WO2000003681A2

WO2000003681A2 - Process for the synthesis of benzopyran derivatives

Info

Publication number: WO2000003681A2
Application number: PCT/US1999/015993
Authority: WO
Inventors: James Guy Breitenbucher; Hon C. Hui; Gianine M. Figliozzi
Original assignee: Axys Pharmaceuticals, Inc.
Priority date: 1998-07-16
Filing date: 1999-07-14
Publication date: 2000-01-27
Also published as: WO2000003681A3; AU4997199A

Abstract

The present invention provides a process for the synthesis of benzopyran based compounds represented by Formula (1). Also disclosed are novel benzopyran based compounds represented by Formula (E) and Formula (3).

Description

PROCESS FOR THE SYNTHESIS OF BENZOPYRAN DERIVATIVES

FIELD OF INVENTION

The present invention relates to a process for synthesis of compounds having a benzopyran skeleton.

BACKGROUND OF THE INVENTION

It is known that compounds having benzopyran related structures possess useful biological activity. One of the early benzopyran known to be biologically active was Cromakalim, as reported by Ashwood et. al., in J. Med. Chem. 1986,

29, 2194-2201. Synthesis of benzopyran compounds has been widely reported along with their potential biological activity.

Gadwood et. al., in J. Med. Chem., 1993, 36, 1480-1487, report the synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers. This article reports benzopyran compounds having a significantly higher in vitro and in vivo hypotensive potency than Cromakalim.

Atwal et. al., in J. med. Chem., 1995, 38, 3236-3245, report the structure activity relationship studies on benzopyranyl cyanoguanidines (which have a benzopyran nucleus) as a selective ATP-sensitive potassium channel opener. It has also been reported by Sarges et. al., in J. Med. Chem., 1990, 33, 1859-1865, that benzopyran based compounds, such as spiro hydantoins, have aldose reductase inhibitory activity useful in treating diabetes.

As discussed above, benzopyran based compounds seem to possess useful biological activity. Efforts continue to make a wider variety of compounds having a benzopyran nucleus. Current synthetic methods useful in making benzopyran derivatives are slow and time consuming. There is thus a need for a new process that will synthesize a plurality of benzopyran compounds in a short amount to time. Such a library of compounds can then be evaluated for its biological activity. SUMMARY OF THE INVENTION

Keeping the above discussed needs in mind the present invention provides a process to synthesize benzopyran compounds of Formula 1 :

Formula 1

wherein:

R ^a and R^1b are independently selected from a group consisting of H, C C₄ alkyl radical, -C C₄ alk-C₆-C₁₀ aryl, -C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or

R^1a and R^1b along with the carbon atom that they are attached form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R² is selected from a group consisting of -(CH₂)₁^-O-C₁-C₄ alkyl, C C₆ alkyl optionally substituted with C C₄ alkyl radical, C₄-C₁₀ cycloalkyl, C₄-C₁₀ partially saturated cycloakyl, C₅-C₁₀ heterocycloaklyl, -N(C_rC₄)₂ alkyl, -O-alkyl, aryl, heteroaryl, or

R³ is selected from a group consisting of C,-C₄ alkyl radical, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical -NH- C_rC₄ alkyl, -CH₂-O-C₆C₁₀ aryl, -(CH₂) (-S-(CH₂)^-C(O)-O-C alkyl, -(CH₂)_1-4-C₆-C₁₀ aryl, C₆-C₁₀ aryl, said alkyl groups being optionally substituted with one or more of C _Λ alkyl, halo, -S-C^ alkyl, -O-C^ alkyl, and -C₆.₁₀ aryl;

R^4a is selected from a group consisting of H, C₄-C₆ cyclo alkyl radical, C_1J} alkyl-O- C^ alkyl, and C C₆ alkyl optionally substituted with C₁-C₄ alkyl radical, -NH₂, - N(C₁-C₄)₂ alkyl, OH, -O-alkyl, aryl, heteroaryl, or

R^4b represents H; or

R^4a and R⁴ along with the nitrogen to which they are attached form

R⁵ is selected from a group consisting of H, Q,_Λ alkyl, -O-C^ alkyl,

-C₄_₈ branched alkyl, and aryl; R⁶ is selected from a group consisting of H, C,-C₄ alkyl radical, -(CH₂)₁^-C₆-C₁₀ aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O-

C alkyl;

R⁹ independently at each occurrence is selected from OH, heteroaryl, and R⁶;

X is selected from -C(O)-, -NH-C(O)-, NH-C(S)-, and -S0₂; and Q is selected from a group consisting of -CH₂, O, S, SO, S0₂, -N-heteroaryl,

-NR⁶, and -N-C(O)R⁶; O 00/03681

the process comprising the steps of:

(i) reacting a compound of Formula A

SS-(CH₂) halo Formula A

where SS is a solid support and halo represents Cl, Br, F, or I, with a compound of Formula B

.Formula B

to yield a compound of Formula C

.Formula C;

(ii) reacting a compound of Formula C with a compound of Formula D

.Formula D

to yield a compound of Formula E

... Formula E, wherein SS, and R¹ are as defined earlier;

(iii) coupling a compound of Formula E with a compound of Formula F:

R²-NH, .Formula F

where R² is as defined above, in the presence of a titanium alkoxide reagent, and a borohydride reagent, to yield a compound of Formula G

.Formula G;

(iv) acylating a compound of Formula G with a compound of Formula H

R³-Y Formula H

where Y is -C(O)-CI, -NCO, S0₂CI, or -NCS to yield a compound of Formula J

.Formula J

where X is as defined above; and

(v) cleaving compounds of Formula J using an amine represented by Formula K

R ^aR^4b-NH Formula K wherein R^4a, and R^4b are as defined above, to yield a compound of Formula 1.

The process and procedures of the present invention can also be used for parallel synthesis of a library of compounds of Formula 1.

Another aspect of the present invention provides a compound of Formula E which is useful in synthesizing benzopyran compounds of Formula 1 :

Formula E

where SS is a solid support;

R^1a and R¹ are independently selected from a group consisting of H, C C₄ alkyl radical, -(CH₂)_1-t-C_β-C₁₀ aryl, -C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or R^1a and R^1b along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R⁵ is selected from a group consisting of H, C_lJt alkyl, -O-C^ alkyl,

-C₄.₈ branched alkyl, and aryl;

R⁶ is selected from a group consisting of H, C_rC₄ alkyl radical,

aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O-

C^ alkyl;

In yet another aspect of the present invention is provided a compound of Formula 3 which is useful in synthesizing benzopyran compounds of Formula 1 :

Formula 3 wherein:

R^1a and R^1b are independently selected from a group consisting of H, C_rC₄ alkyl radical,

aryl, -C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or

R^1a and R¹ along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R² is selected from a group consisting of -(CH₂)₁^-O-C₁-C₄ alkyl, C,-C₆ alkyl optionally substituted with C,-C₄ alkyl radical, C₄-C₁₀ cycloalkyl, C₄-C₁₀ partially saturated cycloakyl, C₅-C₁₀ heterocycloaklyl, -N(C₁-C₄)₂ alkyl, -O-alkyl, aryl, heteroaryl, or

R³ is selected from a group consisting of C C₄ alkyl radical, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical -NH- C,-C₄ alkyl, -CH₂-O-C₆C₁₀ aryl, -(CH₂)_M(-S-(CH₂)_M-C(O)-O-C alkyl, -(CH₂)^-C₆-C₁₀ aryl, C₆-C₁₀ aryl, said alkyl groups being optionally substituted with one or more of C^ alkyl, halo, -S-C_M alkyl, -O-C^ alkyl, and -C₆.₁₀ aryl;

R⁵ is selected from a group consisting of H, C_1-4 alkyl, -O-C^ alkyl,

-C₄.₈ branched alkyl, and aryl; R⁶ is selected from a group consisting of H, C C₄ alkyl radical, -(CH₂)₁^-C₆-C₁₀ aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O-

C^ alkyl; and

Z is selected from H, -C(O)-, -H-C(O)-, -NH-C(S)-, and -SO₂; with the proviso that when Z represents H, R³ does not exist.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the present invention provide a process wherein the titanium alkoxide reagent in step (iii) is Ti(O-iPr)₄, Ti(OEt)₄, Ti(OMe)₄, or mixtures thereof. Another preferred embodiment provides a process wherein the borohydride reagent in step (iii) is Na(OAc)₃BH, Na(CNBH₃), NaBH₄, BH₃.pyr, or mixtures thereof.

A further preferred process is one wherein, R^1a and R¹ are independently selected from C C₂ alkyl radical, or R^1a and R^1b along with the carbon atom that they are attached to forms

R² is selected from a group consisting of -C₂.₃ alk-O-CH₃, and C^ alkyl substituted with

R³ is selected from -CH₃,

R^4a is selected from a group consisting of C₄-alkyl, benzyl,

or R^4a and R^4b along with the nitrogen to which they are attached forms the following structure:

R⁵ is H; R⁶ is H; R⁷ at each occurrence is selected from H, and F; R8 is H; R⁹ is H; and X represents -C(O)-, -NHC(S), or -NH-(CO)-.

Another aspect of the present invention provides preferred embodiments of a compound of Formula 2, wherein R^1a and R¹ are independently selected from C C₂ alkyl radical, or R^1a and R^1b along with the carbon that they are attached to forms

R⁵ is selected from a group consisting of H, and C^ alkyl; and R⁶ is H, or -CH₃. A third aspect of the present invention provides a preferred embodiment of a compound of Formula 3 wherein, R^1a and R^1b are independently selected from C C₂ alkyl radical, or R^1a and R ^b along with the carbon that they are attached to forms

R² is selected from -C^ alk-O-CH₃, and C^ alkyl radical, said alkyl radical optionally substituted with

R³ is selected from -CH₃, -C^ alk-C₆ aryl, -CH[C₂H₅-O-C(O)]-(CH₂)₃-S-CH₃, and C₆ aryl, said aryl groups substituted with at least one of H, F, Cl, -CH₃, -C₂H₅, -C₆ aryl, -O-CH₃, and -SCH₃; R⁵ is selected from a group consisting of H, and C,^ alkyl; and R⁶ is H, or -CH₃.

EXPERIMENTAL DETAILS

The following general procedure will further illustrate the process of the present invention. A schematic representation of the process of the present invention is as shown below:

Scheme

Formula J

Formula 1

GENERAL PROCEDURES

The following general procedures further illustrate the process of the present invention.

Preparation of a Compound of Formula C (Thiophenol Resin)

To a DMF solution of sodium methoxide was added 4-hydroxy thiophenol (Formula B) at a temperature ranging from about -20°C to about room temperature. This mixture was stirred for up to 2 hours at room temperature. To this mixture was then added Merrifield resin (Compound of Formula A) (obtained from Midwest Biotech) and the resulting mixture was stirred with mixing for up to about 72 hours at temperatures ranging from about 40°C to about 75°C. This resin mixture was transferred to a filter funnel and washed with solvents in the following sequence: DMF, MeOH, AcOH, 5% HCI in AcOH, methylene chloride, and methanol. Residual solvents were removed by placing the resin in a vacuum oven for up to three days at temperatures of up to about 70°C.

Preparation of a Compound of Formula E

Compounds of Formula E were generally prepared by coupling a benzopyran carboxylic acid (Formula D) to the thiophenol resin of Formula C. To a solution of DIC, and the benzopyran carboxylic acid (Formula D) in methylene chloride was then added a methylene chloride solution of the thiophenol resin (Formula C). To this mixture was further added a base, preferably NMM, and pyridyl base, preferably DMAP, and the resulting mixture was then mixed with shaking for up to 24 hours. The resin thus obtained was washed with methylene chloride, DMF, MeOH, and dried in a vacuum oven for 24 hours at temperatures ranging up to 60°C to yield a compound of Formula E.

Preparation of compounds of Formula G

The general procedure for preparing compounds of Formula G involved reductive amination of a compound of Formula E. The resin of Formula E was swollen with a hydrocarbon based solvent, preferably toluene, to which was then added a titanium alkoxide, and R²-NH₂, an amine of Formula F. This reaction mixture was agitated by bubbling nitrogen gas for up to four hours. The reaction mixture was then diluted with AcOH, and anhydrous THF. To the diluted mixture was then added a borohydride reducing agent and this resulting mixture was further agitated by bubbling nitrogen gas through it for up to two days. The resin from the reaction mixture was then washed with MeOH, THF, Pyridine, MeOH, and DCM. The washed resin was dried under reduced pressure.

Preparation of a compound of Formula J

This was accomplished by acylating a compound of Formula G with a compound of Formula H by mixing the two compounds in an inert solvent, preferably DCM, followed by addition of DIPEA and mixing the resulting mixture for up to 6 hours. The reaction mixture was washed with DCM, DMF, MeOH, pyridine, and DCM. This washed product was dried using conventional methods known to one skilled in the art.

Cleaving compounds of Formula 1 from the solid support

This task was accomplished by reacting for up to three days, a cleaving amine represented by Formula K, with a compound of Formula J, in the presence of a base, preferably pyridine, and DIPEA, in an inert solvent, preferably methylene chloride. The solvents were removed by conventional methods to yield a compound of Formula 1. Benzopyran carboxylic acid compounds of Formula D were generally synthesized as illustrated by the synthetic Scheme II:

Scheme II

R^laR^lb CO, pyrolidine

Formula D

The general synthetic procedure is as described below. The first step involved the synthesis of the 3-hydroxymethyl-4-hydroxy benzoic acid, followed by the synthesis of compounds of Formula D.

Synthesis of 3-carboxymethyl-4-hydroxy benzoic acid

Aluminum chloride (333 g, 2.5 mol) was mixed with 4-hydroxybenzoic acid (138 g, 1.0 mol) and 1 ,1 ,2,2-tetra-chloroethane (400 mL). This reaction mixture was stirred under anhydrous conditions, followed by drop wise addition of acetyl chloride (98 g, 1.25 mol) over 1 hour. The reaction mixture was then heated to 90-100 °C and stirred for ~1 hr to provide a clear solution. The reaction was then heated to reflux for an additional 3-4 hr. The reaction mixture was then cooled to RT and stirred overnight.

The solution was then removed from the solid product by decanting and discarded. The solid product was washed with ether (5X). Ice water (2.0 L) was then slowly added to the solid (CAUTION: vigorous effervescence). After the foaming subsided, HCI (500 mL, 6N) was added and the mixture was stirred for 0.5 - 1 hr forming a yellow solid which was collected by filtration. This solid was then transferred to an erlenmeyer flask, suspended in water and filtered again. This step was repeated a second time to thoroughly clean the solid. The solid was then washed with ether (4X) and dried under high vacuum for two days providing 131 g of pure 3-carboxymethyl-4-hydroxybenzoic acid (73% yield). ¹H- NMR (CD₃OD): d 8.6 (s, 1 H), 8.2 (d, 1 H), 7.0 (d, 1 H), 2.7 (s, 3H). MS (+CI): 181 (MH+).

The 3-carboxymethyl-4-hydroxy benzoic acid above, was then used to prepare compounds of Formula D. Procedures to synthesize illustrative examples of compounds of Formula D are outlined below.

Synthesis of compounds of Formula D

2,2-dimethyl-6-carboxybenzopyran-4-one

The 3-carboxymethyl-4-hydroxy benzoic acid, above, (45 g, 250 mmol) was mixed with toluene (500 mL) and activated molecular sieves (120 g) with stirring. A mixture of acetone (46 mL, 625 mmol) and pyrrolidine (20 mL, 250 mmol) was added to this reaction mixture over 5 min. The solution was then refluxed for 3-4 hr. After cooling the molecular sieves were removed by filtration and washed with EtOAc. The filtrate was then extracted with Na₂CO₃ (10% aq). The aqueous extract was washed with EtOAc, acidified to pH 2-3 with HCI (6N) and extracted with EtOAc. The organic extracts were washed with water followed by brine, dried (Na₂SO₄), and concentrated in vaccuo. Resulting solid was suspended in ether and collected by filtration providing the desired benzopyran (22.5 g, 41 % yield). ¹H-NMR (CDCI₃): d 8.7 (s, 1 H), 8.2 (dd, 1 H), 7.0 (d, 1 H), 2.8 (s, 2H), 1.5 (s, 6H). MS (+CI): 221 (MH+).

2,2-(4-(1-acetyl)-spiropiperdinyl)-6-carboxybenzopyran-4-one

N-Acetyl-piperidone (78.5 mL, 640 mmol) was added to toluene (700 mL) and stirred under anhydrous conditions. Pyrolidine (18.0 mL, 212 mmol) was then added over 15-30 min via an addition funnel. The 3-carboxymethyl-4- hydroxy benzoic acid, above, (77 g, 425 mmol) was then added in one portion. This reaction mixture was refluxed with a Dean-Stark trap for 3-4 hr. Upon cooling to RT the solid product was separated from the solution by decanting. HCI (800 mL, 1.0N) was added to the solid and stirred to provide a fine powder. The solid was then collected by filtration and washed with water and ether. The solid was dried under high vacuum for two days to provide the desired benzopyran (109 g, 85% yield). ¹H-NMR (DMSO-d₆): d 13.0 (s, 1 H), 8.3 (s, 1 H), 8.1 (d, 1 H), 7.3 (d, 1 H), 4.1 (d, 1 H), 3.6 (d, 1 H), 3.4 (t, 1 H), 3.0 (t, 1 H), 2.9 (s, 2H), 2.0 (s, 3H), 1.9-1.5 (m, 4H). MS (ESI): 304 (MH+).

2,2-(spirocyclohexyl)-6-carboxybenzopyran-4-one

Pyrolidine (25.0 mL, 300 mmol) and cyclohexanone (93.1 mL, 900 mmol) were added sequentially to toluene (800 mL) at 80°C with stirring. After about 5 min 3-carboxymethyl-4-hydroxy benzoic acid, above, (108 g, 600 mmol) was added to the solution. The reaction mixture was then heated to reflux with a Dean Stark trap to collect water. After 2 h the reaction mixture was cooled, HCI (100 mL, 2N) was added to yield a precipitate which was collected on a Buchner funnel and washed with water (4x) and ether (4x), and dried in vaccuo to provide the benzopyran product (76.4 g, 49% yield). ¹H-NMR (DMSO-d₆): d 12.9 (bs, 1 H), 8.2 (s, 1 H), 8.0 (d, 1 H), 7.1 (d, 1 H), 2.7 (m, 2H), 1.9-1.4 (m, 10H). MS (ESI): 261 (MH+).

EXAMPLES

The following detailed procedures further illustrate the process of the present invention.

Synthesis of the Thiophenol Resin: Preparation of a Compound of Formula C (Thiophenol Resin)

4-Hydroxy thiophenol (50 g, 396 mmol) was added to a 0°C solution of NaOMe (21.4 g, 396 mmol) in DMF (400 mL), the cooling bath was then removed and the solution was stirred for 1 hr Merrifield resin (sold by Midwest Biotech) (74.6 g, 1.34 mmol/g) was then added to the DMF solution and the resulting mixture was heated to 60°C for 60 hr under N₂. The resin mixture was then transferred to a filter funnel and washed using the following solvent sequence: (DMF, MeOH, AcOH, 5% 1 N HCI in AcOH)x2, (CH₂CI₂, MeOH)x2. The resin was then dried in a vacuum oven for 48 hr at 60°C.

The resin was analyzed by elemental analysis for chlorine and sulfur content to determine loading. Anal. Calculated: S 3.97%, Found: S 3.96%.

Coupling of Benzopyran carboxylic acid to the thiophenol resin: Preparation of a Compound of Formula E

DIC (51.6 mL, 330 mmol) was added to a CH₂CI₂ suspension (800 mL) of 2,2-dimethyl-6-carboxybenzopyran-4-one, (300 mmol) and the resulting solution was allowed to sit for 5 min. The mixture was then added to the thiophenol resin (compound of Formula C) (78 g, 100 mole equivalents (meq)) in CH₂CI₂ (300 mL) forming a slurry. NMM (36.0 mL, 330 mmol) and DMAP (4.0 g, 33 mmol) were then added to the slurry and the mixture was shaken for 14 hr. The resin was then washed using the following solvent sequence: (CH₂CI₂, DMF, MeOH)x4; (MeOH, CH₂CI₂)x2. The resin was then dried in a vacuum oven for 24 hr. at 40°C to yield a compound of Formula E.

IR showed absorption as follows; 1697 cm^"1 (-C(O)-), 1735 cm^"1 (ester). A FeCI₃/pyr test gave no color indicating the absence of a phenol, compound of Formula C.

Reductive Amination: Preparation of a compound of Formula G

The resin (Formula E) (2.0 g, 2.5 meq) was placed in a LAMPS vessel and swollen with anhydrous toluene (15 mL). Ti(Oi-Pr)₄ (2.58 mL, 8.75 mmol) was then added to the vessel under N₂, followed by an amine, R²-NH₂, (6.25 mmol) of Formula F. The reaction was agitated by bubbling nitrogen gas for 2.5 h. The reaction mixture was then diluted with AcOH (1.5 mL), anhydrous inhibitor-free THF (10 mL), followed by the addition of solid Na(OAc)₃BH (5.0g, 23.6 mmol). The reaction mixture was agitated by bubbling nitrogen gas for an additional 18- 24 h. Upon completion of the reaction the resin was washed with the following solvent sequence: (MeOH, THF)x4; (Pyr, MeOH)x3; DCMx3. The solvents were removed and the resulting resin was then dried under vacuum for 14+h. IR; 1735 cm ¹ (ester).

Illustrative examples of the amines used in the reductive amination step above are: benzyl amine, methoxypropylamine, tetrahydrofurfurylamine, N- aminopropylpyrolidine-2-one, 2-fluorophenethylamine, and 3,4- dimethoxyphenethylamie.

Acylation: Preparation of a compound of Formula J

The resin (Formula G) from the reductive amination was distributed into polyfiltronics plates (2.7 m) using the Falcon Plate Method (85 mg/well). Using SOP "Resin transfer via Falcon plates". The plates were then clamped with an open top clamp. The appropriate acylating agent (compound of Formula H) was then added as a solution in DCM (330 mL/well; 1.0 M) using the Robins Hydra (see library layout). The wells were then diluted with DCM (800mL/well) followed by the addition of DIPEA (70 mL). The plates were then shaken for 3.0 h, and washed using the following sequence: (DCM, DMF, MeOH)x4; Pyridine x3. Precaution was exercised since some of the acylating agents were lacromators.

Illustrative examples of acylating agents (compounds of Formula H) used to prepare compounds of Formula G are p-toluyl chloride, methyl thioisocyanate, acetyl chloride, benzyl isocyanate, and 3-methylthio phenylisocyanate.

Cleavage of Compounds of Formula 1 From Resin

The plates from the acylation step above were clamped with closed top clamps. Appropriate (Cleaving) amines (compounds of Formula K) (360 mL, 1.0

M soln. in Pyridine) were then added to a compound of Formula J using the Robins Hydra. This mixture was then diluted with additional pyridine (0.6 mL) followed by DIPEA (70 mL). The plates were then capped with plate clamps and shaken for 60 h. The products were collected into Beckman plates using a vacuum box (plate freezing was not necessary). The polyfiltronics plates were then washed once with pyridine (0.80 mL) and the effluent collected into the same Beckman plate. The cleaved product solutions were then concentrated using the speed vac (5 h. on high).

Illustrative examples of (cleaving) amines (compounds of Formula K) used to cleave the compounds of Formula 1 from the solid support are butylamine, 1- aminoethyl morpholine, aminopropyl pyrolidine-2-one, piperidine, benzyl amine, and 3,4-dimethoxyphenethylamine.

The following particular compounds of Formula 1 were synthesized using the above discussed procedure.

Example 1 :

¹H-NMR (CDCIg): δ 7.6 (d, 1 H), 7.5 (s, 1 H), 7.3 (m, 8H), 7.0 (m, 2H), 6.9 (d, 1 H), 6.2 (bs, 1 H), 6.1 (bs, 1 H), 4.8 (dd, 1 H), 4.4 (m, 2H), 4.1 (m, 2H), 3.2 (m, 2H), 2.1 (m, 1 H), 1.9 (m, 1H), 1.6 (m, 4H), 1.4 (s, 3H), 1.3 (s, 3H), 0.9 (t, 3H).

MS (ESI): 500 (MH+). Example 2:

Example 2 (MJH2-B): δ 8.1 (s, 1 H), 7.5 (s, 1 H), 7.2 (m, 3H), 7.0 (m, 1 H), 6.8 (d, 1 H), 6.0 (bs, 1 H), 4.1 (m, 3H), 3.5 (s, 3H), 3.4 (m, 4H), 3.0 (m, 2H), 2.5 (s, 3H), 2.0-1.6 (m, 10H), 1.4 (s, 3H), 1.3 (s, 3H).

MS (ESI): 526 (MH+).

Example 3:

¹H-NMR (CDCI₃): d 8.2 (bs, 1 H), 7.6 (d, 2H), 7.4 (d, 2H), 7.2 (m, 3H), 7.1 (t, 1 H), 7.0 (t, 1 H), 6.8 (d, 1 H), 5.0 (dd, 1 H), 3.9 (m, 4H), 3.8 (m, 3H), 3.6 (m, 2H), 3.4 (t, 2H), 3.1 (t, 2H), 2.9 (m, 2H), 2.7 (m, 1 H), 2.4 (s, 3H), 1.8 (m, 1 H), 1.6 (m, 1 H), 1.4 (s, 3H), 1.0 (s, 3H). MS (ESI): 574 (MH+).

Example 4:

¹H-NMR (CDCI₃): d 7.5 (s, 1H), 6.9-6.7 (m, 5H), 6.3 (m,1H), 5.0 (m, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 3.6 (m, 2H), 3.4 (t, 1H), 3.2 (m, 3H), 2.9 (t, 2H), 2.4 (m, 2H), 2.3 (s, 2H), 2.1-1.7 (m, 6H), 1.5 (2s, 3H), 1.3 (2s, 3H). MS (ESI): 552 (MH+).

Example 5:

¹H-NMR (CDCI₃): δ 8.1 (s, 1H), 7.6 (m, 2H), 7.4 (d, 2H), 7.2 (m, 3H), 7.1 (t, 1H), 6.9 (t, 1H), 6.7 (d, 1H), 5.0 (dd, 1H), 4.0 (m, 4H), 3.9 (m, 2H), 3.6 (m, 2H), 3.4 (t, 2H), 3.1 (t, 2H), 2.9 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.7 (t, 1H), 1.6 (dd, 1H), 1.4 (s, 3H), 0.9 (s, 3H).

MS (ESI): 574 (MH+).

Example 6:

¹H-NMR (CDCI₃): δ 7.3 (m, 5H), 6.8 (m, 2H), 6.7 (m, 2H), 6.5 (m, 2H), 6.4 (m, 1 H), 5.0 (dd, 1 H), 4.1 (m, 4H), 3.8 (s, 6H), 2.7 (m, 2H), 2.3 (s, 3H), 1.9 (t, 1 H), 1.6 (dd, 1 H), 1.5 (s, 3H), 1.3 (s, 3H).

MS (ESI): 517 (MH+).

Example 7:

¹H-NMR (CDCI₃): δ 7.7 (m, 2H), 7.4-7.1 (m, 15H), 6.9 (t, 1 H), 5.9 (bs, 2H), 4.7 (m, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.3 (m, 2H), 3.0 (m, 1 H), 2.9 (s, 3H), 2.8 (s, 3H), 2.7 (m, 1 H), 2.5 (m, 2H), 2.2 (s, 3H), 2.1 (m, 3H), 1.9 (t, 1 H), 1.7 (dd, 1 H), 1.4 (d, 3H).

MS (ESI): 716 (MH+).

Example 8:

¹H-NMR (CDCI₃): δ 7.7 (m, 2H), 7.6 (s, 1 H), 7.3 (m, 2H), 7.1 (m, 2H), 5.6 (m, 1 H), 4.6 (dd, 1 H), 3.9 (m, 2H), 3.7 (m, 4H), 3.5 (s, 3H), 3.4 (t, 2H), 3.0 (t, 2H), 2.6 (s, 3H), 2.4 (m, 2H), 2.3 (s, 3H), 2.2-1.6 (m, 16H).

MS (ESI): 649 (MH+).

Proton NMR, IR, and Mass Spec. (MS) were obtained using methods known to one skilled in the art. The FeCI₃/pyr. and the ninhydrin tests were performed by procedures known to one skilled in the art. Detailed procedures can be found in The Systematic identification of Organic Compounds, by Shriver Felson Curtin and Morril, John Wiley and Son's publication, 6^th edition, 1980.

DEFINITIONS AND ABBREVIATIONS

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

Parallel synthesis: This term indicates simultaneous synthesis of independent (individual) compounds by the process of the present invention.

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 a divalent hydrocarbon having from 1 to 10 carbon atoms. Illustrative examples are methylene (-CH₂-), ethylene (-CH₂-CH₂-), and propylene (-CH₂-

CH₂-CH₂~). The term "alkelene" 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, NR ², O , S(O), S(O)₂ and S, wherein R¹² is (C_1-6)alkyl, hetero(C₂.₆)alkyl or hydrogen. Illustrative examples of the term heterocyclo(C_5.14)alkyl are morpholinyl, indolinyl, piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.). As used in the present invention, the illustration:

generally indicates a 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 "aryl" means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing from 4 to 14 carbon atoms indicated. Thus a C₆- C₁₄ 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.

"Optional substituents" for aryl, hetero aryl, and Ph groups are R⁷ and R⁸. These R⁷, and R⁸ substituents at each occurrence are independently selected from a group consisting of H, -NH₂, halo, -0-C_lJt alkyl, , -NHC₁-C₄ alkyl, , -N(C_r C₄)₂ alkyl, and CF₃; while R⁸ is selected from H, and C _Λ alkyl.

"Optional" "or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally is substituted with one to three substituents" means that the group referred to may or may not be substituted in order to fall within the scope of the invention.

The term "halo" or "halogen" represents at least one of chlorine, bromine, iodine, and fluorine radicals. The term "solid support" (SS), as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule, and solid support can be found in The Combinatorial Index, B. A. Bunin, 1998, which is incorporated herein by reference.

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. The following abbreviations used in describing the process of the present invention have the following meaning:

DCM: dichloromethane

THF: tetrahydrofuran

DIEA: diisopropylethylamine

MeOH: methanol

MeCN: acetonitrile.

DMF N,N-dimethylformamide

DIC Diisopropylcarbodiimide

DMAP Dimethylaminopyridine

NMM N-methylmorpholine

DIPEA N,N-diisopropylethylamine pyr Pyridine

Claims

1. A process to make compounds of Formula 1 :

Formula 1

wherein:

R^1a and R are independently selected from a group consisting of H, C C₄ alkyl radical, -(CH₂)₁^-C₆-C₁₀ aryl, -C_╬▓-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or R^1a and R^1b along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R² is selected from a group consisting of -(CH₂)_1J,-0-C₁-C₄ alkyl, C_rC₆ alkyl optionally substituted with C C₄ alkyl radical, C₄-C₁₀ cycloalkyl, C₄-C₁₀ partially saturated cycloakyl, C₅-C₁₀ heterocycloaklyl, -N(C₁-C₄)₂ alkyl, -O-alkyl, aryl, heteroaryl, or

R³ is selected from a group consisting of C C₄ alkyl radical, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical -NH- C C₄ alkyl, -CH₂-O-C₆C₁₀ aryl, -(CH₂)^(-S-(CH₂)^ C(O)-O-C^ alkyl, -(CH₂)^-C₆-C₁₀ aryl, C₆-C₁₀ aryl, said alkyl groups being optionally substituted with at least one of C_1-4 alkyl, halo, -S-C^ alkyl, -O-C^ alkyl, and -C₆.₁₀ aryl;

R^4a is selected from a group consisting of H, C₄-C₆ cyclo alkyl radical, -(CH₂)_1^,-O- C_1J} alkyl, and C C₆ alkyl optionally substituted with C C₄ alkyl radical, -NH₂, - N(C C₄)₂ alkyl, OH, -O-alkyl, aryl, heteroaryl, or

C_1-4 alkyl

C₆.₁₀ aryl ;

R^4b represents H; or

R^4a and R^4b along with the nitrogen to which they are attached form

R⁵ is selected from a group consisting of H, C^ alkyl, -O-C^ alkyl,

-C₄.g branched alkyl, and aryl; R⁶ is selected from a group consisting of H, C C₄ alkyl radical,-(CH₂)₁^-C₆-C₁₀ aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O-

C_1-4 alkyl;

X is selected from -C(O)-, -NH-C(O)-, NH-C(S)-, and -S0₂; and Q is selected from a group consisting of -CH₂, O, S, SO, SO₂, -N-heteroaryl,

-NR⁶, and -N-C(O)R⁶; the process comprising the steps of:

(i) reacting a compound of Formula A

SS-(CH₂)_1J( halo Formula A

.Formula B

to yield a compound of Formula C

.Formula C;

(ii) reacting a compound of Formula C with a compound of Formula D

.Formula D

to yield a compound of Formula E

... Formula E, wherein SS, and R¹ are as defined earlier;

(iii) coupling a compound of Formula E with a compound of Formula F:

R²-NH, .Formula F

(iv) acylating a compound of Formula G with a compound of Formula H

R³-Y Formula H

where Y is -C(O)-CI, -NCO, SO₂CI, or -NCS to yield a compound of Formula J

.Formula J

where X is as defined above; and

(v) cleaving compounds of Formula J using an amine represented by Formula K

R^4aR⁴ -NH Formula K

wherein R^4a and R^4b are as defined above, to yield a compound of Formula 1.

2. A process of Claim 1 wherein the titanium alkoxide reagent in step (iii) is Ti(O-iPr)₄, Ti(OEt)₄, Ti(OMe)₄, or mixtures thereof.

3. A process of Claim 2 wherein the borohydride reagent in step (iii) is Na(OAc)₃BH, Na(CNBH₃), NaBH₄, BH₃.pyr, or mixtures thereof.

4. A process of claim 3 wherein:

R^1a and R^1b are independently selected from C C₂ alkyl radical, or R^1a and R^1b along with the Nitrogen atom that they are attached to forms

R² is selected from a group consisting of -C₂.₃ alk-O-CH₃, and C^_₃ alkyl substituted with

R³ is selected from -CH₃,

R^4a is selected from a group consisting of C₄-alkyl, benzyl,

or

R^4a and R^4b along with the nitrogen to which they are attached form the following structure:

R⁵ is H;

R^e is H;

R⁷ at each occurrence is selected from H, and F;

R⁹ is H; and

X represents -C(O)-, -NHC(S), or -NH-(CO)-.

5. A compound of Formula E

Formula E where SS is a solid support;

R^1a and R^1b are independently selected from a group consisting of H, C,-C₄ alkyl radical, -C_rC₄ alk-C₆-C₁₀ aryl, -C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or

R^1a and R^1b along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R⁵ is selected from a group consisting of H, C,^ alkyl, -O-C^ alkyl, -C₄.₈ branched alkyl, and aryl;

R⁶ is selected from a group consisting of H, C,-C₄ alkyl radical, C C₄ alk-C₆-C 10 aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O- C_1-4 alkyl;

6. A compound of Claim 5 wherein R¹ is selected from

R^1a and R^1b are independently selected from C_rC₂ alkyl radical, or R^1a and R^1b along with the Nitrogen atom that they are attached to forms

R⁵ is selected from a group consisting of H, and C^ alkyl; and R⁶ is H, or -CH₃.

7. A compound of Formula 3

Formula 3 wherein:

R^1a and R^1b are independently selected from a group consisting of H, C,-C₄ alkyl radical, -C C₄ alk-C₆-C₁₀ aryl, -C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, and C₄-C₁₀ branched alkyl radical; or R^1a and R^1b along with the carbon atom that they are attached to form an optionally substituted, saturated or partially unsaturated C₄-C₁₀ cyclo alkyl or hetero cycloalkyl ring;

R² is selected from a group consisting of -(CH₂)₁^-0-C₁-C₄ alkyl, C,-C₆ alkyl optionally substituted with C_rC₄ alkyl radical, C₄-C₁₀ cycloalkyl, C₄-C₁₀ partially saturated cycloakyl, C₅-C₁₀ heterocycloaklyl, -N(C₁-C₄)₂ alkyl, -O-alkyl, aryl, heteroaryl, or

R³ is selected from a group consisting of C C₄ alkyl radical, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical -NH- C_rC₄ alkyl, -CH₂-O-C₆C₁₀ aryl, -C^ alkylene(-S-C^ alkyl) C(O)-O-C^ alkyl, C_rC₄ alk-C₆-C₁₀ aryl, C₆-C₁₀ aryl, said alkyl groups being optionally substituted with at least one of C^ alkyl, halo, -S-C^

₄ alkyl, -O-C_M alkyl, and -C₆.₁₀ aryl;

R⁵ is selected from a group consisting of H, C^ alkyl, -O-C^ alkyl,

-C₄ΓÇ₧g branched alkyl, and aryl;

R⁶ is selected from a group consisting of H, C_rC₄ alkyl radical, C_rC₄ alk-C₆-C₁₀ aryl, C₆-C₁₀ aryl, C₄-C₁₀ cycloalkyl radical, C₄-C₁₀ branched alkyl radical, and -O-

C,^ alkyl; and

Z is selected from H, -C(O)-, -N=C=O, and -SO₂; with the proviso that when Z represents H, R³ does not exist.

8. A compound of Claim 7 wherein:

R² is selected from -C,_₃ a!k-O-CH₃, and C,.₃ alkyl radical, said alkyl radical optionally substituted with

R³ is selected from -CH₃, -C^ alk-C₆ aryl, -CH[C₂H₅-O-C(O)]-(CH₂)₃-S-CH₃, and

C₆ aryl, said aryl groups substituted with at least one of H, F, Cl, -CH₃, -C₂H₅, -C₆ aryl, -O-CH₃, and -SCH₃;

R⁵ is selected from a group consisting of H, and C_M alkyl; and

R⁶ is H, or -CH₃.