g) was dissolved in ether (50 mL), cooled to 0 ° C. and then slowly added lithium aluminum hydride 1M solution dissolved in ether (14 mL). After complete addition, the mixture was heated to reflux for 1 hour.

After cooling, the reaction was quenched by sequentially adding water (0.53 mL), 15% NaOH solution (0.53 mL) and water (1.59 mL). As a result, the mixture was dried (MgSO ₄ ), filtered and evaporated to give exo-alcohol 51 (2.7 g) as a colorless liquid.

GC / MS (m / e = 124) results matched the assigned structure.

To a stirred mixture of potassium hydride (1.0 g) in anhydrous THF (25 mL), a solution of Compound 51 (2.7 g) in THF (10 mL) was carefully added.

After the addition was completed, the mixture was stirred for 30 minutes at room temperature and trifluoromethyl benzylbromide (5.98 g) was added at once (exothermic reaction).

The reaction was heated to reflux for 2 hours, cooled and poured into water (150 mL).                 

Ether extraction (2 × 75 mL), drying (MgSO ₄ ) and solvent evaporation yielded a yellow oil which was purified by chromatography (silica gel, 97: 3 hexanes / acetone) to give a colorless oil as a pure substance 52 (5.2 g). Got.

NMR (CDCl ₃ ) and GC / MS (m / e = 282) results were consistent with the structure of 52. The conversion of compound 52 to the diastereomeric mixture of amine 53 was through the borane / hydroxylamine-0-sulfoic acid sequence described above (20% yield).

<3- (3-pyridyl) -1-propane amine>

The amines B. Jursic et al., Synthesis, 1988, (II), 868, first convert 3- (3-pyridyl) -1-propanol to the corresponding chlorides, which are then converted into DJDumas et al. , J. Org. Chem. It was obtained by converting into an amine in the order of 1988, 53, 4650.

<3-[[5- (trifluoromethyl) -2-pyridyl] oxy] -1-propanamine>

2-Fluoro-5-trifluoromethylpyridine (1.831 g, 11 mmol) was dissolved in dry THF (15 mL) with stirring under nitrogen atmosphere and cooled to 0 ° C in an ice bath. Here, a solution of 3-amino-1-propanol (0.76 mL, 10 mmol) in arsenic THF (15 mL) and 1 M potassium tert-butoxide solution in THF (10 mL, 10 mmol) were added directly over 30 minutes. The yellow solution was stirred and warmed to room temperature overnight.

The reaction mixture was poured into water (75 mL) and extracted with ether (2 × 50 mL). The organic phase was washed with brine (50 mL), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give almost pure yellow liquid as a result of MS and NMR, which was used without further purification.

<(+)-Trans-1-hydroxy-2-aminocyclopentane hydrobromide>

(+)-Trans-1-benzyloxy-2-amino cyclopentane hydrobromide (8.2 g, 42.8 mmol) was treated with 40% HBr (60 mL). After stirring for 3 days, the solution was concentrated in vacuo to afford 7.09 g (91%) ¹ H-NMR (DMSO-d ₆ ) pure orange solid hydrobromide salt.

<2,3-dihydro-2,2-dimethyl-1H-inden-1-amine>

This amine was prepared according to the procedure described in WO9927783.

<10-Amino-endo-2,5-methanobicyclo [4,4,0] deck (DEC) -3-ene (ENE) (56)>

This mixture was prepared according to the procedure of Method 10 above. Aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) dissolved in toluene (200 mL).

After 40 minutes, freshly distilled cyclopentadiene (13.7 g, 208 mmol) was added and heated to 100 ° C. for 2 hours. After cooling, the mixture was diluted with Et ₂ O (300 mL) and washed with saturated NaHCO ₃ (2 × 150 mL) and brine (100 mL).

The combined organic layer was dried (MgSO ₄ ), filtered and concentrated. The residue was purified by flash chromatography using 50: 1 hexanes: Et ₂ O as eluent to afford 2.5-methanobicyclo [4,4,0] dec-3-en-10-one (54). Endo- (1.74 g) and exo- (943 mg) isomers were obtained, which were pure by ¹ H-NMR and GC / MS.

Sodium acetate (1.79 g, 21.8 mmol) was added to endo-2,5-methanobicyclo [4,4,1] dec (dec) -3-dps (en) -10-one 54 (1.61 g) , 9.9 mmol) and hydroxylamine hydrochloride (758 mg, 10.9 mmol) were added in portions to a solution dissolved in methanol (33 mL) and stirred overnight at room temperature.

The reaction was quenched with H ₂ O and extracted with ether (2 × 50 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give endo-2,5-methanobicyclo [4,4,0] dec-3-en-10-one oxime (55). , ¹ H-NMR and GC / MS results were pure.

Endo-2,5-methanobicyclo [4.4.1] dec-3-en-10one oxime (55) (500 mg, 2.79 mmol) was dissolved in EtOAc (25 ml) and 10% Pd / c (50 mg) Was added.

를 통해 여과하고 농축하였다.After 3 hours under H ₂ (40 psi), the suspension was

Filtered through and concentrated.

-Ni(1.0g)으로 장입하였다.As a result, the residue was dissolved in EtOH (25 ml) and Raney

Charged with -Ni (1.0 g).

The suspension was saturated with NH ₃ and pressurized with H ₂ (45 psi).

를 통해 여과하고, EtOAc(100ml)로 희석시키고, 포화 NaHCO₃(100ml)로 세척하였다. 결합한 유기층을 MgSO₄상에서 건조시키고, 여과 및 농축하였다.After 6 hours, the suspension was

Filtered through, diluted with EtOAc (100 ml) and washed with saturated NaHCO ₃ (100 ml). The combined organic layer was dried over MgSO ₄ , filtered and concentrated.

¹ H-NMR and GC / MS results showed the desired amine 56 as a 2: 1 mixture of diastereomers (418 mg).

<10-Amino-4- (4'-methylpent-3'-enyl) -bicyclo [4.4.0] dec-3-ene (59)>

This compound was prepared as shown in Method 11.

Aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) dissolved in toluene (100 ml).

After 40 minutes, myrcene (17 g, 125 mmol) was added and heated to 100 ° C. for 25 hours.

After cooling the mixture was diluted with Et ₂ O (300 ml) and washed with saturated NaHCO ₃ (2 × 150 ml) and brine (100 ml). The combined organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified via flash chromatography using 50: 1 hexanes: Et ₂ O as eluent to afford 4- (4'-methylpent-3'-enyl) -bicyclo [4.4.0] dec-3-ene. -10-one (57) (2.55 g) was provided, which was pure by ¹ H-NMR and GC / MS.

4- (4'-Methyl-pent-3'-enyl) -bicyclo [4.4.0] dec-3-en-10-one (57) (2.23 g, 9.6 mmol) and hydroxylamine hydrochloride (733 mg) , 10.5 mmol) was added sodium acetate (1.73 g, 21 mmol) in portions to a solution dissolved in methanol (32 ml) and stirred overnight at room temperature.

The reaction was quenched with H ₂ O and extracted with ether (2 × 50 ml).

The combined organic layer was dried over MgSO ₄ , filtered and concentrated.

As a doughy residue, 4- (4'-methyl-pent-3'-enyl) -bicyclo [4.4.0] dec-3-en-10-one oxime (58) was obtained with ¹ H-NMR and GC / MS results were pure.

-Ni(1.0g)을 장입하였다. 그 서스펜션을 NH₃로 포화시키고 H₂(45psi)로 가압하였다.4- (4'-Methylpent-3'-enyl) -bicyclo [4.4.0] dec-3-en-10-one oxime (600 mg, 2.42 mmol) was dissolved in EtOH (25 ml) and Raney

-Ni (1.0 g) was charged. The suspension was saturated with NH ₃ and pressurized with H ₂ (45 psi).

를 통해 여과하고, EtOAc(100ml)로 희석시켰으며 포화 NaHCO₃(100ml)로 세척하였다. 합한 유기층을 MgSO₄상에서 건조하고, 여과및 농축하였다. ¹H-NMR및 GC/MS결과 순수한 바라는 아민(550mg)이었다.After 6 hours, the suspension was Celite

Filtered through, diluted with EtOAc (100 ml) and washed with saturated NaHCO ₃ (100 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated. Pure desired amine (550 mg) by ¹ H-NMR and GC / MS.

<2-Amino-7-furyl-3-methyl-4-chromanone hydrochloride (63)>                 

This amine hydrochloride salt was prepared according to Method 12 above. 7-trifluoromethanesulfonate-3-methyl-4-chromanone (3.0 g, 9.7 mmol) (prepared according to the procedures of K. Koch, and MS Biggers, J. Org. Chem. 1994, 59, 1216) 2- (tributylstannyl) furan (3.79 g, 10.6 mmol), Pd (PPh ₃ ) ₄ (223 mg, 0.19 mmol), LiCl (1.23 g, 29.0 mmol) and 2,6-di-t of 2 crystals -Butyl-4-methylphenol was added to the solution dissolved in 1,4-dioxane (50 ml) and heated for reflux for 12 hours.

After cooling, the mixture was quenched with saturated NH ₄ Cl (40 ml) and extracted with Et ₂ O (2 × 50 ml).

The combined organic layer was dried over MgSO ₄ , filtered and concentrated.

The residue was purified by flash chromatography using 20: 1 hexanes: EtOAc as eluent to give a yellow solid, mp 94-95 ° C., 7-puryl-3-methyl-4-chromanone (60) (1.78 g). Got.

Sodium acetate (395 mg, 4.82 mmol) in a solution of 7-puryl-3-methyl-4-chromenone (60) (500 mg, 2.19 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol) dissolved in methanol (5 ml). ) Was added in portions and stirred overnight at room temperature.

The reaction was quenched with H ₂ O and extracted with ether (2 × 25 ml).

The combined organic layers were dried over MgSO ₄ , filtered and concentrated to afford 7-puryl-3-methyl-4-chromanone oxime (61) as mp175-177 ° C. as a white solid.

Toluenesulfonylchloride (397 mg, 2.08 mmol) was added 7-furyl-3-methyl-4-chromanone oxime (61) (461 mg, 1.89 mmol) and pyridine (0.5 ml).

It was added to a 0 ° C. solution dissolved in CH ₂ Cl ₂ (10 ml).

After 6 h the mixture was diluted with CH ₂ Cl ₂ (30 ml) and washed with 5% HCl (20 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated.

The residue was purified by flash chromatography using 5: 1 hexanes: EtOAc as eluent to afford 7-puryl-3-methyl-4-chromanone 0- (toluenesulfonyl, mp 163-164 ° C. (dec) as a pink solid. ) -Oxime (62) (429 mg) was obtained.

Ethanol solution of sodium ethoxide (0.35) in a stirred solution of 7-puryl-3-methyl-4-chromanone-0- (toluenesulfonyl) -oxime (62) (410 mg, 1.0 mmol) dissolved in benzene (4 ml). ml, 2.87M, 1.0 mmol) was added.

After 18 h, 3N HCl (6 ml) was added and the layers separated.

The organic phase was extracted with 3N HCl (2 × 10 ml) and the combined aqueous extracts were concentrated to yield crude Compound 63 as an orange solid (388 mg), which was used as such without further purification.

<2-amino-7- (3'methoxypropynyl) -3-methyl-4-chromenonehydrochloride (65)>

This amine hydrochloride was prepared as shown in Method 13.

7-trifluoromethanesulfonate-3-methyl-4-chromenone (3.10 g, 10 mmol) (prepared according to the procedures of K. Koch, and MS Biggers, J. Org. Chem. 1994, 59, 1216) Methyl propargyl ether (1.05 g, 15 mmol), (Ph ₃ P) ₄ Pd (210 mg, 0.30 mmol) and Et ₃ N (6 ml) were added to a solution dissolved in DMF (30 ml) and heated at 70 ° C. for 1 hour. It was.

After cooling, the mixture was quenched with saturated NH ₄ Cl (40 ml) and extracted with Et ₂ O (2 × 50 ml).

The combined organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash chromatography using 9: 1 hexane-EtOAc as eluent to afford 7- (3'-methoxypropynyl) -3-methyl-4-chromanone (mp 60-63 ° C. as a white solid). 64) (1.40 g).

Compound 64 was converted to compound 65 in the same manner as described for 2-amino-7-furyl-3-methyl-4-chromanone hydrochloride.

<2-amino-α-tetraron hydrochloride>

This compound was prepared from α-tetraron as shown in Method 14, in the same manner as described above for 2-amino-7-furyl-3-methyl-4-chromenonehydrochloride.

<2-Amino-endo-6,9-ethanocyclocyclo [4.4.0] deck-7-enone hydrochloride (70)>

This amine hydrochloride was prepared as shown in Method 15.

Aluminum chloride (700 mg, 5.2 mmol) was added to a solution of 2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (100 ml). After 40 minutes cyclohexadiene (8.3 g, 104 mmol) was added and heated to 100 ° C. for 2 hours.

Upon cooling, the mixture was diluted with Et ₂ O (300 ml) and washed with saturated NaHCO ₃ (2 × 150 ml) and brine (100 ml).

The combined organic layer was dried over MgSO ₄ , filtered and concentrated.

The residue was purified by flash chromatography using 50: 1 hexanes-Et ₂ O as eluent to give endo-2,5-ethanocyclo [4.4.0] dec-7-en-10-one (67) ( 2.77 g), which was pure by ¹ H-NMR and GC / MS.

A solution of endo-2,5-ethanocyclo [4.4.0] dec-7-en-10-one (67) (2.17 g, 12.3 mmol) in THF (20 ml) was dissolved in THF (30 ml). (6.7 ml, 2.0 M in THF, 13.5 mmol) was added to the dissolved -78 ° C solution.

After 45 minutes, trimethylsilyl chromide (2.0 g, 18.5 mmol) was added and the mixture was slowly warmed to 0 ° C. The mixture was diluted with saturated NaHCO ₃ solution (30 ml) and extracted with Et ₂ O (2 × 30 ml), dried (MgSO ₄ ) and concentrated. The residue was dissolved in THF (60 ml) and N-bromosuccinimide (2.6 g, 14.7 mmol) was added.

After 30 minutes, the mixture was diluted with saturated NH ₄ Cl solution (30 ml) and extracted with Et ₂ O ( ₂ × 40 ml). The combined organic layer was dried (MgSO ₄ ) and concentrated. Purify the residue by flash chromatography using 33: 1 hexanes-Et ₂ O as eluent to give the pale yellow oil, 2-bromo-endo-6,9-ethanocyclo [4.4.0] dec-7-enone. (68) (1.44 g) was obtained and purified by ¹ H-NMR and GC / MS.

Sodium azide (280 mg, in a solution of 2-bromo-endo-6,9-ethanocyclocyclo [4.4.0] deck-7-enone (68) (850 g, 3.9 mmol) dissolved in DMF (20 ml) 4.3 mmol) was added.

After 2 h the mixture was diluted with water (30 ml) and extracted with Et ₂ O ( ₂ × 40 ml).

The combined organic layer was dried (MgSO ₄ ) and concentrated. Purify the residue by flash chromatography using 20: 1 hexanes: Et ₂ O as eluent to afford 2-azido-endo-6,9-ethanocyclo [4.4.0] dec-7-enone (oil phase). 69) (469 mg) was obtained by ¹ H-NMR.

Triphenylphosphine (486 mg) in a solution of 2-azido-endo-6,9-ethanocyclo [4.4.0] dec-7-enone (69) (310 mg, 1.42 mmol) dissolved in THF (10 ml). , 1.85 mmol) was added. After stirring for 12 hours, the mixture was diluted with 6N HCl (10 ml) and layered. The organic phase was extracted with 6N HCl (2 × 5 ml) and the combined aqueous layers were concentrated to give compound 70, which is required as a dark orange oil (500 mg) and its ¹ H-NMR (DMSO-d ₆ ) is consistent with the given structure.

<Isopropyl endo-2-aminonorbornan-5-carboxylate (71) and

 Isopropyl endo-2-aminonorbornane-6-carboxylate (72)>

These amines are prepared in the same manner as described above (see Method 9).

Prepared from isopropyl norborn-2-ene-5-carboxylate.

General procedure for reductive amination of ketones to amines

Ketone (1 mmol), ammonium acetate (20 mmol) and 3A molecular sieves (2.8 equiv., Weight) were mixed with dry methanol in a dry flask under nitrogen atmosphere. Sodium cyanoborohydride (4 mmol) was added and the resulting mixture was stirred at room temperature until the starting ketone disappeared as indicated by TLC analysis. Methanol was separated from the reaction mixture under vacuum and the residue was dissolved in 6N HCl. After stirring for 15 minutes, the non-basic substance was extracted and removed with diethyl ether. The pH of the aqueous phase was raised to 8 using 50% aqueous NaOH solution, and the amine was extracted with EtOAc (3 times). The EtOAc extracts were combined, brine, dried (Na ₂ SO ₄ ), filtered and concentrated to The corresponding amine was obtained.

Crude amine was pure in its entirety and used without further purification.

<General procedure for BOC-protection of amines.>

Triethylsilane (0.5 ml) and trifluoroacetic acid (1 ml) were added to an ice-cooled solution in which BOC-protected amine (1 mmol) was dissolved in dry CH ₂ Cl ₂ (1 ml).

Reaction progress was monitored with a decrease in starting material. (5 min to 1.5 h) The reaction mixture was diluted with toluene and concentrated.

The residue was dissolved in water (10 ml) and EtOAc (20 ml), the pH adjusted to 8 and the organic phase separated.

The aqueous phase was extracted with EtOAc (2x15 ml).

The organic phases were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give an amine.

Preparation of Amine 73 and 74

These amines were prepared from the corresponding known ketodilactones (J. Org. Chem. 1998, 63, 9889-94) through the standard reductive amination conditions described above.

¹ H, ¹³ C NMR and IR spectrum analysis were consistent with the given structure.

Preparation of Amine 77 and 78

The preparation of these amines is shown in Method 16 above.

Macrodilactone 75 is J. Org. Chem. Prepared according to the procedure of 1998, 63, 9889-94.

Nt-BOC-aspartic acid (2.33 g) was mixed with 2-chloromethyl-3-chloropropane (1.25 g) and Cs ₂ CO ₃ (7.0 g) in DMF (100 ml) under the standard macrolactoneization conditions described above. Reaction gave 1.12 g (40% yield) of the said compound 75 which is a glassy solid.

Mass spectrum (EI-) results (m / e) showed [M-1] + at 284 and the ¹ H, ¹³ CNMR and IR spectra results were consistent with the structure of 75.

To a solution of the alkene 75 (288 mg, 1.01 mmol) in anhydrous EtOAc (6 ml) was added 10% Pd / carbon (60 mg).

The resulting mixture was nitrogen purged and stirred for 2.5 h under 45 psi hydrogen pressure in a Parr hydrogenator.

The reaction mixture was purged with nitrogen, filtered and concentrated.

Purification by flash column chromatography (silica gel, 7: 3 hexanes-EtOAc mixtures) gave 91 mg (32% yield) of the reduced product 76.

¹ H, ¹³ C-NMR and IR spectrum analysis were consistent with the structure 76.

Amine 77 and 78 were obtained by removing BOC protecting groups from compounds 75 and 76 according to the general BOC-deprotection procedure described above.                 

¹ H, ¹³ C-NMR and IR spectrum analysis were consistent with the given structure.

<Synthesis of Phenyldilactone 81>

The preparation of this compound is shown in Method 17 above.

BOC-serinol (Synthesis 1998, 1113) under nitrogen atmosphere in a well stirred solution at 0 ° C. in which phenylsuccinic acid (0.922 g, 5.2 mmol) and DMAP (0.064 g, 0.52 mmol) were dissolved in anhydrous CH ₂ Cl ₂ (55 ml). -1118) (1.0 g, 5.2 mmol) was added to the solution over 30 minutes. The resulting mixture was slowly warmed to room temperature, stirred for another 12 hours, diluted with CH ₂ Cl ₂ (40 ml) and extracted with saturated aqueous sodium bicarbonate solution (3 × 10 ml).

The basic extracts were combined, carefully acidified with 2N HCl and extracted with EtOAc (3 × 20 ml).

The combined EtOAc extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give a white foam (1.7 g).

¹ H-NMR showed a 1: 1 diasteremic mixture of acid 79.

Diethyl azodicarboxylate (0.52 g) in THF (55 ml) in a well stirred ice cold suspension in which acid 79 (1.00 g, 2.72 mmol) and triphenylphosphine (786 mg, 3.0 mmol) were added to anhydrous THF (122 ml). , 3.0 mmol) was dissolved in a solution added over 3 hours.

As a result, the mixture was slowly warmed to room temperature, stirred for another 5 hours, and then concentrated to 5 ml. The residual mixture was diluted with EtOAc (50 ml) and water (20 ml). The organic phase was separated, washed with aqueous NaHCO ₃ (10 ml) and brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give an oily residue.

Flash chromatography gave (silica gel, hexane) to give 228 mg (22% yield) of a 1: 1 mixture of dilactone 80 with mp = 161-162 ° C.

Mass spectrum (EI) results showed M + at m / c 349.                 

The amine 81 was obtained by removing the BOC protecting group under the standard BOC deprotection conditions described above.

<Synthesis of dilactone amines 84 and 85>

The preparation of these compounds is shown in Method 18.

N-CBz aspartic anhydride (3.52) in a stirring solution in which cerinol (3.0 g, 15.7 mmol), pyridine (1.24 g, 0.98 mol) and DMAP (0.19 g, 1.57 mmol) were dissolved in anhydrous CH ₂ Cl ₂ (140 ml). g, 14.13 mmol) was added to the solution dissolved in anhydrous THF (20 ml).

After stirring for 2 hours at room temperature, the reaction mixture was concentrated to about 10 ml volume and diluted with EtOAc (100 ml) and water (30 ml).

The pH was adjusted to 8.5 (NaHCO ₃ aqueous solution) and the aqueous phase was separated, acidified to pH 3 with 2N HCl and extracted with EtOAc (3 × 20 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 5.8 g of compound 82 as a foamy white substance.

¹ H-NMR showed very pure and contained diastereomeric mixtures.

The acid 82 (5.5 g, 12.5) in a solution in which triphenyl phosphine (3.6 g, 13.75 mmol) and 1,3-diisopropylcarbodiimide (2.8 g, 13.75 mmol) were dissolved in anhydrous THF (1.15 L). mmol) was added to the solution dissolved in anhydrous THF (100 ml) over 3 hours.

The resulting mixture was stirred for another 6 h, concentrated in vacuo to about 20 ml and diluted as ether (200 ml) and water (100 ml).

The organic phase was separated, washed with 5% aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo.

Flash column chromatography of the residue on the oil gave 1.3 g (23% yield) of the required dilactone 83.

The mass spectrum (ES−) showed m / e 421 (M-1) +.

¹ H, ¹³ C-NMR and IR spectra were consistent with structure 83.

Dilactone 83 was deprotected under standard BOC deprotection conditions to afford amine 84.

10% Pd / C (40 mg) was added to a solution of N-CBz-protected dilactone 83 (200 mg, 0.47 mmol) in EtOAc (10 ml), and the resulting mixture was stirred under hydrogen gas pressure for 12 hours. The reaction mixture was purged with N _2, filtered through a calcined glass panel and concentrated to give amine 85 (126 mg). The crude amine was used without further purification.

Preparation of Amine 86 and 88

Synthesis of 2,6,6, -trimethyl-2,4-cycloheptadienylamine (86) and 2,3,6,6-tetramethyl-3-cycloheptenone (87), precursors to amine 88 This is shown in Method 19 above.

Eucarvone (Can. J. Chem. 1974, 52, 1352) can be readily matched using the titanium isopropoxide / NaBH ₄ / Et ₃ N-mediated reductive amination procedure described in Synlett 1999, 1781. Was converted to amine 86.

Using the procedure described in Tetrahedron 1995, 51, 743-754, Cu (I) -catalyzed Michael addition of trimethyl aluminum to milk carbon resulted in 2,3,5,5-tetramethyl-3-cycloheptenone ( 87).

This was again converted to 2,3,5,5-tetramethyl-2-cycloheptenylamine 88 according to the procedure described in WO 9927783.

<N-methyl-N- (2- (phenylethyl)-(1,5,5-trimethyl-3-aminocyclohexyl) carbamide (89)>

1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (MSZiegler and RM Herbst, J. Org. Chem. 1951, 16, 920) was subjected to N using standard HOAt, EDCI and DMAP-mediated binding conditions. -Methyl-2-phenylethylamine was bonded to give [N-methyl-N- (2-phenylethyl)]-1,5,5-trimethyl-3-oxo-1-cyclohexylcaroxamide as light yellow oil. .

The mass spectrum showed moieties at m / e 301.

¹ H and ¹³ C-NMR spectra were consistent with this structure.

Ni의 존재하에 수소화시켜 이 케톤으로부터 아민 89를 제조하였다. 아민의 ¹H-NMR은 1:1 부분입체 이성질체 혼합물을 나타내었다.
Conversion to the corresponding N-hydroxyoxime according to the general procedure of WO9927783 and Raney

Amine 89 was prepared from this ketone by hydrogenation in the presence of Ni. ¹ H-NMR of the amine showed a 1: 1 diastereomeric mixture.

<3- (3,3-dimethylbutoxycarbonyl) -3,5,5, -trimethylcyclohexylamine (90)>

1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (3.0 g) (MS Ziegler and RM Herbst, J. Org. Chem. 1951, 16, 920) was added to CH ₂ Cl ₂ ( 3- (3,3-dimethylbutoxycarbo) treated with 3,3-dimethylpentanol (1.84 g), DMAP (2.21 g) and 1,3-diisopropyl carbodiimide (2.17 g) in 80 ml) 2.41 g (55% yield) of 3,5,5-trimethylcyclohexanone was obtained. The mass spectrum (EI) showed a parention at m / e 268.

Ni의 존재하에 수소화하여 아민 90으로 변환시켰다.After converting this canton into the corresponding oxime according to the general procedure of WO9927783, Raney

Hydrogenation in the presence of Ni was converted to amine 90.

<4- (4,6-bis) trifluoromethyl-2-pyridyl) oxy-3,3,5,5, -tetramethylcyclohexylamine (93)>

The synthesis of this amine is shown in Method 20 above.

4-hydroxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethyleneglycol acetal (900 mg, 4.2 mmol) was dissolved in anhydrous DMF (8.4 ml) and the mixture was cooled to 0 ° C 35% (wt) oil suspension of KH (591 mg, 5.04 mmol) was added.

After stirring the mixture for 1 hour, a solution of 2-chloro-4,6-bis-trifluoromethyl-2-pyridine (1.48 g, 6.3 mmol) dissolved in DMF (2 ml) was titrated. The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 12 hours and carefully quenched with ammonium chloride. Diethyl ether (100 ml) was added and the phases were separated, washed with brine, dried (MgSO ₄ ) and concentrated to give a dark brown solid.

Recrystallized from hot hexane to give 4- (4,6-bis-trifluoromethyl-2-pyridyl) oxy-3,3,5,5, -tetramethylcyclohexyl-1,1-ethylene glycol acetal ( 91) (mp = 105-106 degreeC) were obtained.

The acetal 91 (900 mg) was dissolved in a 1: 1: 1 mixture (30 ml) of THF, dioxane and 2N HCl, and as a result, GC showed complete disappearance of starting material when the solution was stirred at room temperature for 12 hours. It was. The mixture was diluted with water and diethyl ether (50 ml each), the organic phase was separated, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give an oily residue.

This residue was chromatographed on silica gel (hexane-EtOAc, 5: 1) to give 712 mg (96% yield) of colorless oil ketone 92. The mass spectrum (EI) showed a moion m / e of 383.

92 was prepared as amine 93 by reductive amination according to the general procedure of WO 9927783.

<3- (2,3-Dichloropropyloxy) methyl-3,5,5, -trimethylcyclohexylamine (97)>

The synthesis of amine 97 is shown in Method 21 above.

Tetrahedron Lett. The acetal 95 was obtained by dichloroating the alkene 94 following the procedure of 1991, 32, 1831-4.

The acetal (500 mg) was dissolved in a 1: 1 mixture of THF and 2N HCl, and the result was stirred for 1 hour at room temperature, at which time TLC showed no starting material.

The mixture was diluted with EtOAc and water (30 ml each), the orange phase was separated, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 383 mg of ketone 96 as an oil.

¹ H-NMR was consistent with the diastereomeric mixture of isomers.

Amine 97 was obtained by reductive amination according to the standard procedure described above.

<3-benzoyl-3,5,5-trimethylcyclohexylamine (100)>

The preparation of this amine is shown in Method 22 above.

After reacting 3-cyano-3,5,5, -tetramethylcyclohexyl-1,1-ethylene glycol acetal (98) (WO9927783) with phenyllithium, the acid was hydrolyzed to obtain ketone 99. According to the method was converted into amino ketone (100).

<5β- (2-phenylethyl) -3β-methoxy-4β-methyl-4-nitro-cyclohexylamine (105)>

The preparation of amine 105 is shown in Method 23 above.

Nitroethane was condensed with dihydrocinnamaldehyde according to the procedures of Bull.Chem.Soc.Jap.1968, 41, 1441 to afford the corresponding nitroalcohol 101.

Compound 101 was dehydrated following the procedure of Synthesis, 1982, 1017 and then polymer-supported triphenylphosphine-mediated isomerization (Tetrahedron Lett. 1998, 39, 811-812) to obtain alkene 103.

Tetrahedron Lett. Compound 103 was subjected to Diels-Alder cycloaddition with a diene of Danishefsky following the procedure of 2000, 41, 1717 to obtain ketone 104.                 

The ketone 104 was converted to amine 105 according to the standard procedure of WO 9927783.

<3-cyano-3,5,5-trimethylcyclohexylamine (106)>

This compound was prepared by reductive amination of 3-cyano-3,5,5-trimethylcyclohexanone according to the standard reductive amination procedure described above (Method 24).

The mass spectrum (EI) showed a parent ion of m / e of 167.

<3-amino-5-phenylthiopyran (107)>

This compound was prepared as shown in Method 25, above.

7.7 g (100 mmol) of ammonium acetate in 0.96 g (5 mmol) of 5-phenyl-3-thiopyranone (PTLansbury, et al., J. Am. Chem. Soc. 1970, 92, 5649) dissolved in 50 ml of anhydrous methanol. And 6.5 g of 3A molecular sieve.

After stirring for 30 minutes at room temperature, sodium cyanoborohydride 1.25 g (20 mmol) was added in portions.

After stirring for 16 hours, the mixture was gravity filtered and the methanol was evaporated under vacuum. The residue was partitioned between ice / HCl and ether.

The acidic aqueous phase was extracted twice with ether and then basified with ice and 50% aqueous NaOH solution.

The mixture was extracted with CH ₂ Cl ₂ , dried (MgSO ₄ ) and evaporated to afford 0.19 g (20%) of the desired compound.

GC / MS showed 100% purity with a molecular ion of 193.

<4- (4-Trifluoromethyl) phenoxy cyclohexylamine (109)>

This compound was prepared according to Method 26.

A solution of 1,4-dioxaspiro [4,5] decane-8-ol (7.5 g, 0.047 mol) dissolved in 15 ml of DMF in a stirring solution in which sodium hydride (1.2 g, 0.05 mol) was dissolved in 50 ml of DMF. Titration was added over 10 minutes.

The mixture was stirred at ambient temperature for 30 minutes, 4-fluorobenzotrifluoride (7.71 g, 0.047 mol) was added in one portion and the reaction was stirred at room temperature for 2 hours and at 70 ° C. overnight. The reaction mixture was poured into cold water (700 ml) and 1N HCl was added to make the solution slightly acidic. The mixture was filtered and the aqueous filtrate was extracted with hexane (2x150 ml).

The filtered solid was dissolved in hexane extract and washed with water (50 ml).

The solution was dried over MgSO ₄ , filtered and concentrated to give a white solid. This solid was recrystallized from methanol / water to give pure ketal (8.6 g, 61%).

Silica gel (30 g) was suspended in 150 ml of CH ₂ Cl ₂ .

To this suspension was added 7 ml of a 12% HCl solution dissolved in water over 5 minutes. The mixture was stirred vigorously to prevent crowding. To 75 ml of CH ₂ Cl ₂ was added a solution of the ketal (8.0 g, 26.49 mmol) and the reaction was stirred for 3 hours. The mixture was then filtered and the silica gel pad washed with 500 ml CH ₂ Cl ₂ .

The solvent was evaporated to give 5.8 g (86%) of 4- (4-trifluorophenoxy) cyclohexanone (108).

According to the standard reduction amination method described above, ketone 108 was reduced amination to obtain compound 109.

<4-benzoyloxy-3,3,5,5-tetramethylcyclohexylamine (111)>

This compound was prepared according to the procedure of Method 27.

To a stirred solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro [4,5] decane-8-ol (0.37 g, 1.73 mmol) dissolved in 6 ml of THF cooled to 0 ° C. n-BuLi (2.5M in hexanes, 1.73mmol, 0.7ml) was titrated.

The reaction was stirred for 10 minutes. After adding benzoyl chloride (1.73 mmol, 0.2 ml), the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was attached to 50 ml of 0.5 N NaOH and extracted with ether (3 × 20 ml).

The ether layer was dried over MgSO ₄ , filtered and concentrated.

The residue was purified by radial chromatography using 4: 1 hexane-EtOAc as eluent. The result was 0.55 g (up to 100%) of benzoyloxyketal.

Silica gel (2.2 g) was suspended in 10 ml of CH ₂ Cl ₂ .

To this suspension was added 0.5 ml of a 12% aqueous HCl solution over 5 minutes. The mixture was stirred vigorously to prevent crowding.

A solution of the benzoyloxy ketal dissolved in 5 ml CH ₂ Cl ₂ was added and the reaction stirred for 3 hours. The mixture was then filtered and the silica gel pad was washed with 100 ml CH ₂ Cl ₂ .

The solvent was evaporated to obtain 0.46 g (90%) of benzoyloxycyclohexanone 110 as a transparent oil.

Hydroxylamine hydrochloride (0.23 g, 3.25 mmol) and potassium acetate (0.32 g, 3.25 mmol) were dissolved in 4 ml of water in a stirred solution in which benzoyl oxycyclohexanone 110 (0.46 g, 1.68 mmol) was dissolved in 4 ml of methanol. The solution was added at once. The reaction was stirred overnight at room temperature. Water (20 ml) was added and the resulting mixture was extracted with ether (3 × 10 ml). The ether extracts were combined and washed with saturated NaHCO ₃ (1 × 20 ml) and brine (1 × 15 ml). The ether layer was dried over MgSO ₄ , filtered and concentrated to afford the desired oxime (0.39 g, 80%) as a mixture of E and Z isomers.

니켈(0.8g 습윤중량, Aldrich Chemical Co.)을 물 (3x20ml)로 세척한 후 에탄올(3x20ml)로 세척하였으며, 그 세척용매는 매번 따뤘다.Raney in 500ml Parr Pressure Bottle

Nickel (0.8 g wet weight, Aldrich Chemical Co.) was washed with water (3x20ml) followed by ethanol (3x20ml), the washing solvent followed every time.

To this washed catalyst was added a solution of oxime (0.39 g, 1.35 mmol) dissolved in anhydrous ethanol (30 ml).

Heating of the solution was required for dissolution.

As a result, the mixture was saturated with ammonia by bubbling ammonia gas through the solution. This solution was placed on a Parr shaker under hydrogen atmosphere (initial hydrogen pressure = 50 psi) and shaken for 7 hours.

패드를 통해 여과하였으며 용매를 증발시켜 거의 무색인액체(0.37g, 정량수율)를 얻었다.The reaction mixture was Celite

Filtration through the pad and evaporation of the solvent gave a nearly colorless liquid (0.37 g, quantitative yield).

Quantum NMR and GC / MS were consistent with this material, which was a diastereomeric (4: 1 ratio) mixture of amines 111. This material was used as is without further purification.

<4-Amino-2,2,6,6-tetramethylcyclohexyl-6-chloro-2-pyridinecarboxylate (113)>

This compound was synthesized as shown in Method 28.

N in a stirred solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro [4,5] decane-8-ol (0.32 g, 1.50 mmol) dissolved in 5 ml of THF cooled to 0 ° C. -BuLi (2.5 M, 1.50 mmol, 0.6 ml in hexene) was titrated.

The mixture was stirred for 10 minutes.

6-chloropicolinoyl chloride (1.50 mmol, 0.26 g) was then added as a solution in 1 ml THF and the reaction was allowed to warm to room temperature. The solution was solidified, 5 ml of THF was added and the reaction stirred overnight. The reaction mixture was poured into 0.5N NaOH and extracted with ether (3x20ml).

The ether layer was dried over MgSO ₄ , filtered and concentrated. Quantum NMR showed a 1.6: 1 ratio of product with starting material.

These compounds could not be separated by silica gel chromatography, so the mixture was continued to the next step and purified there.

Silica gel (1.4 g) was suspended in 10 ml of CH ₂ Cl ₂ .

0.3 ml of 12% aqueous HCl solution was added to the suspension over 5 minutes. The mixture was stirred vigorously to prevent crowding. A solution of the mixture dissolved in 5 ml CH ₂ Cl ₂ was added and the mixture was stirred for 3 hours.

The mixture was then filtered and the silica gel pad was washed with 100 ml CH ₂ Cl ₂ .

The solvent was evaporated to give an oil.

10 ml of a 4: 1 hexane-EtOAc solution was added to precipitate the required picoline ester 112.

The resulting solid was filtered and washed with 10 ml 4: 1 hexane-EtOAc. The hexane-EtOAc washes were combined and evaporated to give an oil.

This procedure was repeated three times to give picolin ester 112 as a white solid (214 mg, 46% for step 2).                 

Quantum NMR and GC / MS results showed the required purity of 95% or more.

This ester (200 mg, 0.65 mmol), titanium (IV) isopropoxide (1.30 mmol, 0.38 ml), ammonium chloride (1.30 mmol, 70 mg) and triethylamine (1.30 mmol, 0.18 ml) were pure ethanol (10 ml). The mixture was then stirred under nitrogen atmosphere for 12 hours at ambient temperature.

Sodium borohydride (0.97 mmol, 40 mg) was then added and the resultant mixture was stirred for an additional 8 hours at ambient temperature.

The reaction was then poured into ammonia water (20 ml, 2.0 M) and quenched, resulting in extraction of the solution with ether (3 × 20 ml).

The combined ether extracts were extracted with 2N HCl (2 × 20 ml) to separate non-basic materials. The acidic solution was washed once with ether (20 ml) and then treated with NaOH (2N) to adjust the pH to 10-12 and extracted with EtOAc (3 × 20 ml).

The combined EtOAc washes were dried over MgSO ₄ , filtered and concentrated to an oil.

This material was consistent with the 6: 1 diastereomeric mixture of the desired cyclohexylamine.

Quantum NMR and GC / MS showed the desired product with 75% purity.

This amine mixture was used without further purification.

<Trans-2-thiomethylcyclohexylamine>

This amine is B.M. Trost and T. Shibata, J. Am. Chem. Soc. Prepared from cyclohexane using the azasulphenylation technique of 1982, 104, 3225.

<4-phenylthiocyclohexylamine (115)>

This compound was prepared according to the procedure shown in Method 29 above.

Benzyloxyamine hydro dissolved in 20 ml of water in a stirring solution of 4-phenylthiocyclohexanone (VKYadav and DA Jeyaraj, J. Org. Chem. 1998, 63, 3474) (1.20 g, 5.83 mmol) dissolved in 20 ml of methanol. Chloride (1.80 g, 11.22 mmol) and potassium acetate (1.10 g, 11.22 mmol) solutions were added in one portion. The reaction was stirred overnight at room temperature. Water (60 ml) was added and the resulting mixture was extracted with ether (3 × 40 ml). The ether extracts were combined and washed with saturated NaHCO ₃ (1 × 50 ml) and brine (1 × 40 ml).

The ether layer was dried over MgSO ₄ , filtered and concentrated to an oil.

This material was purified by radial chromatography (9: 1 hexanes- EtOAc) to give the corresponding 0-benzyloxime 114 (1.72 g, 95%) as a mixture of E and Z isomers.

Lithium aluminum hydride (5.08 mmol, 0.19 g) was suspended in 10 ml of anhydrous ether and cooled to 0 ° C.

0-benzyloxime 114 dissolved in 5 ml of ether was titrated and the reaction was allowed to come to room temperature and stirred for 4 hours.

Excess lithium aluminum hydride was neutralized by careful simultaneous addition of water (0.2 ml) and 1N NaOH (0.2 ml).

The mixture was filtered and the salt washed with 50 ml of ether.

The solvent was evaporated to yield 0.62 g (93%) of amine 115 as an oily phase.

Quantum NMR and GC / MS results indicate that the product is a 1.3: 1 mixture of diastereomeric amines with a purity of at least 95%.

<3-{[3- (trifluoromethyl) -2-pyridinyl] sulfanyl} -cyclohexylamine (117)>

This amine was prepared according to the method shown in Method 30 above.

Bismuth tree in a stirring solution in which 2-cyclohexen-1-one (0.44 ml, 4.58 mmol) and 2-merkato-5-trifluoromethylpyridine (0.82 g, 4.58 mmol) were dissolved in 20 ml CH ₂ Cl ₂ . Chloride (60 mg, 0.18 mmol) was added.

The reaction was stirred at rt overnight and concentrated. The residue was purified by radial chromatography using 4: 1 hexene-EtOAc as eluent to yield 1.12 g (89) of the conjugate adduct 2- (3-oxo-cyclohexylthio) -5-trifluoromethylpyridine (116) %) Was obtained.

A solution of benzyloxyamine hydrochloride (0.29 g, 1.83 mmol) and potassium acetate (0.18 g, 1.83 mmol) in 3 ml of water was added to a stirred solution in which Compound 116 (0.26 g, 0.95 mmol) was dissolved in 3 ml of methanol. Added.

The reaction was stirred at rt overnight.

Water (10 ml) was added and the resulting mixture was extracted with ether (3 × 10 ml). The ether extracts were combined and washed with saturated NaHCO ₃ (1 × 15 ml) and brine (1 × 15 ml).

The ether layer was dried over MgSO ₄ , filtered and concentrated to an oil.

This material was radial chromatographed (9: 1 hexane-EtOAc) to give isolated oxime (0.32 g, 89%).

E-isomers (Rf = 0.33) and Z-isomers (Rf = 0.25) showed consistent quantum NMR and GC / MS spectrum characteristics.

Lithium aluminum hydride (1.33 mmol, 50 mg) was suspended in 3 ml of anhydrous ether and cooled to 0 ° C. The combined oximes were dissolved in 1 ml of ether and titrated.                 

The reaction was allowed to come to room temperature and stirred for 4 hours.

Excess lithium aluminum hydride was neutralized by the simultaneous addition of water (50 ml) and 1N NaOH (50 ml).

The mixture was filtered and the salt washed with ether to 100 ml volume.

The non-basics were separated by extracting the ether solution with 2N HCl (2 × 50 ml). The acidic aqueous solution was washed once with ether (50 ml) and treated with aqueous NaOH (2M) solution to obtain a pH of 10-12 and extracted with ether (3 × 50 ml).

The ether layer was dried over MgSO ₄ , filtered and concentrated to give 121 mg (52%) of the desired amine 117 in oil.

Quantum NMR and GC / MS results showed that the product had a 1.3: 1 ratio of diasteric amine with a purity of at least 95%.

<1- (5-Amino-1,2,3-trimethylcyclohexyl) -4-phenyl-1-butanone (120)>

Synthesis of this amine was carried out by the method of Method 31 above.

A suspension suspended in 10 ml THF with naphthalene (1.23 g, 9.57 mmol) and lithium granules (67 mg, 9.57 mmol) was stirred overnight at ambient temperature.

This lithium naphthalide solution was cooled to -60 ° C and phenyl 3-phenylpropyl sulfide (1.1 g, 4.78 mmol) was added.

The reaction was heated to -20 ° C to complete the reaction and recooled to -60 ° C.

A solution of 7-cyano-7,9,9-trimethyl-1,4-dioxaspiro [4.5] decane (0.5 g, 2.39 mmol) dissolved in 5 ml THF is added and the solution is warmed to 0 ° C. It stirred at that temperature for 2 hours.

10 ml of saturated ammonium chloride solution was added and then treated with 2N HCl to adjust the pH to 4 and stirred overnight at room temperature.

The mixture was extracted with ether (3 × 30 ml), dried over MgSO ₄ , filtered and evaporated. The residue was purified by radial chromatography using 6: 1 hexanes-EtOAc as eluent. This was obtained with 3- (2-oxo-4-phenylbutyl) -3,5,5-trimethylcyclohexanone 118 (136 mg, Rf = 0.18) and its ketal as an incomplete hydrolysis product (509 mg, Rf = 0.33). It was a 1: 3 mixture of and the total product to add 1-rithio-3-phenylpropane to the nitrile was calculated to be 85%.

Silica gel (1.82 g) was suspended in 10 ml of CH ₂ Cl ₂ .

0.41 ml of an aqueous 12% HCl solution was added to the suspension over 5 minutes. The mixture was stirred vigorously to prevent crowding. The ketal solution dissolved in ₂ ml CH ₂ Cl ₂ was added and the silica gel pad was washed with 50 ml CH ₂ Cl ₂ .

0.48 g (100%) of 3- (1-oxo-4-phenylbutyl) -3,5,5, -trimethylcyclohexanone (118) as evaporated solvent, consistent with its NMR and GC / MS properties as transparent oil. Got.

This bis-ketone (0.62 g, 2.17 mmol) dissolved in 7 ml of methanol was dissolved in hydroxylamine hydrochloride (0.16 g, 2.28 mmol) and sodium acetate (0.25 g, 3.03 mmol) in 7 ml of water. Was added at once. The reaction was stirred at rt for 1 h, water (20 ml) was added and the resulting mixture was extracted with ether (3 × 20 ml). The ether extracts were combined and washed with saturated NaHCO ₃ (1 × 20 ml) and brine (1 × 20 ml). The ether layer was dried over MgSO ₄ , filtered and concentrated to afford the desired mono-oxime 119 (0.57 g, 87%) as a mixture of E and Z isomers.

니켈(0.8g, 습윤중량, Aldrich Chemical Co.)을 물 (3x20ml)로 세척한 후, 에탄올(3x 20ml)로 세척하고, 세척용매는 매번 따뤄 내었다.Raney in 500ml Parr pressure vessel

Nickel (0.8 g, wet weight, Aldrich Chemical Co.) was washed with water (3x20ml), followed by ethanol (3x20ml) and the washing solvent was decanted each time.

To this washed catalyst was added a solution of oxime 119 (0.57 g, 1.89 mmol) dissolved in anhydrous ethanol (40 ml).

As a result, the mixture was saturated with ammonia by bubbling ammonia gas through the solution for 1 minute.                 

The solution was placed on a Parr shaker under hydrogen atmosphere (initial hydrogen pressure = 50 psi) and shaken (shaking) for 7 hours.

패드로 여과하고 용매증발시켜 오일(0.43g, 80%)을 얻었다.The reaction mixture is then Celite

Filtration with a pad and solvent evaporation gave an oil (0.43 g, 80%).

GC / MS analysis showed a 1: 1 diastereomeric mixture of amine 120 with a small amount of unidentified by-products.

This amine mixture was used as is without further purification.

<2-benzyl-6-methyl-4-pyranylamine (122)>

This amine was prepared according to Method 32 above.

0.22 g (3.1 mmol) of hydroxylamine hydrochloride and 0.16 g of sodium acetate in 10 ml of methanol in 0.37 g of 2-benzyl-6-methyl-4-pyranone (G.Piancatilli, et al., Synthesis, 1982, 248) (2 mmol) was added.

After stirring overnight, the mixture was separated with CH ₂ Cl ₂ and water.

The organic phase was dried and evaporated. The oily residue was left at room temperature to solidify to give the desired oxime 121-0.4 g (99%) identified as Z / E isomer 1: 1 mixture by GC / MS with a molecular ion of 219.

니켈 0.8g(습윤중량)을 첨가하였다. 이 혼합물을 Parr 세이커내에서 41 psig 수소대기하에 32시간동안 방치하였다.Raney washed three times with water and three times with ethanol in 0.4 g of 2-benzyl-6-methyl-4-pyranone oxime (121) (1.8 mmol) dissolved in 50 ml of 95% ethanol.

0.8 g nickel (wet weight) was added. This mixture was left in a Parr shaker for 32 hours under 41 psig hydrogen atmosphere.

After ventilation, the mixture was gravity filtered and evaporated in vacuo. The residue was separated by CH ₂ Cl ₂ and sodium carbonate aqueous solution.

The organic phase was dried and evaporated in vacuo to give 0.19 g of a mixture of the desired amine 122 and oxime 121 in a 2: 1 (GC / MS analysis) mixture.

This mixture was used as is without further separation.

<1-benzoyl-4-aminopiperidine>

This compound was prepared according to the method of Bhattacharyya, et al., SynLett, 1999, 11, 1781.

<1- (4-Methylbenzyl) -4-piperidinylamine (125)>

This compound was synthesized according to Method 33 above.

To dissolve 5.05 g (50 mmol) of 4-hydroxypiperidine and 7.08 g (50 mmol) of P-methylbenzylchloride in tert-butanol was added an excess of solid potassium carbonate, and the mixture was heated in a steam bath for 3 hours. .

The mixture was cooled to rt and separated into ether and water.

The organic phase was extracted with cooled dilute HCl and the acidic aqueous phase was extracted twice with ether.

The aqueous phase was basified with ice and 50% aqueous NaOH solution and then extracted with ether.

The ether phase was washed with dilute sodium bicarbonate solution, brine, dried and evaporated in vacuo to give 5.3 g (52%) (123) of 1- (4-methylbenzyl) -4-hydroxy piperidine in oil phase. Got it. GC / MS showed 100% purity with molecular ion 205.

To a solution of 2.8 ml (32 mmol) of oxalyl chloride in 75 ml of CH ₂ Cl ₂ was added 4.6 ml (64 mmol) of DMSO at 78 ° C.

To this mixture was added a solution of 5.3 g (26 mmol) of 1- (4-methylbenzyl) -4-pipyridinol 123 dissolved in 10 ml of CH ₂ Cl ₂ , and the mixture was stirred at low temperature for 5 hours.

The mixture was quenched with 18 ml (129 mmol) of triethylamine and brought to room temperature and saturated aqueous ammonium chloride solution was added. The organic phase was washed with water and brine, dried and evaporated to afford 4.27 g (81%) of 1- (4-methylbenzyl) -4-piperidinone (124), which was used as such without further purification.

GC / MS showed 100% purity with a molecular ion of 203.

To the solution of 4.25 g (21 mmol) of 1- (4-methylbenzyl) -4-piperidinone 124 in 200 ml of anhydrous methanol, 32.2 g (420 mmol) of ammonium acetate and 25 g of 3A molecular sieve were added.

After stirring for 30 minutes, 5.25 g (84 mmol) of sodium cyanoborohydride were added in portions.

After stirring for 16 hours, the mixture was gravity filtered and the methanol was evaporated under vacuum. The residue was separated by ether and ice / HCl.

The acidic aqueous layer was extracted twice with ether, basified with 50% aqueous NaOH solution and ice, and extracted with CH ₂ Cl ₂ to give 2.1 g (48%) of a thick oily amine 125.

GC / MS showed molecular ion 204. The product was used as is without further purification.

<1- (3-Trifluoromethylbenzyl) -4-piperidinylamine (127)>

Prepared according to Method 34.

0.8 g (3.1 mmol) of 1- (3-trifluoromethylbenzyl) -4-piperidone [prepared in the same manner as in 1- (4-methylbenzyl) -4-piperidinone) 123 in 7 ml of pyridine To this was dissolved 0.22 g (3.1 mmol) of hydroxylamine hydrochloride and the mixture was stirred overnight.

The mixture was evaporated in vacuo and the residue partitioned between ether and dilute sodium bicarbonate aqueous solution.

The organic phase was dried and evaporated in vacuo to yield 0.52 g (62%) of oxime in oil phase, which was used as such in the following hydrogenation step. GC / MS showed a molecular ion of 272.

니켈 0.5g(습윤중량)을 첨가하였다.
Raney washed three times with water and ethanol in a solution of 0.5 g (2 mmol) of dioxime in 75 ml of ethanol

0.5 g (wet weight) of nickel was added.

Ammonia gas was bubbled into the mixture for several minutes and all were placed in a Parr shaker under 45 psig of hydrogen for 7 hours. The vessel was vented and the mixture was filtered filtered.

The residue was dissolved in ether, filtered and evaporated to afford 0.43 g (81%) of amine 127, which was used as such without further purification. GC / MS showed a single peak with a molecular ion of 258.

<Cis / trans-2-methyl-3-tetrahydrofurylamine (128)>

This amine was obtained following the method in Method 35.

니켈 1g(습윤 중량)을 첨가하고 수소 44psig하에 Parr 세이커내에 놓았다.2-methyltetrahydrofuran-3-one oxime dissolved in 50 ml of methanol (prepared from a commercially available 2-methyltetrahydrofuran-3-one as a standard process) in 1.15 g (10 mmol) of water and ethanol, respectively, 3 Raney Washed Times

1 g nickel (wet weight) was added and placed in a Parr shaker under 44 psig hydrogen.

After 18 hours, the mixture was degassed and gravity filtered.

Methanol was evaporated under vacuum and the residue was collected in ether and dried. The ether acid was evaporated in vacuo to yield 0.6 g (59%) of amine 128 as a cis / trans mixture.

GC / MS showed 41% of molecular ion 101 and 59% of molecular ion 101. This amine mixture was used as is without further purification.

<2-benzyl-2,6-dimethyl-4-pyranylamine (133)>

This amine was obtained following the procedure shown in Method 36 above.

To 4.88 g (19.7 mmol) of 3-trimethylsilyloxybutyric acid trimethylsilyl ester dissolved in 40 ml of CH ₂ Cl ₂ , 2.4 g (18 mmol) of phenylacetone and 1 drop of trimethylsilyl triflate were added at -78 ° C. The mixture was left at low temperature for 2 days, then quenched with 0.5 ml pyridine and brought to room temperature.

The organic phase was diluted. Washed with aqueous sodium bicarbonate solution, dried and evaporated in vacuo.

The residue was distilled under vacuum to afford 2.89 g (67%) of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one (129) (bp 125-32@0.6 mm). Got it. GC / MC results showed two isomers of each steel with base peak 134 (phenylacetone).

Bis- (cyclopentyl) -bis-methyl titanocene dissolved in 1.5 ml of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one (129) in 20 ml anhydrous THF under nitrogen. 2.9 g (13.9 mmol) were added. The mixture was heated to reflux for 16 h.

The reaction mixture was cooled to room temperature and quenched with excess ether. The entire mixture was filtered using ether as eluent through a silica gel bed.

The filtrate was evaporated and chromatographed with EtOAc with 0.2% triethylamine and hexane (1: 4).

Fractions containing the product were evaporated, slurried in petroleum ether and filtered under vacuum to give 1.2 g of solid.

GC / MS results showed a 3: 1 mixture of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxane (130) with molecular ion 218 and starting material 129. This mixture was used as is in the rearrangement below.

To a solution of 1.2 g (5.5 mmol) of this mixture in 5 ml of toluene was added 10.99 ml (11 mmol) of tri-isobutyl aluminum hydride at −78 ° C. under nitrogen.

The reaction was left for 16 hours to cool and quenched with a few drops of water. The mixture was brought to room temperature and excess saturated aqueous ammonium chloride solution was added.

The mixture was extracted with 10 ml of excess CH ₂ Cl ₂ and difficult to separate from aluminum salts. The organic layer was dried and evaporated to give 1.1 g (90%) of 2-benzyl-2,6-dimethyl-4-hydroxypyranol as a 75:25 isomer mixture (by GC / MS).

To 1.1 g (5 mmol) of Compound 131 dissolved in 10 ml of CH ₂ Cl _2, 1.6 g (7.5 mmol) of pyridinium chlorochromate was added in portions with magnetic stirring. After 1 hour at room temperature ether was added and the mixture was filtered through a silica gel bed and washed with ether.

The filtrate was evaporated to yield 0.88 g (80%) of 2-benzyl-2,6-dimethyl-4-pyranone (132).

GC / MS showed 99% purity with a base peak of 127 (M-benzyl).

This isomer mixture was used as such for the following reductive amination.

To 0.88 g (4 mmol) of Compound 132 charged in 40 ml of anhydrous methanol, 6.16 g of ammonium acetate and 5 g of 3A molecular sieve were added. After stirring for 45 minutes at room temperature,

Sodium cyano borohydride 1.02 g (16 mmol) was added in portions while magnetically stirring. The mixture was gravity filtered and methanol was evaporated in vacuo.

The residue was partitioned between ether and dilute cold HCl.

The aqueous phase was extracted twice with ether and then basified with ice and 50% aqueous NaOH solution.

The product was extracted with CH ₂ Cl ₂ , dried and evaporated to afford 0.43 g (49%) of a two-component isomer mixture of amine 133.

GC / MS showed 128% molecular ion and 42% molecular ion.

<1- (3-phenylpropionyl) -4-aminopiperidine (136)>

This amine was synthesized according to the method of Method 37 above.

To a solution of 4 g (40 mmol) of 4-hydroxypiperidine in 20 ml of toluene was added phenyl propionyl chloride (derived by dissolving 6 g (40 mmol) of phenylpropionic acid in excess thionyl chloride).

To this mixture was added excess 2N NaOH aqueous solution.

After stirring for 24 hours, the toluene layer was discarded and the aqueous phase was extracted with CH ₂ Cl ₂ , dried and evaporated in vacuo to give 3.63 g (39%) of 1- (3-phenylpropionyl) -4-hydroxypiperidine (134). )

GC / MS showed a purity of 100% with a molecular ion of 233.

Dissolving the oxalyl chloride, 1.68ml (19.2mmol) in CH ₂ Cl ₂ 35ml and was added to a solution obtained by dissolving the anhydrous DMSO 2.73ml (38.5mmol) in CH ₂ Cl ₂ 5ml at -78 ℃. After addition, 3.6 g (15.4 mmol) of 1- (3-phenylpropionyl) -4-hydroxypiperidine 134 dissolved in 5 ml of CH ₂ Cl ₂ was added, and the mixture was stirred in cold air for 5 minutes.

10.73 ml (77 mmol) of triethylamine dissolved in 5 ml of CH ₂ Cl ₂ were added and the mixture was allowed to come to room temperature.

The mixture was quenched with saturated aqueous ammonium chloride solution.                 

The organic acid was washed twice with water and then with saturated brine, dried and evaporated to give 3.2 g (89%) of 1- (3-phenylpropionyl) -4-ketopiperidine (135). GC / MS showed molecular ion 231 and showed 100% purity.

To 3.2 g (13.8 mmol) of Compound 135 was dissolved in 125 ml of anhydrous methanol, 21.3 g of ammonium acetate and 20 g of 3A molecular sieve were added.

After stirring for 30 minutes, 3.47 g (55.2 mmol) of sodium cyanoborohydride were added in portions with stirring. After 3 hours the mixture was gravity filtered and methanol evaporated in vacuo. The residue was partitioned between ice / HCl and ether.

The acidic aqueous phase was extracted twice more with ether. The aqueous phase was basified by treatment with ice and 50% aqueous NaOH solution.

The mixture was extracted with CH ₂ Cl ₂ , dried and evaporated in vacuo to give 1.5 g (47%) of amine 136.

GC / MS showed molecular ion of 232 and showed purity of 100%.

Preparation of Amine 139

This amine was synthesized according to Method 38 above.

Into a screw cap Teflon tube was loaded Compound 137 (M. Shimano et al., Tetrahedron, 1998, 54, 12745) (0.80 g, 1.21 mmol) and 6 ml of pyridine. The solution was cooled to 0 ° C. and treated with 1.1 ml HF-pyridine complex and the solution was allowed to warm to room temperature and stirred for 17 hours.

Then 1.1 ml of HF-pyridine was added and the reaction stirred for another 30 hours. This mixture was poured into a stirred ice cold solution of 40 ml 1N HCl and 20 ml 1: 1 hexane-diethyl ether. The layers were separated and the aqueous layer was extracted with 1: 1-hexane-diethyl ether (2 × 20 ml).

The combined organic layers were washed with ice-cold 1N HCl (1 × 20 ml) and brine (1 × 20 ml).                 

The solution was dried over MgSO ₄ , filtered and concentrated.

The crude product was subjected to radial chromatography (3: 1 hexanes-EtOAc) to give 282 mg (+ small amount of impurities) of hydroxy ester, which was used directly in the next step.

Isobutyryl chloride (0.2 ml, 1.92 mmol) was added to the stirring solution cooled to 0 ° C. in which crude hydroxyester (282 mg, 0.48 mmol) was dissolved in pyridine. The cooling bath was removed and the mixture was stirred for 5 hours. Water (2 ml) was added and the mixture was stirred for 30 more minutes.

The solution was extracted ether (3 × 10 ml).

The ether layer was washed continuously with ice cold 1N HCl ( ₂ × 10 ml), saturated NaHCO ₃ (1 × 10 ml) and brine (1 × 10 ml). The solution was dried over MgSO ₄ , filtered and concentrated.

The crude product was purified by radial chromatography (4: 1 hexane-EtOAc) to give 171 mg of isobutyryl ester 138 (23% total in 2 steps).

The BOC group of this ester was removed according to the previously described standard BOC-unprotection conditions to afford the desired 139.

Preparation of Amine 145

This amine was prepared according to Method 39 above.

Hydroxyester 140 (M. Shimano et. Al., Tetrahedron, 1998, 54, 12745) (6.27 mmol) was dissolved in 15 ml DMF and cooled to 0 ° C. DMAP (1.53 g, 12.53 mmol), EDCI (1.8 g, 9.40 mmol) and N-BOC-O-Bn- (L) -threonine (2.52 g, 8.15 mmol) were continuously added to this solution.

The reaction was warmed to room temperature and stirred overnight.

The solution was poured into a mixture of rapidly stirred 30 ml ice cold 0.5N HCl and 5 ml 4: 1 hexane-ether.

The layers were separated and the aqueous layer was extracted with 4: 1 hexane-ether (1 × 30 ml). The combined organic layers were washed with 0.5N HCl (1 × 20 ml) and brine (2 × 20 ml). This solution was dried over MgSO ₄ , filtered and concentrated.

Chromatography on silica gel (150 g) using 1.25 L of 3: 1 CH ₂ Cl ₂ -hexane to elute anisealdehyde and 65:10:25 CH ₂ Cl to elute binding product 141 (3.95 g, 88%) ₂ -ether-hexane was used.

Benzyl ether 141 (1.32 g, 1.84 mmol) dissolved in 25 ml of EtOAc and 200 mg 10% Pd / C were shaken in a Parr container for 5 hours under hydrogen pressure of 50 Psi.

패드로 여과하고 농축시켜 NMR 분석결과 아주 순수한 히드록시 산 142(680mg, 70%)를 얻었다.The mixture is Celite

Filtration with pad and concentration gave NMR analysis, which gave very pure hydroxy acid 142 (680 mg, 70%).

Solid sodium bicarbonate (1.2 g, 14.27 mmol) was added to a stirring solution in which hydroxy acid 142 (1.54 g, 2.86 mmol) and benzyl bromide (1.5 ml, 12.29 mmol) were dissolved in 7 ml DMF. The mixture was stirred at rt for 24 h and then partitioned between 25 ml water and 10 ml 4: 1 hexane-ether. The layers were separated and the aqueous layer was extracted with 4: 1 hexane-ether (2 × 10 ml). The combined organic layers were washed with 0.1N NaOH (1 × 10 ml) and water (1 × 10 ml).

The solution was dried over MgSO ₄ , filtered and concentrated.

The crude product was purified by radial chromatography (4: 1 hexane-EtOAc) to give 1.04 g (60%) of hydroxybenzyl ester 143.

DMAP (40 mg, 0.67 mmol) was added to a stirred solution of ester 143 (840 mg, 1.34 mmol) and acetic anhydride (1.0 ml, 10.68 mmol) in 7 ml pyridine.                 

The reaction was stirred at rt for 4 h and diluted as 80 ml EtOAc. This solution was washed successively with saturated CaSO ₄ ( ₃ × 30 ml), 1N HCl (1 × 30 ml), saturated NaHCO ₃ (1 × 30 ml) and brine (1 × 30 ml).

The solution was dried over MgSO ₄ , filtered and concentrated to give 0.9 g (100%) of very pure acetate 114 by spectral analysis. This acetate 144 was converted to amine 145 in the same manner as previously described.

<2,3,4-tri-0-alkyl-beta-D-gyropyranosylamine 147c, d, e>

The synthesis of these amines is shown in Method 40 above.

Sodium methoxide 1M solution dissolved in methanol at room temperature in a stirred solution of triacetoxy-2-azidoxylopyranosyl azide> 146 (Acros Chemicals Co.) dissolved in CH ₃ OH 1.1 ml (1.06 ml) was added.

The reaction was stirred overnight and neutralized with 5 × 8-100 acidic resin (˜0.6 g). The solution was filtered and concentrated.                 

The obtained azidotriol 147a was immediately used in the next step.

Crude triol 147a was dissolved in 15 ml DMF and NaH (60% dispersion, 0.53 g, 13.28 mmol) was added four times over 15 minutes. The reaction was stirred at rt for 30 min and allyl bromide (2.7 ml, 33.20 mmol) was added and the mixture was stirred overnight.

Saturated ammonium chloride (10 ml) was added carefully followed by 50 ml of water.

The aqueous solution was extracted with EtOAc (3x30ml).

The organic layer was washed successively with water (4x30ml) and brine (2x30ml).

The solution was dried over MgSO ₄ , filtered and concentrated.

The crude material was purified by radial chromatography (6: 1 hexane-EtOAc) to give 753 mg (77%) of tri-O-n-allyl-2-azidodoxyparanose 147b.

패드를 통해 여과하고 증발시켜 아민 147c를 얻었다.The resulting azide and allyl fractions were reduced by adding 150 mg of 10% Pd / C in 40 ml EtOAc and stirring for 4 hours under 1 atmosphere of hydrogen. The resulting solution was transferred to Celite

Filtration through the pad and evaporation gave amine 147c.

Preparation of amine 147d was similar to 147c but the use of benzylbromide in the alkylation step reduced the azide to amine as described above. Azide 146 was hydrogenated at 1 atmosphere of hydrogen, similar to 10% Pd / C in EtOAc to afford amine 147e.                 

<Preparation of 2,3,4-tri-0-acetyl-beta-L-fucopyranosyl amine 148>

120 mg of 10% Pd / c was added to a solution of 2,3,4-tri-0-acetyl-beta-L-fucopyranosylazide (Acros) (750 mg, 2.38 mmol) dissolved in 40 ml of EtOAc.

The solution was stirred for 3 hours under 1 atmosphere of hydrogen gas.

패드를 통해 여과하고 그 패드를 EtOAc(25ml)로 세척하였다. 그 용액을 증발하여 원하는 아민 148(688mg, 100%)을 얻었다.
The mixture is Celite

Filter through a pad and wash the pad with EtOAc (25 ml). The solution was evaporated to afford the desired amine 148 (688 mg, 100%).

<Preparation of 1,3,4,6-tetra-0-acetyl-2-amino-2-deoxy-alpha-D-glucopyranose 149>

패드를 통해 여과하였으며, 그 패드를 EtOAc(20ml)로 세척하였다. Dissolve 1,3,4,6-tetra-0-acetyl-2-azido-2-deoxy-alpha-D-glucopyranose (TCI-US) (300 mg, 0.80 mmol) in 25 ml of EtOAc. 180 mg of 10% Pd / C was added to the resulting solution. The solution was stirred for 3 hours under 1 atmosphere of hydrogen gas. The mixture is Celite

Filter through a pad and wash the pad with EtOAc (20 ml).

The solution was evaporated to afford the desired amine 149 (282 mg, 100%).                 

<Preparation of benzyl and methyl 3-amino-tridoxy-L-arabinohexopyranoside 150a and 150b>

These amines are described in L. Daley, et al., Synth. Commun. It was synthesized by the method of 1998, 28,61.

Preparation of Amine 153

This amine was prepared as shown in Method 41, above.

[(3S, 7R, 8R, 9S) -7-benzyl-8-hydroxy-9-methyl-2,6-dioxo- [1,5] dioxonan-3-yl] -carbamic acid tert- Butyl ester 151 was prepared as described in M. Shimano et Al., Tetrahedron, 1998, 54, 12745.

Methacryloyl chloride (0.10 ml, 1.0 mmol) was added over 5 minutes to a stirring solution in which this ester (120 mg, 0.3 mmol) was dissolved in pyridine (5 ml). The resulting mixture was stirred overnight at room temperature under N ₂ atmosphere.

The reaction mixture was partitioned between EtOAc (75 ml) and 1N HCl (50 ml).

The organic layer was washed with water, washed with saturated NaCl, dried over MgSO ₄ and concentrated to give a transparent oil.

This crude oil was chromatographed on silica gel using a solution of 30% EtOAc in hexane as eluent to obtain acrylated intermediate 152 (138 mg) as a clear glassy substance.

From this intermediate the BOC groups were removed as described above to afford the desired amine 153.

<Preparation of Aniline (154) of Antimycin A ₃ >

Antimycin A ₃ (25 mg, 0.048 mmol) was dissolved in 2.5 ml CH ₂ Cl ₂ and pyridine (11 ml) and PCl ₅ (27 mg, 0.13 mmol) were added to the stirred solution cooled to 0 ° C. The mixture was refluxed for 1.5 hours, then cooled to -30 ° C and methanol (2.5 ml) was added, and the mixture was allowed to come to room temperature and stirred overnight.

The solution was poured into a 0 ° C. mixture of 13 ml CH ₂ Cl ₂ and 13 ml saturated sodium bicarbonate. The mixture was shaken on a split panel and layered. The aqueous layer was extracted with CH ₂ Cl ₂ ( ₂ × 5 ml) and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give aniline of antimycin A ₃ .

General method of coupling an amine to an ortho-hydroxy heteroaromatic carboxylic acid to produce heterocyclic aromatic amide 2

Coupling Procedure A : Preparation of N- (2- (4-chlorophenyl) ethyl) -3-hydroxypyridine-2-carboxamide (233).

The stirred mixture in which 3-hydroxypyridine-2-carboxylic acid (1.39 g, 0.01 mol) was dissolved in anhydrous THF (60 ml) was cooled to -20 ° C under argon. The 20% solution of phosgene dissolved in toluene (5.1 g, 0.01 mol) was added at once, and the resulting mixture was stirred for 90 minutes while slowly raising the temperature to 0 ° C.

The reaction mixture was then recooled to -20 ° C

A solution in which diisopropylethylamine (2.58 g, 0.02 mol) was dissolved in THF (20 ml) was titrated over 30 minutes.

After the addition was completed, the mixture was stirred for another 2 hours while slowly raising the temperature to 0 ° C. Stirring continued at 0 ° C. overnight.

2- (4-chlorophenyl) ethylamine (1.56 g, 0.01 mol) was added to this stirred mixture at once, and the mixture was stirred at room temperature for 6 hours.

The mixture was diluted with ether (100 ml), washed with 1N HCl (100 ml), dried (MgSO ₄ ) and concentrated to afford the desired compound as an off-white solid. (1.95 g) Mass spectrum (MS) Result in m / e 276 And 3: 1 molar ratio at 278.

Coupling Procedure B: Preparation of 3-hydroxy-4-methoxy-N- (4- (4-trifluoro methylphenoxy) phenyl) -pyridine-2-carboxamide 425

3-benzyloxy-6- in a stirred solution of 4- (4-trifluoromethylphenoxy) aniline (0.20 g, 0.8 mmol) and DMAP (0.10 g, 0.085 mmol) dissolved in CH ₂ Cl ₂ (10 ml). A solution of bromo-4-methoxypyridine-2-carbonylchloride (3) (0.29 g, 0.8 mmol) dissolved in CH ₂ Cl ₂ (5 ml) was added at once.

The resulting mixture was stirred at rt overnight and then poured into 2N HCl (10 ml). The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ ( ₂ × 10 ml). The organic layers were combined, dried (MgSO ₄ ) and concentrated to give a gum solid.

This solid was collected in EtOAc (20 ml) and triethylamine (0.80 g, 0.8 mmol) and 5% Pt / C (0.10 g) were added. As a result, the mixture was treated with hydrogen atmosphere (initial pressure = 50 psi) for 30 minutes on a Parr shaker.                 

The mixture was filtered, washed with 0.1 N HCl (20 ml), dried (MgSO ₄ ) and concentrated to afford the desired compound (0.14 g) as an off-white solid (mp = 122-129 ° C.).

Coupling Procedure C : Preparation of N- (4-cyclohexylphenyl) -3-hydroxypyridine-2-carboxamide

3-hydroxypyridine-2-carboxylic acid (0.42 g, 3 mmol) and 4-cyclohexyl aniline (0.35 g, 2 mmol) obtained from compound 16 by catalytic hydrogenation in the presence of Pd / C as described above To the stirred solution dissolved in anhydrous DMF (5 ml) was continuously added 1-hydroxybenzotriazole (0.48 g), EDCI (0.65 g) and N-methylmorpholine (1.41 g).

More DMF (5 ml) was added and the reaction mixture was stirred at rt overnight. The mixture was poured into water (200 ml) and extracted with EtOAc (2 × 75 ml).

The organic extracts were combined, washed with water (100 ml) and saturated NaCl solution (50 ml), dried (MgSO ₄ ) and concentrated.

The crude oil solidified on standing was chromatographed (4: 1 petroleum ether-EtOAc) on silica gel to give the desired compound (0.42 g) as a pale yellow solid (mp 91-93 ° C.).

Modification of heterocyclic aromatic amides to other heterocyclic aromatic amides

Preparation of 4-hydroxythiophene-N- (3,3,5,5, -tetramethylcyclohexyl) -3-carboxamide 554

4-methoxythiophenecarboxylic acid and 3,3,5,5-tetramethylcyclohexylamine were coupled according to the general coupling procedure C described above to produce 4-methoxythiophene N- (3,3,5,5- Tetramethylcyclohexyl) -3-carboxamide was obtained.

A solution of 500 mg of this methoxythiophenamide in 15 ml chloroform under a dry tube was stirred for 5 minutes in a dry ice-acetone bath. To this solution, a solution in which 940 mg of boron tribromide (2 equivalents) was dissolved in 10 ml of chloroform was appropriately added over 15 minutes.

Stirring was continued until the reaction mixture was brought to room temperature and then stirred overnight.

The reaction mixture was then placed in a cold water bath and 15 ml of water was titrated. After stirring for 15 minutes, the mixture was diluted with 50 ml of CH ₂ Cl ₂ and the organic layer was separated. Water Layers CH ₂ Cl ₂

Wash with 50 ml.

The combined organic extracts were washed with 25 ml of water and saturated salt solution and dried. The extract was filtered and concentrated. Chromatography on silica gel using CH ₂ Cl ₂ -5% EtOAc as eluent gave 310 mg of the desired compound as light yellow crystals, mp 170-174 ° C.

The sample was recrystallized from petroleum ether-EtOAc to give a pale yellow needle. (M.p 171-173 ° C.)

Preparation of Bound Intermediates 156a-d

These intermediates were prepared as shown in Method 42 above.

Isopropyl ester of (±) -serine hydrochloride (2.75 g) and triethylamine (3.55 g) were dissolved in CH ₂ Cl ₂ (75 ml) in 3-benzoyloxy-6-bromo-4-meth A solution of oxypyridine-2-carbonylchloride (3) (5.32 g) in CH ₂ Cl ₂ (15 ml) was added over 5 minutes.

The mixture was stirred over 30 minutes at room temperature

Pour into 1N HCl (75 ml).

The organic layer was separated, washed with water (25 ml), dried (Na ₂ SO ₄ ) and solvent evaporated to give a yellow gum (6.7 g).

This material was recrystallized from ether / hexane to give a white solid 155a with a m.p of 100 to 103 ° C.

The methyl ester intermediate 155b was obtained by the same process using the methyl ester of (±) -serine hydrochloride.

Α-methyl hydrocinnamoyl chloride (0.46 g) was added to the stirred solution in which Compound 155a (1.17 g), triethylamine (0.31 g) and DMAP (0.06 g) were dissolved in CH ₂ Cl ₂ (25 ml).

As a result, the mixture was stirred at room temperature for 4 hours and then poured into 2N HCl (15 ml).

The organic layer was separated, washed with 1N NaOH (15 ml), dried (MgSO ₄ ) and evaporated to yield yellow oil 156a (1.45 g).

NMR (CDCl ₃ ) showed this oil was a diastereomer 1: 1 mixture.

3- (t-butyldimethylsilyloxy) butyryl chloride (prepared from the corresponding t-butyldimethylsilylester by the method of A. Wissner and CV Grudzinskas, J. Org. Chem., 1978, 43, 3972) 3.55 g) was dissolved in CH ₂ Cl ₂ (10 ml) and quickly added to a cold (0 ° C.) stirred solution in which compound 155b (6.6 g) and DMAP (0.18 g) were dissolved in anhydrous pyridine (25 ml).

The reaction mixture was stirred at 0 ° C. for 15 minutes and then at room temperature for 3 hours.                 

Dilution with ether (200 ml) then the mixture was extracted with water (2 × 100 ml), dried (MgSO ₄ ) and solvent evaporated.

Toluene (25 ml) was added to the residue and the solvent was evaporated again.

The yellow oily residue was purified by chromatography (silica gel, 7: 3 hexanes / acetone) to give compound 156b as a mixture of diastereomers.

2-benzyl-3- (t-butyldimethylsilyloxy) propionic acid (7.36 g) (NPPeet, NL Lentz, MW Dudley, AML Ogden, DE McCarty and MMRacke, J. Med. Chem., 1993, 36, 4015 T-butyldimethylsilyl chloride (4.52 g) was added in one portion to a stirring solution dissolved in DMF (20 ml), and then imidazole (4.1 g) was added, and the resulting mixture was stirred at room temperature for 24 hours.

The mixture was diluted with water (300 ml) and extracted with pentane (3 × 100 ml). The pentane phase was washed with water, dried (Na ₂ SO ₄ ) and solvent evaporated to give a colorless oil (9.5 g). NMR (CDCl ₃ ) was consistent with the diastereomeric mixture. This ester (4.1 g) was obtained from NP Peete, et al., J. Org. Converted to the corresponding acid chloride according to the method of Chem., 1978, 43, 3972.

This acid chloride was condensed with compound 155b (4.4 g) as described above to afford the desired 156c as a silica gel chromatography (4: 1 hexanes / acetone) diastereomeric mixture.

To the stirred solution in which Compound 156c (4.5 g) was dissolved in methanol (35 ml), concentrated HCl (1.5 ml) was added.

The resulting mixture was stirred at room temperature for 30 minutes, diluted with water (200 ml) and then

Extracted with CH ₂ Cl ₂ ( ₂ × 100 ml). The organic phase was dried (MgSO ₄ ) and the solvent extracted. The residue was purified by silica gel chromatography (7: 3 hexane / acetone) to give 156 d (2.8 g) as a pale yellow gum.

NMR (CDCl ₃ ) results showed a diastereomeric mixture.

The 156a-d were converted to the corresponding unprotected heterocyclyl aromatic amide by hydrogenation in the presence of Pd / C as described.

<Production of Intermediate 158>

The synthesis of this intermediate is shown in Method 43 above.

Amide 157 is (+)-trans-1-hydroxy-2-aminocyclopentanehydrobromide (7.09 g, 38.9 mmol) and 3-benzyloxy-6-bromo-4-methoxypyridine-2-carbonylchloride (3) (13.8 g, 38.9 mmol) was prepared following the general coupling procedure B from a solution dissolved in CH ₂ Cl ₂ (150 ml) and purified by flash chromatography using 1: 1 hexane-EtOAc as eluent.

This resulted in compound 157 (13.4 g) as a white solid. mp 56-57 ° C.

Dimethyl sulfoxide (7.4 ml, 104.1 mmol) was slowly added to oxalyl chloride (4.54 ml, 52.08 mmol) in 78 ° C. solution dissolved in CH ₂ Cl ₂ (100 ml), followed by amide 157 (10.46 g, 24.8 mmol). To the solution dissolved in CH ₂ Cl ₂ (25 ml).

After 30 minutes, Et ₃ N was added and the solution was slowly warmed to room temperature. The mixture was poured into saturated NH ₄ Cl (100 ml) and extracted with CH ₂ Cl ₂ ( ₂ × 100 ml).

The combined organic layers were washed with brine, dried and solvent evaporated.

The residue was purified by column chromatography using 1: 1 EtOAc-hexane as eluent to afford ketone 158 (9.64 g, 94%), which was pure by GC / MS and ¹ H-NMR.

Both compounds 157 and 158 were hydrogenated in the presence of Pd / C as described above to convert to the corresponding unprotected heterocyclic aromatic amides.

<Production of Intermediate 160a-d>

These intermediates were prepared according to Method 44 above.

Serinol was coupled with 3-benzyloxy-6-bromo-4-methoxypicolinic acid (16) following the general coupling procedure C to give 1,3-diol 159 as colorless oil and ¹ H, ¹³ C. -NMR and IR spectra results were pure.

1,3-diol 159 (1 mmol) was refluxed in benzene (20 ml / mmol) in the presence of a catalytic amount of p-toluenesulfonic acid (0.1 mmol) in a Dean-Stark setup to obtain the appropriate carbonyl compound (2 mmol) or the corresponding Condensation with dimethyl acetal (2 mmol).

Condensation of compound 159 with 1,3,3, -trimethoxypropane provided Acetan 160a as a 2: 1 mixture of Syn and anti diastereoisomers.

The mass spectrum (ES) shows [M +] at (m / e) 495 and 497. ¹ H- ¹³ C-NMR and IR spectra were consistent with structure 160a.

Condensation of compound 159 with 2-methyl-3- (4-tert-butyl) phenylpropanone gave acetal 160b as a 3: 1 mixture of Syn- and anti diastereomers. Mass spectrum (ES) shows [M +] at (m / e) 597.

¹ H, ¹³ C-NMR and IR spectra were consistent with structure 160b.

Condensation of Compound 159 with dihydro-β-ionone gave acetal 160c as a 2: 1 mixture of Syn and anti diastereomers. Mass spectrum (EI) showed [M +] at (m / e) 587.

¹ H, ¹³ C-NMR and IR spectra were consistent with structure 160c.

Condensation of compound 159 with 3,3,5,5-tetramethylcyclohexanone provided acetal 160d and was consistent with ¹ H, ¹³ C-NMR and IR spectra results.

The intermediates 160a-d were converted to the corresponding unprotected heterocyclic aromaticamides by hydrogenation in the presence of Pd / C as described above.

Preparation of Compounds 280 and 281

Method 45 describes the preparation of these compounds.

First, Intermediate 161 was obtained by coupling 2,3,6,6-tetramethyl-2-cycloheptenylamine to 2-hydroxy-3-methoxy-2-picolinic acid using standard coupling procedure C. .

Tetrahedron Lett. Compound 161 was dichlorolated according to the procedures of 1991, 32, 1831-1834 to give dichloro derivative 281.

Compound 161 was prepared by oxidation of the compound 161 in CH ₂ Cl ₂ with standard m-CPBA to prepare an N-oxide-containing epoxy analog 162, followed by treatment with H ₂ (45 psi) and 10% Pd / c under standard catalytic hydrogenation conditions. Formed.

<Production of trans-4-hydroxy-3,3,5,5-tetramethylpicolinamide (264)>

This compound was prepared according to Method 46 above.

Sodium borohydride (20 mg, 0.53 mmol) was added to the stirred solution in which keto-picolinamide 266 (56 mg, 0.18 mmol) was dissolved in 2 ml of methanol. The reaction was stirred for 5 hours and methanol was evaporated. The crude was diluted with 5 ml water and extracted with EtOAc (3 × 5 ml).

The organic layer was washed with water (1 × 5 ml) and brine (1 × 5 ml).

The solution was dried over MgSO ₄ , filtered and concentrated.

NMR and GC analyzes were consistent with compound 264 having a trans stereochemistry with a purity of 95%.

Preparation of Compound 341

The preparation of this compound is shown in Method 47 above.

Benzyl ester precursor 139 (method 39) (33 mg, 0.046 mmol) was dissolved in 10 ml EtOAc and 110 mg of Pearlman catalyst was added.

The mixture was shaken for 12 h in a Parr vessel under hydrogen pressure 50 psi. The solution was then filtered and concentrated.

The residue was then dissolved in a minimum amount of ether and petroleum ether was added until a precipitate formed. The solid was collected by filtration and dried to give compound 341.

<Preparation of N- (3-hydroxy-4-methoxy-2-pyridylcarbonyl) -2-amino-2-deoxy-alpha-D-glucopyranose 334>

1,3,4,6-tetra-0-acetyl-2-amino-2-deoxy-alpha-D-glucopyranose (151) and 3-hydroxy-4-methine using standard coupling procedure C Toxy picolinic acid was bound together.

Lithium hydroxide monohydrate (0.92 mmol, 40 mg) was added to a solution of the resulting picolinamide (0.19 g, 0.39 mmol) in 6 ml of methanol.

The reaction mixture was stirred at rt overnight.

5x8-100 산성수지(0.5g)을 첨가하여 중성화시켰다. 그 혼합물을 여과하고 농축시켜 원하는 화합물(110mg, 88%)을 얻었다.DOWEX the solution

5x8-100 acidic resin (0.5 g) was added to neutralize. The mixture was filtered and concentrated to afford the desired compound (110 mg, 88%).

<General preparation method of exocyclic ester 166a, carbamate 166b, and carbonate 166c>

These compounds were prepared as shown in Method 48 above using amine 164 prepared according to the method of M. Shimono, et al., Tetrahedron, 1998,54,12745.

This amine was combined with 3-benzyloxy-6-bromo-4-methoxypicolinic acid 16 according to the standard coupling procedure C described above, and then the resulting intermediate 165 was added in the presence of a suitable carboxylic acid chloride, alkylisocyanate, Or reacted with alkylchloroformate to give the desired protected ester 166a, carbamate 166b, or carbomate 166c, respectively.

These compounds were deprotonated using H ₂ in the presence of Pd / c according to the procedure described above to obtain the required ester, carbamate or carbomate.

The above steps were used to prepare other cognate esters, carbamate and carbomate.

Preparation of 166a

Cyclopropane carbonyl chloride (0.45 ml, 5 mmol) was slowly added to the stirred solution in which Compound 165 (180 mg, 0.29 mmol) was dissolved in pyridine (10 ml) over 5 minutes.

The mixture was stirred overnight at room temperature under N ₂ atmosphere.

The resulting mixture was poured into 1N HCl (30 ml) and extracted with EtOAc (2 × 75 ml).

The organic layers were combined, washed with water (25 ml) then washed with saturated NaCl (25 ml), dried over MgSO ₄ and concentrated to give an orange oil.

The crude oil was chromatographed on silica gel using 30-50% EtOAc in hexane gradient as eluent to afford compound 166a (100 mg) as a clear oil.

Preparation of 166b

Triethylamine (2 drops), DMAP (1 mg), and isopropyl isocyanate (0.2 ml, 2 mmol) were added to a stirred solution of compound 165 (200 mp, 0.33 mmol) dissolved in CH ₂ Cl ₂ (5 ml).

The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere.

The reaction mixture was poured into 1N HCl (25 ml) and extracted with EtOAc (2 × 50 ml). The organic layers were combined, washed sequentially with water and saturated NaCl, dried over MgSO ₄ and concentrated to give a pink foam. Chromatography on silica gel using 30% to 50% EtOAc in hexane gradients as a double eluent gave compound 166b (90 mg) as a white solid.

Preparation of Compound 166c

Compound 165 (180 mg, 0.29 mmol) dissolved in pyridine (5 ml) and CH ₂ Cl ₂ (5 ml) was cooled to 0 ° C. in an ice bath under a nitrogen atmosphere.

Isopropyl chloro formate (1M in toluene, 5 ml) was added slowly to the cooled mixture over 1 minute.

The ice bath was removed and the mixture was stirred at rt overnight.

The reaction mixture was partitioned between 1N HCl (25 ml) and EtOAc (75 ml). The organic layer was washed sequentially with water and saturated NaCl, dried over MgSO _4, and concentrated to give a transparent oil. The crude oil was chromatographed on silica gel using 30% -50% EtOAc in hexane gradient as eluent to afford compound 166c (80 mg) as a clear oil.

<Production of Intermediates 167 and 168>

The diastereomeric mixture of amine 53 (see method 9) obtained as described above was combined with acid chloride 3 via the general coupling procedure A described above to give a diastereomer 167 and 168 mixture. These were subjected to silica gel chromatography (85:15 hexanes / acetone) to give pure compounds 167 and 168 in 35% yield.

They were deprotected with H ₂ in the presence of Pd / c as described above.

Heterocyclic aromaticamides (2) include 0-acyl heterocyclic aromatic amides (2Y: M = acyl), 0-acyl heterocyclic aromatic amides (2Y: M = silyl) and 0-sulfonyl heterocyclic aromatics. General formula to convert to amide (2Y: M = sulfonyl)>

Preparation of 0- (3,3-dimethyl) butanoyl Compound 610

The preparation of this compound starting with Compound 169 (prepared according to the method of M. Shimano et al., Tetrahedron 1998, 54, 12745) is shown in Method 50 above.

A stirred solution of Compound 169 (100 mg, 0.19 mmol) and DMAP (5 mg, 0.04 mmol) dissolved in anhydrous pyridine (5 ml) was treated with 3,3-dimethylbutanoyl chloride and the mixture was stirred at ambient temperature for 5.5 hours. It was.

Then treated with water (15 ml) and extracted with EtOAc (20 ml).

The organic extract was washed successively with water and saturated aqueous NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated.

Chromatography on silica gel using ether as eluent gave the compound m.p 151-152 ° C. as an off-white solid.

¹ H-NMR and MS data were consistent with the assigned structure.

Other 0-acyl heterocyclic aromatic amides were prepared by modifications based on the above recipe. Such modifications include purification by other techniques well known to those of ordinary skill in the art, such as, for example, column chromatography or recrystallization.

Preparation of 0-tert-butyldimethylsilyl Compound 720

The preparation of this compound is shown in Method 50.

Compound 169 (100 mg, 0.19 mmol) and N-methylmorpholine (0.13 ml, 1.18 mmol) dissolved in anhydrous DMF (2 ml) were treated with tert-butyldimethylsilyl chloride (57 mg, 0.38 mmol). The mixture was stirred at ambient temperature for 1 day.                 

The resulting mixture was partitioned between water (10 ml) and EtOAc (15 ml) and the organic phase was washed sequentially with saturated aqueous NaHCO ₃ and brine, filtered and concentrated.

The residue was chromatographed on a flash-graded silica gel column using ether as eluent to afford 74 mg of compound as a clear grease. ^{The 1} H-NMR spectrum was consistent with the assigned structure.

Preparation of 0-p-toluenesulfonyl Compound 722

The preparation of this compound is shown in Method 50.

p-toluenesulfonyl chloride (90 mg, 0.466 mmol) was added to a stirred suspension in which compound 169 (200 mg, 0.388 mmol) and potassium carbonate (65 mg, 0.466 mmol) were suspended in anhydrous acetone (3 ml).

After stirring for 12 h at ambient temperature, the mixture was diluted with EtOAc (25 ml) and washed with H ₂ O ( ₂ × 10 ml).

The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with hexane-EtOAc (1: 1) to give 197 mg of a white solid with mp 153-155 ° C., the ¹ H-NMR spectrum was consistent with the desired compound.

Method I illustrates another compound of formula I prepared from a suitable starting material by the above preparation.

¹ H-NMR spectrum data for all of these compounds was consistent with the assigned structure.

Fungicide Usability

The compounds of the present invention have been found to control fungi, particularly plant pathogens and wood eroding fungi.

When used to treat plant fungal diseases, these compounds are applied to plants in disease inhibiting and botanically acceptable amounts.

Application can be carried out before and / or after the fungus is infected with the plant.

Application can also be through the seed of the plant, the soil in which the plant grows, the sowing field or the spreading solution. Other applications can be carried out through wood treatments to control the destruction of wood and / or wood products.

As used herein, the term "disease suppression and botanically acceptable amount" refers to the invention of the present invention which kills or inhibits plant pathogens and prevents, eradicates or inhibits plant diseases requiring control, but which is not highly toxic to plants. Point to the amount of compound.

This amount may generally be in the range of 1 to 1000 ppm, preferably 10 to 500 ppm.

The exact concentration required will depend on the type of preparation to be used for the fungal disease to be controlled, the method of application, the specific plant, climatic conditions and other factors. Suitable application rates are typically 50-1000 gr / ha (g / Ha).

The compounds of the present invention may also be used to protect stored grain and other places from fungal infections.

The following experiments were conducted in the laboratory to investigate the bactericidal efficacy of the compounds of the present invention.

In vitro ( in vitro ) Biological assessment of fungal growth inhibition.

Cultivation conditions: Suspensions of fungi conidia or mycelium sections were transferred to sterile potato dextrose broth (Difco) Magnaporthe grisea ( Pyricularia oryzae -PYRIOR), li footonia solar you (Rhizoctonia solani) (RHIZSO), Miko Legaspi Relais gras mini-cola (Mycosphaerella graminicola) (counts Astoria tree Tea City (Septoria tritici) - SEPTTR), star and North Fora surf Room (Stagonospora nodorum) (rep toss Feria surf Room ( Leptosphaeria nodorum )-LEPTNO), Ustilago maydis (USTIMA) and rye seed broth with Phytophthora infestans (PHYTIN). The suspension was pipetted into a sterile 96 well microtiter plate containing a sample of experimental fungicides dissolved in dimethyl sulfoxide. The concentration of the fungicide was varied from 0.001-100 ppm with the final solvent concentration not exceeding 1% of the medium. The fungi were incubated for several hours at 24-30 ° C. until wells were opaque to the growth of fungi in wells of controls containing only solvent. At this point, growth inhibition was determined by visual inspection and percent inhibition of each well compared to the solvent treated control.

In Table 2, "+" indicates that the test substance provided at least 80% growth inhibition when the hospital was incorporated into the growth medium at a concentration of 25 ppm, and "-" indicates less than 80% growth inhibition. . Blanks have not been tested.

Biological Evaluation of Control of Whole Plant Fungus Infection in Vivo.

Compound compounding was performed by technical dissolution of the material in acetone in serial dilutions and preparation in acetone at the desired concentration. The final treatment volume is obtained by adding 9 volumes of 0.05% aqueous Tween-20 or 0.01% Triton X-100 (depending on the hospital).

Doy Mildew ( Plasmopara viticola -PLASVI) (24-hour preventive) of grapes: A soil-based peat-based potting mixture of vines (variety Carignane) ("Metromix") grew from seed until the seed was 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were spray inoculated with an aqueous spore sac suspension of Plasmopara viticola and kept in a dew chamber overnight.The plants were then diseased in untreated control plants. It was transferred to the greenhouse until it occurred.

Late Blight of Tomato ( Phytophthora infestans -PhYTIN) (24-hour preventive) : A soil-free peat-earth potting mixture ("Metro") In the mix ") until the seeds are 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were spray inoculated with an aqueous spore sac suspension of Phytophthora infestans and kept overnight in a humidity saturation chamber. The plants were then transferred to the greenhouse until the disease developed in untreated control plants.

Brown Rust of wheat ( Puccinia recondita -PUCCRT) (24 hour preventive) : Wheat (breed Yuma) in soil-free peat-earth potting mixture ("Metromix") From the seeds were grown until the seeds were 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were spray inoculated with an aqueous spore sac suspension of Puccinia recondita and kept overnight in a humidity saturation chamber. The plants were then transferred to the greenhouse until the disease developed in untreated control plants.

Powder Mildew ( Erysiphe graminis -ERYSGT) (24 hour preventive) : Wheat (variety Monon) is a soil-free peat-earth potting mixture ("Metro In the mix ") until the seeds are 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were inoculated by dusting with conidia of powdery powdery mildew infected wheat plants. The plants were then transferred to the greenhouse until the disease developed in untreated control plants.

Wheat jeommunuibyeong (Leaf Blotch) (Counts Astoria Tree Tea City (Septoria tritici) - SEPTTR) ( 24 hours preventive protectant): Wheat (cultivar Yuma (Yuma)) with no soil peat - gito in potting mixture ( "Metro Mix") From the seeds were grown until the seeds were 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were spray inoculated with an aqueous spore suspension of Septoria tritici and kept in a humidified chamber overnight. The plants were then transferred to the greenhouse until the disease developed in untreated control plants.

Wheat Blotch ( Leptosphaeria nodorum -LEPTNO) (24-hour preventive) : Wheat (breed Yuma) soil-free peat-earth potting mixture ("Metromix") The seeds were grown from seeds until they were 10-20 cm in size. These plants were then sprayed with the test compound at a rate of 100 ppm. After 24 hours, the test plants were spray inoculated with an aqueous spore suspension of ( Leptosphaeria nodorum ) and kept overnight in a humidity saturation chamber. The plants were then transferred to the greenhouse until the disease developed in untreated control plants.

In method 2, "++" indicates that the incorporation of the hospital into the growth medium at a concentration of 100 ppm provided at least 75-100% control of fungal infection when compared to disease occurrence for plants that were not treated with the test substance, "+" Indicates 25-74% control of fungal infection, and "-" indicates <25% control of fungal infection. Blanks have not been tested.

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The compounds of the present invention are preferably applied in the form of a composition comprising one or more compounds of formula 1 and a botanically-acceptable carrier. The composition can be a concentrated formulation dispersed in water or other liquids upon application or a powder or granular formulation applied without subsequent treatment. The compositions are prepared by methods generally known in the agricultural arts, but are new and important because of the presence of the compounds of the present invention. Several formulations of the compositions have been presented so that agrochemists can easily prepare the desired compositions.

The dispersions to which the compounds are applied are usually aqueous suspensions or emulsions prepared from concentrated formulations of the compounds. Such water-soluble, water-dispersible or emulsifiable blends are solids, solids generally known as wet powders or aqueous liquids, generally emulsifiable concentrates or liquids known as aqueous suspensions. The present invention is intended to include all vehicles that can be formulated to deliver the compounds of the invention for use as fungicides. It is understood that any substance to which a compound of the present invention may be added may be used as long as it does not significantly inhibit the activity of the compound according to the present invention as a fungicide.

Wet powders that can be compressed into water dispersible granules include the active compound, an inert carrier and surfactant. The concentration of the active compound is generally about 10 w / w% to 90 w / w%, more preferably about 25 w / w% to 75 w / w%. In the preparation of the wet powder compositions, the toxic products are altered andesite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite, It can be mixed with any finely divided solids such as clays, diatomaceous earth, purified silicates and the like. At this time. The finely divided carrier may be ground in a volatile organic solvent or mixed with toxic substances. Effective surfactants comprising about 0.5-10% of wet powders include non-ionic surfactants such as ethylene oxide adducts of sulfonated lignin, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates and alkyl phenols. Include.

Emulsifiable concentrates of the compounds according to the invention are included at a concentration such as about 10-50 w / w% in a suitable liquid. The compound is dissolved in an inert carrier which is a solvent miscible with water or a mixture of an emulsifier and an organic solvent that is not miscible with water. The concentrate may be diluted with water and oil to form a spray mixture in the form of an oil-water emulsion. Useful organic solvents include high boiling naphthalene or olefin moieties of petroleum, such as aromatic, in particular heavy aromatic naphtha. For example, other organic solvents may also be used, such as terpene solvents containing rosin derivatives, aliphatic ketones such as cyclohexanone and complex alcohols such as 2-ethoxyethanol.

Emulsifying agents that can be advantageously used in the present invention can be readily determined by one skilled in the art and include various nonionic, anionic, cationic and amphoteric surfactants or mixtures of two or more surfactants. Examples of nonionic emulsifiers useful in the preparation of emulsifiable concentrates are polyalkylene glycol ethers and propylene oxides and polyols such as alkyl and aryl phenols, aliphatic alcohols, aliphatic amines, or ethylene oxides of fatty acids, ethoxylated alkyl phenols or Condensation products to carboxylic acid esters solubilized with polyoxyalkylenes. Cationic surfactants include quaternary ammonium compounds and fatty acid amine salts. Anionic surfactants include oil-soluble salts of alkylaryl sulfonic acids (eg calcium), oil-soluble salts of sulfated polyglycol ethers and suitable salts of phosphated polyglycol ethers.

Examples of organic liquids that can be used in the preparation of emulsifiable concentrates according to the invention include aromatic liquids such as xylenes, propyl benzene fractions or mixed naphthalene fractions, mineral oils, dioctyl phthalates, kerosene and dialkyl amides of various fatty acids. Substituted aromatic organic liquids such as; Especially dimethyl amides of fatty acid glycols and glycol derivatives such as n-butyl ether, diethyl glycol or methyl ether of diethylene glycol and methyl ether of triethylene glycol. Preferred organic liquids are the xylene and propyl benzene fractions, with xylene being the most preferred.

Surfactant dispersants are generally used in liquid compositions in amounts of 0.1-20% by weight of the total weight of the dispersant and active compound. The active composition may also contain other miscible additives such as plant growth regulators and other biologically active compounds used in agriculture.

Aqueous suspensions include dispersions of water-insoluble compounds of the invention dispersed in aqueous excipients at concentrations of about 5-50 w / w%. Suspensions are prepared by intimately mixing the finely ground compound into water and an excipient comprising a surfactant selected from the same type described above. Inorganic salts and inert ingredients such as synthetic or natural gums may also be added to increase the density and viscosity of the aqueous excipient. It is usually most effective to separate the aqueous mixture and to grind and mix it simultaneously while homogenizing it in a sand mill, ball mill or piston-type homogenizer.

The compounds can also be applied as granule compositions which are particularly useful for application to soil. The granular composition generally contains about 0.5-10 w / w% of the compound dispersed in an inert carrier composed of all or most roughly milled attapulgite, bentonite, diatomite, clay or similar inexpensive material.

Such compositions are generally prepared by dissolving the compound in a suitable solvent and applying the granular carrier preformed with a suitable particle size in the range of about 0.5 to 3 mm. Such compositions can also be blended by preparing a dough or paste of carrier and compound and drying to obtain the desired granulated particles.

The powder containing the compound is prepared by simply mixing the compound in powder form with a suitable powdered agricultural carrier such as, for example, kaolin, viscosity, pulverized volcanic rock and the like. The powder may suitably contain about 1-10 w / w% of the compound.

The active composition may contain auxiliary surfactants to increase deposition, wetting penetration of the composition onto the desired grains and organisms. These co-surfactants may optionally be used as components or container mixtures of the formulation. The amount of co-surfactant may be 0.01-1.0 v / v%, preferably 0.05-0.5 v / v%, based on the spray-volume of water. Suitable cosurfactants may be ethoxylated noryl phenols, ethoxylated synthetic or natural alcohols, salts of sulfosuccinic acid esters, ethoxylated organosilicones, ethoxylated fatty acid amines, and mixtures of surfactants with mineral or vegetable oils.

The composition may optionally comprise a sterile combination comprising at least 1% of one or more compounds of the invention and other pesticidal compounds. Such additional insecticidal compounds are fungicides, insecticides, nematocides, miticides, arthropod killings that are compatible with the compounds of the present invention and do not antagonize the activity of the present invention in the medium chosen for application. Arthropodicides, bactericides or combinations thereof.

Thus, in such an embodiment, different pesticidal compounds are used as toxicants which assist in the use of the same or different pesticides. The compound in the combination may generally be present in a ratio of 1: 100 to 100: 1.

The present invention includes methods for controlling or preventing fungal attack. These methods include the application of one or more compounds or compositions according to the invention in a sterile amount (eg, in cereals or grape plants) in places where fungi are present or where infection is to be prevented. The compounds are suitable for treating various plants at bactericidal levels that exhibit low botanical toxicity. The compound is useful as a protectant or eradicant. The compounds of the present invention can be applied by any of a variety of techniques known as compounds or as compositions comprising the compounds. For example, the compounds can be applied to the roots, seeds or leaves of plants that want to control the various fungi without compromising the commercial value of the plants. The material may be applied in any commonly used combination form, for example as a solution, powder, wet powder, flow concentrate or emulsifiable concentrate. These materials can be generally applied in various known ways.

The compounds of the present invention have a significant bactericidal effect, in particular against agricultural. Many compounds are particularly effective in agronomic grain and horticultural crops or wood, paint, leather or carpet backing.

In particular, the compounds effectively control various undesirable fungi that infect useful plant crops. For example, activity against various fungi has been demonstrated including the following fungal species: Downy Mildew ( Plasmopara viticola -PLASVI), tomato leaf blight (Pi) Phytophthora infestans- PHYTIN, apple red mold disease ( Venturia inaequalis- VENTIN), wheat Brown Rust ( Puccinia recondita- PUCCRT), wheat rust (Stripe Rust) ( Puccinia striiformis- PUCCST), Rice Blast ( Pyricularia oryzae- PYRIOR), Beet (Cerospora Leaf Spot) ( Cercospora Beticola- CERCBE), Wheat Mildew ( Erysiphe graminis- ERYGST), Wheat Blotch ( Septoria Tritici tritici) -SEPTTR), wheat sheath blight (sheath blight) (Rhizopus California solani (Rhizoctonia solani) -RHIZSO), wheat anjeongbyeong (Eyespot) (peuse likelihood SERE course included mozzarella (Pseudocercosporella herpotrichoides) -PSDCHE), peach saline bottles (Brown Rot) (monilriah fruity Cola (Monilinia fructicola) -MONIFC) and Glume Blotch of Wheat ( Leptosphaeria nodorum- LEPTNO). The efficiency of the above fungi of the compounds according to the invention corresponds to the general use of the compounds as fungicides and can be understood by those skilled in the art.

The compounds of the present invention have a wide range of sterilization efficiencies. The exact amount of active substance to be applied depends not only on the specific active substance applied but also on the specific action desired, the fungal species to be controlled and their growth stages, as well as the part of the plant or other product which is in contact with the toxin active ingredient. Thus, all active ingredients and compositions containing them of the compounds according to the invention may not have the same effect on similar concentrations or on the same fungal species. The compounds and compositions of the present invention are effectively used in a botanically acceptable amount for disease control of plants.

Claims (45)

Compound of Formula I (Formula I)

In the above formula (a) X ₁ is N, X ₂ and X ₃ are CH, X ₄ is CH, COMe, CMe, CCl, COEt or CSMe, (b) Z is O, S or NORz and Rz is H or C ₁ -C ₃ alkyl; (c) A represents (Iii) unsubstituted, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, hetero Aryloxy, C ₁ -C ₆ alkylthio, C ₆ or C ₁₀ arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, heteroaryl, C ₁ -C ₆ acyl, carbo C ₆ or C ₁₀ aryloxy, carboheteroaryloxy, C ₁ -C ₆ carboalkoxy and also unsubstituted or 1 or 2 C ₁ -C ₆ alkyl groups C ₃ -C ₁₄ cycloalkyl containing 0 to 3 heteroatoms and 0 to 2 unsaturations, which may be substituted by substituted amido, provided that the heteroaryl moiety in the substituent has 5 or 6 atoms with one or more heteroatoms An aromatic ring; (Ii) unsubstituted, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, hetero Aryloxy, C ₁ -C ₆ alkylthio, C ₆ or C ₁₀ arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, heteroaryl, C ₁ -C ₆ acyl, carbo C ₆ or C ₁₀ aryloxy, carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or unsubstituted or 1 or 2 C ₁ -C ₆ alkyl group C ₆ -C ₁₄ 2 (bi) or 3 (tri) -cyclic ring systems containing 0 to 3 heteroatoms and 0 to 2 unsaturations, which may be substituted with substituted amido, provided heteroaryl in the substituent A part is a 5 or 6 membered aromatic ring having one or more hetero atoms; (Ⅲ)

Where x is the attachment point, Q ₁ , Q ₂ is O or S; W is O, CH ₂ , CHR ₆ , or a bond; R ₁ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ or C ₁₀ aryl or 5 with one or more hetero atoms Or heteroaryl which is a 6 membered aromatic ring; R ₂ is H, C ₁ -C ₃ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl; R ₃ is H, R ₁ , OR ₁ , OC (O) R ₁ , OC (O) OR ₁ or CO (O) NR ₁ R ₆ ; R ₄ and R ₅ are independently H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl, but the total of R ₄ and R ₅ Carbohydrates are 6 or less, and R ₄ and R ₅ may combine to form a C ₃ -C ₆ ring; R ₆ and R ₇ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl or at least one of R ₆ and R ₇ is H; (d) M is C (O) CH ₂ CH ₂ OCH ₃ . delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete The compound of claim 1, wherein A is C ₃ -C ₁₄ cycloalkyl containing 0-3 heteroatoms and 0-2 unsaturation, which is unsubstituted or halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio, C ₆ or C ₁₀ arylthio, heteroarylthio , C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, heteroaryl, C ₁ -C ₆ acyl, carbo C ₆ or C ₁₀ aryloxy, Carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or amido unsubstituted or substituted with 1 or 2 C ₁ -C ₆ alkyl groups, wherein the heteroaryl moiety is substituted with one or more heteroatoms. Compound having a 5 or 6 membered aromatic ring having. The compound of claim 1, wherein A is a C ₆ -C ₁₄ bi- or tricyclic ring system containing 0-3 heteroatoms and 0-2 unsaturation, which is unsubstituted or halogen, Hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio , C ₆ or C ₁₀ arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, heteroaryl, C ₁ -C ₆ acyl, carbo C ₆ or C ₁₀ aryloxy, carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or amido unsubstituted or substituted with 1 or 2 C ₁ -C ₆ alkyl groups, wherein A heteroaryl moiety in a substituent is a compound characterized in that it is a 5 or 6 membered aromatic ring having one or more hetero atoms. The method of claim 1, A is

Is, Where * is the attachment point Q ₁ , Q ₂ is 0 or S; W is 0, CH ₂ , CHR ₆ , or a bond; R ₁ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ or C ₁₀ aryl or 5 with one or more hetero atoms Or heteroaryl which is a 6 membered aromatic ring; R ₂ is H, C ₁ -C ₃ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl; R ₃ is H, R ₁ , OR ₁ , OC (O) R ₁ , OC (O) OR ₁ or CO (O) NR ₁ R ₆ ; R ₄ and R ₅ are independently H, C ₁ -C ₆ alkyl, or C ₂ -C ₅ alkenyl, but the total of R ₄ and R ₅ The sum of carbons is 6 or less, and R ₄ and R ₅ may be taken together to form a C ₃ -C ₆ ring; R ₆ and R ₇ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C ₂ -C ₅ alkenyl Or C ₂ -C ₅ alkynyl, wherein at least one of R ₆ and R ₇ is H. The compound of claim 1, wherein Z is 0. The compound of claim 1, wherein Z is 0 and A is C ₃ -C ₁₄ cycloalkyl containing 0-3 heteroatoms and 0-2 unsaturation, which is unsubstituted, halogen, hydroxy, C _1- C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio, C ₆ or C ₁₀ Arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, heteroaryl, C ₁ -C ₆ acyl, carbo C ₆ Or C ₁₀ aryloxy, carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or amido unsubstituted or substituted with 1 or 2 C ₁ -C ₆ alkyl groups, wherein the heteroaryl portion of the substituent is one Or a 5 or 6 membered aromatic ring having more hetero atoms. The compound of claim 1, wherein Z is 0 and A is a C ₆ -C ₁₄ bi- or tricyclic ring system containing 0-3 heteroatoms and 0-2 unsaturated. Unsubstituted or halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cyano, nitro, C ₆ or C ₁₀ aroyl, C ₆ or C ₁₀ aryloxy, heteroaryloxy, C ₁ -C ₆ alkylthio, C ₆ or C ₁₀ arylthio, heteroarylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₈ acyloxy, C ₆ or C ₁₀ aryl, hetero Aryl, C ₁ -C ₆ acyl, carbo C ₆ or C ₁₀ aryloxy, carboheteroaryloxy, C ₁ -C ₆ carboalkoxy or unsubstituted or 1 or 2 A compound substituted with amido substituted with a C ₁ -C ₆ alkyl group, wherein the heteroaryl portion of the substituent is a 5 or 6 membered aromatic ring having one or more heteroatoms. The compound of claim 1, wherein Z is 0, A is

Wherein * is the point of attachment. Provided that Q ₁ and Q ₂ are O or S; W is 0, CH ₂ , CHR ₆ or bond, R ₁ has C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₆ or C ₁₀ aryl, or one or more hetero atoms Heteroaryl which is a 5 or 6 membered aromatic ring; R ₂ is H, C ₁ -C ₃ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl; R ₃ is H, R ₁ , OR ₁ , OC (O) R ₁ , OC (O) OR ₁ or CO (O) NR ₁ R ₆ ; R ₄ and R ₅ are independently H, C ₁ -C ₆ alkyl, or C ₂ -C ₅ alkenyl, but the sum of the carbon number of R ₄ and R ₅ is 6 or less, and R ₄ and R ₅ are combined Can form a C ₃ -C ₆ ring, R ₆ and R ₇ are independently H, C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, but at least of R ₆ and R ₇ One is H. A bactericidal composition comprising the compound of any one of claims 1 and 35 to 41 and a botanically acceptable carrier. 43. The method of claim 42, further comprising at least one other compound selected from the group consisting of insecticides, fungicides, herbicides, nematode agents, mite killers, arthropod killers, bacterial fungicides, and combinations thereof. Composition. A method of controlling or preventing fungal infection comprising applying a bactericidal effective amount of the compound of any one of claims 1 and 35 to 41 to a bacterial habitat or to a place where the infection is to be controlled or prevented. 42. A composition comprising a hydrate, salt or complex of a compound of any one of claims 1 and 35-41.