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WO1997038963A1 - Procede de fabrication d'alkyl 2-(6-methoxy-naphtyl)propionates - Google Patents

Procede de fabrication d'alkyl 2-(6-methoxy-naphtyl)propionates Download PDF

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Publication number
WO1997038963A1
WO1997038963A1 PCT/US1997/005861 US9705861W WO9738963A1 WO 1997038963 A1 WO1997038963 A1 WO 1997038963A1 US 9705861 W US9705861 W US 9705861W WO 9738963 A1 WO9738963 A1 WO 9738963A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
naphthyl
propionates
methoxy
methoxynaphthyl
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.)
Ceased
Application number
PCT/US1997/005861
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English (en)
Inventor
Rafael Shapiro
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.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours 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 EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of WO1997038963A1 publication Critical patent/WO1997038963A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups

Definitions

  • This invention relates to a process for the manufacture of alkyl 2- (6-methoxynaphthyl) propionates, which are racemic ester precursors to the antianflammatory drug, (S) -naprosyn [2- (S) - + - 2 - (6- methoxy-2-naphthyl) propanoic acid] .
  • U.S. Patent No. 4,922,010 Kashima et al, discloses a process involving the condensation of 2-methoxynaphthalene with pyruvate esters followed by a hydrolytic workup to provide 2-hydroxy-2- (6-methoxy- 2-naphthyl) propionic acid.
  • the hydrogenation of this carboxylic acid intermediate to (R, S) -naprosyn [R,S-2- (6-methoxy-2-naphthyl) propanoic acid] is also disclosed.
  • R, S-2- (6-methoxy-2-naphthyl) propanoic acid is also disclosed.
  • there is no disclosure of the isolation of alkyl 2- (6-methoxynaphthyl) propionates No reaction besides hydrolysis of the alkyl 2- (6- methoxynaphthyl)propionates is disclosed.
  • the present invention provides a process for the preparation of racemic alkyl 2- (6-methoxynaphthyl) - propionates comprising contacting alkyl 2-hydroxy-2- (6-methoxynaphthyl) propionates with hydrogen and a supported palladium catalyst, optionally in the presence of a dehydrating agent .
  • the catalyst should be present in sufficient amount to minimize the formation of dimeric impurities.
  • the invention relates to a process for the preparation of a precursor to 2- (S) -+-2- (6-methoxy-2- naphthyl)propanoic acid (naprosyn) a known pharmaceutical having antiphlogistic, antipyretic and analgesic properties.
  • the precursor compounds, alkyl 2- (6-methoxynaphthyl) propionates, of formula I (shown below) are converted to the pharmaceutical compound by methods known in the art, e.g., by a crystallization-induced asymmetric transformation to the corresponding (S) -enantiomers, according to the teachings of U.S. Patent No. 4,417,070, followed by hydrolysis according to the teachings of C. Giordano et al., Tetrahedron, 1989, Vol. 45, No. 13, pp. 4243-4252, the entire contents of which are incorporated herein.
  • the alkyl group in the ester, R can be any alkyl group stable to the stated hydrogenation reaction conditions, i.e., hydrogenation under acidic conditions.
  • R is generally derived from Cx to C ⁇ primary alcohols, R being methyl ethyl, propyl, and the like, or simple Ci to C 6 secondary alcohols, e.g., cyclohexanol, R being cyclohexyl.
  • the most preferred R groups are methyl and ethyl .
  • the process of the present invention prepares compounds of formula I from alkyl 2-hydroxy-2- (6- methoxy-2-naphthyl)propionates, formula II, according to equation 1.
  • R in formula II is the same as defined for formula I .
  • the indicated hydrogenation is carried out in the presence of a supported palladium catalyst, optionally in the presence of a dehydrating agent, and in the presence of a solvent .
  • Equation 2 The process of equation 2 is generally carried out by mixing 1.5 to 5 molar equivalents of 2-methoxynaphthalene with 0.9 to 2.1 equivalents of aluminum chloride in a suitable Friedel-Crafts solvent, preferably dichloromethane or
  • the crude product which contains about 6-10 percent yield of a regioisomer and lesser amounts of dimeric by-products, before conducting the hydrogenation reaction of equation 1.
  • This purification may be accomplished by crystallization and washing with a suitable solvent such as cyclohexane or isopropanol.
  • the process of the present invention is generally carried out by combining 1 molar equivalent of the intermediate of formula II with 2 to 20 parts by weight of a suitable solvent.
  • Hydrocarbon solvents e.g., toluene, benzene, xylenes and the like are generally suitable, as are ester-based solvents such as dimethyl carbonate and methyl butyrate. Most preferred are toluene and methyl butyrate. It is not necessary that all reagents be uniformly dissolved, i.e., a slurry of reagents is acceptable, as long as there is sufficient solubility of reagents that the reaction can occur.
  • the hydrogenation is carried out in the presence of a strong acid, typically 0.005 to 0.1 molar equivalents of a strong acid, such as p-toluenesulfonic acid, PTSA.
  • a strong acid such as p-toluenesulfonic acid, PTSA.
  • Other acceptable acids include methane sulfonic acid and sulfuric acid.
  • the strong acid p-toluenesulfonic acid is preferred.
  • the hydrogenation reaction is optionally carried out in the presence of 0.3 to 1.3 equivalents of a dehydrating agent, such as acetic anhydride or another organic acid anhydride such as propionic anhydride or a physical dehydrating agent, e.g., molecular sieves. It is preferred that the dehydrating agent be present and that the dehydrating agent be acetic anhydride.
  • the hydrogenation catalyst employed is typically, 0.2 to 2 wt. % (w/w of formula II) of a catalyst consisting of palladium metal on a solid support.
  • a variety of inert support materials are usable, e.g., carbon, silica or zirconia. Carbon is the preferred support. 2-5 wt . % palladium-on-carbon is the preferred catalyst. Too little catalyst can lead to increased formation of dimeric impurities so a suitable amount is necessary to minimize such formation.
  • the reaction is carried out with agitation, usually mechanical, but possibly from hydrogen introduction.
  • the temperature range employed can be from about zero to about 120°C, preferably from about 40 to about 120°C, and most preferably from about 80 to about 120°C. Temperatures above about 120°C can lead to the formation of ring-hydrogenated impurities.
  • the reaction is typically carried out under a hydrogen atmosphere, from about 0 to about 60 psig, more preferably from about 0 to about 20 psig. Generally, lower pressures are preferred to minimize the formation of ring-hydrogenated impurities.
  • the time of the reaction is dependent on temperature, agitation and pressure and is typically from about two to about five hours, most typically about 3 hours.
  • the product may be isolated by filtration to recover the catalyst, washing with water, and removal of solvent. If desired, the product may be purified by recrystallization from a suitable solvent such as methanol, ethanol, isopropanol, pentane, or mixtures of water and water-miscible solvents.
  • a primary advantage of the instant process compared to known processes is its utility in providing esters which are direct precursors to the acid analogs, in a minimum number of chemical steps from relatively inexpensive commercially available raw materials, namely 2-methoxynaphthalene and methyl or ethyl pyruvate, using procedures and conditions well- suited to commercial manufacture .

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

Abstract

La présente invention concerne un procédé de fabrication d'alkyl 2-(6-méthoxy-naphtyl)propionates qui sont les précurseurs d'ester racémique d'un médicament anti-inflammatoire, en l'occurrence la (S)-naprosyne de l'acide 2-(S)-+-2-(6-méthoxy-2-naphtyl)propanoïque.
PCT/US1997/005861 1996-04-18 1997-04-10 Procede de fabrication d'alkyl 2-(6-methoxy-naphtyl)propionates Ceased WO1997038963A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1558196P 1996-04-18 1996-04-18
US60/015,581 1996-04-18

Publications (1)

Publication Number Publication Date
WO1997038963A1 true WO1997038963A1 (fr) 1997-10-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/005861 Ceased WO1997038963A1 (fr) 1996-04-18 1997-04-10 Procede de fabrication d'alkyl 2-(6-methoxy-naphtyl)propionates

Country Status (1)

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WO (1) WO1997038963A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036366A1 (fr) * 1999-11-17 2001-05-25 Dsm Fine Chemicals Austria Nfg Gmbh & Cokg Procede de production d'esters d'acide phenylacetique
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4922010A (en) * 1987-12-18 1990-05-01 Ube Industries, Ltd. Processes for preparing 2-substituted propionic acid and derivatives thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4922010A (en) * 1987-12-18 1990-05-01 Ube Industries, Ltd. Processes for preparing 2-substituted propionic acid and derivatives thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036366A1 (fr) * 1999-11-17 2001-05-25 Dsm Fine Chemicals Austria Nfg Gmbh & Cokg Procede de production d'esters d'acide phenylacetique
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof

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