WO2001002355A2 - Indole synthesis - Google Patents

Indole synthesis Download PDF

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Publication number
WO2001002355A2
WO2001002355A2 PCT/US2000/017580 US0017580W WO0102355A2 WO 2001002355 A2 WO2001002355 A2 WO 2001002355A2 US 0017580 W US0017580 W US 0017580W WO 0102355 A2 WO0102355 A2 WO 0102355A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
phenyl
aryl
compound
Prior art date
Application number
PCT/US2000/017580
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English (en)
French (fr)
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WO2001002355A3 (en
Inventor
Barry A. Bunin
Original Assignee
Axys Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axys Pharmaceuticals, Inc. filed Critical Axys Pharmaceuticals, Inc.
Priority to AU57687/00A priority Critical patent/AU5768700A/en
Publication of WO2001002355A2 publication Critical patent/WO2001002355A2/en
Publication of WO2001002355A3 publication Critical patent/WO2001002355A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to a process of synthesizing substituted or unsubstituted mdoles or an array of substituted or unsubstituted mdoles
  • the present invention provides a process for synthesizing substituted mdoles of Formula I
  • the process of the present invention can also be used to synthesize an array of substituted indoles of Formula I
  • the process of the present invention can be used to synthesize doles with substituents on both the phenyl as well as the imidazole portion of the indole ring.
  • an array of compounds of Formula I Also provided is an array of compounds of Formula I.
  • the present invention provides a process for synthesizing a compound or an array of compounds of Formula I:
  • R represents H, C ⁇ -4 -alkyl, C 3 . i -branched alkyl, C 5 _ ⁇ -cycloalkyl, aryl, (CH 2 ) ! . 3 - heteroaryl or (CH 2 ) ⁇ _ 3 -aryl;
  • R z represents H, C 1 -4 -alkyl, (CH 2 ) ⁇ -3 -aryl, (CH 2 ) ! _ 3 -CO-R 2 z 0 ⁇ or CH 2 -CN;
  • R 3 and R independently at each occurance represent a group capable of forming a stable covalent bond with a nitrogen atom; alternatively
  • R 3 and R 1 along with the nitrogen atom to which they are attached form l,4-Dioxa-8- aza-spiro[4.5]dec-8-yl or a heterocyclyl ring optionally substituted with 1 to 3 substituents selected from C ⁇ . 6 -alkyl, (CH 2 ) -OH, C(O)-N(C ⁇ _ 4 alkyl) 2 , OH, O-
  • Ph COOCi- alkyl, 2-methoxy phenyl, 4-fluoro phenyl, 3-trifluoro methyl phenyl, 4-Benzo[l,3]dioxol-5-ylmethyl and 4-(3-Phenyl-allyl);
  • R 12 represents C ⁇ -4 -alkyl, C 5 . ⁇ 0 cycloalkyl, heteroaryl or aryl;
  • R 14 and R 16 independently at each occurance represent H, C ⁇ . 4 -alkyl, halogen, O-C 1 .4- alkyl, phenyl, C 5 - ⁇ o cycloalkyl or heteroalkyl;
  • R 18 represents H or C 1- -alkyl; alternatively, R 16 and R 18 can be taken together to form
  • R , 2 z 0 u represents NH 2 , C ⁇ _ 6 -alkyl, aryl, O-alkyl or O-aryl, C(0)-alkyl, aryl, COO-alkyl or COO-aryl; said process comprising:
  • R 1 , R 12 , R 14 , R 16 and R 18 are as defined above;
  • R 1 , R 2 , R 12 , R 14 , R 16 and R 18 are as defined above;
  • R 1 , R 2 , R 12 , R 14 , R 16 and R 18 are as defined above,
  • Preferred embodiment of the present invention provides a process wherein the suitable solvent in step (i) is selected from mtromethane, acetic acid, acetone, ethanol and mixtures thereof.
  • Another preferred embodiment provides a process wherein the compound of formula 3 in step (I) falls out of solution upon formation
  • step (in) is selected from potassium t ⁇ methyl silanoate, sodium hydroxide and potassium hydroxide; step (iv) is earned out in the presence of an additive; and wherein the dehydrating agent in step (iv) is selected from a carbodimide and the additive in step (iv) is hydroxybenzot ⁇ azole.
  • the present invention m a present invention provides a process wherein R 1 represents H, Ci 4 -alkyl, C 3 6 -branched alkyl, aryl, (CH ) ⁇ 2 aryl or 4- benzo[l,3]d ⁇ oxol-5-ylmethyl; R 3 and R 10 independently at each occurance represent H, C 5-6 -cycloalkyl, C ]2 -cycloalkyl, (CH 2 ) ⁇ 4 -aryl, 3-Pyrrol ⁇ d ⁇ n-l-yl-propyl, 3-(2- Oxo-pyrrolidin- 1 -yl)-propyl ; tetrahydro-f uran-2-ylmethy 1 , 3-Morphol ⁇ n-4-y 1-propy 1 , 2-Morphohn-4-yl-ethyl, 2-P ⁇ pe ⁇ d ⁇ n-l-yl-ethyl, alternatively R 3 and R 10 along with the nitrogen atom to which they are attached form
  • R 3 and R 10 groups are independently at each occurance selected from cycloundecylammo, (Naphthalen-l-ylmethyl)-am ⁇ no, th ⁇ azol ⁇ dm-3-yl, 2- Hydroxymethyl-pyrrol ⁇ dm-1-yl, 4-(2-Methoxy-phenyl)-p ⁇ peraz ⁇ n-l-yl, 4-(4-
  • Another aspect of the present invention provides an array of compounds of Formula I.
  • a mixture/suspension of 1,4-benzoquinone (lb) (from 1 eq to about 1.5 eq.) in an inert solvent (e.g., nitromethane) is stirred at a temperature ranging from about 0°C to about 25°C.
  • an inert solvent e.g., nitromethane
  • a freshly prepared solution of a compound of Formula la (1 eq.) in nitromethane is added to the benzoquinone mixture at a rate sufficient to maintain the temperature of the reaction mixture under about 20°C.
  • the reaction mixture is agitated at ambient temperature from about 5 hours to about 72 hours.
  • the reaction mixture then is cooled an ice bath (about 0°C to about 10°C) to yield a precipitate
  • the precipitate is isolated and d ⁇ ed to yield a compound of Formula 2.
  • a compound of Formula 2 (1 eq.) dissolved in a minimum amount of a polar solvent (e.g., DMSO) is mixed with a base (e.g , TMAH; about 1.1 to about 2 eq ).
  • a compound of Formula 2b (R 2 -X, about 1.1 to about 1 9 eq.) then is added to the mixture in portions over a pe ⁇ od of from about 30 minutes to about 3 hours
  • the reaction mixture is maintained at a temperature below about 75°C du ⁇ ng the addition of a compound of Formula 2b.
  • the reaction mixture is agitated from about 10 hours to about 24 hours leading to the formation of a precipitate.
  • the precipitate is isolated and washed in succession with water and methanol to yield a compound of Formula 3.
  • Compound of Formula 3, above can be pu ⁇ fied by pu ⁇ fication techniques known to one skilled in the art.
  • a mixture of an inert solvent, a compound of Formula 3 and a hydrolyzing agent is agitated at temperatures ranging from about 50°C to about 80°C fiom about 1 hour to about 72 hours. Conversion of the compound of Formula 3 to Formula 4 can monitored by HPLC. Additional equivalent of the hydrolyzing agent is added if the conversion of Formula 3 to Formula 4 is less than about 90%.
  • This reaction mixture is diluted with water, the aqueous layer is isolated and washed with ether (x2). The aqueous layer then is acidified to form a precipitate This precipitate is isolated, washed with water (x2) and d ⁇ ed to yield a compound of Formula 4.
  • Compound(s) of Formula 4 can be pu ⁇ fied by lyophilization followed by recrystallization. Recrystallization can be accomplished by techniques known to one skilled in the art. Desirable recrystallization solvents are acetonitrile, methanol and water or mixtures thereof.
  • a mixture of a compound of Formula 4 (1 eq.), a dehydrating agent (e.g., HOBt; about 1 eq. to about 2.5 eq.), an optional additive (e.g., HOBf. about 1 eq.) and DCM/DMF (3:1) is combined with a solution of a compound of Formula 4b (about 1 to about 2.5 eq.) in DCM/DMF (3:1).
  • a dehydrating agent e.g., HOBt; about 1 eq. to about 2.5 eq.
  • an optional additive e.g., HOBf. about 1 eq.
  • DCM/DMF (3:1 DCM/DMF
  • reaction mixture then is diluted with an inert solvent, preferably chloroform or methylene chloride, and washed in succession with 2N HC1 and 3N NaOH.
  • organic layer is separated, dried (MgSO ) and concentrated to yield a compound of Formula I.
  • Compounds of Formula la are enamines and they can be prepared by reacting the corresponding primary amines with methyl acetoacetate by the procedure discussed by Pawalk, J.M.; Khau, V.v.; Hutchinson, D. R.; Martinelli, M.J.; Org. Chem. 1996, 61, 9055-9059.
  • Preferably compounds of Formula la are prepared just prior to their use in STEP-A.
  • Compounds of Formula lb are benzoquinones which are commercially available from Aldrich Chemicals.
  • Compounds of Formula 2b, which can be classified as alkylating agents, are commercially available from Aldrich Chemicals.
  • Hydrolyzing agents used in STEP-C of the process of the present invention are potassium trimethyl silanoate (KOTMs) and NaOH and are commercially available from Aldrich Chemicals.
  • Amines of Formula 4b, used in STEP-D of the process of the present invention are commercially available from Aldrich Chemicals and Lancaster. It should be noted that any primary or secondary amine can be used in the present process. The only limitation on the amines of Formula 4b being that they cannot be tertiary amines.
  • a mixture of 1,4-benzoquinone (Formula lb; 3.4 mol) and nitromethane (1.5 1) was maintained at a temperature of about 5°C to about 15°C in an inert atmosphere, e.g., nitrogen.
  • a solution of a compound of Formula la ( 3.0 mol) in nitromethane (750 mL) was added to the above mixture of benzoquinone and nitromethane. This addition was accomplished in about 30 to about 45 minutes while maintaining the temperature of the reaction mixture under about 15°C.
  • the resulting reaction mixture was agitated for about 30 minutes at a temperature ranging from about 5°C to about 15°C, and the agitation was continued at ambient temperature from about 2 hours to about 48 hours.
  • the reaction mixture then was cooled to a temperature of from about 0°C to about 10°C leading to the formation of a precipitate. This precipitate was isolated, washed with cold nitromethane (x2) and dried to yield a compound of Formula 2.
  • a compound of Formula 2 (1 eq.) dissolved in a minimum amount of a polar solvent (e.g., DMSO) was mixed with a base (e.g., TMAH; about 1.1 to about 2 eq.).
  • a base e.g., TMAH; about 1.1 to about 2 eq.
  • a compound of Formula 2b (R 2 -X, about 1.1 to about 1.9 eq.) then was added to the mixture in portions over a period of from about 30 minutes to about 3 hours.
  • the reaction mixture was maintained at a temperature below about 75°C during the addition of a compound of Formula 2b.
  • the reaction mixture was agitated from about 10 hours to about 24 hours leading to the formation of a precipitate.
  • the precipitate was isolated and washed in succession with water and methanol to yield a compound of Formula 3.
  • a mixture of an inert solvent, a compound of Formula 3 and a hydrolyzing agent was agitated at temperatures ranging from about 50°C to about 80°C from about 1 hour to about 72 hours. Conversion of the compound of Formula 3 to Formula 4 can be monitored by HPLC. Additional equivalent of the hydrolyzing agent was added if the conversion of Formula 3 to Formula 4 was less than about 90%.
  • This reaction mixture was diluted with water, the aqueous layer was isolated and washed with ether (x2). The aqueous layer then was acidified to form a precipitate. This precipitate was isolated, washed with water (x2) and dried to yield a compound of Formula 4.
  • Compound(s) of Formula 4 can be purified by lyophilization followed by recrystallization. Recrystallization can be accomplished by techniques known to one skilled in the art. Desirable recrystallization solvents are acetonitrile, methanol, water and mixtures thereof.
  • a solution of activated indole (compound of Formula 4; 1.0 mL; 0.08 mmol) was dispensed in to each well of a Polyfiltronics plate.
  • the activated indole solution was prepared by combining a compound of Formula 4 (1 eq.), EDC (1.8 eq.), anhydrous HOBt (1.8 eq.) and a mixture of DCM/DMF (3:1; v/v) to provide a 0.08 M activated indole carboxylic acid solution.
  • Solutions of compounds of Formula 4b (0.2 mmol; 2.5 eq.) are added to each well.
  • a teflon sheet was secured on top of each plate and the plate was shaken on an Orbital shaker from about 12 hours to about 60 hours at ambient temperature.
  • the reaction mixture was transferred to Polyfiltronics plates (type GF/D; 10 ⁇ M) with wells previously filled with hydromatrix material preactivated with 2N HCl and placed over 2 mL square-wall Beckman collection plate. Each source well was rinsed with 600 ⁇ L chloroform and the rinse transferred to the corresponding well of the Polyfiltronics plate. The preceding filtering procedure was repeated with Polyfiltronics plates filled with hydromatrix material preactivated with 3N HCl. The solution in the collection plates was concentrated in a Genevac evaporator (Atlas, catalog number HT-12-CDOP) for 3 to 4 hours to yield a library of compounds of Formula I.
  • array of compounds is intended to represent a collection of compounds or mixtures of compounds with a common structural element, synthesized simultaneously in a parallel fashion using the same synthetic reaction sequence.
  • the precise structure of a single compound within an array of compounds or the compounds of a mixture within an array of mixtures is determined by the sequence of reactants which give rise to this compound or mixture and can be deduced from the recorded reaction-protocol. The spatial arrangement of the array is irrelevant.
  • alkyl as used herein is meant to indicate a saturated or partially unsaturated straight chain, branched or cyclic hydrocarbon moiety of up to 14 carbon atoms, unless indicated otherwise. This hydrocarbon is generally attached to at least one other atom, and can be straight chain, or branched, or cyclic, or a combination thereof, illustrative examples are methyl, ethyl, allyl, propyl, ⁇ -pentyl, cyclo pentyl, cyclo hexyl, /-butyl, 2-cyclohexyl-ethyl and 3-ethyl-4-methyl-hexyl.
  • halo or "halogen” is intended to represent Cl, Br, I and F.
  • base represents an alkali metal salt.
  • Illustrative examples are KOTMs and NaOH.
  • suitable solvent is intended to represent solvents which do not react with the reagents dissolved therein.
  • suitable solvents are tetrahydrofuran (THF), methylene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, nitromethane, acetic acid, acetone, ethanol and DMSO.
  • dehydrating agent represents an agent which facilitates removal of any water or moisture which may be present in a reaction mixture or formed during a reaction.
  • Typical dehydrating/drying agents known to one skilled in the art are intended to be included herein.
  • Representative examples of dehydrating/drying agents are magnesium sulfate, sodium sulfate, methyl orthoformate, ethyl orthoformate, EDC, DCC, DIC, carbodimide, methyl ortho acetate and ethyl ortho acetate, or any moisture which may be present in
  • additive is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product.
  • additives are N-hydroxybenzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HO At) and N-hydroxysuccinimide.
  • aryl means an aromatic monocyclic, bicyclic, or a fused polycyclic hydrocarbon radical containing from about 6 to about 14 carbon atoms or the number indicated.
  • An aryl group can be optionally substituted with C ⁇ -4 alkyl, C 3- ⁇ o branched alkyl, halogen, OC i04 alkyl or N)C 1-4 alkyl) 2 .
  • a C 6 -C ⁇ 4 aryl group includes phenyl, naphthyl, anthracenyl, etc.
  • heteroaryl means aryl, as defined above, containing 5-14 atoms or the number indicated 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.
  • Sulfur (S) can exist as a sulfide, sulfoxide, or sulfone.
  • heteroaryl groups are thienyl, furyl, pyrrolyl, indolyl, pyrimidinyl, isoxazolyl, purinyl, imidazolyl, pyridyl, pyrazolyl, benzo[l,3]dioxol-yl-alkyl, 4-benzo[l,3]dioxol-5-ylalkyl, quinolyl, 4- benzo[l,3]dioxol-5-ylmethyl and pyrazinyl.
  • This phrase is intended to represent substituents that are known to and capable of forming a covalent bond with a nitrogen atom thereby forming a primary, secondary or tertiary amine
  • a list of said amines can be found in, for example, the Ald ⁇ ch Structure Index, 1996-97, Ald ⁇ ch Chemical Company Inc
  • Illustrative examples of groups capable of forming a stable covalent bond with a nitrogen atom are H, alkyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, heterocyclyl, cycloalkyl or a combinations thereof.
  • polar solvent as used herein represents a solvent which has a high dielectric constant
  • polar solvents are dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and methanol (MeOH)
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • MeOH methanol
  • hydrolyzing agent as used herein represents an agent which hydrolyzes an ester to an acid.
  • allyl represents an aliphatic hydrocarbon moiety which can be substituted or unsubstituted.
  • Illustrative examples of an aliphatic moiety are propylene, butylene and hexylene.
  • heterocyclyl ⁇ ng represents a stable 5- to 7- membered monocyc c or 7- to 10- membered bicychc heterocychc ⁇ ng which is saturated, partially unsaturated, or unsaturated (aromatic), which consists of carbon atoms and from one to 4 hetero atoms independently selected from a group consisting of N, O and S.
  • the nitrogen and the sulfur hetero atoms can exist in their respective oxidized states.
  • the heterocychc ⁇ ng may be attached to its pendent group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocychc ⁇ ngs desc ⁇ bed herein may be substituted on a carbon or a nitrogen atom if the resulting compound is stable
  • the nitrogen in the heterocycle can exist in its quaternized form It is preferred that when the total number of hetero atoms in the heterocycle exceeds 1, then the heteroatoms are not adjacent to one another.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/US2000/017580 1999-07-01 2000-06-26 Indole synthesis WO2001002355A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57687/00A AU5768700A (en) 1999-07-01 2000-06-26 Indole synthesis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14216399P 1999-07-01 1999-07-01
US60/142,163 1999-07-01

Publications (2)

Publication Number Publication Date
WO2001002355A2 true WO2001002355A2 (en) 2001-01-11
WO2001002355A3 WO2001002355A3 (en) 2001-06-28

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AU (1) AU5768700A (zh)
WO (1) WO2001002355A2 (zh)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62138469A (ja) * 1985-12-11 1987-06-22 Yoshitomi Pharmaceut Ind Ltd インド−ル誘導体
WO1988005432A1 (en) * 1987-01-23 1988-07-28 Yoshitomi Pharmaceutical Industries, Ltd. 5-hydroxyindole-3-carboxamide compound and medicinal use thereof
EP0708751A1 (en) * 1993-07-16 1996-05-01 The Regents Of The University Of California Synthesis of combinatorial arrays of organic compounds through the use of multiple component combinatorial array syntheses
GB9610811D0 (en) * 1996-05-23 1996-07-31 Pharmacia Spa Combinatorial solid phase synthesis of a library of indole derivatives
GB2316941A (en) * 1996-07-02 1998-03-11 Merck & Co Inc Combinatorial sythesis on soluble polyvalent supports
WO1998035923A1 (en) * 1997-02-14 1998-08-20 Massachusetts Institute Of Technology Process for creating molecular diversity
AU9025898A (en) * 1997-08-21 1999-03-08 American Home Products Corporation Solid phase synthesis of 2,3-disubstituted indole compounds

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Publication number Publication date
AU5768700A (en) 2001-01-22
WO2001002355A3 (en) 2001-06-28

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