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WO1993017989A1 - Preparation de phenylglyoxals substitues ou non substitues - Google Patents

Preparation de phenylglyoxals substitues ou non substitues Download PDF

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Publication number
WO1993017989A1
WO1993017989A1 PCT/US1993/001348 US9301348W WO9317989A1 WO 1993017989 A1 WO1993017989 A1 WO 1993017989A1 US 9301348 W US9301348 W US 9301348W WO 9317989 A1 WO9317989 A1 WO 9317989A1
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WO
WIPO (PCT)
Prior art keywords
substituted
radical
unsubstituted
acetophenone
carbon atoms
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/US1993/001348
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English (en)
Inventor
Graham N. Mott
John R. Durrwachter
Ahmed Tafesh
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.)
CNA Holdings LLC
Original Assignee
Hoechst Celanese Corp
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 Hoechst Celanese Corp filed Critical Hoechst Celanese Corp
Priority to JP5515691A priority Critical patent/JPH07504656A/ja
Priority to EP93905964A priority patent/EP0632797A4/fr
Publication of WO1993017989A1 publication Critical patent/WO1993017989A1/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
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation

Definitions

  • the present invention relates to substituted and unsubstituted phenylglyoxals and, more particularly, to a method for the preparation thereof. Still more particularly, the present invention discloses methods for preparing substituted and unsubstituted phenylglyoxals from corresponding substituted and unsubstituted acetophenones.
  • Substituted phenylglyoxals such as hydroxyphenyl- glyoxal (hereinafter referred to sometimes as "HPGO") are well known compounds that are useful in the production of intermediate products which are utilized for the preparation of pharmaceutical products.
  • HPGO hydroxyphenyl- glyoxal
  • a method is disclosed for the production of unsubstituted phenylglyoxals from an acetophenone. That method uses the toxic substance selenium dioxide (Se0 2 ) thereby posing undesirable health hazards and disposal problems.
  • U.S. Patent No. 4,272,453 discloses a method for the preparation of 1-chloro-l-p-methoxybenzoylformal- doxime bytheadditionofp-methoxyacetophenone to nitrosyl chloride in carbon tetrachloride.
  • U.S. Patent No. 3,794,620 discloses the reaction of nitrosyl chloride with aromatic acetyl derivatives. According to that patent, three moles of nitrosyl chloride are required for each acetal group.
  • German Patent DE 2,432,563 discloses the oxidation of substituted acetophenones using alkyl nitrites in alcohol and hydrochloric acid to prepare substituted phenylglyoxalacetals.
  • German Patent DE 3,539,629 discloses a method of oxidizing substituted acetophenones using dinitrogen trioxide in alcohol/hydrochloric acid to prepare appropriate substituted phenylglyoxal acetals.
  • Copending United States patent application Serial No. 07/755,913, filed on September 6, 1991 discloses the reaction of a substituted acetophenone with a primary or a secondary alcohol in the presence of a source of a hydrogen ion (H + ) and a source of a nitrosonium ion (N0 + ) to form a corresponding substituted phenylglyoxalacetal. That application, however, does not disclose the formation of the substituted phenylglyoxal.
  • the present invention discloses an improved method for the preparation of a substituted or an unsubstituted phenylglyoxal from a corresponding substituted or unsubstituted acetophenone.
  • the method involves fewer steps for the addition of reactants, avoids the use of toxic materials and complicated extraction procedures, and provides for the reaction to be carried out in one reactor.
  • a substituted or an unsubstituted phenylglyoxal is prepared from a corresponding substituted or unsubstituted acetophenone, preferably, a hydroxyaromatic methyl ketone and, more preferably, 4- hydroxyacetophenone.
  • a substituted or an unsubstituted acetophenone is reacted, in a first step, with a primary or a secondary alkyl alcohol in the presence of a source of a hydrogen ion and a source of a nitrosonium ion to form a corresponding substituted or unsubstituted phenylglyoxalacetal.
  • the source of the hydrogen ion is a strong mineral acid such as hydrochloric acid or sulfuric acid.
  • the source of the nitrosonium ion is an alkyl nitrite or a nitrite salt used in combination with an acid source such as sulfuric acid or hydrochloric acid or a compound NO + X ⁇ available from an outside source, wherein X is a halogen, a sulfite, a sulfate, phosphite or a phosphate.
  • the substituted or unsubstituted phenylglyoxal acetal is then hydrolyzed, in a second step, in the same reactor to form the substituted or unsubstituted phenylglyoxal.
  • a substituted or an unsubstituted acetophenone is reacted with a source of a nitrosonium ion in water in the presence of a strong acid to form the substituted or the unsubstituted phenylglyoxal directly, in one step.
  • the source of the nitrosonium ion is a nitrite salt which reacts with the acid to generate the nitrosonium ion in situ or a compound N0 + X " , as defined above, which is brought in to the reactor from an external source.
  • R ! is a straight or a branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 1 to 10 carbon atoms, a phenyl group, a naphthyl group, a halogen or hydrogen.
  • Ar represents an unsubstituted phenyl or naphthyl radical, a substituted phenyl radical substituted at one or more of the ortho, para, or meta positions or a substituted naphthyl radical substituted at one or more of the substitutable positions wherein the substituents to the phenyl or naphthyl radicals are independently selected from the groups of hydroxyl radicals, alkoxy radicals, acyloxy substituted radicals or unsubstituted branched or unbranched alkyl radicals R containing one to ten carbon atoms, substituted or unsubstituted phenyl radicals R,,, and substituted or unsubstituted benzyl radicals R 5 .
  • the substituted alkyl radicals R are substituted in one or more positions with radicals which are independently selected from the group of halogen, hydroxyl, sulfonic acid and sulfuric acid radicals.
  • the substituted phenyl radicals R 4 and the substituted benzyl radicals R 5 are independently substituted in one or more positions with radicals selected independently from the group of hydroxyl radicals, sulfonic acid radicals, sulfinic acid radicals, alkyl radicals having one to ten carbon atoms, and alkoxy radicals having one to eight carbon atoms.
  • An example of a substituted phenylglyoxal prepared in accordance with the present invention is 4- hydroxyphenylglyoxal (hereinafter referred to as
  • R * is hydrogen
  • the representation of the compound of Formula I is generally accepted by that formula, the more accurate structure formula thereof is the
  • the substituted acetophenone is oxidized, in a first step, by reacting it with a primary or a secondary alcohol of the formula R 2 -OH (hereinafter "Formula III") in the presence of a source of a hydrogen ion (H + ) and a source of nitrosonium ion (NO + ) to form a corresponding substituted phenylglyoxalacetal.
  • a primary or a secondary alcohol of the formula R 2 -OH hereinafter "Formula III”
  • a source of a hydrogen ion (H + ) and a source of nitrosonium ion (NO + ) to form a corresponding substituted phenylglyoxalacetal.
  • the phenylglyoxalacetal is then hydrolyzed, in a second step, in the presence of an acid catalyst to form the substituted phenylglyoxal of Formula I.
  • the substituted phenylglyoxal of Formula I is prepared in a one-step process by reacting the corresponding substituted acetophenone of Formula II with a source of a nitrosonium ion (N0 + ) in an aqueous solution in the presence of a strong mineral acid.
  • R 2 is a primary or a secondary alkyl group having typically 1 to 10 carbon atoms. It should be understood that, unless stated otherwise, the above definitions of Ar, R, and R 2 shall be applicable hereinafter.
  • a substituted or an unsubstituted acetophenone of Formula II is converted to a substituted phenylglyoxal of Formula I in a two- step process.
  • the two steps are carried out in sequence in the same reactor.
  • the substituted or unsubstituted acetophenone is oxidized by reacting it with a primary or a secondary alkyl alcohol of the formula R 2 -OH in the presence of a source of a hydrogen ion (H+) and a source of a nitrosonium ion (NO+) to form a corresponding substituted or unsubstituted phenylglyoxalacetal.
  • the primary or secondary alcohol R 2 -OH is typically methyl alcohol, isopropyl alcohol, sec-butyl alcohol, n-butyl alcohol or isoamyl alcohol.
  • the amount of alcohol R 2 -OH used is from about two (2) to about ten (10) times the weight of the 4-hydroxyacetophenone or, more preferably, from about two (2) to about five (5) times the weight of the 4-hydroxyacetophenone.
  • the source of the hydrogen ion (H+) is a strong mineral acid, preferably hydrogen chloride or sulfuric acid.
  • the acid should be present in at least a catalytic amount in the range of about 0.01 to about 0.9 moles of acid per mole of substituted or unsubstituted acetophenone; preferably, however, it should be present in an amount of from about one (1) to about six (6) mole equivalents of the amount of the substituted or unsubstituted acetophenone such as 4-hydroxyacetophenone, more preferably, from about one (1) to about three (3) mole equivalents and, most preferably, from about one (1) to about two (2) mole equivalents.
  • R 3 is an alkyl group having typically one (1) to ten (10) carbon atoms. This definition of R 3 will be applicable hereinafter, unless stated otherwise. Examples of such nitrites are methyl nitrite, ethyl nitrite or isopropyl nitrite.
  • the alkyl nitrite is preferably present in an amount of from about one (1) to about five (5) mole equivalents of the amount of substituted or unsubstituted acetophenone, and, more preferably from about one (1) to about three (3) mole equivalents.
  • nitrosonium ion is an alkyl nitrite of Formula IV wherein R 3 is a primary or a secondary radical, substituted or unsubstituted phenylglyoxal acetals of the formula R 2 /
  • R 3 is a tertiary radical group, no substituted or unsubstituted phenylglyoxal acetals of Formulas VII or VIII are formed.
  • the oxidation reaction is carried out in the liquid phase. It presently appears that the components of the reaction mixture used to form the substituted or unsubstituted phenylglyoxal acetals of Formulas VI, VII and VIII may be combined in any order.
  • the reaction mixture is preferably free of water.
  • the reaction is exothermic and requires no heating to drive the reaction.
  • the reaction may be cooled to a convenient working temperature.
  • the reaction is preferably conducted at a temperature of from about -20°C to about 50°C, or more preferably from about -10°C to about 40°C or, most preferably, at about 0°C.
  • the conversion of the substituted or unsubstituted acetophenone to the corresponding substituted or unsubstituted phenylglyoxalacetal is completed in about one (1) hour to about four (4) hours.
  • the source of the nitrosonium ion (NO+) can also be a nitrite salt, preferably an alkali metal nitrite salt and, more preferably, sodium nitr ' ite. That salt in combination with the strong mineral acid, preferably hydrochloric acid or sulfuric acid, generates in situ a compound which makes the nitrosonium ion (N0+) available to the reaction.
  • the generation of the compound N0 + X " in situ from the nitrite salt and the acid is not preferred because it forms water in the reaction mixture.
  • the source of the nitrosonium ion can also be a reactant N0 + X ⁇ which is available from a source outside of the reaction, wherein X is a halogen, an acetate, a sulfate, or a phosphate. X is preferably a halogen and, most preferably, chlorine.
  • the source of the nitrosonium ion is a nitrite salt or a reactant N0 + X" which is available from an outside source
  • the substituted or unsubstituted phenylglyoxal acetal formed is of the Formula VI.
  • the second step of the process of the first embodiment is carried out by hydrolyzing the substituted or unsubstituted phenylglyoxal acetal or acetals so formed in the same reactor.
  • the hydrolysis is carried out by adding water to the reaction mass.
  • the hydrolysis step requires the presence of catalytic amounts of a strong mineral acid. In the present invention, that acid is already present in the reaction mass because it is required in the first step, i.e. the oxidation step.
  • the products of the hydrolysis reaction are the substituted phenylglyoxals of Formula I and an alcohol or alcohols.
  • the alcohol products are alcohols of the Formulas III and V.
  • the source of the nitrosonium ion (NO + ) is a nitrite salt or a reactant NO + X ' available from an outside source
  • the alcohol product is an alcohol of the Formula III.
  • the hydrolysis reaction is carried out at temperatures which are sufficiently high to vaporize the alcohol or alcohol products.
  • the hydrolysis reaction is carried out at a temperature in the range of from about 25°C to about 100°C and, preferably, from about 50°C to about 100°C and the water is added as hot water or steam.
  • the hydrolysis reaction is carried out for about thirty minutes to about six hours.
  • the substituted or unsubstituted phenylglyoxal formed falls out of the solution and can be separated therefrom by well known techniques. Furthermore, the phenylglyoxal may remain in the reaction mass and can be used to produce further products in the same reactor.
  • a substituted or an unsubstituted acetophenone of Formula II is converted to a substituted or unsubstituted phenylglyoxal of Formula I in a one-step process.
  • the substituted acetophenone such as 4-hydroxyacetophenone, is reacted with a source of nitrosonium ion in water in the presence of a strong mineral acid.
  • Ar which was previously defined, should be such that the compound of Formula II is sufficiently soluble in water to provide sufficient contact between the reactants for the reaction therebetween to proceed.
  • the source of a nitrosonium ion is a compound NO+X- wherein X is a halogen, a sulfite, a sulfate, a phosphite or a phosphate. X is preferably a halogen and, most preferably, chlorine.
  • the reactant NO+X- can be available from an outside source or, preferably, can be generated in situ by reacting a nitrite salt, preferably an alkali metal nitrite salt and, more preferably, sodium nitrite, with a strong acid such as hydrochloric acid or sulfuric acid.
  • Reaction 3 shows that two (2) mole equivalents of a nitrosonium ion (NO+) are required stoichiometrically to convert one (1) mole equivalent of substituted or unsubstituted acetophenone. Therefore, at least two moles of sodium nitrite are required to generate the stoichiometric requirements of nitrosonium one (N0+) to effect maximum conversion of the substituted or unsubstituted acetophenone. Satisfactory conversions, however, are obtained with lower amounts of nitrite salt.
  • the reaction is carried out by using from about one (1) to about three (3) and preferably, about 2.2 moles of sodium nitrite per mole of substituted or unsubstituted acetophenone and from about one (1) to about ten (10) and, preferably, about six (6) moles of hydrochloric acid per mole of substituted or unsubstituted acetophenone.
  • the reaction is carried out at a temperature in the range of about 30°C to about 90°C and, preferably, in the range of about 40°C to about 65°C.
  • the Reaction 3 is carried out by going through several intermediates to eventually form the substituted or unsubstituted phenylglyoxal.
  • the first equivalent of NOCl which is generated by the reaction of sodium nitrite with hydrochloric acid reacts with the enol form of 4- hydroxyacetophenone to produce a nitroso compound which then tautomerizes to 4-hydroxy- ⁇ -isonitroso- acetophenone (hereinafter "HINAP”) .
  • the HINAP then reacts with the second molecule of NOCl to form an intermediate which is attacked by a molecule of water and which by proton transfer forms another intermediate.
  • the latter loses N 2 0 and H 2 0 to form hydroxyphenylglyoxal.
  • EXAMPLE 1 Preparation of 4-Hydroxyphenylglyoxal in an Alcohol Solution (Two-Step Process) Approximately 0.808 moles of methylnitrite were added to a solution containing 50 grams (0.3672 moles) of 4-hydroxyacetophenone in 200 milliliters of methanol and 8 grams of hydrocholoric acid (HCL) . The reactor was stirred during the reaction and for a short time following addition of the methylnitrite. Following completion of the oxidation, the reactor was allowed to cool to about 30 °C. 400 milliliters of distilled water were added to the flask and distilled into a Dean-Stark trap.
  • HCL hydrocholoric acid

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

Abstract

L'invention se rapporte à un phénylglyoxal substitué ou non substitué qui est préparé à partir d'une acétophénone correspondante substituée ou non substituée, par oxydation de l'acétophénone substituée ou non substituée pour former un phénylglyoxalacétal correspondant substitué ou non substitué dans un réacteur, et par hydrolyse du phénylglyoxalacétal dans le même réacteur pour former le phénylglyoxal substitué ou non substitué. En outre, le phénylglyoxal substitué est préparé à partir d'une acétophénone correspondante substituée ou non substituée par réaction de l'acétophénone substituée ou non substituée dans l'eau avec une source d'ion nitrosonium en présence d'un acide fort.
PCT/US1993/001348 1992-03-13 1993-02-16 Preparation de phenylglyoxals substitues ou non substitues Ceased WO1993017989A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5515691A JPH07504656A (ja) 1992-03-13 1993-02-16 置換および非置換フェニルグリオキサールを対応する置換および非置換アセトフェノンから製造する方法
EP93905964A EP0632797A4 (fr) 1992-03-13 1993-02-16 Preparation de phenylglyoxals substitues ou non substitues.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85062692A 1992-03-13 1992-03-13
US07/850,626 1992-03-13

Publications (1)

Publication Number Publication Date
WO1993017989A1 true WO1993017989A1 (fr) 1993-09-16

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PCT/US1993/001348 Ceased WO1993017989A1 (fr) 1992-03-13 1993-02-16 Preparation de phenylglyoxals substitues ou non substitues

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EP (1) EP0632797A4 (fr)
JP (1) JPH07504656A (fr)
MX (1) MX9301360A (fr)
WO (1) WO1993017989A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6861473B2 (en) 2003-02-28 2005-03-01 Baxter International Inc. Macromolecular ketoaldehydes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3794620A (en) * 1971-04-30 1974-02-26 Ciba Geigy Corp Preparation of aromatic carbonyl hydroxamoyl chlorides
DE2432563A1 (de) * 1973-07-06 1975-02-27 Union Carbide Corp Verfahren zur herstellung von aryldialkoxymethylketonen
US4013680A (en) * 1974-06-28 1977-03-22 Glaxo Laboratories Limited Process for the preparation of aromatic α-keto carboxylic acids
US4272453A (en) * 1980-07-24 1981-06-09 Morton-Norwich Products, Inc. 1-Chloro-1-p-methoxybenzoylformaldoxime-N-methylcarbamate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3794620A (en) * 1971-04-30 1974-02-26 Ciba Geigy Corp Preparation of aromatic carbonyl hydroxamoyl chlorides
DE2432563A1 (de) * 1973-07-06 1975-02-27 Union Carbide Corp Verfahren zur herstellung von aryldialkoxymethylketonen
US4013680A (en) * 1974-06-28 1977-03-22 Glaxo Laboratories Limited Process for the preparation of aromatic α-keto carboxylic acids
US4272453A (en) * 1980-07-24 1981-06-09 Morton-Norwich Products, Inc. 1-Chloro-1-p-methoxybenzoylformaldoxime-N-methylcarbamate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0632797A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6861473B2 (en) 2003-02-28 2005-03-01 Baxter International Inc. Macromolecular ketoaldehydes
US7544737B2 (en) 2003-02-28 2009-06-09 Baxter International Inc. Macromolecular ketoaldehydes

Also Published As

Publication number Publication date
EP0632797A4 (fr) 1995-05-24
MX9301360A (es) 1993-09-01
JPH07504656A (ja) 1995-05-25
EP0632797A1 (fr) 1995-01-11

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