EP1140832A1 - Process for preparing arylpiperidine carbinol intermediates and derivatives - Google Patents

Process for preparing arylpiperidine carbinol intermediates and derivatives

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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
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Prior art keywords
compound
structural formula
trans
alkyl
halogen
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EP99966475A
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German (de)
French (fr)
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EP1140832A4 (en
Inventor
Bruce Ronsen
Subhash P. Upadhyaya
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Pentech Pharmaceuticals Inc
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Pentech Pharmaceuticals Inc
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    • 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.

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

Abstract

A process for the synthesis of arylpiperidine carbinol intermediates and derivatives is disclosed. A preferred process embodiment provides the synthesis of intermediate compounds of structural formula (I) and structural formula (II), where X is halogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, hydroxy, or hydrogen; and R2 and R3 each is C1-C4 alkyl and R2 and R3 are the same. The compound of structural formula (I) is made by condensing a corresponding cinnamonitrile with a corresponding diester malonate. The compound of structural formula (II) in the (±)-trans configuration is obtained by hydrogenating the compound of structural formula (I). The compounds of structural formula (I) and structural formula (II) are useful chemical intermediates for synthesizing 4-arylpiperidine-3-carbinols and their derivatives in (-)-trans configuration.

Description

PROCESS FOR PREPARING ARYLPIPERIDINE CARBINOL INTERMEDIATES AND DERIVATIVES
Technical Field
This invention relates to arylpiperidine carbinol intermediates and derivatives, as well as methods for their preparation. Background of the Invention
The preparation of pharmacologically active arylpiperidine derivatives by conversion of the primary hydroxyl residue of the carbinol from the arylpiperidine into an ether with either an aliphatic and/or aromatic residue has been described in U.S. Patent No. 4,007,196 by Christensen et al. , and in U.S. Patent No. 4,902,801 by Faruk, et al., and by others. Further, derivatives of the secondary amine of the piperidine residue can have significance both biologically and chemically.
The arylpiperidine carbinols can be represented by the following general structural formula (A).
which can be derivatized by substituents on the heterocyclic nitrogen atom, on the aromatic ring, as well as for the hydrogen of the hydroxymethyl group.
Of particular interest is paroxetine, i.e. , (-)-trans-4-(p-fluorophenyl)-3[[3,4- (methylenedioxy) phenoxy] methyl] -piperidine. Its hydrochloride salt (paroxetine HC1), preferably in an amorphous form as described in U.S. Patent No. 5,672,612 by Ronsen and El-Rashidy, has been shown to be pharmacologically active. 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. Further, 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. However, 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.
It is known that 4-arylpiperidine-3-carbinols may be prepared by the Grignard reaction shown generally in the following synthesis scheme:
wherein R can be an alkyl group or the like.
Alternatively, several other methods of preparing arylpiperidine carbinols have been disclosed. For example, U.S. Patent No. 4,902,801 to Faruk, et al. , describes in situ cyclization of the branched derivative prepared by the reaction of fluorobenzaldehyde with ethyl acetate followed by Michael addition of amidomalonate to the adduct; and U.S. Patent No. 4,861,893 to Borrett, et al. describes the derivativization of pyridine followed by the reduction of the aromatic pyridine to the piperidine. However, the foregoing methods described do not account for the four stereo specific isomers so formed and tend to produce less than optimum yields of (-)-trans isomer because the (+)cis, (-)-cis, and the (- -)-trans isomers also all form.
The present invention provides a process for the synthesis of arylpiperidine carbinol intermediates and derivatives for synthesizing arylpiperidine carbinols in the
(-)-trans configuration. Summary of the Invention
A process for the synthesis of arylpiperidine carbinol intermediates and derivatives is disclosed. In particular, 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.
The inventive process synthesizes novel intermediate compounds having structural formula (I) and structural formula (II):
(I) (") where X is halogen, C,-C10 alkyl, C,-C10 alkoxy, CrC10 haloalkyl, hydroxy, or hydrogen; and each of R2 and R3 is C4 alkyl and R2 and R3 are the same.
In preferred process embodiments, compounds of structural formula (I) can be synthesized by condensing a cinnamonitrile of structural formula:
wherein X is as defined in structural formula (I) with a diester malonate of structural formula:
wherein each of R2 and R3 is as defined in structural formula (I) . In another preferred process embodiment, 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.
In one preferred process embodiment, 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. Beneficially, 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. Thus, this inventive process avoids the need for additional workup to remove cis configured compound and simplifies the process for purification of the inventive intermediate of structural formula (II) to the desired biologically active (-)-trans-4-(4 ' -fluorophenyl)-piperidine-3-carbinol . Detailed Description of Preferred Embodiments
As used herein, the term "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" as used herein refers to fluoro, chloro, bromo, or iodo. The term "aryl" as used herein, refers to a carbocyclic aromatic moiety, such as phenyl, benzyl, naphthyl, and the like. The term "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.
One process embodiment of this invention is illustrated generally by Synthesis Scheme (1), below which 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). Preferably 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).
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. To the resulting solution is added a solution of appropriate chiral acid, e.g., (-)-Di-p-toluoyl tartaric acid or other tartaric acid, or derivative thereof, dissolved in the same or an appropriate solvent to form a salt. The salt so formed with (-)-trans-arylpiperidine carbinol crystallizes while the salt formed with the (+)-trans-compound remains in solution. In 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.
In general Synthesis Scheme (1):
X in each of Compounds A, B, C, D, E, F, and G is halogen, CrC10 alkyl, Cr C10 alkoxy, CrCI0 haloalkyl, hydroxy, or hydrogen; each of R2 and R3 is CrC4 alkyl and R2 and R3 are the same; and in each of Compounds F and G, R4 is C,-C10. 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.
In a preferred process embodiment, Compound A is 4-fluorobenzaldehyde, the alkali metal hydroxide is potassium hydroxide, the diester malonate is diethyl malonate and the base and solvent medium comprises sodium ethoxide and ethyl acetate, respectively, and Compound F is methyl-N-substituted as illustrated generally in synthesis Scheme (2). Compound G can be prepared as described above.
Advantageously, 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.
Synthes is Scheme 2
(±) - trans (±) - trans (±) - trans (-) - trans
Beneficially, 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). Advantageously, 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.
The following examples illustrate preferred embodiments of the preparation and characterization of the inventive intermediates and inventive process prepared by Synthesis Scheme 2 without limitation thereto.
Example 1. Synthesis of 4-Fluorocinnamonitrile (Compound B)
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). An upper organic layer separated and was washed with brine (50 mL), dried over sodium sulfate and the solvent was evaporated under reduced pressure to provide a substantially semi-solid crude material (17.8 g). The crude material was passed through silica gel (30 g) using 25 % ethyl acetate in hexane to provide the title Compound (B) in the form of a pale yellow semi-solid product (16.7 g, 70% yield, trans/cis or E/Z ratio about 4.0 by NMR). Analysis by High Performance Liquid Chromatography (HPLC) showed it to be >95% pure. Compound (B) was characterized as follows.
Η-NMR (CDClj): trans-B, δ 5.83 (d, 1H, J = 16.8 Hz), 7.00-7.90 (m,5H); cis-B, δ 5.48 (d, 1H, J = 12.3 Hz), 7.00-7.90 (m, 5H).
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
C9H6FN: C 73.46, H 4.11, N 9.52; Found: C 72.65, H 4.24, N 9.04. A small sample (0.22g) was rechromatographed on silica gel (0.5 g) using 5 % ethyl acetate in hexane (10 mL) to give white crystalline solid (0.16 g). Analysis: Calculated for C9H6FN: C 73.46, H 4.11, N 9.52; Found: C 73.44, H 4.04, N 9.32.
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"). However, 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.
Example 2. Synthesis of Diethyl[l-cyanomethyl-l-(4'- fluorophenyl)methyl]malonate (Compound C)
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 was determined to be incomplete, based on analysis by Thin Layer Chromatography (TLC) (Rf values of 4-fluorocinnamonitrile = 0.58; of diethylmalonate = 0.54; and of reaction product = 0.41), employing a solvent system of hexane and ethyl acetate (7:3), ultraviolet light and iodine vapor to expose the spots. Silica gel fluorescent plates were used.
Therefore, more sodium ethoxide (0.54 g) was added and the reaction mixture was refluxed further for about 2 hours. Completion of the reaction was determined by TLC as described above. The reaction mixture was then cooled to ambient room temperature and quenched with a solution of glacial acetic acid (1.5 g) in water (10 mL). Ethyl acetate (10 mL) was then added and an upper organic layer separated. The organic layer was washed with brine (10 mL), dried over sodium sulfate and the solvent was evaporated under reduced pressure to provide 3.2 g crude product in the form of a dark yellow oil. This crude oil product (3.0 g) was purified by flash column chromatography using silica gel (20 g, 230-400 mesh) using hexane and then 1-2% ethyl acetate in hexane to provide the title Compound C (2.07 g, 72% yield) in the form of a substantially colorless oil which, on standing, crystallized and was recoverable as an off-white solid having a melting point in the range of about 45° to about 48 °C. Compound C was analyzed as having the following spectral characteristics. Η-NMR (CDC13): δ 1.03 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H),
2.88 (d, J = 7.2 Hz, 2H), 3.75 (m, 1H), 3.83 (d, J = 10.2, 1H), 3.98 (q, J = 7.2 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 7.00 - 7.35 (m, 4H).
13C-NMR (CDCI3): δ 13.6, 13.8, 22.7, 40.4, 55.8, 61.7, 62.1, 115.8 (d, J= 14.7 Hz), 117.4, 129.5, 133.7, 161.8 (d), 166.7, 167.3. Mass Spectra (El); m/e (relative intensity): 307 (M+, 45), 262 (12), 234 (90),
216 (33), 205 (78), 149 (96), 148 (100). Mass Spectra (CI, Methane); m/e (relative intensity): 308 (M+ + 1, 100), 262 (43), 234 (6), 216 (14).
Analysis: Calculated for C16H18FNO4: C 62.53, H 5.90, F 6.18, N 4.56: Found: C 62.43, H 6.04, F 6.32, N 4.22.
Example 3. ( + )-trans-3-Ethoxycarbonyl-4-(4 ' -fluorophenyl)piperidin-2-one
(Compound D)
Compound C of Example 2 (1.5 g) was dissolved in methanol (30 mL) and to the solution was added activated Raney nickel (1.45 g, 50% wet) catalyst. The reaction mixture was purged with nitrogen and then stirred under hydrogen atmosphere (H2) at atmospheric pressure in a water bath set at a temperature of about 40 °C for a period of about 16 hours. The reaction mixture was then cooled to ambient room temperature and TLC analysis was performed as described in Example 2. TLC analysis showed that the reaction was complete (Rf values of starting material = 0.41; of reaction product = 0.12). The cooled reaction mixture was filtered through Celite. The reaction flask and Celite residue were each washed with methanol (15 mL) and the filtrates combined.
The combined filtrate was evaporated under reduced pressure to provide a pale yellow solid crude product (1.2 g). This crude product was suspended in a 4: 1 mixture of hexane and ethyl acetate (10 mL) and the mixture was stirred at about 5°C for about 1 hour, and then filtered and air dried to give the title Compound D (0.91g, 70% yield) recovered in the form of a crystalline white powder, having a melting point in the range of about 145° to about 147°C. Compound D was analyzed as having the following spectral characteristics.
Η-NMR (CDC13): δ 1.08 (t, J = 7.2 Hz, 3H), 2.05 (m, 2H), 3.35-3.60 (m, 4H), 4.09 (q, J = 7.2 Hz, 2H), 6.89 (br. S. 1H), 6.95-7.25 (m, 4H).
13C-NMR (CDCI3): 613.8, 29.0, 41.2, 41.6, 56.2, 61.1, 115.5 (d, J= 10.2 Hz), 128.4, 137.2, 161.8 (d), 168.3, 169.5. Mass Spectra (El): m/e (relative intensity): 265 (M+, 3), 220 (5), 192 (100),
163 (4), 162 (3), 149 (13). Mass Spectra (CI, Methane); m/e (relative intensity): 266 (M+ + 1, 100), 246 (4), 220 (18), 294 (7), 192 (9);
Analysis: Calculated for C14H16FNO3: C 63.39, H 6.08, F 7.16, N 5.28; Found: C 63.28, H 6.26, F 7.28, N 5.14.
Example 4. Diethyl[l-cyanomethyl-l-(4'-fluorophenyl)methyl]malonate
(Compound C)
Compound B of Example 1 (10 g) was dissolved in ethyl acetate (100 mL) and diethyl malonate (10.88 g) was added to the solution. The resulting mixture was stirred under nitrogen atmosphere at ambient room temperature. Sodium ethoxide (7.5 g) was slowly added to the mixture, and after the addition was complete, the mixture was refluxed for about 1.5 hours. The reflux mixture was then cooled to ambient room temperature. TLC analysis was performed as described in Example 2 and showed the presence of starting material, so more sodium ethoxide (2.5 g) was added and the mixture was further refluxed for about 3.5 hours. TLC analysis showed that the reaction was complete. 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 Η-NMR data were substantially the same as the data obtained for Compound C prepared in Example 2.
Example 5. ( ± )-trans-3 -Ethoxycarbonyl-4-(4 ' -fluorophenyl)piperidin-2-one (Compound D)
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.
Analysis: Calculated for C14H16FNO3: C 63.39, H 6.08, F 7.16, N 5.28; Found: C 63.34, H 6.16, N 5.22.
Example 6. (±)-trans-4-(4'-Fluorophenyl)-3-hydroxymethylpiperidine
(Compound E)
Compound D of Example 5, (4.4g) was suspended in tetrahydrofuran (30 mL) and then added slowly to a slurry of lithium aluminum hydride (LiAlH4) (1.5 g) in anhydrous tetrahydrofuran (30 mL) while concurrently cooling in an ice-water bath. The reaction mixture was then refluxed for about six hours under a nitrogen atmosphere. The reflux mixture was then cooled to ambient room temperature. The cooled mixture was then quenched by concurrently adding water (10 mL) slowly while further cooling the mixture in an ice water bath set at a temperature of about zero to about 4°C, followed by the addition of 10% aqueous sodium hydroxide (2 mL) at about ambient room temperature. The resultant slurry was stirred for about one hour and then the aluminum hydroxide containing solids were filtered and the reaction vessel and solids were washed with ethyl acetate (50 mL) and the filtrates combined. The combined filtrate was dried over sodium sulfate and the solvent was evaporated under reduced pressure to an oily residue. The oily residue was dissolved in ethyl acetate (25 mL) and allowed to stand undisturbed overnight at ambient room temperature. A solid product separated which was then filtered and washed with cold (zero to about 5°C) ethyl acetate (10 mL). The title Compound E (0.80 g, 25% yield) was recovered as a crystalline white powder having a melting point of 123-124°C. Compound E was analyzed as having the following spectral characteristics.
Η-NMR (CDC13): δ 1.56-1.92 (m, 5H), 2.58 (t. 1H), 2.71 (m, 1H), 3.16 (d, 1H), 3.24 (dd, 1H), 3.38 (m, 1H), 6.98 (m, 2H), 7.17 (m, 2H).
Mass Spectra (CI, Methane); m/e (relative intensity): 210 (M+ + 1, 100), 202 (24), 192 (54), 178 (3), 126 (84);
Analysis: Calculated for C12H16FNO: C 68.88, H 7.71, F 9.08, N 6.69; Found: C 68.47, H 7.74, F 8.99, N 6.59.
Example 7. (±)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine
(Compound F)
Compound E of Example 6, (0.37 g) was dissolved in methanol (10 mL).
Activated Raney Nickel (0.30 g, 50 % wet) catalyst and aqueous formaldehyde (Formalin) solution (0.30 g, 37 wt %) were added to the solution. The reaction mixture was stirred at a temperature of about 50 °C under hydrogen (H2) at atmospheric pressure for about 17 hours. The mixture was diluted with methanol (10 mL) and filtered through celite (1 g). The filtrate was evaporated under reduced pressure to give an oil (0.41 g). This oil was stirred with hexane (10 mL) overnight. A solid separated which was filtered and washed with hexane (5 mL) to give the title Compound (F) as a white solid (0.33 g, 84% yield), with a melting point of 117- 120°C. Compound F was characterized as follows. Η-NMR (CDC13): δ 1.70-2.15 (m,5H), 2.20-2.45 (m,4H), 2.60-2.80 (m, lH),
2.90-3.00 (d,lH), 3.10-3.30 (m,2H), 3.35-3.45 (dd, lH), 6.95-7.25 (m,4H) ppm. Mass Spectra (CI, Methane); m/e (relative intensity): 224 (100), 206 (93), 179 (3), 128 (7).
Analysis: Calculated for CI3HlgFNO: C 69.93, H 8.13, F 8.51, N 6.27; Found: C 69.37, H 8.11, F 8.59, N 6.16.
Example 8. (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl-piperidine
(Compound G)
Compound F of Example 7 (2.5 g), was dissolved in 25 mL of acetone and added directly to a solution of (-)-bis-p-toluoyl tartaric acid (5.6 g) dissolved in 25 mL acetone at ambient room temperature. The resulting acetone solution was stirred for about one hour at ambient room temperature and then at a cooled temperature in the range of about zero to about 5°C for an additional 30 minutes.
A crystalline salt formed which was isolated by filtering through a Whatman #2 filter paper. The filtrate was concentrated to about 50% volume and then cooled as above. A second crop of crystalline salt was isolated as before. The first and second salt crops were combined and suspended in methylene chloride (50 mL) and aqueous IN potassium hydroxide (50 mL) was added and the resulting mixture was agitated in a separatory funnel. The organic layer was then separated and dried over sodium sulfate, anhydrous, and evaporated under reduced pressure to yield a semi- solid material. The semi-solid material was triturated with hexane and produced a white crystalline powder, ([α]D 26=-36° at a concentration of 1 % in methanol), having a melting point in the range of about 100° to about 102 °C. The recovered powder (1 g yield) had spectral characteristics (Η-NMR and Mass Spectra data) that were consistent with the data of the compound produced in Example 7.

Claims

WE CLAIM
1. A process for synthesis of a compound having structural formula
(I):
(I) where X is halogen, C,-C10 alkyl, C,-C10 alkoxy, C,-C10 haloalkyl, hydroxy, or hydrogen; and R2 and R3 each is CrC4 alkyl and R2 and R3 are the same; which process comprises condensing a cinnamonitrile represented by the structural formula:
wherein X is as defined in structural formula (I) with a diester malonate represented by the structural formula:
wherein each of R2 and R3 is as defined in structural formula (I) .
2. A process for synthesis of compounds having structural formula (II):
(±) - trans
(II) where X is halogen, C,-C10 alkyl, C,-C10 alkoxy, Cι-C10 haloalkyl, hydroxy, or hydrogen; and R2 is CrC4 alkyl; which process comprises hydrogenating the compound of claim 1.
3. The process of claim 2, further comprising the step of reducing the compound of structural formula (II) to (±)-trans arylpiperidine carbinol.
4. The process of claim 3, further comprising the step of alkylating the (±)-arylpiperidine carbinol to (±)-trans N-substituted arylpiperidine carbinol.
5. The process of claim 4, further comprising the step of isolating (-)- trans- arylpiperidine carbinol from the (±)-trans-N-substituted arylpiperidine carbinol.
6. The process of claim 1 further including the step of recovering the compound of structural formula (I).
7. The process of claim 2 further including the step of recovering the compound of structural formula (II).
8. The process of claim 1, wherein X is a halogen and R2 and R3 are each ethyl.
9. The process of claim 8, where the halogen is fluoro.
10. The process of claim 2, wherein X is a halogen, and R2 is ethyl.
11. The process of claim 10, where the halogen is fluoro.
12. The process of claim 1 wherein the cinnamonitrile is 4- fluorocinnamonitrile and the diester malonate is diethyl malonate.
13. A compound having structural formula (I):
where X is halogen, C,-C10 alkyl, CrC10 alkoxy, CrC10 haloalkyl, hydroxy, or hydrogen; and R2 and R3 each is CrC4 alkyl and R2 and R3 are the same.
14. The compound of claim 13 wherein X is fluoro and R2 and R3 are each ethyl.
15. A compound having structural formula (II):
where X is halogen, C,-C10 alkyl, -CJQ alkoxy, CrC10 haloalkyl, hydroxy, or hydrogen; and R2 is C C4 alkyl having 1-4 carbon atoms.
16. The compound of claim 15 wherein X is fluoro and R2 is ethyl.
17. A product of the process of claim 1 having structural formula (I).
18. A product of the process of claim 2 having structural formula (II).
19. Diethyl[l-cyanomethyl-l-(4'-fluorophenyl) methyl] malonate characterized by a melting point in the range of about 40° to about 55 °C.
20. (+)-trans-3-Efhoxy carbonyl-4-(4'-fluorophenyl) piperidine-2-one characterized by a melting point in the range of about 140° to about 150°C.
21. The process of claim 5 wherein the isolating step comprises adding a chiral acid of (-) optical characteristic to form a diasteriomer salt in an organic solvent, neutralizing the resulting mixture with an aqueous base to provide (-)-trans configured arylpiperidine carbinol.
EP99966475A 1998-12-22 1999-12-17 Process for preparing arylpiperidine carbinol intermediates and derivatives Withdrawn EP1140832A4 (en)

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