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WO1993010071A1 - Procede de production de carbonyles - Google Patents

Procede de production de carbonyles Download PDF

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Publication number
WO1993010071A1
WO1993010071A1 PCT/US1992/010097 US9210097W WO9310071A1 WO 1993010071 A1 WO1993010071 A1 WO 1993010071A1 US 9210097 W US9210097 W US 9210097W WO 9310071 A1 WO9310071 A1 WO 9310071A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
formaldehyde
acetophenone
hydroxy
phenyl
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/US1992/010097
Other languages
English (en)
Inventor
Roy A. Periana
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.)
Catalytica Inc
Original Assignee
Catalytica Inc
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 Catalytica Inc filed Critical Catalytica Inc
Publication of WO1993010071A1 publication Critical patent/WO1993010071A1/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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/75—Reactions with formaldehyde
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups

Definitions

  • This invention is a noncatalyzed process for the production of carbonyls, particularly /S-hydroxy aldehydes or ketones, by the aldol condensation of, for example, acetophenone and formaldehyde.
  • this process neither base nor acid is present nor added to the reaction mixture.
  • Operation of a specific variation of the process results in a high yield of 3-hydroxy-l- phenyl-1-propanone and, because of the absence of added catalysts and of the choice of reaction conditions, does not produce significant amounts of dehydration products such as l-phenyl-2-propene-l-one (in the case of a desired 3-hydroxy-l-phenyl-l-propene product) or of overcondensation products.
  • Aldol condensations are among the most well known and important carbon-carbon forming reactions available to the chemist.
  • aldol reactions two molecules of a carbonyl combine to form a /3-hydroxyaldehyde or a S-hydroxyketone.
  • the product results from addition of one molecule of aldehyde or ketone to another aldehyde or ketone molecule such that the ⁇ -carbon of the second becomes attached to the carbonyl carbon of the first.
  • These reactions typically require the use of acid or base catalysts.
  • the aldol product (3-hydroxy-ketone) can readily react to produce 1,2-unsatura ed carbonyl compounds by dehydration reactions or 3,4-dihydroxy-ketones by further reaction of the aldol product with more aldehyde. Since dehydration and overcondensation reactions are predominant reaction pathways in aldol reaction media, many workers have developed techniques to avoid these reactions and allow isolation of the intermediate S-hydroxy-carbonyl products. These techniques all require the use of added regents used in stoichiometric amounts (e.g., lithium diisopropyl amide, trimethyl silyl fluoride, ZnCl 2 , or TiCl 4 ) . See, for instance, J. March, Advanced Organic Chemistry.
  • 3-hydroxy-l-phenyl-l-propanone is a material used in the manufacture of pharmaceutical intermediates and as a precursor to perfume intermediates. It is typically made using the selective reduction of methyl-3- phenyl-3-keto-l-propionate (Chem. Pharm. Bull., 34(7) 3029, 1986) or by the selective oxidation of 1,3- dihydroxy-1-phenyl-propane (Tet. Lett. 30(19), 2559, 1989).
  • reaction is typically initiated by the formation of enolate species by reaction of the base with the acidic alpha-hydrogens of the ketone. These species then attack the aldehyde in a condensation reaction to produce the hydroxy-ketone.
  • the acidity of the alpha-hydrogens in the ketone is an important factor in determining the relative reactivity of ketones in the reaction. Since ⁇ - hydroxy-ketones are relatively acidic and readily produce reactive enolates, these materials are also susceptible to overcondensation with aldehydes in base-catalyzed aldol reactions.
  • the condensation reaction is between an "acceptor compound” which is capable of forming an anion at the carbon o. to the carbonyl and a “donor compound” which provides the electron poor carbonyl carbon.
  • This invention is a process for the condensation of aldehydes or ketones or mixtures of ketones and aldehydes to produce jS-hydroxyketones.
  • the process does not use either an acid or a base catalyst nor any other identifiable catalytic material.
  • This process may employ acceptor aldehydes or ketones of the formula:
  • each of R 1 and R 2 is independently H, a branched or linear alkyl or alkylene group having one to 12 carbon atoms, an alkylaryl group having seven to 20 carbon atoms, or an aryl group having six to 20 carbon atoms; wherein any of said aryl group is unsubstituted or substituted by 1-5 substituents such as alkyl(1-6C), nitro, halo, alkoxy(l-6C) and the like, with the proviso that at least one of R 1 and R 2 must contain an ⁇ H.
  • the carbonyl donor is of the similar formula,
  • R 3 and R 4 are defined as for R 1 and R 2 , except that the proviso is not required.
  • one of R 3 and R 4 is H.
  • the process may use single ketones, mixtures of ketones, single aldehydes, mixtures of aldehydes, and mixtures of ketones and aldehydes.
  • Preferred embodiments of the acceptor compound include those wherein one of R 1 or R 2 is alkyl(1-6C) and the other is aryl.
  • Especially preferred aryl substituents include phenyl, optionally substituted with
  • An especially preferred alkyl substituent in the compound of formula (1) is methyl.
  • Preferred embodiments of the donor compound include those wherein one of R 3 and R 4 is H, especially wherein both of R 3 and R 4 are H.
  • the process couples a ketone to an aldehyde.
  • the reaction as noted elsewhere, is carried out in the substantial absence of all general bases (species tending to form the generation of enolates) and all general acids (species tending to coordinate to carbonyl oxygen and generate carbonyl species) . No acidic or basic material is added to the reaction mixture, and the feedstocks are treated to remove, in a substantial fashion, any acids or bases which may be found in those feeds.
  • the temperature of reaction is somewhat higher than that used in classical aldol reactions, typically 100°C or greater. Preferred is 100°C to the boiling point of the feeds at the pressure of operation. More preferred is 100°C to 225°C.
  • Pressure of operations is not important except to the extent required to maintain the reaction mixture in the liquid phase and at the chosen temperature.
  • Reaction solvents may be used, if so desired.
  • Polar solvents are particularly suitable.
  • the reaction with acetophenone and formaldehyde should be run about 100°C. Decomposition can occur at higher temperatures and the reaction is best run between 100°C and 225°C. The yield of product is also dependent upon reaction time and upon the reaction temperature. In general, shorter reaction times are required with higher temperatures, and at 175°C a desirable reaction time is 1 hr. At longer reaction times, product decomposition occurs, leading to lower yields.
  • the ratio of reactants acetophenone:formaldehyde
  • the reaction is best run with an excess of the acetophenone over the formaldehyde.
  • reaction solvents may be used, so long as the solvent is stable to the reaction conditions.
  • the reaction may also be run without a solvent.
  • acetophenone and formalin a 37°C aqueous solution of formaldehyde
  • agitation of the reaction mixture is desirable.
  • stirring is not required.
  • pressurizing the reactor so to maintain the reactants in the liquid phase is desirable.
  • reaction is stopped by cooling the mixture, preferably to less than 50°C.
  • Product isolation can be carried out simply by flash distillation to remove excess reagents or solvents, followed by a second flash distillation to isolate the product. Any reaction vessel capable of containing the reaction without excessive corrosion would be suitable.
  • formaldehyde In the reaction between acetophenone and formaldehyde, various forms of formaldehyde may be used. Reaction with formalin (a commercial solution of 37% formaldehyde in water) , dimethoxy methane (the dimethyl acetal of formaldehyde) , trioxane (the trimer of formaldehyde) or gaseous formaldehyde will result in formation of 3-hydroxy-propiophenone. However, because of its commercial availability, formalin is the most preferred form.
  • a 5-gallon reactor (carefully cleaned to remove any impurities that may act as catalysts) was charged with 13.41 of acetophenone and 1.7 1 of 37 wt% formaldehyde in water (5:1 molar ratio of acetophenone to formaldehyde) .
  • the reactor was sealed, purged with N 2 , and heated to 175°C with stirring. After 70 minutes, the reaction was stopped by cooling the reactor to room temperature. The solution was allowed to separate into aqueous and organic layers. The organic layer was removed.
  • the organic layer was flash-distilled to remove the excess acetophenone (100 ⁇ C under 10 mmHg) and the crude 3-hydroxy-1-phenyl-propanone was obtained by distillation of the crude material, discarding the first and last cuts.
  • the yield of 3-hydroxy-1-phenyl-l- propanone was 1.6 kg (47% based on added formaldehyde).
  • Example 2 To show that para-formaldehyde was suitable as a feedstock in the process, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 0.68 g of finely ground solid para-formaldehyde. The yield of 3- hydroxy-l-phenyl-l-propanone was 0.2 g (6% based on added formaldehyde) .
  • trioxane was suitable as a feedstock in the process
  • the procedure of Example 1 was repeated with 13.4 ml of acetophenone, 0.68 g of trioxane (a tri er of formaldehyde) and 1 g of water.
  • the yield of 3-hydroxy-l-phenyl-l-propanone was 0.1 g (3% based on added formaldehyde) .
  • Example 2 To show that dimethoxymethane was suitable as a feedstock in the process, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 1.74 g of dimethoxy methane (an acetal of formaldehyde) and 1 g of water. The yield of 3-hydroxy-l-phenyl-l-propanone was 0.6 g (18% based on added formaldehyde) .
  • Example 1 To show that removal of acidic and basic impurities is a useful process step, the procedure of Example 1 was repeated with 13.4 ml of freshly distilled acetophenone and 1.7 ml of 37 wt% formalin which was neutralized by passing over basic alumina. The yield of 3-hydroxy-l-phenyl-l-propanone was 2 g (59% based on added formaldehyde) .
  • Example 1 To show the effect of reaction time on yield, the procedure of Example 1 was repeated with 13.4 of acetophenone and 1.7 ml of 37 wt% formalin. In contrast to the reaction time of Example 1 (70 minutes) , the reaction time was extended to 2 hours. The yield of 3- hydroxy-l-phenyl-l-propanone was 0.1 g (3% based on added formaldehyde) .
  • Example 7 In order to show the effect of temperature on the reaction, the procedure of Example 1 was repeated with 13.4 ml of acetophenone and 1.7 ml of 37 wt% formalin with a reaction temperature of 250°C. 3-hydroxy-l-phenyl-l-propanone could not be detected in or isolated from the reaction stream.
  • Example 1 To show the positive effect of stirring upon the reaction, the procedure of Example 1 (in which vigorous stirring was utilized) was again repeated using 13.4 ml of acetophenone and 1.7 ml of 37 wt% formalin but without stirring. In sharp contrast to the high yield of Example 1, the yield of 3-hydroxy-l-phenyl-l-propanone in this example was 0.7 g (21% based on added formaldehyde) .
  • Example 1 As comparative examples showing the effect of acids and bases upon the reaction, the procedure of Example 1 was repeated in a series of runs, both at 80°C and at 25°C variously in the presence of 5 mol% (based on formaldehyde) of: i) H 2 S0 4 , ii) H 3 P0 5 , iii) NaOH, and iv) KOH.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (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 procédé non catalysé de production de carbonyles, en particulier de β-hydroxy aldéhydes, au moyen de la condensation d'aldol de, par exemple, acétophénone et formaldéhyde. Dans ledit procédé, on n'ajoute ni base ni acide au mélange réactionnel. Une variation spécifique du procédé permet d'obtenir un rendement élevé de 3-hydroxy-1-phényle-1-propanone et, étant donné l'absence de catalyseurs ajoutés et du choix des conditions de réaction, ne produit pas des quantités importantes de produits de déshydratation, tels que 1-phényle-2-propène-1-one ou de produits de surcondensation.
PCT/US1992/010097 1991-11-22 1992-11-23 Procede de production de carbonyles Ceased WO1993010071A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79588691A 1991-11-22 1991-11-22
US07/795,886 1991-11-22

Publications (1)

Publication Number Publication Date
WO1993010071A1 true WO1993010071A1 (fr) 1993-05-27

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Application Number Title Priority Date Filing Date
PCT/US1992/010097 Ceased WO1993010071A1 (fr) 1991-11-22 1992-11-23 Procede de production de carbonyles

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WO (1) WO1993010071A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1090899A3 (fr) * 1999-10-06 2003-10-15 Basf Aktiengesellschaft Procédé de préparation de 1,3-dioles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3544634A (en) * 1966-09-15 1970-12-01 Basf Ag Production of 3-ketobutanol-(1)
US3662001A (en) * 1968-05-07 1972-05-09 Basf Ag Production of 3-ketobutanol-(1)
US4704479A (en) * 1980-04-30 1987-11-03 Btl Inc. Process for producing methylol ketones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3544634A (en) * 1966-09-15 1970-12-01 Basf Ag Production of 3-ketobutanol-(1)
US3662001A (en) * 1968-05-07 1972-05-09 Basf Ag Production of 3-ketobutanol-(1)
US4704479A (en) * 1980-04-30 1987-11-03 Btl Inc. Process for producing methylol ketones

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1090899A3 (fr) * 1999-10-06 2003-10-15 Basf Aktiengesellschaft Procédé de préparation de 1,3-dioles

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