WO2000053545A1 - Process for the synthesis of dihydropyridones - Google Patents

Abstract

This invention relates to a process of synthesizing dihydropyridone compounds of Formula (I). The process of the present invention can also be used to synthesize a library of dihydropyridone compounds represented by Formula (I).

Description

PROCESS FOR THE SYNTHESIS OF DfflYDROPYRJDONES

FIELD OF INVENTION

The present invention relates to a process for the synthesis of dihydropyridone compounds of Formula I.

BACKGROUND OF THE INVENTION

A variety of small organic molecules are of interest since they can have potentially useful pharmacological activity. Among small organic molecules, nitrogen heterocycles hold a special place as historical pharmacophores.

Recent advances in combinatorial chemistry have significantly accelerated the process of drug discovery. In particular, combinatorial chemistry techniques have enabled synthesis of a large number of small organic molecules in a very expeditious manner.

Combinatorial library i.e., a library containing a large number of small organic molecules is useful as a research tool. In particular use of such libraries allows determination of biological binding properties of a large number of molecules. There is thus a need of an efficient process which will allow synthesis of small organic molecules, in particular nitrogen heterocycles, as well as a combinatorial library of such molecules.

SUMMARY OF THE INVENTION

Keeping the above discussed needs in mind the present invention provides a process for the synthesis of dihydropyridone compounds of Formula I. The process of the present invention can also be used to synthesize combinatorial libraries of dihydropyridone compounds of Formula I. DETAILED DESCRIPTION OF THE INVENTION

The present invention thus provides a process for the synthesis of a compound of Formula I:

.Formula I

wherein:

R¹ represents H, an amino acid side chain, (CH₂)_0-4-ρhenyl, (CH₂)ι.₆-NH-C(O)-O-alkyl,

(CH₂)_1-4-phenoxy, (CH₂)_1-6-NH-C(O)-O-(CH₂)-Ph, (CH₂)₀-₄-indole, C_1-4 alkyl, or (CH₂)_0-

4-S-alkyl;

R² represents Cι_-4-alkoxyphenyl, di-C_1-4-dialkylphenyl, Cι_-8-alkylphenyl, halophenyl, halo-C_1-4-alkyl phenyl, benzyl, cyanophenyl, -Cs-io-cycloalkyl, biphenyl, or Cι- -alkyl;

R represents C_1-14-alkyl, C_2-ι₄-alkenelene, aryl, substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalkyl, or -Ci-g alkyl-R⁵;

R⁴ represents H or alkyl;

R⁵ represents aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, C_1-8-alkylethers, -C_1- -alkyltertiaryamines, or

X represents O, NH or S; the process comprising the steps of:

(i) reacting a compound of Formula A

with a compound of Formula B

.Formula B,

to yield a compound of Formula C

where SS represents a solid support, and R¹ and R² are as defined before; (ii) treating a compound of Formula C with a compound of Formula D

R -X-H .Formula D,

where R , and X are as defined before, to yield a compound of Formula I.

One preferred embodiment of the present invention provides a process wherein, step(i) comprises reacting a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, DCC and EDC, and a dialkyl amino pyridine catalyst; and step (ii) comprises treating a compound of Formula C with a compound of Formula D in the presence of an amine base. A further preferred embodiment provides a process wherein the coupling agent in step(i) is DIC, the catalyst is dimethyl amino pyridine(DMAP); and the amine is triethyl amine.

Another preferred embodiment of the present invention provides a process wherein, R¹ represents CH₂-Ph, Ph, (CH₂)₄-NH-C(O)-Cι_-4-alkyl,

— -H,C- ^■o- ^•(CH₂) '₍0^"3 ^•CH, or

R represents p-Cj_-4-alkoxy phenyl, 3,5-dialkyl phenyl, Cι_-4-alkyl phenyl, p-halophenyl, 3,5-trifluoromethyl phenyl, benzyl, 4-cyanophenyl, 4-alkyl-phenyl, cyclohexyl, biphenyl, or alkyl; and R³ represents C₂H₅,

A further preferred embodiment is one wherein R² represents p-methoxy phenyl, 3,5-dimethyl phenyl, p-bromo phenyl or 4-methyl phenyl. EXPERIMENTAL DETAILS

General Comments

Discussed below are processes for the synthesis of compounds of Formula B (Scheme I) and the novel process for the synthesis of dihydropyridone compounds of Formula I (Scheme II).

Preparation of Compounds of Formula B

Scheme I:

Step- A: General Procedure

In a reaction vessel was placed an amino ester 1, and from about 0.5 to about 1.6 mole equivalents of an aldehyde 2, both preferably as inert solvent solutions, for example THF solutions. To this mixture was added about 1.5 to about 2 mmol of magnesium sulfate, as a drying agent. This resulting mixture was mixed and was then combined with additional magnesium sulfate (0.8 to 2 equivalents). After cooling this mixture to low temperatures, preferably from about 10°C to about -78°C, one mole equivalent of zinc chloride was added, while maintaining the reaction mixture at a temperature of about 0°C.

To this cold reaction mixture was then added l-methoxy-3-trimethylsilyl-oxy-l,3- butadiene (Danishefsky's Diene) in four equal portions over a period of four hours (once every hour). A total of about 1 to 2 mole equivalents of the Danishefsky's Diene was added. The reaction mixture was maintained at a low temperature of about 0°C throughout the diene addition, and then stirred for 12-18 hours at about 0°C after the addition of the diene was completed.

The magnesium sulfate was separated from the reaction mixture and the magnesium sulfate was washed with DCM. The DCM washings were mixed with the filtered reaction mixture and this new reaction mixture was extracted, in succession, with an inorganic acid, preferably 2N HC1, NaHCO₃ (x 2), dried (Na₂SO ) and concentrated under reduced pressure to yield a compound of Formula 3 as an oil.

Step-B: General Procedure

The hydrolysis procedure, converting a compound of Formula 3 to Formula B, comprises combining an alcohol and an inert solvent, preferably a mixture of methanol- THF solution of a compound of Formula 3 with from about 2 to about 6 mole equivalents of NaOH and stirring this mixture for 8-16 h. This reaction mixture was then diluted with ether and extracted with water (x2). The aqueous layers were combined and further washed with ether (xl), and acidified (preferably with HC1) to a pH of about 0.5 to about 2.5. This acidic mixture was then extracted with DCM (x3), dried with sodium sulfate and concentrated to yield a compound of Formula B.

Amino Esters (Compounds of Formula 1):

Most amino esters 1 with side chain protecting groups can be used in Scheme I, step A for the hetero-Diels Alder reaction with Danishefsky's Diene. Hydrophobic aminoesters are preferred. Illustrative examples of the hydrophobic aminoesters are tryptophan methyl ester (Trp-OMe), lysine (epsilon Boc-amine) methyl ester (Lys(BOC)- OMe), and tyrosine (benzyl ether) methyl ester (Tyr(Bz)OMe). Listed in Table I are additional examples of the amino esters, compounds of Formula 1 that can be used in Step A of Scheme I.

Table I

Aldehydes (Compounds of Formula 2)

Aliphatic, aromatic, and heteroaromatic aldehydes, represented by Formula 2, were useful in Step A, Scheme I, to yield compounds of Formula 3. Hydrophobic aldehydes were preferred since they seemed to enhance the solubility of the products during the extractive workup. Table LT lists representative aldehydes, compounds of Formula 2, that can be used in the novel process of the present invention. Table II

R²-CHO

Table π (Continued)

R²-CHO

Synthesis of Compounds of Formula I

The following synthetic Scheme LI outlines the novel process for synthesis of dihydropyridone compounds of Formula I.

Scheme LI

Formula A Formula B

Formula C

Formula I Step (i) Acylation of Thiophenol resin: Preparation of a compound of Formula C

A solution of DIC and a compound of Formula B, (approx. 1 mole equivalent relative to the thiophenol resin (Formula A) in DCM was allowed to sit for about 15 to about 30 min. To this mixture was added a thiophenol resin of Formula A, and from about 0.08 to about 0.2 equivalents (relative to the thiophenol resin) of DMAP. This reaction mixture was mixed for about 10 to 24 hours leading to the formation of a compound of Formula C, as a solid. The solid was collected by filtration and washed in succession (up to five times each), with DCM, an inert solvent (preferably THF) MeOH, THF, and dried by conventional methods, preferably air dried, to yield a compound of Formula C.

Step (ii): Preparation of a compound of Formula I

To a mixture of an inert solvent (preferably dioxane), an amine, and a cleaving nucleophile (R³-X-H, Formula D) was added a compound of Formula C. The ratio of dioxane/triethylamine/R XH (Formula D), was preferably maintained at 8:1:1. Any amine, known to one skilled in the art, which is capable of acting as a base can be used instead of triethyl amine. Should the compound of Formula D be volatile, an excess amount of a compound of Formula D can be used in order to maintain the desired concentration. The resulting mixture was placed in a preheated oven at about 40 °C for 10 to 24 hours. This reaction mixture was then filtered, by conventional means, and the filtered residue was washed with dioxane. The combined dioxane mixture was frozen and was then lyophilized. Lyophilization was generally accomplished, by conventional methods known to one skilled in the art, at about 5°C and over a period of about 10-18 hours. This process yielded compounds of Formula I as a solid. Cleaving Nucleophiles (R³-X-H, Formula D)

A variety of primary, secondary, and tertiary alcohols can be used as cleaving nucleophiles (R³-X-H, Formula D) in the novel process of the present invention. Preferred cleaving nucleophiles are low boiling, low molecular weight primary alcohols.

Table LLI, lists alcohols (compounds of Formula D) that are useful as cleaving nucleophiles in the novel process of the presently claimed invention.

Table HI

R'-X-H

Table HI (Continued)

R'-X-H

Table HL (Continued)

R³-X-H

Table LU (Continued)

R'-X-H

The process of the present invention can also be used to synthesize a library of compounds of Formula I. The following experimental procedure outlines a general procedure for the synthesis of such a library.

Experimental Procedure:

Dihydropyridone scaffolds (compounds of Formula 3) were prepared in sets of 30, by reaction between two free amino esters (compound 1) and fifteen different aldehydes (compound 2). In individual Pyrex jars, an amino ester 1 (50 mmol each, in its free base form following extraction with bicarbonate) and an aldehyde 2 (50 mmol each) were dissolved in 50 mL of dry THF. Approximately 9.0 g (75 mmol, 1.5 equiv) of magnesium sulfate was added to each reaction mixture in the individual pyrex jars. After shaking for 10 minutes at ambient temperature the reaction mixtures were transferred to fresh Pyrex jars containing fresh 6.0 g (50 mmol) of magnesium sulfate. These Pyrex jars were cooled in a freezer ( to -78 °C) for 10 minutes and then zinc chloride (100 mL, 50 mmol, 1 equivalent) was added as a 0.5 M solution in THF (available from Aldrich Chemicals) to each jar. The jars were then placed in the freezer for 15 minutes at -78 °C.

Danishefsky's diene (l-methoxy-3-trimethylsilyl-oxy-l,3-butadiene) (1.2 equiv, 60 mmol, 12.5 mL total) was added to each reaction mixture in four 3.15 mL portions over a four hour period (once/hour). In between additions the reaction mixtures were stored at 0°C. After the addition of Danishefsky's diene was completed the resulting reaction mixtures were maintained at 0°C for 8-16 hours.

These reaction mixtures were then individually decanted in to a mixture of 100 mL 2N HC1 and 25 mL DCM in separatory funnels leaving the magnesium sulfate behind. After extraction and separation, the aqueous layer was rinsed twice with 15 mL DCM. The combined organic layers were backwashed with about 100 mL (+ 10 mL) saturated aqueous sodium bicarbonate (NaHCO₃). After collecting the organic layer, approximately 2.5 g of sodium sulfate (Na_sSO ) was added as a drying agent, followed by 1.0 g of decolarizing carbon.

The resulting solutions were filtered through fritted syringes (catalog #2456, Applied Separations, ca. 1 inch diameter) packed with 0.75 inches of silica gel topped with 0.75 inches of Celite (the silica gel was primed with 10 mL DCM). The eluents were individually collected in respective appropriately labeled 50 mL Falcon Tubes (two Falcon Tubes per product to keep the volume in each Falcon tube below 35 mL and avoid bumping in the Savant vacuum centrifuge). The solvent from the samples in the Falcon Tubes was concentrated in parallel with a commercially available Savant vacuum centrifuge fitted with an adapter for Falcon Tubes to yield an oily residue. Alternatively, the solutions can be individually concentrated in round-bottom flasks using a rotary evaporator.

After concentration the resulting oily residues were hydrolysed by individually redissolving/suspending in MeOH/THF (1:3, total volume: 150 mL) and transferring in to 250 mL pyrex jars followed by addition of 50 mL of 3 N NaOH (3 equiv, 150 mmol). These resulting individual mixtures were shaken for 8-12 hours.

The reaction mixtures were individually added to a mixture of ether (150 mL) and water (100 mL) in separatory funnels. Following extraction, the aqueous layer was collected in appropriately labeled containers and was washed two more times with ether (150 mL). The combined aqueous layer was acidified to a pH of 1 using hydrochloric acid. The acidified aqueous layer was extracted with 3 x 10 mL of DCM. The combined organic layers (ca. 30-35 mL) were backwashed with 50 mL saturated aqueous NaCl, dried(Na₂SO ) and then concentrated either in pretared Falcon tubes with a commercially available Savant vacuum centrifuge (Savant Instrument Company, Holbrook, NY) or individually in round-bottom flasks via standard rotary evaporation, to yield compounds of Formula 3.

Employing the above optimized procedure, scaffolds (compounds of Formula 3) were reliably obtained in sufficient purity and quantity (as determined by in-process analysis) for further use. Specifically, every scaffold that was selected to load onto resin (compound of Formula A) was identified by LC-MS and was present as greater than 50% AUC at 214 nm. The mass balance of each selected scaffold also correlated to greater than 0.8 molar equivalents relative to resin (loading 1.0 mmol/g). Enough resin was used with all scaffolds to provide 100 mg of resin (1.0 mmol/g)/well for a yield of 0.1 mmol well of final products.

The selected scaffolds derived from each amino ester were acylated onto a thiophenol resin (Formula A) according to the following procedure. A 0.1 M solution of DIC and the appropriate scaffold, of Formula 3, (5-10 mmol, depending on the mass balance of the particular scaffold) in 50-100 mL in DCM was allowed to react for 15 min. Then 5.0 g (5.55 mmol based on theoretical loading 1.11 g/mol) thiophenol resin was added followed by 63 mg (0.5 mmol) of DMAP catalyst. The reaction mixtures in the jars were sealed and shaken for 18 h.

After the acylation was complete, the resins were rinsed thoroughly with DCM (5x), THF (5x), MeOH (5x), THF (5x), and anhydrous dioxane (3x).

The derivatized thiophenol resin was transferred into clamped Polyfiltronics plates (2.7 μ) either as slurries in dioxane or as dry samples with shallow well (<0.5 cm high) microtiter plates. With the Robbins Scientific Hydra (96 automated parallel syringes in a microtitor plate format, Robbins Scientific, Sunnyvale, CA) 1.0 mL of a 8:1:1 (v/v/v) mixture of dioxane/triethylamine/alcohols (#1-X) was added to each resin. The top of the plates were clamped shut and the plates were placed in a preheated oven at 40°C for up to 12 h. The plates were removed from the oven and the products were collected in a pretared 2 mL Beckman microtitor plate by gravity filtration followed by positive nitrogen pressure. The plates were rinsed in parallel with 0.7 mL of dioxane employing an ATR moduline apparatus (ATR Biotech, Inc., Emeryville, CA). The resulting dioxane solutions were placed in a -78 °C freezer until frozen. The solvent was removed in parallel via lyophilization at 5°C with a tray lyophilizer (Virtis, Gardiner, NY). The plates were then removed from the tray lyophilizer and placed in a desiccater under high vacuum overnight prior to quality analysis of the resulting library products. Library products were identified by Mass Spectroscopy (MS).

SYNTHESIS OF SPECIFIC EXAMPLES

Representative compounds of Formula C (Standards 1-6) were prepared using the novel process of the present invention as discussed below.

Step (i): Acylation of Thiophenol resin: Preparation of a compound of Formula C.

A 0.1 M solution of DIC and a compound of Formula B (5-10 mmol) in 50-100 mL in DCM was allowed to react for 15 min. Then 5.0 g (5.55 mmol based on theoretical loading 1.11 g/mol) thiophenol resin (compound of Formula A) was added followed by 63 mg (0.5 mmol) of DMAP catalyst. The reaction vessel was sealed and shaken for 18 h.

The resin was rinsed thoroughly with DCM (5x), THF (5x), MeOH (5x), THF (5x), and anhydrous dioxane (3x), and then air dried to yield a compound of Formula C.

Step (ii): Preparation of a compound of Formula I:

The derivatized resin, compound of Formula C above, was mixed with 1.0 mL of a 8:1:1 (v/v/v) mixture of dioxane/triethylamine/alcohol. This reaction mixture was maintained at about 40°C for 12 hours. The product formed was then collected by filteration and diluted with about 1 mL dioxane. The dioxane solution was lyophilized at about 5°C over 12 hours, the product thus obtained was dried and identified by mass spectroscopy

N-[(S)-l-(-'e -Butoxyethoxycarboπyl)-2-phenylpropyl]-(6R) 2,3-didehydro-6-p- toluoylpiperidin-4-one (Standard 5) was prepared by the process of the present invention. This compound was obtained as a 9:1 ratio of diastereomers. The major diastereomer was purified by HPLC and characterized:

1H NMR (300 Mhz, CDC1₃) D = 1.20 (s, 9 H; CH₃), 2.34 (s, 3 H; CH₃), 2.66 (dd, J = 6.3 Hz, 16.9 Hz, 1 H; CH₂), 2.70 (dd, J = 13.3 Hz, 16.9 Hz, 1 H; CH₂), 2.97 (dd, J = 10.4 Hz, 14.1 Hz, 1 H; CH₂), 3.24 (dd, J = 5.1 Hz, 14.1 Hz, 1 H; CH₂), 3.54 (t, J = 4.2 Hz, 2 H; CH₂), 3.91 (dd, J = 5.1 Hz, 10.4 Hz, 1 H; CH), 4.23 (t, J = 4.2 Hz, 2 H; CH₂), 4.71 (dd, J = 6.3 Hz, 13.3 Hz, 1 H; CH), 5.42 (d, J = 7.8 Hz, 1 H; CH), 6.71 (d, J = 7.8 Hz, 1 H; CH), 7.30 (b, m, 7 H; Ar), 7.52 (d, J = 7.8 Hz, 2 H; CH); LC-MS: 436 for (M + H).

Standard 2

Standard 1

C2δH 27N0₄ C25H27NO₃

Exact Mass: 405.19 Exact Mass: 389.20

Mol. Wt.: 405.49 Mol. Wt.: 389.49

C, 74.05; H, 6.71 ; N, 3.45; O, 15.78 77.09; H, 6.99; N, 3.60; O, 12.32

Standard 3 Standard 4

C₂₅H3₅Nθ3 CsgHgsNOg

Exact Mass: 397.26 Exact Mass: 477.25

Mol. Wt.: 397.55 Mol. Wt.: 477.59

C, 75.53; H, 8.87; N, 3.52; O, 12.07 C, 72.93; H, 7.39; N, 2.93; O, 16.75

Standard 6

Mol. Wt.: 571.50

C, 60.95; H, 6.17; Br, 13.98; N, 4.90; O, 14.00 C2₉H₃₀F6N2Q5

Exact Mass: 600.21

Mol. Wt.: 600.55

C, 58.00; H, 5.04; F, 18.98; N, 4.66; O, 13.32 Analysis Methods:

LC-MS: Mass Spectra data was obtained using the following instruments and conditions.

Sciex 150 MCA

Sample: 10 μL injection

Solvent A: 99% water + 1% methanol + 0.1% acetic acid

Solvent B : 99% methanol + 1 % water + 0.1% acetic acid

Flow rate: 0.5 mL/min

UV detection at 214 and 254 nm

Turbo ion spray source

LC: Shimadzu LC-10

UV: Shimadzu SDD-10

Auto sampler: Gilson 215.

HPLC: HPLC data was obtained using the following instruments and conditions.

HP1100 with Zorbax SB-C18 4.6 mm x 7.5 cm column

Solvent A: 99.9% water + 0.1% trifluoroacetic acid

Solvent B: 99.9% methanol + 0.1% trifluoroacetic acid

Sample: 5 μL injection

Flow rate: 1.0 mL/min

Ramp: 1-100% Solvent B over 9 min, then 100% Solvent B for 2 min

UV detection at 214 and 254 nm

DEFINITIONS

As used in the present invention the following terms and abbreviations have the following meaning, unless otherwise indicated.

Library of compounds: This term indicates a collection of independent (individual) compounds that are synthesized by the process of the present invention. Generally the term library of compounds indicates a collection of individual compounds distinct from one another. Also included in the library of compounds is a mixture of the individual compounds.

"Alkyl", or "alkyl radical" is meant to indicate a hydrocarbon moiety of up to 8 carbon atoms. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic.

The term "alkylene" represents an alkyl group, as defined above, except that it has at least one center of unsaturation, i.e., a double bond. Illustrative examples are butene, butadiene, propene, and pentene.

The term "cycloalkyl", "cycloalkyl ring", or "cycloalkyl radical" indicates a saturated or partially unsaturated three to ten carbon monocyclic or bicyclic hydrocarbon moiety which is optionally substituted with an alkyl group. The term straight chain alkyl is meant to represent an unbranched hydrocarbon moiety of up to 8 carbon atoms. An example of a straight chain alkyl is a n-pentyl group.

The term "hetero cycloalkyl" or "hetero cycloalkyl radical" means cycloalkyl, as defined above, except one or more of the carbon atoms indicated are replaced by a hetero atom chosen from N, NR¹², O , S(O), S(O)₂ and S, wherein R¹² is (C,.₆)alkyl, hetero(C_2-6)alkyl or hydrogen. Illustrative examples of the term heterocyclo(C_5-ι₄)alkyl are morpholinyl, indolinyl, piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

The term "aryl" means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated. Thus a C₆-Cι₄ aryl group includes phenyl, naphthyl, anthracenyl, etc. The term "heteroaryl" means aryl, as defined above, wherein one or more of the carbon atoms is replaced by a hetero atom chosen from N, O, and S. The hetero atoms can exist in their chemically allowed oxidation states. Thus Sulfur (s) can exist as a sulfide, sulfoxide, or sulfone. Each heteroaryl ring comprises from five (5) to fourteen (14) atoms. Illustrative examples of heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, quinolyl, and pyrazinyl.

The term "amino acid side chain" as used herein represents a natural or unnatural amino acid. The term "natural amino acid", as used herein is intended to represent the twenty naturally occurring amino acids in their L' form, which are some times also referred as 'common amino acids', a list of which can be found in Biochemistry, Harper & Row Publishers, Inc. (1983). The term "unnatural amino acid", as used herein, is intended to represent the 'D' form of the twenty naturally occurring amino acids described above. It is further understood that the term unnatural amino acid includes homologues of the natural amino acids, and synthetically modified form of the natural amino acids. The synthetically modified forms include amino acids having alkylene chains shortened or lengthened by up to two carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids comprised halogenated groups, preferably halogenated alkyl and aryl groups.

The term "natural amino acid side chain" is intended to represent a natural amino acid ("natural amino acid" as defined above) wherein a keto (C=O) group replaces the carboxylic acid group in the amino acid. Thus, for example, an alanine side chain is C(=O)-CH(NH₂)-CH₃; a valine side chain is C(=O)-CH(NH₂)-CH(CH₃)₂; and a cysteine side chain is C(=O)-CH(NH₂)-CH₂-SH. The term "unnatural amino acid side chain" is intended to represent an unnatural amino acid ("unnatural amino acid" as defined above) wherein a keto (C=O) group replaces the carboxylic acid group forming unnatural amino acid side chains similar to ones illustrated under the definition of "natural amino acid side chain" above.

"Optional substituents" for aryl, hetero aryl, and Ph groups are R⁷ and R⁸. These R , and R substituents at each occurrence are independently selected from a group consisting of H, NH₂, halo, O-Cι_-4 alkyl, NHC₁-C₄ alkyl, N(Cι-C₄)₂ alkyl, and CF₃; while R⁸ is selected from H and C_1-4 alkyl.

The term "amine base" as used herein is intended to represent a tertiary amine, preferably having a low boiling point. Illustrative examples of an amine base are triethyl amine and trimethyl amine. The term "alkyl amine" is intended to represent an amino compound wherein the nitrogen atom is substituted with at least one alkyl group (alkyl as defined earlier).

The term "cleaving nucleophile" as used herein represents a molecule containing a hydroxy, thiol or a primary or secondary amine group capable of functioning as a nucleophile. Preferred cleaving nucleophiles are compounds containing a hydroxy group, i.e., compounds generally referred to as alcohols.

As used in the present invention, the illustration:

generally indicates the point of attachment of the group, comprising the illustration, to another group or atom. The term "Ph" represents an optionally substituted phenyl radical or group. The term . "inert solvent" as used herein represents solvents which do not react with the reagents dissolved therein. Illustrative examples of inert solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.

ABBREVIATIONS AND COMMON NAMES

ACD: Available Chemicals Directory

ACN: acetonitrile

AcOH: acetic acid

AUC: area under the curve

Danishefsky's Diene: l-methoxy-3-trirnethylsilyloxy-l,3-butadiene

DCC: Dicyclo hexyl carbodimide

DCM: dichloromethane

DIC: diisopropylcarbodiimide DMAP: dimethylaminopyridine

EDC: ethyl dimethyl amino propyl carbodimide

HC1: hydrochloric acid

HPLC: high performance liquid chromatography

LC/MS: liquid chromatography/mass spectroscopy

MeOH: methanol

NaCl: sodium chloride

NaOH: sodium hydroxide

Na₂SO : sodium sulfate

PyBOP: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophossphate

THF: tetrahydrofuran

Yb(OTf)₃: ytterbium triflate

ZnCl₂: zinc chloride

Claims

A process for the synthesis of a compound of Formula 1:

.Formula 1

wherein:

R¹ represents H, an amino acid side chain, (CH₂)₀.₄ -phenyl, (CH₂)_1-6-NH-C(O)-O-alkyl,

(CH₂)_1-4-phenoxy, (CH₂)_1-6-NH-C(O)-O-(CH₂)-Ph, (CH₂)_0-4-indole, C_1-4 alkyl, or (CH₂)_0-

4-S-alkyl;

R² represents Cι_-4alkoxy phenyl, di-C_1-4dialkyl phenyl, C_1-8-alkyl phenyl, halo phenyl, halo-Cι_-4alkyl phenyl, benzyl, cyano phenyl, -C_5-1o cycloalkyl, biphenyl, or C_]-4-alkyl;

R represents Cι_-14 alkyl, C_2-ι₄ alkenelene, aryl, substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalkyl, or -Cι_-8 alkyl-R⁵;

R⁴ represents H or alkyl;

R represents aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, C_1-8-alkylethers, -Cι_-4-alkyltertiaryamines, or

X represents O, NH or S; the process comprising the steps of: (i) reacting a compound of Formula A

.Formula A,

with a compound of Formula B

.Formula B,

to yield a compound of Formula C

where SS represents a solid support, and R and R are as defined before; (ii) treating a compound of Formula C with a compound of Formula D

R -X-H .Formula D,

where R , and X are as defined before, to yield a compound of Formula 1.

2. A process of claim 1 wherein, step(i) comprises reacting a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, DCC and EDC, and a dialkyl amino pyridine catalyst.

3. A process of Claim 2 wherein step (ii) comprises treating a compound of Formula C with a compound of Formula D in the presence of an amine base.

4. A process of claim 2 wherein the coupling agent in step(i) is DIC; the catalyst is DMAP; and the amine is triethyl amine.

5. A process of claim 1 wherein:

R¹ represents CH₂-Ph, Ph, (CH₂)₄-NH-C(O)-d_-4 alkyl,

R² represents p-C_1-4-alkoxy phenyl, 3,5-dialkyl phenyl, d- -alkyl phenyl, p-halo phenyl, 3,5-trifluoromethyl phenyl, benzyl, 4-cyano phenyl, 4-alkyl-phenyl, cyclohexyl, biphenyl, or alkyl; and R³ represents C₂H₅,

6. A process of Claim 5 wherein

R² represents p-methoxy phenyl, 3,5-dimethyl phenyl, p-bromo phenyl, or 4-methyl phenyl.