WO1994027985A1 - Procede de preparation de 3-halomethyl-benzothiophenes, -benzofuranes et -indoles substitues et intermediaires associes - Google Patents

Procede de preparation de 3-halomethyl-benzothiophenes, -benzofuranes et -indoles substitues et intermediaires associes Download PDF

Info

Publication number
WO1994027985A1
WO1994027985A1 PCT/US1994/005929 US9405929W WO9427985A1 WO 1994027985 A1 WO1994027985 A1 WO 1994027985A1 US 9405929 W US9405929 W US 9405929W WO 9427985 A1 WO9427985 A1 WO 9427985A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
process according
bromide
compound
Prior art date
Application number
PCT/US1994/005929
Other languages
English (en)
Inventor
Lendon Norwood Pridgen
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1994027985A1 publication Critical patent/WO1994027985A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • 4,959,360, 4,963,547, 4,978,660, and 5,006,521 may be prepared from C 1-2 alkyl
  • this invention is a process for preparing compounds of formula (I):
  • X 1 , X 2 , and X 3 independently are any accessible combination of H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR2, CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SC 1-4 alkyl, S(CH 2 ) 0-6 phenyl or SCF 3 ;
  • Y is Br or Cl
  • A is S, O, or NH
  • each R 2 independently is C 1-6 alkyl or (CH 2 ) 0-6 phenyl;
  • each R 3 independently is H, C 1-6 alkyl, COR 2 , or SO 2 R 2 ;
  • R 4 is H or C 1-6 alkyl
  • R 5 is C 1-6 alkyl,C 3-5 alkenyl, or (CH 2 ) 0-6 Phenyl; which comprises reacting a compound of the formula (II):
  • X 1 , X 2 , X 3 , A and R 1 are as defined above for formula (I),
  • a feature of this invention is novel intermediate compounds of the formula (VI):
  • X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 , CN, NO 2 , NR 3 R 4 , OR 3 , SC 1-4 alkyl, S(CH 2 ) 0-6 phenyl or SCF 3 ;
  • Y is Br or Cl
  • A is S, O, or NH.
  • the present invention discloses useful intermediates and a process for the preparation of compounds of formula (I):
  • X 1 , X 2 , and X 3 independently are any accessible combination of H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 CN, NO 2 , NR 3 R 4 , OR 3 ,
  • SC 1-4 alkyl S(CH 2 ) 0-6 phenyl or SCF 3 ;
  • Y is Br or Cl
  • A is S, O, or NH
  • each R 2 independently is C 1-6 alkyl or (CH 2 ) 0-6 phenyl;
  • each R 3 independently is H, C 1-6 alkyl, COR 2 , or SO 2 R 2 ;
  • R 4 is H or C 1-6 alkyl; and R 5 is C 1-6 alkyl,C 3-5 alkenyl, or (CH 2 ) 0-6 phenyl; which comprises reacting a compound of the formula (II):
  • X 1 , X 2 , X 3 , A and R 1 are as defined above for formula (I), with a halomethylating agent, in the presence of a phase-transfer catalyst.
  • alkyl and alkenyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
  • the process can be used to prepare compounds according to formula (III):
  • A, Y and R 1 are as defined above for formula (I);
  • X 1 is H, Cl, Br, F, I, CF 3 , C 1-6 alkyl, COR 2 , CO 2 R 2 , CONR 2 R 2 , CN,
  • a and R 1 are as defined in formula (I);
  • X 2 is defined in formula (III).
  • the process can be used to prepare compounds of formula (III) in which X 1 is Cl, Br, F, or I, A is S or O, and R 1 is C 1-6 alkyl.
  • the process can be used to prepare formula (III) compounds in which X 1 is Cl, A is S, R 1 ethyl and Y is Br, which is 2-ethyl-3-bromomethyl-5-chlorobenzo[b]thiophene.
  • the reaction is carried out on compounds of formula (II) in which X 1 , X 2 , X 3 , A and R 1 are as required in the formula (I) product.
  • the process is conducted with formula (IN) compounds.
  • phase-transfer catalyst used in the present invention is a quaternary salt of the formula (N): (R') 4 M + U- (V) wherein:
  • M is nitrogen, arsenic, phosphorous, antimony, or bisbuth
  • each R' independently is C 1-25 alkyl, with the total carbon content of (R') 4 being greater than 16 carbon atoms, but not greater than 50 carbon atoms.
  • M is a pentavalent ion
  • R 1 is an organic portion of the salt molecule bonded to M by four covalent linkages
  • U- is an anion.
  • the preferred halide quaternary salts are those wherein M is nitrogen and U is Cl or Br.
  • Suitable quaternary salts are cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetyldimethylethylammonium bromide, cetyltrihexylammonium bromide, trioctylethylammonium bromide, tridecylmethylammonium chloride,
  • the preferred quaternary salts are cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
  • the halomethylating agent used in the present invention is generated from formaldehyde, or an equivalent thereof, and aqueous hydrobromic or hydrochloric acid.
  • the halomethylating agent is generated from formaldehyde, formalin or 1, 3, 5-trioxane, preferably 1, 3, 5-trioxane, and 48% hydrobromic acid in glacial acetic acid.
  • the process is carried out by reacting a 2-substituted- benzo[b]thiophene, -benzo[b]furan, or -indole, preferably 2-ethyl-5-chlorobenzo[b]thiophene, with a halomethylating agent, preferably generated from 1, 3, 5-trioxane and 48% hydrobromic acid in glacial acetic acid, in the presence of a phase-transfer catalyst, such as a quaternary salt, preferably
  • cetyltrimethylammonium bromide or myristyltrimethylammonium bromide are examples of cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
  • novel intermediates of formula (VI) are prepared by reacting a
  • a phase-transfer catalyst for example cetyltrimethylammonium bromide or myristyltrimethylammonium bromide.
  • the formula (II) and (IV) compounds are prepared from the appropriately substituted phenol, thiophenol or aniline starting materials, such as 4-chlorothiophenol, in a reaction with ⁇ -bromobutyraldehyde diethyl acetal, followed by acid-catalyzed cyclization.
  • the flask was then allowed to warm to room temperature, and sodium iodide (67.6 g, 0.451 mol) and ⁇ -bromobutyraldehyde diethyl acetal (1015.33 g, 4.51 mol) were added bulkwise over 15 min.
  • the reaction was heated to reflux for 18 hr. and then checked by GC [120°(1)/15° min/275° (5); DB-1, 15 meter column] for the disappearance of the starting materials.
  • the reaction was allowed to heat under reflux 2 hr. more and then allowed to cool to room temperature.
  • the reaction solution was partitioned between ethyl acetate and water (3.0 L each).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à de nouveaux intermédiaires et procédés destinés à la préparation d'intermédiaires utiles répondant à la formule (I) et aptes à être utilisés pour la synthèse d'agents à activité pharmaceutique.
PCT/US1994/005929 1993-05-28 1994-05-26 Procede de preparation de 3-halomethyl-benzothiophenes, -benzofuranes et -indoles substitues et intermediaires associes WO1994027985A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6891493A 1993-05-28 1993-05-28
US08/068,914 1993-05-28

Publications (1)

Publication Number Publication Date
WO1994027985A1 true WO1994027985A1 (fr) 1994-12-08

Family

ID=22085524

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/005929 WO1994027985A1 (fr) 1993-05-28 1994-05-26 Procede de preparation de 3-halomethyl-benzothiophenes, -benzofuranes et -indoles substitues et intermediaires associes

Country Status (1)

Country Link
WO (1) WO1994027985A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0919552A1 (fr) * 1996-07-24 1999-06-02 Teikoku Hormone Mfg. Co., Ltd. Procede de preparation de composes de benzothiophene 2,6-disubstitue

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2553495A (en) * 1950-05-04 1951-05-15 Nat Drug Co N-(3-benzothenyl)-n-ethyl-betachloroethylamine adrenolytic
US3331854A (en) * 1964-12-14 1967-07-18 American Cyanamid Co Novel furan and thiophene compounds
US5196429A (en) * 1986-12-31 1993-03-23 Hoechst-Roussel Pharmaceuticals Inc. Method of inhibiting the activity of leukocyte derived cytokines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2553495A (en) * 1950-05-04 1951-05-15 Nat Drug Co N-(3-benzothenyl)-n-ethyl-betachloroethylamine adrenolytic
US3331854A (en) * 1964-12-14 1967-07-18 American Cyanamid Co Novel furan and thiophene compounds
US5196429A (en) * 1986-12-31 1993-03-23 Hoechst-Roussel Pharmaceuticals Inc. Method of inhibiting the activity of leukocyte derived cytokines

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEMCIAL ABSTRACTS, Volume 87, issued 1977, ARESCHKA et al., "Studies on the Benzofuran Series", Abstract No. 102105. *
CHEMICAL ABSTRACTS, Volume 77, issued 1972, ARESCHKA et al., "Benzofurans. Benzofurarylmethylimidazolines", Abstract No. 164591. *
CHEMICAL ABSTRACTS, Volume 77, issued 1972, BINON et al., "2-Ä (2-Alkylbenzofuran)MethylÜ-2-Imidazolones", Abstract No. 140068. *
CHEMICAL ABSTRACTS, Volume 80, issued 1973, DESCAMPS et al., "Antihypertensive Acetamidine Derivatives", Abstract No. 96017. *
CHEMICAL ABSTRACTS, Volume 80, issued 1973, KHILYA et al., "Synthesis and Properties of Heterocyclic Analogs of Isoflavones", Abstract No. 59825. *
CHEMICAL ABSTRACTS, Volume 85, issued 1976, ARESCHKA et al., "New Piperazine Amidines and Related Compounds", Abstract No. 160029. *
CHEMICAL ABSTRACTS, Volume 85, issued 1976, WITIAK et al., "Synthesis and Antilipidemic Properties of Cis-7-Chloro-3a,8b-Dihydro.....Benzofuran", Abstract No. 116536. *
CHEMICAL ABSTRACTS, Volume 99, issued 1983, CROSS et al., "Thromboxane Synthetase Inhibitors and Pharmaceutical Compositions Comprising Them", Abstract No. 105247. *
J. MARCH, "Advanced Organic Chemistry", 4th Edition, Published 1992, by WILEY-INTERSCIENCE (N.Y.), see pages 362-363. *
J. MCMURRY, "Organic Chemistry", 2nd Edition, Published 1988, by BROOKS/COLE (CA), see pages 1039-1040. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0919552A1 (fr) * 1996-07-24 1999-06-02 Teikoku Hormone Mfg. Co., Ltd. Procede de preparation de composes de benzothiophene 2,6-disubstitue
EP0919552A4 (fr) * 1996-07-24 1999-09-15 Teikoku Hormone Mfg Co Ltd Procede de preparation de composes de benzothiophene 2,6-disubstitue
US6020531A (en) * 1996-07-24 2000-02-01 Teikoku Hormone Mfg. Co., Ltd. Process for the preparation of 2,6-disubstituted benzothiophene compounds

Similar Documents

Publication Publication Date Title
CA1167036A (fr) Synthese de benzothiophenes acyles
US8748636B2 (en) Process for preparing benzofuran derivatives substituted at position 5
CA1130296A (fr) Obtention et emploi pharmaceutique de composes du type hydroxypropyl-triazole
CH616161A5 (fr)
HU200740B (en) Process for producing alkadiene derivatives and pharmaceutical compositions comprising same
WO1994027985A1 (fr) Procede de preparation de 3-halomethyl-benzothiophenes, -benzofuranes et -indoles substitues et intermediaires associes
JP2012516868A (ja) ２−ハロゲノメチルフェニル酢酸誘導体の製造方法
US4158007A (en) Carbazole methyl malonates
US4154743A (en) 3-Oxobenzofuranyl-2-idenyl, haloacetic acids
WO2008139057A2 (fr) Procede de preparation de 2-(n-butyl)-3-(4-hydroxybenzoyl)-5-nitrobenzofurane
HU208533B (en) Process for selective etherification of ascorbinic acid derivatives
JPH0794420B2 (ja) 置換フェノキシアセトアルデヒドオキシム類の製造方法
HU208320B (en) Process for producing 0-carboxypyridyl and 0-carboxyquinolyl imidazolinones
US5580989A (en) Process for the preparation of N-4-[(substituted phenyl)alkylheterocyclic]-N
CZ61093A3 (en) BENZOL(b)THIOPHEN-5-YL DERIVATIVES, AND PROCESS FOR PRODUCING THEREOF
CA1197511A (fr) Haloalkyl-8-4h-¬1|-benzopyran-4-ones, et procede de preparation
US4891433A (en) Process for the preparation of dibenzothiepin derivative
GB2120663A (en) Allylamine derivatives, processes for their preparation and their use
US4931574A (en) Process for the preparation of benzopyrans
CA1119179A (fr) Procede d'obtention de composes a base de n-tritylimidazole
US4334088A (en) 2-Alkynyl-5-indanyloxyacetic acids
JP3534816B2 (ja) メチルチオベンゼン類の製造方法
US4982008A (en) Process for preparing p-bromophenoxyacetaldehyde dialkylacetal compounds
US4226774A (en) Carbazole melonates
US4193923A (en) Tetrahydro 2-carbazolyl methyl malonate derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase