FriendlyFinger (Hive Bee)
07-15-03 00:24
No 447359
      How is propiophenone used in fragrance     

Does anybody know where and how propiophenone is used in the fragrance industry?

(Chief Bee)
07-15-03 17:35
No 447622
      Propiophenone Fragrancies     

Request the catalog you can find on page 21 of Aldrichimica Acta Vol 36, No 1. (
It's free, they'll send the Flavors & Fragrances brochure to anyone, and is likely to give you an answer, and/or references.
(Active Asperger Archivist)
07-15-03 20:22
No 447669

But do they take orders from just about anyone?

That's the real key.

Act quickly or not at all.
(Chief Bee)
07-15-03 21:21
No 447689
      bad english     

sorry, I meant that the brochure will yield answers/references... Aldrich will not sell chems to common people, but they usually doesn't have anything against giving away free literature.
(Hive Bee)
07-16-03 16:55
No 447872
      Thanks I'll do that. I've noticed a lot of...     

Thanks I'll do that. I've noticed a lot of Chineese supplyers on the web offering butt loads of the stuff.


Be joyful, though you've concided the facts!
(Hive Bee)
07-17-03 00:02
No 447955

From the German "Riechstofflexikon" :
(Hive Bee)
07-17-03 03:55
No 448000
      Thanks, I'm concidering doing just that     

Thanks, I'm concidering doing just that with AlCl3

07-18-03 08:17
No 448287
      Info on propiophenone repost
(Rated as: good read)

7.2. 1-Phenyl-1-propanone

1-Phenyl-1-propanone [93-55-0] , ethyl phenyl ketone, propiophenone, C6H5COCH2CH3, C9H10O, Mr 134.12.
Properties. 1-Phenyl-1-propanone is a colorless liquid with a flowery odor, insoluble in water, readily soluble in organic solvents. Typical reactions can be carried out at the methylene group, the carbonyl group, and at the aromatic nucleus.
mp     18 C
bp     218 C
d 420  1.009
nD20   1.5258
Flash point 87 C

Production. Propiophenone is produced by Friedel Crafts acylation of benzene with propionic acid chloride in the presence of an equivalent amount of aluminum chloride (99). Another industrial method is the catalytic ketonization of benzoic acid with propionic acid over a calcium acetate aluminum oxide catalyst at 440 520 C ^(100).

Uses. 1-Phenyl-1-propanone is used mainly as an intermediate for pharmaceuticals such as D-Propoxyphen(101) , phenylpropanolamine, and Phenmetrazine(102)

(99)  A. I. Vogel, J. Chem. Soc. 1948, 614.

(100) Union Carbide Corp., Patent US4172097, 1979 (C. A. Smith, L. F. Theiling).

(101)  Eli Lilly, Patent US2728779, 1955 (A. Pohland).

(102) Boehringer Ingelheim, Patent US2835669, 1958 (O. Thoma).

(Active Asperger Archivist)
05-12-04 17:14
No 506745
      Propiophenone US pat 4172097     

US Patent 4172097

Production of Propiophenone

Abstract:  In the production of propiophenone by a vapor-phase, cross-decarboxylation process, an undesirable by-product isobutyrophenone, is suppressed by addition of water or steam to the reactant stream.

Propiophenone is used as a starting material in pharmaceutical applications particularly for the manufacture of dextropropoxyphene or alpha-d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol propionate. Propiophenone can be produced by a Friedel-Crafts reaction of benzene and propionic acid, propionic anhydride or propionyl chloride catalyzed by Lewis acids. Although Friedel-Crafts processes produce no significant amounts of aromatic ketone by-products, such processes suffer from very high costs involved in corrosion of production facilities and waste disposal required for environmental protection.

An attractive alternative synthesis of propiophenone and other specialty ketones utilizes a vapor-phase cross-decarboxylation process. In the case of propiophenone, benzoic acid is reacted with propionic acid at high temperatures over a catalyst. Propiophenone, diethyl ketone, carbon dioxide, and water are the major products. Numerous by-products are also formed in small amounts, including other dialkyl ketones, other phenylalkyl ketones and biphenol. One of the by-products produced in the vapor-phase process is isobutyrophenone. Depending upon the process conditions used, isobutyrophenone production may equal 10 percent or more of the propiophenone production. Separation of isobutyrophenone from propiophenone is impossible using conventional distillation techniques, inasmuch as the boiling points of these two compounds are within C. of each other. Other separation techniques, such as fractional crystallization or extractive distillation are costly and have not been perfected for this particular separation problem.

Dextropropoxyphene is used medically as an analgesic. Drug dependence associated with its use has been found to be uncommon. Unfortunately, its isomer prepared from isobutyrophenone rather than propiophenone has been found to be an addictive narcotic. Therefore, it is essential that propiophenone used for the preparation of dextropropoxyphene be of high purity such that the isobutyrophenone content shall be as low as possible.

It is therefore an object of this invention to provide a vapor-phase, cross-decarboxylation synthesis for the preparation of alkyl aryl ketones with a minimum of by-products.

It is a specific object of this invention to prepare propiophenone by the catalytic vapor-phase cross-decarboxylation of benzoic acid with propionic acid, in which the content of the by-product isobutyrophenone is held to a minimum.

this invention is benzoic acid although other aromatic carboxylic acids such as benzoic acid alkyl substituted derivatives where the alkyl group contains 1 to about 4 carbon atoms can also be used.

It is preferred to use about 4 to about 8 moles of water or secondary alcohol per mol of aromatic carboxylic acid. Of the two, water is the preferred modifying agent.  It is preferred to use a ratio of aromatic carboxylic acid to propionic acid of about 1:2 to about 1:4. The preferred reaction temperature is about to about C.
The nature of the catalyst used in this reaction is not critical. Thus, although calcium acetate supported on alumina has been found to serve satisfactorily, other catalysts which can be used include cobalt acetate, manganous oxide, and the like. It is preferred to use superatmospheric pressure of about 10 to about 100 psig but this is not critical and other pressures above and below atmospheric pressure as well as atmospheric pressure can be used if desired. 

The invention can be practiced as a batch or continuous system with the latter being more efficient.

Example 1:

The reactor used for the preparation of propiophenone in accordance with this invention consisted of a reactor fabricated from 1-inch by 48-inch stainless steel pipe, insulated and electrically heated. Temperatures were determined at four points by thermocouples positioned in a 1/4" thermowell which extended through the entire length of the reactor.

Reactants were fed, via a small diaphram pump from a calibrated feed tank through a steam-jacketed line to the top of the reactor. The feed tank and pump were warmed by infrared heat lamps to prevent crystallization of benzoic acid.

The catalyst bed consisted of two layers. A 13" bed of inert material in the top end of the vertically oriented reactor served as a preheat section. The bottom 31" consisted of calcium acetate on alumina.

Activated alumina (Alcoa F-1 grade, 4-8 mesh) is immersed in a 25 percent aqueous solution of calcium acetate for 2 to 24 hours. The calcium acetate solution is drained off, and most of the excess water adhering to the alumina is removed by vacuum evaporation. The impregnated catalyst is then heated overnight at C. to remove the last traces of water. The amount of calcium impregnated on the catalyst depends on how long the alumina is dipped in the calcium acetate solution and on how many times the procedure is repeated. The catalyst used in these examples contained 2.95 percent calcium by weight (3.87 percent by weight when calculated as calcium oxide).

The reactants consisted of a 2:1 mole ratio of propionic and benzoic acids, with water or secondary alcohol diluent added as indicated in Table I. Controls A and C where no diluent was used and Control B where methanol was used are also shown in Table I.

In Example 1, using the reactor described above, together with ancillary equipment, a mixture containing 2 moles of propionic acid per mole of benzoic acid was fed to the reactor together with 4 moles of water per mole of benzoic acid at a rate of 249 ml/hr. for 4.5 hours. The reaction temperature was maintained between C. and C. Analysis of the condensed organic layer by gas chromatography indicated that 4.68 pounds of isobutyrophenone were produced per 100 pounds of propiophenone. These data are delineated in Table I. The instrument used was a Bendix Model 2300 dual column programmed temperature gas chromatograph having a thermal conductivity detector. The bridge current was 200 ma. with a 0-1 mv. recorder. The column consisted of two, 10 feet by 1/8 inch stainless steel tubing packed with silicone on an inert support. The column temperature was C. The carrier gas was helium at 30 cc/minute.

Example 1 was repeated except that no water was present in the feed mixture fed to the reactor; the feed rate was 279 ml/hr, the reaction time was 5.5 hours. Analysis of the condensed organic layer by gas chromatography indicated that 5.04 pounds of isobutyrophenone were produced per 100 pounds of propiophenone

The following conclusions can be drawn from an examination of the experimental data. Co-production of isobutyrophenone on a laboratory scale decreased steadily as the water concentration in the feed stream was increased. Addition of 8 moles of water per mole of benzoic acid resulted in an isobutyrophenone content of 2.3-2.8 percent based on contained propiophenone. With no water, isobutyrophenone production increased to 5.0-6.4 percent.

Addition of isopropanol at ratio of 1 mole per mole of benzoic acid to the mixed acid feed gave low production of isobutyrophenone (3.2 percent) while methanol at the same level showed exactly the opposite trend affording 10.4 percent isobutyrophenone. This demonstrated the unexpected finding that whereas secondary aliphatic alcohols suppress the formation of the undesirable by-product, isobutyrophenone, a primary alcohol had the opposite effect, actually increasing the production of isobutyrophenone.

It was also found that water could be added to the reaction stream in the form of steam to suppress isobutyrophenone production. This is important for plant-scale production of propiophenone containing minimum amounts of isobutyrophenone. In plant-scale runs the effect of steam was even greater than for the bench-scale run so that production runs of propiophenone routinely contained from about 0.15 percent isobutyrophenone down to no measurable amount. This is important for pharmaceutical use where a limit of about 0.5% is required.

Surface-to-volume ratio of the reactor appeared to have no major effect on by-product formation.

In laboratory runs addition of water to the reaction stream resulted in a slight increase in another by-product, i.e., acetopheone. In the plant, however, acetophenone production was 1% or lower. Without steam addition, plant runs usually produced about 0.05 to about 0.1 pound of acetophenone per pound of propiophenone.

While isopropanol is more effective on a molar basis than water or steam in suppressing isobutyrophenone formation, it is not as economical.

Although the invention has been described in its preferred forms with a certain degree of particularity, it is understood that the present disclosure of the preferred forms has been made only by way of example and that numerous changes may be resorted to without departing from the spirit and scope of the invention.

Act quickly or not at all.
(Active Asperger Archivist)
05-12-04 21:07
No 506779
      Aminobutanes US pat 2728779     

US Patent 2728779

Esters of Substituted Aminobutanes

This invention relates to substituted 1,2-diphenylbutanes and more particularly to esters of 1,2-diphenyl-2-hydroxy-3-methyl-4-(substituted amino)-butanes and their acid addition salts.

R1 = Me, Et  ; R2 = dimethylamino and pyrrolidino radicals.

These bases are generally low melting and soluble in common organic solvents and water insoluble.  The acid addition salts are generally water soluble.

The new substituted diphenylbutanes and their acid salts are analgesics, and are characterized by their ability to produce analgesia without toxic side effects such as respiratory depression.  The compounds can be utilized for therapeutic use by parenteral injection in aq. Solution or other pharmaceutical extending media, or they may  be administered orally in pharmaceutical preparations suitable for that purpose, such as tablets, capsules, elixirs, suspensions and the like.

Alpha-methyl-beta-pyrrolidinopropiophenone is reacted with benzylmagnesium chloride to form 1,2-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane hydrochloride, which is esterified with propionic anhydride to form 1,2-diphenyl-2-propionoxy-3-methyl-4-pyrrolidinobutane hydrochloride.

The esterified substituted diphenylbutanes each possess two centers of asymmetry, and therefore occur in diastereoisomeric forms.  In accordance with the usual practice, the less soluble diastereoisomer is designated as the alpha-dl-isomer, and the more soluble as the beta-dl-isomer; and that terminology is used herein to designate the substituted diphenylbutanes of this invention.  The alpha-dl-isomers are the preferred compounds of the invention since they possess marked analgesic activity in contrast to the beta-dl-isomers, which are substancially inactive.

Example 1: 1,2-Diphenyl-2-Propionoxy-3-Methyl-4-Dimethylaminobutane Hydrochloride

A sol. of benzylmagnesium chloride prepd from 63.3g (0.5mol) of benzyl chloride, 30.5g  (1.25mol) of Mg metal and 750cc of ether was added dropwise with stirring to a sol. of 61.9g (0.35mol) of alpha-methyl-beta-dimethylaminopropiophenone (prepd by the method of Burchalter et al., JACS 70, 4186, Post 1948 (not existing)), in 150ml of ether.  When all of the Grignard reagent had been added, the sol. was refluxed for one hour.  The reaction mix was then quenched with sat. aq. ammonium chloride.  The ether sol. containing the 1,2-diphenyl-2-hydroxy-3-methyl-4-dimethylaminobutane formed in the reaction was decanted from the granular precipitate and dried over anhydrous Mg sulfate.  Dry HCl gas was passed into the ether solution until precipitation was completed.  The solid was removed by filtration and was recrystallized from methanol and ethyl acetate.  The HCl salt had a MP: 231-232*C

A mix of 50g of the HCl salt formed above, 50g of propionic anhydride and 50cc of pyridine was refluxed for about 5 hours.  The reaction mix was cooled to 50*C and ethyl ether was added to the point of incipient precipitation.  The HCl salt of the 2-propionoxy ester precipitated upon cooling and was removed by filtration and washed with anhydrous ether.  On recrystallization from a mix of methanol and ethyl acetate, alpha-dl-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane hydrochloride melted at 170-171*C.

Example 2:  1,2-diphenyl-2-acetoxy-3-methyl-4-dimethylaminobutane hydrochloride

Rxn mix containing 5g of alpha-dl-1,2-diphenyl-2-hydroxy-3-methyl-4dimethylaminobutane hydrochloride (as in Example 1), 5ml of acetic anhydride and 25ml of pyridine was heated on a steam bath for sixteen hours.  The rxn mix was cooled and ether added to the point of incipient precipitation, and the mix was cooled in the refrigerator.  The resulting crystalline precipitate of alpha-2-acetoxy ester was recryst. From methanol and ethyl acetate, MP: 177-178*C

Example 3: 1,2-diphenyl-2-propionoxy-3-methyl-4-pyrrolidinobutane hydrochloride

A rxn mix of 108g pyrrolidine, 134g propiophenone, 39.4g p-formaldehyde, 200ml ethanol and 1.7ml conc. HCl (aq.) was refluxed overnight.  The ethanol was removed in vacuo, the residue dissolved in about 100ml water, washed with about 100ml of ether and the aq. solution was made alkaline with ammonium hydroxide.  An oil consisting of beta-pyrrolidinoisobutyrophenone formed and was extracted with three 50ml portions of ether, dried with Mg sulfate and frac. dist. in vacuo.  BP: 117-118*C/0.3mmHg, Ref. Index @ 26*C = 1.5302.

A sol. of 54.2g of the product above in 100ml of ether was added dropwise to a grignard reagent prepd from 24.3g of Mg metal, 63.3g of benzyl chloride, and 600ml of ether.  The rxn mix was refluxed for an hour and then quenched with sat. aq. ammonium chloride.  The ether layer with 1,2-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane was removed and dried over anhydrous Mg sulfate.  Dry HCl was bubbled through the ether solution and the salt was filtered off and recryst. from methanol/ethyl acetate with the addition of ether. The alpha-dl-1,2,-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane hydrochloride had MP: 188-189*C.  Evap. Of the mother liquors from recrystallization yields the Beta isomer that has MP: 202-203*C.

A rxn mix with 10g of the alpha product above, 10ml pyridine, 10ml of propionic anhydride was refluxed 2 hours.  The mix was cooled and ether added to cloudiness whereupon the product precipitated.  Recryst. from methanol/ethyl acetate, the material had MP: 196-197*C w/decomp.

Several other examples were present.  All followed similar synthetic pathways and methods.  The valuable statistics are listed below.

alpha-dl-1,2-diphenyl-2-acetoxy-3-methyl-4-pyrrolidinobutane hydrochloride: recryst. methanol/ethyl acetate w/added ether.  MP: 202-203*C.

alpha-dl-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminopropane: recryst. pet. Ether.  MP: 70-71*C.

Most of the freebases obtained were oils that only crystallized after standing several weeks.

Act quickly or not at all.