EP1140832A1 - Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol - Google Patents

Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol

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Publication number
EP1140832A1
EP1140832A1 EP99966475A EP99966475A EP1140832A1 EP 1140832 A1 EP1140832 A1 EP 1140832A1 EP 99966475 A EP99966475 A EP 99966475A EP 99966475 A EP99966475 A EP 99966475A EP 1140832 A1 EP1140832 A1 EP 1140832A1
Authority
EP
European Patent Office
Prior art keywords
compound
structural formula
trans
alkyl
halogen
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Withdrawn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
EP99966475A
Other languages
German (de)
English (en)
Other versions
EP1140832A4 (fr
Inventor
Bruce Ronsen
Subhash P. Upadhyaya
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.)
Pentech Pharmaceuticals Inc
Original Assignee
Pentech 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 Pentech Pharmaceuticals Inc filed Critical Pentech Pharmaceuticals Inc
Publication of EP1140832A1 publication Critical patent/EP1140832A1/fr
Publication of EP1140832A4 publication Critical patent/EP1140832A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • This invention relates to arylpiperidine carbinol intermediates and derivatives, as well as methods for their preparation.
  • the arylpiperidine carbinols can be represented by the following general structural formula (A).
  • paroxetine i.e. , (-)-trans-4-(p-fluorophenyl)-3[[3,4- (methylenedioxy) phenoxy] methyl] -piperidine.
  • hydrochloride salt praroxetine HC1
  • Paroxetine is useful in managing diseases of the central nervous system. In particular, depression, obsessive compulsive disorder, PMS (premenstrual syndrome), social anxiety disorder, and the like.
  • paroxetine has been found to be of particular benefit in treating premature ejaculation, a sexual performance condition affecting men. See, for example, U.S. Patent No. 5,276,042, to Crenshaw et al.
  • the pharmacological properties of the substituted arylpiperidine carbinols are primarily expressed by a specific stereo chemical arrangement of the residue. Only the (-)-trans substituted configuration of arylpiperidine carbinols show the desired pharmacodynamic properties. This requires the synthesis and purification of the selected desired enantiomer of the arylpiperidine carbinol.
  • a particularly desired enantiomer precursor for preparing pharmacologically active arylpiperidine carbinols is the 4-arylpiperidine-3-carbinol in (-)-trans configuration.
  • 4-arylpiperidine-3 -carbinols may exist in four stereo-specific isomers since there are two chiral centers in this molecule. Thus the synthesis of this precursor requires reactions and purification steps favoring the desired enantiomer.
  • R can be an alkyl group or the like.
  • the present invention provides a process for the synthesis of arylpiperidine carbinol intermediates and derivatives for synthesizing arylpiperidine carbinols in the
  • a process for the synthesis of arylpiperidine carbinol intermediates and derivatives is disclosed.
  • the inventive process provides for the synthesis of ( ⁇ )-trans intermediate compounds and derivatives, which are useful precursors for simplifying the synthesis of arylpiperidine carbinols in (-)-trans configuration.
  • compounds of structural formula (I) can be synthesized by condensing a cinnamonitrile of structural formula:
  • each of R 2 and R 3 is as defined in structural formula (I) .
  • compounds of structural formula (II) can be synthesized by hydrogenating compounds of structural formula (I).
  • a preferred compound of structural formula (I), diethyl-[l-cyanomethyl-l-(4'- fluorophenyl)methyl] -malonate can be synthesized in the form of a substantially pure, crystalline solid having a melting point temperature in the range of about 40° to about 55 °C, preferably in the range of about 45° to about 48 °C.
  • the compounds of structural formula (I) and structural formula (II) are useful chemical intermediates for the synthesis of 4-arylpiperidine-3-carbinols in (-)-trans configuration.
  • the inventive process advantageously provides compounds of structural formula (II) as a ( ⁇ )-trans configured mixture, thereby avoiding the need to remove cis configured compounds.
  • an intermediate compound of structural formula (II), ( ⁇ )-trans 4-(4'-fluorophenyl)-3-ethoxycarbonyl-piperidin-2-one was synthesized which, upon reduction, produced (+)-trans 4-(4'-fluorophenyl)piperidine- 3-carbinol.
  • 4-(4'-fluorophenyl)-3-ethoxycarbonyl-piperidin-2-one can be synthesized in the form of a substantially pure, crystalline solid having a melting point temperature in the range of about 140° to about 150°C and ( ⁇ )-trans configuration.
  • alkyl includes both branched and straight-chain saturated aliphatic hydrocarbons; and the term “haloalkyl” means that the alkyl group is as defined above and substituted with one or more halogen atoms.
  • Halogen refers to fluoro, chloro, bromo, or iodo.
  • aryl refers to a carbocyclic aromatic moiety, such as phenyl, benzyl, naphthyl, and the like.
  • alkali metal refers to sodium, potassium, lithium and the like. The inventive process is particularly well suited for the synthesis of 4- arylpiperidine-3-carbinols in (-)-trans configuration and derivatives thereof.
  • Synthesis Scheme (1) comprises reacting a substituted benzaldehyde (Compound A) with acetonitrile in the presence of alkali metal hydroxide to a cinnamonitrile (Compound B); condensing Compound B with dialkyl malonate in a base, preferably an alkali metal alkoxide, and solvent, preferably an alkyl ester, medium to a diester intermediate of structural formula (I) (Compound C).
  • a base preferably an alkali metal alkoxide
  • solvent preferably an alkyl ester
  • the alkyl group of each of the dialkyl malonate, alkali metal alkoxide and alkyl ester is the same to avoid the formation of mixed ester groups in the intermediate compound of structural formula (I).
  • Synthesis Scheme (1) Also illustrated in Synthesis Scheme (1) is a further process embodiment of this invention which comprises hydrogenating Compound C to a (+)-trans monoester piperidin-2-one intermediate compound of structural formula (II) (Compound D); and further process embodiments of reducing Compound D to ( ⁇ )-trans arylpiperidine base (Compound E); alkylating Compound E to the ( ⁇ )-trans N-substituted compound (Compound F); and isolating from Compound F the all (-)-trans configured arylpiperidine carbinol (Compound G).
  • Compound G can be isolated by resolving Compound F in two steps as illustrated in Synthesis Scheme (1). In step 1, Compound F is dissolved in a suitable solvent, preferably acetone.
  • step 2 the crystallized salt is neutralized with aqueous base, preferably potassium hydroxide, to the (-)-trans- arylpiperidine carbinol (Compound G).
  • Compound G can then be readily recovered and purified.
  • X in each of Compounds A, B, C, D, E, F, and G is halogen, C r C 10 alkyl, C r C 10 alkoxy, C r C I0 haloalkyl, hydroxy, or hydrogen; each of R 2 and R 3 is C r C 4 alkyl and R 2 and R 3 are the same; and in each of Compounds F and G, R 4 is C,-C 10 .
  • the inventive intermediates and inventive process greatly simplify the preparation from Compound E to the desired biologically active (-)-trans arylpiperidine carbinol compound and derivatives thereof, and 4-arylpiperidine-3 -carbinols in particular.
  • Compound A is 4-fluorobenzaldehyde
  • the alkali metal hydroxide is potassium hydroxide
  • the diester malonate is diethyl malonate
  • the base and solvent medium comprises sodium ethoxide and ethyl acetate, respectively
  • Compound F is methyl-N-substituted as illustrated generally in synthesis Scheme (2).
  • Compound G can be prepared as described above.
  • Compound C is provided in Synthesis Scheme (2) as diethyl-[l- cyanomethyl-1 -(4 '-fluorophenyl)methyl] -malonate and recoverable in the form of a substantially pure, crystalline solid having a melting point temperature in the range of about 40° to about 55 °C, preferably in the range of about 45° to about 48 °C.
  • Compound D is provided in Synthesis Scheme (2) as ( ⁇ )-trans 4-(4'-fluorophenyl)-3-ethoxycarbonyl-piperidin-2-one, which upon reduction produces ( ⁇ )-trans 4-(4'-fluorophenyl)piperidine-3-carbinol (Compound E).
  • Compound D is also recoverable in the form of a substantially pure, crystalline solid having a distinct melting point temperature in the range of about 140° to about 150° C. Further advantages of this process are that Compound D so formed is in ( ⁇ )-trans configuration, and thus requires no additional work up to remove cis configured material.
  • Powdered KOH (13.5 g, 85%) was suspended in acetonitrile (100 mL) solvent and mixed with stirring in a water bath at a temperature in the range of about 45 ° to about 50 °C.
  • 4-Fluorobenzaldehyde (20 g) (Compound A) was dissolved in acetonitrile (30 mL) solvent and the resulting solution was added in a stream to the stirred mixture.
  • the resulting reaction mixture was further stirred at the foregoing temperature for about 30 minutes after which the reaction mixture was quenched by pouring it into a beaker containing crushed ice (130 g).
  • Mass Spectra Mass Spectra (CI, Methane); m/e (relative intensity): 148 (M + + lm 100), 272 (79), 254 (56), 125 (10), 109 (34). Analysis: Calculated for
  • DiBiase Process A description of another process for the synthesis of 4-fluorocinnamonitrile can be found in DiBiase, S. A. et al., J. Organic Chemistry, 44(25), 4640-4649 (1979), the relevant disclosures of which are incorporated herein by reference (hereafter the "DiBiase Process").
  • the DiBiase et al. process employs higher temperatures (reflux), a further extraction of the product with dichloromethane, drying over sodium sulfate and evaporation in vacuo at a bath temperature of 30°C and produced only a 50% yield. Therefore, the foregoing procedure was found to be an improvement over the DiBiase process, because it minimizes cinnamonitrile reaction in situ due to the lower temperature employed and affords easier workup of the product.
  • Compound B was prepared by the DiBiase process described in Example 1. Sodium ethoxide (0.7 g) base was added to a solution of Compound B (1.47 g) dissolved in ethyl acetate (15 mL) solvent at ambient room temperature. Diethyl malonate (1.8 g) was added to the solution. The resulting reaction mixture was stirred overnight at ambient room temperature and then refluxed for 4 hours.
  • the reaction mixture was then cooled to ambient room temperature and the procedure for obtaining Compound C from the cooled reaction mixture as described in Example 2 was followed, except that no acetic acid was employed.
  • the title Compound C was provided in the form of a light yellow oil, which on standing, crystallized recovered as an off-white solid having a melting point in the range of about 44° to about 46°C (15.2 g, 73% yield).
  • the chromatography data and spectral ⁇ -NMR data were substantially the same as the data obtained for Compound C prepared in Example 2.
  • Example 3 Compound C of Example 3 (12.0 g) was reacted with activated Raney Ni (9.4 g, 50% wet) catalyst in methanol (150 mL), following the catalytic hydrogenation procedure of Example 3 except that a reaction period of about 48 hours (weekend) was employed.
  • the title Compound D was recovered in the form of a crystalline white solid (9.0 g, 87% yield) having a melting point of 141-142°C.
  • the TLC and HPLC results for Compound D were similar to those of Compound D prepared in Example 3.
  • the recovered powder (1 g yield) had spectral characteristics ( ⁇ -NMR and Mass Spectra data) that were consistent with the data of the compound produced in Example 7.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de synthèse d'intermédiaires et de dérivés de arylpipéridine carbinol. Un procédé de réalisation préféré concerne la synthèse de composés intermédiaires représentés par les formules développées (I) et (II), dans lesquelles X représente halogène, C1-C10 alkyle, C1-C10 alcoxy, C1-C10 haloalkyle, hydroxy, ou hydrogène; et R2 et R3 représentent chacun C1-C4 alkyle et R2 et R3 sont identiques. En outre, on obtient le composé de la formule développée (I) en condensant un cinnamonitrile correspondant avec un malonate diester correspondant. On obtient par ailleurs le composé de la formule développée (II) dans la position trans-(±) en hydrogénant le composé de la formule développé (I). En l'occurrence, les composés des formules développées (I) et (II) sont des intermédiaires chimiques utilisés dans la synthèse de 4-arylpipéridine-3-carbinols et de leurs dérivés dans la position trans-(-).
EP99966475A 1998-12-22 1999-12-17 Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol Withdrawn EP1140832A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21839398A 1998-12-22 1998-12-22
US218393 1998-12-22
PCT/US1999/030365 WO2000037443A1 (fr) 1998-12-22 1999-12-17 Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol

Publications (2)

Publication Number Publication Date
EP1140832A1 true EP1140832A1 (fr) 2001-10-10
EP1140832A4 EP1140832A4 (fr) 2004-11-03

Family

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EP99966475A Withdrawn EP1140832A4 (fr) 1998-12-22 1999-12-17 Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol

Country Status (5)

Country Link
EP (1) EP1140832A4 (fr)
JP (1) JP2002533325A (fr)
AU (1) AU2200400A (fr)
HU (1) HUP0104036A3 (fr)
WO (1) WO2000037443A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9930577D0 (en) * 1999-12-23 2000-02-16 Smithkline Beecham Plc Novel process
CN114437085B (zh) * 2020-11-03 2023-06-23 烟台弘邦医药科技有限公司 一种瑞卡帕布中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026187A1 (fr) * 1998-11-02 2000-05-11 Synthon B.V. Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1422263A (en) * 1973-01-30 1976-01-21 Ferrosan As 4-phenyl-piperidine compounds
CH636858A5 (de) * 1977-01-17 1983-06-30 Ciba Geigy Ag Verfahren zur herstellung neuer phenylazacycloalkane.
EP0190496A3 (fr) * 1984-12-13 1987-05-27 Beecham Group Plc Dérivés de la pipéridine à activité gastro-intestinale
JP3446468B2 (ja) * 1996-04-15 2003-09-16 旭硝子株式会社 ピペリジンカルビノール類の製造方法
JPH11240869A (ja) * 1997-12-22 1999-09-07 Sumika Fine Chemicals Co Ltd ラクタムカルボン酸誘導体およびその製法、ならびにそれを用いたピペリジン誘導体の製法
ES2137131B1 (es) * 1998-02-06 2000-09-16 Vita Invest Sa Derivado de piperidinona procedimiento de obtencion y procedimiento para su utilizacion.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026187A1 (fr) * 1998-11-02 2000-05-11 Synthon B.V. Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE HCAPLUS ACS; 12 May 1984 (1984-05-12), XP002285821 retrieved from STN Database accession no. 80:95438/DN & POPANDOVA, K. ET AL.: GODISHNIK NA SOFIISKIYA UNIVERSITET SV. KLIMENT OKHRIDSKI, KHIMICHESKI FAKULTET, vol. 65, 1970, - 1971 pages 251-260, *
DATABASE HCAPLUS ACS; 9 September 1999 (1999-09-09), XP002285822 retrieved from STN Database accession no. 131:184870/DN & JP 11 240869 A (SUMIKA FINE CHEMICALS CO.) 7 September 1999 (1999-09-07) *
MEGLIO DE P G ET AL: "DERIVATI PIRROLIDONICI E PIPERIDONICI AD ATTIVITA' ANTIISTAMINICA ED ANTIANAFILATTICA. SINTESI E STUDIO FARMACOLOGICO" IL FARMACO, ROME, IT, vol. 42, no. 5, 1987, pages 359-382, XP009014555 ISSN: 0014-827X *
REED, PETER E. ET AL.: J. MED. CHEM., vol. 34, 1991, pages 1162-1176, XP002285820 *
See also references of WO0037443A1 *

Also Published As

Publication number Publication date
AU2200400A (en) 2000-07-12
HUP0104036A2 (hu) 2002-02-28
HUP0104036A3 (en) 2003-04-28
WO2000037443A1 (fr) 2000-06-29
JP2002533325A (ja) 2002-10-08
EP1140832A4 (fr) 2004-11-03

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