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WO2014060596A1 - Process for preparing indole derivatives - Google Patents

Process for preparing indole derivatives Download PDF

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Publication number
WO2014060596A1
WO2014060596A1 PCT/EP2013/071890 EP2013071890W WO2014060596A1 WO 2014060596 A1 WO2014060596 A1 WO 2014060596A1 EP 2013071890 W EP2013071890 W EP 2013071890W WO 2014060596 A1 WO2014060596 A1 WO 2014060596A1
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Prior art keywords
formula
compound
defined above
alkyl
acid
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PCT/EP2013/071890
Other languages
French (fr)
Inventor
Paolo Maragni
Mariella PATTAROZZI
Raffaella Volpicelli
Mauro Maffini
Alberto Guidi
Elisa Melotto
Livius Cotarca
Massimo Verzini
Original Assignee
Zach System S.P.A.
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Publication of WO2014060596A1 publication Critical patent/WO2014060596A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to a process for preparing indole derivatives as intermediates for producing Chemo-attractant Receptor-homologous receptor expressed on Th2 cells (CRTH2) receptor antagonists useful for the treatment of various prostaglandin-mediated diseases and disorders.
  • CRTH2 Chemo-attractant Receptor-homologous receptor expressed on Th2 cells
  • CRTH2 is one of the two high-affinity transmembrane receptors for prostaglandin d2 (PGD2) that have been identified to date.
  • PGD2 has been implicated as a mediator of allergic inflammation and diseases including asthma, allergic rhinitis, and atopic dermatitis.
  • CRTH2 receptor antagonist for the potential treatment of respiratory disease.
  • WO 2010/099039 provides other compounds active as CRTH2 receptor antagonists having a 1,2,3-triazole group directly linked to the tricyclic ring system, such as, for example, the compounds of formula la: (la)
  • Rj a is selected from H, halogen, -OCi_ 6 alkyl, -0-haloCi_ 6 alkyl, -C i_ 6 alkyl, haloCi_ 6 alkyl, optionally substituted aryl and -(Ci_ 3 alkylene)-optionally substituted aryl; and Yi is selected from optionally substituted aryl and - C(R 2 )(R 3 )(R 4 ); R2 is selected from H, -Ci_ 6 alkyl optionally substituted with halogen, -OH or -NHS0 2 CH 3 , -OH, -OCi_ 6 alkyl, -S(0)nCi_ 6 alkyl, -CN, optionally substituted aryl, optionally substituted -O-aryl and optionally substituted heteroaryl, wherein n is 0, 1 or 2; R3 is selected from H, -Ci_ 6 alkyl, -Ci_ 6 haloalkyl
  • the compound of formula (8 A) can be prepared following the teachings of EXAMPLE 8A of WO 2010/099039.
  • the present invention relates to a novel alternative process for the preparation of an "alcohol" intermediate of formula (I)
  • R is Ci_ 4 alkyl and its use in the manufacture of the compound of formula (8A), which can be useful for preventing, treating or ameliorating prostaglandin mediated disease or disorder in a mammalian, especially a human subject.
  • the present invention refers to a process for preparing a compound of formula (I)
  • R is Ci_ 4 alkyl, which comprises:
  • R is as defined above;
  • X is an halogen atom including Bromine, Chlorine and Iodine
  • PG is a hydroxyl protecting group
  • R is as defined above
  • Ri Ci_ 4 alkyl or R and Ri taken together are a group -(CH2) n - wherein n is 2 or 3, to obtain a compound of formula (V)
  • Ci_ 4 alkyl refers to alkyl moieties including methyl, ethyl, propyl (n- propyl or isopropyl) and butyl (n-butyl, isobutyl or t-butyl).
  • R is methyl or ethyl.
  • protecting group means a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Such protecting groups are well-known to those skilled in the art and are described, for example, in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
  • hydroxyl protecting group means a protecting group suitable for preventing undesirable reactions at a hydroxy group.
  • Representative hydroxyl protecting groups include, but are not limited to, acetyl (Ac), formyl, benzoyl (Bz), benzyl (Bn, Bnl), benzyloxymethyl (BOM), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (DPM), beta methoxyethoxymethyl ether (MEM), dimethoxytrityl [bis-(4- methoxyphenyl)phenylm ethyl, DMT], methoxymethyl ether (MOM), methoxytrityl [(4- methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trity
  • mineral acid means an inorganic acid which is an acid derived from one or more inorganic compounds.
  • Representative “mineral acid” include, but are not limited to, sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and polyphosphoric acid.
  • organic acid means an organic compound with acidic properties including carboxylic acids, whose acidity is associated with their carboxyl group -COOH and sulfonic acids, containing the group -S0 2 OH.
  • an organic acid is, preferably, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, more preferably p-toluenesulfonic acid also in mixture with residual trifluoroacetic acid.
  • step i) can be carried out, for example, by reacting the compound of formula (II) with an alcohol of formula R-OH wherein R is defined above in the presence of catalytic amounts of a "mineral acid” or an "organic acid", which are defined above.
  • the reaction under step ii) can be carried out, for example, by reacting the compound of formula (III) with a suitable base in a polar aprotic solvent, followed by addition of a compound of formula (IV).
  • suitable bases include, but are not limited to, sodium hydride, potassium tert-butoxide, sodium tert-butoxide and sodium methoxide.
  • Representative polar aprotic solvents include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methyl-2-pyrrolidone (NMP).
  • cyclization can be carried out under a variety of conditions.
  • the cyclization can generally be carried out by the action of a mineral acid or an organic acid as defined above.
  • the cyclization step is performed in the presence of an organic acid, such as p-toluenesulfonic acid also in mixture with residual trifluoroacetic acid.
  • the reduction of the double bond of a compound of formula (VI) according to step iv) can be carried out by any catalytic hydrogenation procedure known in the art.
  • the hydrogenation can be carried out by using Pd/C and a source of hydrogen such as gaseous hydrogen (H 2 ) or hydrogen-donors in place of H 2 .
  • a source of hydrogen such as gaseous hydrogen (H 2 ) or hydrogen-donors in place of H 2 .
  • Representative "hydrogen-donors" include, but are not limited to, formic acid, sodium formate, ammonium formate and cyclohexene.
  • Deprotection of a compound of formula (VII) according to step v) gives the corresponding compound of formula (I).
  • Methods for the removal of hydroxyl protecting groups are known in the art; see, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
  • deprotection of a compound of formula (VII) where the hydroxyl protecting group (PG) is tert-butyldimethylsilyl (TBDMS) can be accomplished by using Tetra-n-butylammonium fluoride (or TBAF) as a solution in tetrahydrofuran (THF).
  • THF Tetra-n-butylammonium fluoride
  • the compound of formula (II) can be prepared according to the general method for Fischer indole synthesis; for example, following the teachings reported in Scheme 1 and, in particular, Example 1(b) of EP 1296676.
  • the compounds of formula (IV) can be prepared, for example, following the teachings of B. Jiang et ah, Tetrahedron: Asymmetry 12 (2001) 2835-2843 (see, in particular, Scheme 1).
  • the compounds of formula (I) are useful intermediates for the preparation of the compound of formula (8A) as defined above.
  • the conversion of the compound of formula (I) wherein R is ethyl to the compound of formula (8A) can be carried out following the teaching of Example 8A of WO 2010/099039.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a process for preparing indole derivatives of formula (I), wherein R is C1-4alkyl as intermediates for producing Chemo-attractant Receptor- homologous receptor expressed on Th2 cells (CRTH2) receptor antagonists useful for the treatment of various prostaglandin-mediated diseases and disorders.

Description

PROCESS FOR PREPARING INDOLE DERIVATIVES
FIELD OF THE INVENTION
The invention relates to a process for preparing indole derivatives as intermediates for producing Chemo-attractant Receptor-homologous receptor expressed on Th2 cells (CRTH2) receptor antagonists useful for the treatment of various prostaglandin-mediated diseases and disorders.
BACKGROUND OF THE INVENTION
According to JOC 2012, 77, 2299-2309, CRTH2 is one of the two high-affinity transmembrane receptors for prostaglandin d2 (PGD2) that have been identified to date. PGD2 has been implicated as a mediator of allergic inflammation and diseases including asthma, allergic rhinitis, and atopic dermatitis.
Merck disclosed the compound identified as MK-7246 of formula
Figure imgf000003_0001
as CRTH2 receptor antagonist for the potential treatment of respiratory disease. WO 2010/099039 provides other compounds active as CRTH2 receptor antagonists having a 1,2,3-triazole group directly linked to the tricyclic ring system, such as, for example, the compounds of formula la:
Figure imgf000004_0001
(la)
wherein Rja is selected from H, halogen, -OCi_6alkyl, -0-haloCi_6alkyl, -C i_6 alkyl, haloCi_6alkyl, optionally substituted aryl and -(Ci_3alkylene)-optionally substituted aryl; and Yi is selected from optionally substituted aryl and - C(R2)(R3)(R4); R2 is selected from H, -Ci_6alkyl optionally substituted with halogen, -OH or -NHS02CH3, -OH, -OCi_6alkyl, -S(0)nCi_6alkyl, -CN, optionally substituted aryl, optionally substituted -O-aryl and optionally substituted heteroaryl, wherein n is 0, 1 or 2; R3 is selected from H, -Ci_6alkyl, -Ci_6haloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R4 is selected from H, -Ci_6alkyl, -Ci_6haloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R3, R4 and the carbon atom to which they are attached together form -C3_6Cycloalkyl, fluorenyl or -C3_6heterocyclyl having a ring heteroatom selected from -N(Ra)-, -O- and -S-; or R3, R4 together represent - Ci_6alkylidene; and Ra is H, -Ci_6alkyl or -C(0)Ci_6alkyl; and the optional substituent for aryl and heteroaryl is 1 to 4 groups independently selected from halogen, -Ci_3alkoxy, -Ci_3halo alkyl, hydroxy-Ci_3 alkyl, -S(0)n-Ci_3alkyl, amino, and mono- and di-(Ci_3alkyl)amino.
A particular example of the compounds of formula (la) is the compound of formula (8A)
Figure imgf000005_0001
(8A)
The compound of formula (8 A) can be prepared following the teachings of EXAMPLE 8A of WO 2010/099039.
SUMMARY OF THE INVENTION
The present invention relates to a novel alternative process for the preparation of an "alcohol" intermediate of formula (I)
Figure imgf000005_0002
(I)
wherein R is Ci_4alkyl and its use in the manufacture of the compound of formula (8A), which can be useful for preventing, treating or ameliorating prostaglandin mediated disease or disorder in a mammalian, especially a human subject. DETAILED DESCRIPTION OF THE INVENTION
In details, the present invention refers to a process for preparing a compound of formula (I)
Figure imgf000006_0001
(I)
wherein R is Ci_4alkyl, which comprises:
i) esterifying the compound of formula (II)
Figure imgf000006_0002
(II)
with an alcohol of formula R-OH, wherein R is as defined above to obtain a compound of formula (III)
Figure imgf000006_0003
wherein R is as defined above;
ii) reacting a compound of formula (III) with a compound of formula (IV)
Figure imgf000007_0001
(IV)
wherein X is an halogen atom including Bromine, Chlorine and Iodine, PG is a hydroxyl protecting group, R is as defined above, Ri is Ci_4alkyl or R and Ri taken together are a group -(CH2)n- wherein n is 2 or 3, to obtain a compound of formula (V)
Figure imgf000007_0002
(V)
wherein PG, R and RI are as defined above;
iii) providing intramolecular Friedel-Craft cyclization of a compound of formula (V) with a mineral or an organic acid to obtain a compound of formula (VI)
Figure imgf000007_0003
(VI)
wherein PG and R are defined above;
iv) hydrogenating the double bond of a compound of formula (VI) thereby producing a compound of formula (VII)
Figure imgf000008_0001
(VII)
wherein PG and R are defined above; and
v) deprotecting a compound of formula (VII) to obtain a compound of formula
(I)-
The term "Ci_4alkyl" refers to alkyl moieties including methyl, ethyl, propyl (n- propyl or isopropyl) and butyl (n-butyl, isobutyl or t-butyl).
Preferably R is methyl or ethyl.
Preferably, in a compound of formula (IV) R=Ri=ethyl.
The term "protecting group" means a moiety that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Such protecting groups are well-known to those skilled in the art and are described, for example, in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
In particular, the term "hydroxyl protecting group" means a protecting group suitable for preventing undesirable reactions at a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to, acetyl (Ac), formyl, benzoyl (Bz), benzyl (Bn, Bnl), benzyloxymethyl (BOM), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (DPM), beta methoxyethoxymethyl ether (MEM), dimethoxytrityl [bis-(4- methoxyphenyl)phenylm ethyl, DMT], methoxymethyl ether (MOM), methoxytrityl [(4- methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr), carbobenzyloxy (Cbz, and similar carbobenzyloxy derivatives), silyl ethers (e.g, trialkylsilyl such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert- butyldimethylsilyloxymethyl (TOM) and triisopropylsilyl (TIPS) ethers), methyl ethers, and ethoxy ethyl ethers. According to the present invention, a hydroxyl protecting group is, preferably, a trialkylsilyl group, more preferably tert- butyldimethylsilyl (TBDMS).
The term "mineral acid" means an inorganic acid which is an acid derived from one or more inorganic compounds. Representative "mineral acid" include, but are not limited to, sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and polyphosphoric acid.
The term "organic acid" means an organic compound with acidic properties including carboxylic acids, whose acidity is associated with their carboxyl group -COOH and sulfonic acids, containing the group -S02OH. According to the present invention an organic acid is, preferably, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, more preferably p-toluenesulfonic acid also in mixture with residual trifluoroacetic acid.
The reaction according to step i) can be carried out, for example, by reacting the compound of formula (II) with an alcohol of formula R-OH wherein R is defined above in the presence of catalytic amounts of a "mineral acid" or an "organic acid", which are defined above.
The reaction under step ii) can be carried out, for example, by reacting the compound of formula (III) with a suitable base in a polar aprotic solvent, followed by addition of a compound of formula (IV). Representative suitable bases include, but are not limited to, sodium hydride, potassium tert-butoxide, sodium tert-butoxide and sodium methoxide. Representative polar aprotic solvents include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA) and N-methyl-2-pyrrolidone (NMP).
Conditions for conducting the Friedel-Crafts type cyclization according to step iii) are known in the art. The cyclization can be carried out under a variety of conditions. In general, the cyclization can generally be carried out by the action of a mineral acid or an organic acid as defined above. For example, the cyclization step is performed in the presence of an organic acid, such as p-toluenesulfonic acid also in mixture with residual trifluoroacetic acid.
The reduction of the double bond of a compound of formula (VI) according to step iv) can be carried out by any catalytic hydrogenation procedure known in the art. For example, the hydrogenation can be carried out by using Pd/C and a source of hydrogen such as gaseous hydrogen (H2) or hydrogen-donors in place of H2. Representative "hydrogen-donors" include, but are not limited to, formic acid, sodium formate, ammonium formate and cyclohexene.
Deprotection of a compound of formula (VII) according to step v) gives the corresponding compound of formula (I). Methods for the removal of hydroxyl protecting groups are known in the art; see, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006). For example, deprotection of a compound of formula (VII) where the hydroxyl protecting group (PG) is tert-butyldimethylsilyl (TBDMS) can be accomplished by using Tetra-n-butylammonium fluoride (or TBAF) as a solution in tetrahydrofuran (THF).
The compound of formula (II) can be prepared according to the general method for Fischer indole synthesis; for example, following the teachings reported in Scheme 1 and, in particular, Example 1(b) of EP 1296676.
The compounds of formula (IV) can be prepared, for example, following the teachings of B. Jiang et ah, Tetrahedron: Asymmetry 12 (2001) 2835-2843 (see, in particular, Scheme 1).
The compounds of formula (I) are useful intermediates for the preparation of the compound of formula (8A) as defined above. For example, the conversion of the compound of formula (I) wherein R is ethyl to the compound of formula (8A) can be carried out following the teaching of Example 8A of WO 2010/099039.
It is therefore a further object of the present invention the use of a compound of formula (I) for the preparation of a compound of formula (8A) as defined above. It is another object of the present invention a process for preparing a compound of formula (8A) as defined above, which comprises preparing the compound of formula (I) as defined above.

Claims

1. A process for preparing a compound of formula (I)
Figure imgf000012_0001
(I)
wherein R is Ci-4alkyl, which comprises:
i) esterifying the compound of formula (II)
Figure imgf000012_0002
(Π)
with an alcohol of formula R-OH, wherein R is as defined above to obtain a compound of formula (III)
Figure imgf000012_0003
(III)
wherein R is as defined above;
ii) reacting a compound of formula (III) with a compound of formula (IV)
Figure imgf000013_0001
(IV)
wherein X is an halogen atom including Bromine, Chlorine and Iodine, PG is a hydroxyl protecting group, R is as defined above, Ri is
Ci_4alkyl or R and Ri taken together are a group -(CH2)n- wherein n is 2 or 3, to obtain a compound of formula (V)
Figure imgf000013_0002
(V)
wherein PG, R and RI are as defined above;
providing intramolecular Friedel-Craft cyclization of a compound of formula (V) with a mineral or an organic acid to obtain a compound of formula (VI)
Figure imgf000013_0003
(VI)
wherein PG and R are defined above;
iv) hydrogenating the double bond of a compound of formula (VI) thereby producing a compound of formula (VII)
Figure imgf000014_0001
(VII)
wherein PG and R are defined above; and
v) deprotecting a compound of formula (VII) to obtain a compound of formula (I).
2. The process according to claim 1 , wherein R is ethyl.
3. A process according to claim 1 or 2, which further comprises transforming a compound of formula into the compound of formula (8A)
Figure imgf000014_0002
(8a)
PCT/EP2013/071890 2012-10-18 2013-10-18 Process for preparing indole derivatives WO2014060596A1 (en)

Applications Claiming Priority (2)

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EP12189104 2012-10-18
EP12189104.8 2012-10-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017005759A1 (en) 2015-07-07 2017-01-12 Intervet International B.V. A process to make azaindole derivatives
WO2017005766A1 (en) 2015-07-07 2017-01-12 Intervet International B.V. A process to make tricycic alcohol intermediates of crth2 antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100234415A1 (en) * 2009-02-24 2010-09-16 Carl Berthelette Indole derivatives as crth2 receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100234415A1 (en) * 2009-02-24 2010-09-16 Carl Berthelette Indole derivatives as crth2 receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VAN MAARSEVEEN J H ET AL: "An Approach to Canthine Derivatives Using the Intramolecular Pictet-Spengler Condensation", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 51, no. 16, 17 April 1995 (1995-04-17), pages 4841 - 4852, XP004221935, ISSN: 0040-4020, DOI: 10.1016/0040-4020(95)00169-9 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017005759A1 (en) 2015-07-07 2017-01-12 Intervet International B.V. A process to make azaindole derivatives
WO2017005766A1 (en) 2015-07-07 2017-01-12 Intervet International B.V. A process to make tricycic alcohol intermediates of crth2 antagonists

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