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WO1997038963A1 - Process for the manufacture of alkyl 2-(6-methoxy-naphthyl)propionates - Google Patents

Process for the manufacture of alkyl 2-(6-methoxy-naphthyl)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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alkyl
naphthyl
propionates
methoxy
methoxynaphthyl
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PCT/US1997/005861
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French (fr)
Inventor
Rafael Shapiro
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E.I. Du Pont De Nemours And Company
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    • 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

The invention relates to a process for the manufacture of alkyl 2-(6-methoxynaphthyl)propionates, which are racemic ester precursors to the antiinflammatory drug, (S)-naprosyn [2-(S)-+-2-(6-methoxy-2-naphthyl)propanoic acid].

Description

TITLE
PROCESS FOR THE MANUFACTURE OF
ALKYL 2- (6-METHOXY-NAPHTHYL) PROPIONATES
FIELD OF THE INVENTION 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] . BACKGROUND OF THE INVENTION
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. However, 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.
What is needed, and is provided by the present invention, is a process for providing esters which are direct precursors to the acid analogs in a minimum number of steps using relatively inexpensive commercially available raw materials. Other objects and advantages of the present invention will become apparent to those skilled in the art upon reference to the detailed description which hereinafter follows. SUMMARY OF THE INVENTION
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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 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.
Equation 1:
Figure imgf000004_0001
II In formula I, 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 Cζ primary alcohols, R being methyl ethyl, propyl, and the like, or simple Ci to C6 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 .
Equation2:
MeCOCQR
Figure imgf000005_0002
Figure imgf000005_0001
II
The preparation of alkyl 2-hydroxy-2- (6-methoxy- 2-naphthyl)propionates (formula II) , the starting material for the process of the present invention is carried out according to equation 2 shown above. This condensation of 2-methoxynaphthalene with pyruvates follows the method disclosed by Kashima et al, U.S. Patent No. 4,922,010, except that, the reaction is stopped midpoint, at the ester stage.
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
1, 2-dichloroethane, cooling to about -5 to about 10°C, and gradually adding 1 equivalent, most preferably, of methyl- or ethyl pyruvate, preferably diluted in the same solvent used as reaction solvent. The product may be isolated by quenching in a large excess of cold water, separating the organic phases, washing out traces of acid, and distilling to recover solvent and the bulk of the unreacted methoxynaphthalene . Recovery of the latter may be accomplished either by steam-distillation or by distillation at about 15 mm and about 130-160°C. It is generally preferable to purify 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, the hydrogenation process of equation 1, 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. 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 .
EXAMPLE In the following non-limiting example, the reagents used were commercially available and were used as obtained from the vendors. Toluene and acetic anhydride were Baker reagent grade. The PTSA was obtained from Kodak, Rochester, NY. 2-Methoxynaphthalene, aluminum chloride and the 5 wt . % palladium-on-charcoal catalyst were purchased from Aldrich, Milwaukee, WI . Methyl pyruvate was obtained from Chemie Linz, Linz, Austria. Experiment 1: Preparation of Methyl 2-hydroxy-2- (6- methoxy-2-naphthyl) propionate
A dried 500 mL-Morton flask was charged with 22.0 g (0.139 mol) of 2-methoxynaphthalene and 120 mL of 1, 2-dichloroethane and 13.2 g (0.099 mol) of aluminum chloride was added under nitrogen. The solution was cooled to -10°C and stirred vigorously while adding a solution of 6.3 g (~0.062 mol) of methyl pyruvate over 40 minutes at -10 to -5°C. The mixture was allowed to stir for an additional 90 minutes at -5 to 0°C, and then was rapidly quenched with 100 g of crushed ice. The organic phase was separated, washed with water and assayed by gas chromatograph (gc) analysis vs. 2-bromo-6- methoxynaphthalene as an internal standard: assay = 10.4 g of methyl 2-hydroxy-2- (6-methoxy-2- naphthyl) propionate (65% a.i. yield) . Repetition of this experiment on an 0.2-mol scale and steam distillation, for recovery purposes, of 33 g of 2-methoxynaphthalene, followed by recrystallization of the residue from cyclohexane afforded 23 g (44% yield based on methyl pyruvate) of product, mp 85-86°C. iH-NMR (CDC13) δ 1.9 (s, 3) , 3.8 (s, 3), 3.85 (s, 1) ,
3.92 (s, 3) , 7.15 (m, 2), 7. 60 (d of d, 1), 7.75 (m, 2) , and 7.9 (d, 1) ; 13C-NMR (CDCI3) d 26.6, 53.0, 55.2, 75.9, 94.0, 105.6, 119.0, 123.8, 126.9, 128.5, 129.7, 134.0, 137.9, 158.0, 176.1.
EXAMPLE 1 Preparation of (R.S) -Methyl 2- (6-methoxy-2-naphthyl) propionate A mixture of 1.0 g (3.8 mmol) of methyl
2-hydroxy-2- (6-methoxy-2-naphthyl) propionate, 60 mg of p-toluenesulfonic acid monohydrate, 120 mg of 5 wt . % palladium-on-charcoal, 1 mL of acetic anhydride and 3 mL of dimethyl carbonate was charged to a flask equipped with a balloon. The flask was flushed with nitrogen, evacuated, and filled with hydrogen. After two more cycles of evacuation and refilling with hydrogen, the balloon was filled with hydrogen and the hydrogenation was performed by stirring vigorously and heating at reflux for 3 hr.
The mixture was cooled, flushed with nitrogen, and water, ethyl acetate, and hexane were added. The mixture was filtered to remove the catalyst and the filtrate was washed with aqueous NaHC03 and concentrated to dryness on the rotary evaporator. The residue was triturated with ice-cold pentane, filtered, and suction-dried to afford 804 mg of racemic methyl 2- (6-methoxy-2-naphthyl) propionate as a white solid, mp 64-65°C; 41-NMR (CDC13) δ 1.6 (d, 3,
J = 7 Hz) , 3.6 (s, 3) , 3.9 (s, 3), 3.8 (q, 1, J =7Hz) , 7.1 (m,2) , 7.3 (dofd,l) , 7.6(m,3) .
Although particular embodiments of the present invention have been described in the foregoing description, it will be understood by those skilled in the art that the invention is capable of numerous modifications, substitutions and rearrangements without departing from the spirit or essential attributes of the invention. Reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.

Claims

What is claimed is :
1. A process for the preparation of racemic alkyl 2- (6-methoxynaphthyl)propionates comprising contacting an alkyl 2-hydroxy-2- (6- methoxynaphthyl)propionate with hydrogen and a supported palladium catalyst in the presence of a solvent; wherein a sufficient amount of catalyst is present to minimize the formation of dimeric impurities.
2. The process of Claim 1 wherein the palladium catalyst is supported on carbon, silica, or zirconia.
3. The process of Claim 1 wherein the alkyl 2-hydroxy-2- (6-methoxynaphthyl)propionate is also contacted with a dehydrating agent.
4. The process of Claim 3 wherein the dehydrating agent is acetic anhydride or propionic anhydride.
5. The process of Claim 1 wherein the solvent is toluene or methyl butyrate.
6. The process of Claim 1 wherein contacting takes place at a pressure less than about 60 psig.
7. The process of Claim 1 wherein contacting takes place at a temperature less than about 120°C.
PCT/US1997/005861 1996-04-18 1997-04-10 Process for the manufacture of alkyl 2-(6-methoxy-naphthyl)propionates WO1997038963A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036366A1 (en) * 1999-11-17 2001-05-25 Dsm Fine Chemicals Austria Nfg Gmbh & Cokg Method for producing phenylacetic acid esters
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 (en) * 1999-11-17 2001-05-25 Dsm Fine Chemicals Austria Nfg Gmbh & Cokg Method for producing phenylacetic acid esters
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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