EP0983269A4 - Procede utiles pour la preparation de composes heterocycliques - Google Patents

Procede utiles pour la preparation de composes heterocycliques

Info

Publication number
EP0983269A4
EP0983269A4 EP98924912A EP98924912A EP0983269A4 EP 0983269 A4 EP0983269 A4 EP 0983269A4 EP 98924912 A EP98924912 A EP 98924912A EP 98924912 A EP98924912 A EP 98924912A EP 0983269 A4 EP0983269 A4 EP 0983269A4
Authority
EP
European Patent Office
Prior art keywords
mixture
etoac
give
cooled
solution
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98924912A
Other languages
German (de)
English (en)
Other versions
EP0983269A1 (fr
Inventor
Leander Merritt
John Stanley Ward
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0983269A1 publication Critical patent/EP0983269A1/fr
Publication of EP0983269A4 publication Critical patent/EP0983269A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to a process for preparing azabicyclic compounds useful for modulating a muscarinic receptor.
  • Compounds having muscarinic receptor activity can be particularly desired for use in treating conditions such as, but .not limited to, Alzheimers' disease, glaucoma, and for the treatment of pain.
  • Certain known aza-bicyclic thiadiazole containing compounds have demonstrated such muscarinic receptor activity; however, the known preparation methods require a linear synthesis. Further, it can be particularly desired to isolate the diastereomers and enantiomers of the compounds.
  • the known preparation methods provide for resolution of the diastereomers and enantiomers in the final step of the reaction sequence. Resolution of the diastereomers and enantiomers at an early stage of the synthesis could improve the yield and cost of production for such resolved compounds.
  • the presently claimed process fulfills this need for a convergent synthesis useful for the preparation of azabicyclic thiadiazole compounds.
  • R is selected from the group consisting of halo, C.-C 9
  • R is C 1 -C 6 alkyl or hydrogen.
  • halogen means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I.
  • Ci-C n' alkyl wherein n ' can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms.
  • Typical Ci-C ⁇ alkyl groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • substituted (C 5 -C n' ) alkyl refers to an alkyl group as described supra wherein the alkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, aryl, substituted aryl, C -C ⁇ alkyl, NO 2 , halogen, halogen(C ⁇ -C6) alkyl, halogen (C 2 -C6.
  • C 2 -C n' alkenyl wherein n' can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond.
  • C 2 -C 5 alkynyl refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.
  • halogen (C 1 -C 6 . alkyl and "halogen (C 2 - C ⁇ ) alkenyl” refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms.
  • C 2 -C1 0 alkanoyl represents a group of the formula C(O) (C 1 -C 9 ) alkyl.
  • Typical C 2 -C 10 alkanoyl groups include acetyl, propanoyl , butanoyl, and the like.
  • (C ⁇ -C 6 alkyl) amino refers to a monoalkylamino group. Examples of such groups are methylamino, ethylamino, iso-propylamino, ⁇ -propylamino, ( n- propyl) amino, ( iso-propyl ) amino, n-propylamino, t- butylamino, and the like.
  • substituted (Cs-Cn 1 ) cycloalkyl refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C1-C 6 alkyl, NO 2 , halogen, halogen (Ci-C ⁇ ) alkyl, halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, C0 2 R 20 , (Ci-C ⁇ alkyl) amino, -SR 20 , and OR 20 ; wherein R 20 is selected from the group consisting of C ⁇ _i 5 -alkyl, C2-15- alkenyl, and C2-i5-alkynyl .
  • C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl represents an alkyl group substituted at a terminal carbon with a C3-C8 cycloalkyl group.
  • Typical cycloalkylalkyl groups include cyclohexylethyl , cyclohexylmethyl , 3- cyclopentylpropyl, and the like.
  • C 5 -C 8 cycloalkenyl represents an olefinically unsaturated ring having five to eight carbon atoms.
  • Such groups include, but are not limited to, cyclohexyl -1 , 3 -dienyl , cyclohexenyl , cyclopentenyl, cycloheptenyl, cyclooctenyl , cyclohexyl-1 , 4-dienyl , cycloheptyl-1, 4-dienyl, cyclooctyl-1 , 3 , 5 ⁇ trienyl and the like.
  • cycloalkenyl refers to a cycloalkenyl group as described supra , wherein the cycloalkenyl group may be substituted with from one to four' substituents independently selected from the group consisting of hydrogen, C 1 -C. 6 alkyl, NO 2 , halogen, halogen (Ci-C ⁇ ) alkyl, halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, COR 20 , C2-C10 alkanoyl, C 7 -C 16 arylalkyl, CO 2 R 20 , (Ci-C ⁇ alkyl) amino, -SR 20 , and -OR 20 .
  • R 20 is selected from the group consisting of Ci- 15 -alkyl, C2-l5-alkenyl , C2-15- alkynyl .
  • the term "C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl" represents a C 1 -C 3 alkyl group substituted at a terminal carbon with a C5-C 8 cycloalkenyl group.
  • heterocycle means a group containing from one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with Ci-6 -alkyl, -CF3 , phenyl, benzyl or thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group.
  • heterocycle includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes , pyrroles, furans ) ; 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles ) ; 5-membered heterocycles having 3- heteroatoms; 6-membered heterocycles with one heteroatom (e.g.
  • pyridine quinoline, isoquinoline, phenanthrine, 5, 6-cycloheptenopyridine
  • 6-membered heterocycles with two heteroatoms e.g. pyridazines, cinnolines, phthalazines , pyrazines, pyrimidines, quinazolines
  • 6- membered heterocycles with three heteroatoms e.g. 1,3,5- triazine
  • 6-member heterocycles with four heteroatoms particularly preferred are thiophenes , pyridines, and furans .
  • Ci-C ⁇ alkylheterocycle means an alkyl group attached to the nucleus molecule (for example, but not limited to, at the W substituent) and a heterocycle attached at the distal end of the alkyl group.
  • W-CH 2 ⁇ thiophene is one example.
  • heteroaryl refers to a group which is a 5 or 6 membered heterocycle containing one to four N, O, . or S atoms or a combination thereof.
  • carboxy refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.
  • aryl means an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl . Most preferably, aryl refers to CG-CIO aryl, wherein the aryl ring system, including any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3,3- dimethylphenyl , naphthyl, and the like. The aryl radical may be substituted by one or two C1-C 6 straight or branched alkyl.
  • aryl (C 1 -C 3 ) alkyl refers to any aryl group which is attached to the parent moiety via the alkyl group.
  • substituted aryl refers to an aryl group which may be substituted with from one to three substituents selected from the group consisting of halogen(s), -CF 3 , -CN, C ⁇ -15-alkyl, C2-5-alkenyl , C2-5- alkynyl, and C ⁇ - 10 -alkoxy .
  • . 8 5 6 7 the group consisting of halo, C j -C j alkyl, R 0, RS, R NR R , aryl, and substituted aryl;
  • the starting materials for the illustrated process are commercially available or may be prepared using methods known to the skilled artisan.
  • the process of the present invention provide compounds having useful muscarinic receptor activity.
  • A) n is 2 ; B) m is 1 ;
  • R 2 is R 8 S;
  • R is C ⁇ -C 6 alkyl;
  • R is C ⁇ -C 6 alkyl.
  • HPLC analysis of final crystallization products of both enantiomers show less than 3 % of the opposite enantiomer. It could be much better, but present HPLC analysis does not provide good enough resolution to determine much below this limit .
  • HC1 was bubbled into the solution for approximately 5 min while maintaining the temperture below 22 °C . After another 5 min., the reaction was cooled to 15 °C and H 2 0 (20 mL) was added dropwise while maintaining the temperture below 25 °C.
  • the temperature was then allowed to rise to 0 °C over 1 h.

Landscapes

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

Abstract

La présente invention concerne un procédé utile pour la préparation de composés azabicycliques de thiadiazole.
EP98924912A 1997-05-29 1998-05-27 Procede utiles pour la preparation de composes heterocycliques Withdrawn EP0983269A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4788197P 1997-05-29 1997-05-29
US47881P 1997-05-29
PCT/US1998/010757 WO1998054179A1 (fr) 1997-05-29 1998-05-27 Procede utiles pour la preparation de composes heterocycliques

Publications (2)

Publication Number Publication Date
EP0983269A1 EP0983269A1 (fr) 2000-03-08
EP0983269A4 true EP0983269A4 (fr) 2001-06-27

Family

ID=21951533

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98924912A Withdrawn EP0983269A4 (fr) 1997-05-29 1998-05-27 Procede utiles pour la preparation de composes heterocycliques

Country Status (4)

Country Link
EP (1) EP0983269A4 (fr)
AU (1) AU7697298A (fr)
CA (1) CA2291157A1 (fr)
WO (1) WO1998054179A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2582202A1 (fr) * 2004-10-07 2006-04-20 Vitae Pharmaceuticals, Inc. Diaminoalcane inhibiteurs de la protease aspartique
TWI411607B (zh) 2005-11-14 2013-10-11 Vitae Pharmaceuticals Inc 天門冬胺酸蛋白酶抑制劑
CL2007002689A1 (es) 2006-09-18 2008-04-18 Vitae Pharmaceuticals Inc Compuestos derivados de piperidin-1-carboxamida, inhibidores de la renina; compuestos intermediarios; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como hipertension, insuficiencia cardiaca, fibrosis cardiaca, entre otras.
AR077692A1 (es) 2009-08-06 2011-09-14 Vitae Pharmaceuticals Inc Sales de 2-((r)-(3-clorofenil) ((r)-1-((s) -2-(metilamino)-3-((r)-tetrahidro-2h-piran-3-il) propilcarbamoil) piperidin -3-il) metoxi) etilcarbamato de metilo
CN101723879B (zh) * 2009-11-16 2011-12-28 华东师范大学 一种合成(r)-3-哌啶乙酸乙酯盐酸盐的方法
WO2011115943A1 (fr) 2010-03-16 2011-09-22 Aventis Pharmaceuticals Inc. Pyrimidine substituée en tant qu'antagoniste du récepteur d2 de prostaglandines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994020496A1 (fr) * 1993-03-05 1994-09-15 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939140A (en) * 1985-11-07 1990-07-03 Pfizer Inc. Heterocyclic oxophthalazinyl acetic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994020496A1 (fr) * 1993-03-05 1994-09-15 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 33, no. 14, 20 July 1939, Columbus, Ohio, US; PRELOG V ET AL: "1-Azabicyclo[1.2.3]octane" column 5401; XP002165637 *
J. CHEM. SOC., 1939, pages 677 - 678 *
See also references of WO9854179A1 *

Also Published As

Publication number Publication date
EP0983269A1 (fr) 2000-03-08
CA2291157A1 (fr) 1998-12-03
AU7697298A (en) 1998-12-30
WO1998054179A1 (fr) 1998-12-03

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