WO1994001394A1 - Preparation d'amides n-aryle - Google Patents

Preparation d'amides n-aryle Download PDF

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Publication number
WO1994001394A1
WO1994001394A1 PCT/AU1993/000326 AU9300326W WO9401394A1 WO 1994001394 A1 WO1994001394 A1 WO 1994001394A1 AU 9300326 W AU9300326 W AU 9300326W WO 9401394 A1 WO9401394 A1 WO 9401394A1
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process according
ether
mol
phenol
acid
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Christopher Roy Strauss
Paul Gurr
Teresa Cablewski
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Commonwealth Scientific and Industrial Research Organization CSIRO
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Commonwealth Scientific and Industrial Research Organization CSIRO
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Priority to AU44128/93A priority Critical patent/AU4412893A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08

Definitions

  • This invention concerns a novel process for ⁇ the amidation of an aromatic compound to give an N-aryl amide, in particular for production of 4' -hydroxyacetanilide (la) (also known as paracetamol and acetaminophen) , which process can be performed in a single reaction vessel.
  • 4' -Hydroxyacetanilide has commercial applications in the pharmaceutical industry as an analgesic and an antipyretic; it and related compounds are used in the manufacture of azo dyes and photographic chemicals.
  • 4' -Hydroxyacetanilide is generally prepared by two procedures (H.H. Szmant, "Organic Building Blocks of the Chemical Industry” John Wiley & Sons, New York 1989 at p.10 and pp. 503-5) .
  • a para-selective nitrosation of phenol under strong acid conditions is followed by reduction and then N-acylation of the intermediate p-aminophenol.
  • This procedure involves several manipulative steps and presents difficulties with both yield in the nitrosation step and with the nature and volume of the effluent.
  • nitration of phenol can be the first step.
  • Scheme 1 Conventional process to paracetamol from phenol.
  • Scheme 2 shows in more recent method, shown in Scheme 2 and disclosed in US patent 4,524,217 and US 4,560,789 to K.G. Davenport and C.B. Hilton of the Hoechst-Celanese Corporation, phenyl acetate is converted in a Fries rearrangement to 4' -hydroxyacetophenone using hydrofluoric acid as a catalyst.
  • the ketone after isolation is treated with hydroxylamine under basic conditions to give the oxime anti-isomer with respect to the aryl ring.
  • the oxime is isolated and then subjected to a Beckmann rearrangement under acid catalysis.
  • the product (la) may be purified as its 0-acetyl derivative (lb) which is subsequently deacetylated by hydrolysis in dilute methanesulfonic acid.
  • the main difficulties with this procedure are the relatively high cost, the handling and use of the aggressive reagents (particularly HF) , the large number of steps involved and the problems of effluent disposal.
  • the present invention is further distinguishable from the prior art as it is the first reported example of oximation and Beckmann rearrangement being achievable with a catalyst other than formic acid/trifluoromethanesulfonic acid.
  • the present invention provides a process for the preparation of an N-aryl amide in a single reaction vessel, including the reaction of an aromatic compound with a C-acylation reagent and a hydroxylamine salt or derivative in the presence of an acidic catalyst.
  • the process of the invention may be carried out in a single step or in a two step procedure whereby the aromatic compound is first reacted with a C-acylating reagent in the presence of said catalyst followed by addition of the hydroxylamine salt or derivative
  • the reaction of the invention may provide a mixture of products which may be subsequently diluted with water and hydrolysed to produce the product N-aryl amide.
  • the mixture of products may be hydrolysed by adding aqueous alkali and heating under reflux. Any suitable aromatic compound may be used in the invention.
  • Suitable aromatic compounds include, phenol, phenyl acetate, anisole, phenetole, diphenyl carbonate, triphenyl phosphate, triphenyl phosphine, 1,1-diphenoxyethane, triphenylorthoformate, phenyl vinyl ether, t-butyl phenyl ether, dichloromethyl phenyl ether, the tetrahydropyranyl ether of phenol, veratrole, guaiacol, alkyl substituted benzene, di-2-phenoxyethyl ether, chroman, thiophene, 2-methylthiophene, 3-methylthiophene, 2-chlorothiophene, 2-bromothiophene, 2,2' -dithienyl, indole, pyrrole, toluene, xylenes, indane, tetralin, cu ene, catechol, resorcinol,
  • aromatic compounds on the grounds of costs, availability and yield are phenol, phenyl acetate and anisole.
  • Anisole reacts most readily and cleanly to produce p-methoxyacetanilide which may be demethylated by any suitable agent.
  • p-methoxyacetanilide may be demethylated in high yield with A1C1- (approximately 2 equivalents) in the absence of a solvent.
  • phenol is the most appropriate starting material for the production of 4' -hydroxyacetanilide.
  • C-acylation reagent Any suitable C-acylation reagent may be used in the invention.
  • Suitable C-acylation agents are carboxylic acids, anhydrides, or acid halides either alone or in combination. Carboxylic acids or anhydrides are preferred for giving the cleanest product in the shortest time.
  • the key to the process lies with the catalyst, which should be inexpensive and have the capability to fulfill several functions, either in solution or under heterogenous conditions. It should effect the highly para-selective acylation of the aromatic compound and allow oximation" to proceed affording the anti-oxime with respect to the aryl ring. It should also facilitate Beckmann rearrangement of the oxime to give the desired amide. Finally, it should carry out all of the above functions under fairly uniform conditions of temperature, without significant by-product formation, and within a reasonable time.
  • Catalysts for Friedel-Crafts acylations, Fries rearrangements and Beckmann rearrangements are well known. Acidic oximation catalysts are less well known. Catalysts with the combination of properties required for this invention have not previously been recognised.
  • PPA polyphosphoric acid
  • P- ⁇ C in methanesulfonic acid or hydrogen fluoride are suitable catalysts.
  • Polyphosphoric acid (PPA) is preferred because of its solvent properties, its mild acid characteristics and its demonstrated applicability as a catalyst for Friedel-Crafts reactions, Fries rearrangements and Beckmann rearrangements, as reviewed by U lig and Snyder (Adv. in Org. Chem. 1, 35 (1960) ) .
  • PPA has not been reported previously as useful for oximation. This procedure has traditionally been conducted under basic conditions in the presence of compounds such as pyridine.
  • Hydrogen fluoride is a_ useful, albeit less desirable catalyst, because of its corrosive nature.
  • Any suitable quantity of PPA may be used in the invention.
  • the PPA has a composition equivalent " to approximately 121% to 116% H_P0 .
  • the amount of catalyst used is within the range of approximately 7-10g per gram of aromatic compound.
  • Suitable hydroxylamine salts include the hydrochloride, sulphate and phosphate; suitable derivatives include hydroxylamine 0-sulfonic acid and O-acetylhydroxylamine.
  • the reaction may be carried out under any suitable conditions.
  • the process is carried out at moderate temperatures and in the absence of organic solvent.
  • the process may be carried out at a temperature in the range of 70 ⁇ C-120°C. 80°C is the preferred temperature for the production of 4' -hydroxyacetanilide.
  • STEP 1 Formation of a mixture of 4' - hydroxyacetophenone and 4' -acetoxyacetophenone.
  • a mixture of 4' -hydroxyacetophenone and 4' -acetoxyacetophenone is produced by a regioselective Friedel-Crafts reaction from phenol at a moderate temperature (around 80°C) or by a similarly selective Fries rearrangement of phenyl acetate.
  • An esterification of phenol followed by a Fries rearrangement may be carried out as a further alternative.
  • Such reactions on these substrates have been well documented over the past four decades.
  • Friedel-Crafts reaction on phenol or phenyl acetate appears to be the preferred alternative. Under the conditions used here, the Fries rearrangement was slower than Friedel-Crafts acylation and was partially reversible. Since cost is a major consideration, the use of phenol as a starting material is preferable to other aromatic compounds such as anisole or phenyl acetate.
  • the mixture of 4' -hydroxyacetophenone and 4' -acetoxyacetophenone is treated in situ with a salt of hydroxylamine and a mixture of la and lb is formed.
  • the oxime formation-Beckmann rearrangement process i complete within a matter of minutes, when carried out a 80° in PPA. This compares favourably with literatur conditions which employed refluxing formic acid over severa hours to produce a number of amide examples in variabl yields.
  • Beckmann rearrangements ar stereospecific, involving migration of the group, which i anti to the leaving group on nitrogen. This has been so wel established that Beckmann rearrangements have been used t establish the stereochemistry of oximes. In the presen case, if a syn-oxime is formed as an intermediate, th products of the rearrangement would be the undesired N-methy 4' -hydroxybenzamide and N-methyl 4' -acetoxybenzamide. It i important therefore, that oximation occur with the desire stereochemistry to allow optimal yields of (la) and (lb) t be obtained and easily purified. Under the condition established here, little of the unwanted amides were observe in the product distribution after Beckmann rearrangements.
  • phosphate esters may be formed; these phosphate esters would also need to undergo hydrolysis for the phenolics to be liberated.
  • phosphate esters may be hydrolysed at acid pH under conditions which also facilitate hydrolysis of O-acyl groups yet allow an amide linkage to remain intact.
  • the reaction mixture may simply be diluted with water, or alkali may be added and the reaction mixture heated for an appropriate time dependent upon the temperature used.
  • alkali may be added and the reaction mixture heated for an appropriate time dependent upon the temperature used.
  • the hydrolysis is essentially complete after 2 hours at 60°C. At alkaline pH the hydrolysis is more rapid.
  • the process of the invention is carried out as a -one step procedure the aromatic compound, the C-acylating agent and the hydroxylamine salt or derivative are introduced to a suitable reaction vessel at the commencement of the reaction.
  • the ketonic intermediates are rapidly converted to their amide analogues virtually as they form. This has the added advantage of ensuring that the concentration of ketones on the reaction mixture remains low throughout, and hence the opportunities for formation of by-products are significantly reduced.
  • a mixture of amide and its O-acyl derivative is obtained without significant by-product formation and there is considerably less discolouration associated with both the by-product and the solvent.
  • phenol itself is acetylated the reaction gives a mixture of (la) and (lb) which is then converted hydrolytically to (la) .
  • the process is further illustrated in the following non-limiting examples:
  • Phenol (3.0g; 0.032mol) and glacial acetic acid (2.9g; 0.048mol) were heated in PPA (30g) with stirring at 80° C for 40 minutes.
  • Hydroxylamine sulphate (2.6g; O.Olmol) was added in a batch and the mixture stirred for an additional 5 minutes at 80° C, and then cooled. Ice water (50ml) was added and the solution extracted with ethyl acetate
  • the pre-extracted aqueous residue was adjusted to pH4 with aqueous NaOH solution, and heated at reflux for- 1 hour, cooled and further extracted with ethyl acetate (3 x 60ml) .
  • This organic extract afforded an additional oily residue (0.5g) , which by GC analysis, contained 64% (la) and 3% (lb) .
  • Phenol (3.0g; 0.032mol) and glacial acetic acid (3.8g; 0.064mol) were heated in PPA (30g) with stirring at 80°C for 40 minutes.
  • Hydroxylamine sulphate (2.6g; 0.016mol) was added in a batch and the mixture stirred for an additional 5 minutes at 80°C and then cooled.
  • Ice water (50ml) was added and the solution extracted with ethyl acetate (3x60ml) .
  • the pooled organic extract was dried with MgSO , filtered and evaporated to dryness to afford an oily residue (3.3g) , which, by GC analysis, contained 11% (la) and 71% (lb) .
  • a further extraction with ethyl acetate (1 x 60ml) returned additional product (0.4g) which contained 49% (la) and --16% (lb) .
  • Phenol (3.0g; 0.032mol) and glacial acetic acid (3.8g; 0.064mol) were heated in PPA (30g) with stirring at 80°C for 40 minutes.
  • Hydroxylamine sulphate (2.6g; 0.016mol) was added in a batch and the mixture stirred for an additional 5 minutes at 80°C, and then cooled.
  • Phenol (3.0g; 0.032mol), glacial acetic acid (3.8g; 0.064mol) and hydroxylamine sulfate (2.6g; 0.016mol) were heated in PPA (30g) with stirring at 80°C for 30 minutes and then cooled for 15 minutes. Ice water (90ml) was then added and after 15 minutes white crystals were filtered off from the solution and dried to afford 1.7g of solid which was found by GC analysis to contain 85% (lb) and 9% (la) . Extraction of the aqueous layer with ethyl acetate (3 x 60ml) afforded a solid (1.345g) which was found by GC analysis to contain 31% (lb) and 12% (la) .
  • Phenol (3.0g; 0.032mol) , glacial acetic acid (5.8g; 0.096mol) and hydroxylamine hydrochloride (2.4g; 0.036mol) were heated in PPA (30g) with stirring at 80° C for 80 minutes and then cooled for 15 minutes. Ice water (80ml) was added and after 15 minutes light yellow crystals were filtered off from the solution and dried to afford (lb) (3.5g; 53% yield, 99% pure by GC analysis) .
  • Phenyl acetate (3.0g; 0.022mol) , glacial acetic acid (2.64g; 0.044mol) and hydroxylamine hydrochloride (1.68g; 0.024mol) were heated in 30g PPA (116% H-P0 4 ) with stirring at 80° C for 60 minutes and then cooled for 10 minutes. Ice water (100ml) was added and yellow crystals were filtered off from the solution. The yellow crystals were recrystallised from water (30ml) to afford light yellow crystals of (lb) (1.75g; 41% yield, 98% pure by GC analysis) .
  • Veratrole (3.0g; 0.02 mol), glacial acetic acid (1.3g; 0.02 mol) and hydroxylamine hydrochloride (1.7g; 0.02 mol) were added to PPA (30g; 112-116% H3PO4) which was mechanically stirred at 70° for 8 hours and was then cooled to room temperature.
  • Cold water (100 ml) was added with stirring.
  • Extraction with ethyl acetate (3 x 60 ml) followed by evaporation of the solvent afforded a crystalline solid (3.8g; 82% isolated yield) , which was found by GC analysis to contain N- (3, 4-dimethoxyphenyl) acetamide in 92% purity.
  • EIMS m/z (rel. int. %) : 165(M+, 44), 123 (M+-ketene, 66), 108(100), 80(18), 53(11), 52(18), 43(42) .
  • Phenetole 3.0g; 0.02 mol
  • glacial acetic acid 3.0g; 0.05 mol
  • hydroxylamine hydrochloride 1.9g; 0.03 mol
  • PPA 30g; 112-116% H3PO4
  • Phenol 2.0g; 0.02 mol
  • butyric acid 3.g; 0.04 mol
  • hydroxylamine hydrochloride 1.5g; 0.02 mol
  • N- (4-butyroxyphenyl)butanamide mp: 121-122°C was 95% pure by GC analysis .
  • Diamfenetide ie (di- [2- (4-acetamidophenoxy) ethyl] ether) .
  • 2-Phenoxyethyl ether 3.0g; 0.01 mol
  • glacial acetic acid 1.7g; 0.03 mol
  • hydroxylamine hydrochloride 1.8g; 0.03 mol
  • the mixture was heated with stirring for 3 hours at 80°C, then cooled and ice water (200 ml) added.
  • the product crystallised as a pale yellow solid (4.1g; crud yield 95%) which was filtered off and dried, before being recrystallised from acetone-water.
  • Phenol (3.0g; 0.03 mol),glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine hydrochloride (2.4g; 0.04 mol) were added to PPA (30g; 121% H3PO4) with stirring, and the mixture was heated at 80°C for 2 hrs and then cooled for 15 min. Ice-water (80 ml) was then added and after 15 min yellowish crystals were filtered off from the solution and dried to afford 3.7g of solid which was found by GC analysis to contain 96% of 4-acetoxyacetanilide.
  • Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine phosphate (3.2g; 0.02 mol) were added to PPA (30g; 116% H3PO4) with stirring, and the mixture was heated at 80°C for 27 hr, and then allowed to stand for 16 hr at room temperature.
  • GC analysis showed that the yield of 4-acetoxyacetanilide was 64%.
  • Phenol (3.0g; 0.03 mol.), glacial acetic acid (5.8g; 0.1 mol.) and hydroxylamine hydrochloride (2.5g; 0.04 mol.) were placed inside a Kel-F pot equipped with a stirring bead.
  • the vessel was sealed, cooled in liquid nitrogen and evacuated.
  • Hydrogen fluoride (30.lg) was condensed into the reactor and the vessel was warmed to ambient temperature, then placed in a water bath at 84°C for 1.5 hours. During the first 0.5 hour, which was the heating up period, the solution had developed a red colour and this intensified to dark red towards the final stages of heating.
  • Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.10 mol) and hydroxylamine hydrochloride (2.4g; 0.03 mol) were heated in PPA (30g; 116% H3PO4) with stirring at 80°C for 2.5 hrs and the reaction mixture was then cooled to 50°. Ice-water (80 ml) was added and after 15 minutes, yellow crystals were filtered off from the solution and dried to afford 4-acetoxyacetanilide (3.9g, 63% yield) .
  • Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine hydrochloride (2.4g; 0.03 mol) were added to PPA (30g; 121% H3PO4) with stirring and heated at 80°C for 2 hrs and the reaction mixture was then cooled to 50°. Ice-water (60 ml) was added and heating continued at 60° for 75 min. The reaction mixture was allowed to cool and extracted with ethyl acetate (3 x 60 ml)and then washed once with water. The ethyl acetate extracts were combined and treated with charcoal (0.25g), filtered and reduced in volume to afford two crops of crystals.
  • Phenol (3.0g; 0.03 mol), acetic anhydride (6.5g; 0.6 mol) and hydroxylamine hydrochloride (2.4g; 0.04 mol) were added to PPA (30g; 116% H3PO4) with stirring, and heated at 80°C for 3 hrs and the reaction mixture was then cooled for 15 min. Ice-water (80 ml) was added and after 15 minutes, yellow crystals were filtered off from the solution and dried to afford 4-acetoxyacetanilide (3.9g; 63% yield) . Recrystallisation from water gave colourless crystals of 4-acetoxyacetanilide (2.7g; 44% yield, 97.3 % pure by GC analysis) .
  • the aqueous filtrate from the first isolation was extracted with ethyl acetate and afforded 1.8g of crude material which was found by GC analysis to contain 4-acetoxyacetanilide (24%) and 4-hydroxyacetanilide (5%) . Total isolated yield was 71%.

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

Abstract

L'invention concerne un procédé d'amidation d'un composé aromatique dans le but de fournir un amide N-aryle, en particulier pour la production de 4'-hydroxyacétanilide (1a), également connu sous le nom de paracétamol et d'acétaminophène. Ce procédé peut être mis en ÷uvre dans un seul réacteur. Le 4'-hydroxyacétanilide a des applications commerciales dans l'industrie pharmaceutique comme analgésique et comme antipyrétique. Ce composé et des dérivés de celui-ci sont utilisés dans la fabrication de colorants azoïques et de produits chimiques utilisés en photographie.
PCT/AU1993/000326 1992-07-02 1993-07-02 Preparation d'amides n-aryle Ceased WO1994001394A1 (fr)

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Application Number Priority Date Filing Date Title
AU44128/93A AU4412893A (en) 1992-07-02 1993-07-02 Preparation of n-aryl amides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AUPL3282 1992-07-02
AUPL328092 1992-07-02
AUPL328292 1992-07-02
AUPL3280 1992-07-02

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WO1994001394A1 true WO1994001394A1 (fr) 1994-01-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020686A3 (fr) * 2001-08-31 2003-12-04 Bayer Chemicals Ag Procede de production d'ethers 4-amino-1-naphtol
CN101823979A (zh) * 2010-05-17 2010-09-08 无锡宏瑞生物医药科技有限公司 反应器耦合模拟移动床对乙酰氨基苯乙醚清洁生产工艺
CN110981743A (zh) * 2019-11-23 2020-04-10 李宾 一种对乙酰氨基苯乙醚原料药的合成工艺方法和装置
CN116178184A (zh) * 2023-04-21 2023-05-30 淄博鸿润新材料有限公司 一种2,2’-二氨基二苯氧基乙烷的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4195185A (en) * 1984-06-04 1985-12-12 Celanese Corporation Producing n-acyl-hydroxy and n-acyl acyloxy aromatic amines
EP0469742A2 (fr) * 1990-07-20 1992-02-05 Hoechst Celanese Corporation Préparation d'acétaminophen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4195185A (en) * 1984-06-04 1985-12-12 Celanese Corporation Producing n-acyl-hydroxy and n-acyl acyloxy aromatic amines
EP0469742A2 (fr) * 1990-07-20 1992-02-05 Hoechst Celanese Corporation Préparation d'acétaminophen

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020686A3 (fr) * 2001-08-31 2003-12-04 Bayer Chemicals Ag Procede de production d'ethers 4-amino-1-naphtol
US6964963B2 (en) 2001-08-31 2005-11-15 Bayer Aktiengesellschaft Preparation of 4-amino-1-naphthol ethers
CN1315781C (zh) * 2001-08-31 2007-05-16 拜尔化学品股份公司 制备4－氨基－1－萘酚醚类化合物的方法
CN101823979A (zh) * 2010-05-17 2010-09-08 无锡宏瑞生物医药科技有限公司 反应器耦合模拟移动床对乙酰氨基苯乙醚清洁生产工艺
CN101823979B (zh) * 2010-05-17 2014-04-23 无锡宏瑞生物医药科技有限公司 反应器耦合模拟移动床对乙酰氨基苯乙醚清洁生产工艺
CN110981743A (zh) * 2019-11-23 2020-04-10 李宾 一种对乙酰氨基苯乙醚原料药的合成工艺方法和装置
CN116178184A (zh) * 2023-04-21 2023-05-30 淄博鸿润新材料有限公司 一种2,2’-二氨基二苯氧基乙烷的制备方法

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