WO2007039034A1 - Process for preparing n-acetylaminoacetophenones and downstream products - Google Patents

Process for preparing n-acetylaminoacetophenones and downstream products Download PDF

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WO2007039034A1
WO2007039034A1 PCT/EP2006/008630 EP2006008630W WO2007039034A1 WO 2007039034 A1 WO2007039034 A1 WO 2007039034A1 EP 2006008630 W EP2006008630 W EP 2006008630W WO 2007039034 A1 WO2007039034 A1 WO 2007039034A1
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alkyl
crc
formula
alkoxy
halocycloalkyl
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PCT/EP2006/008630
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French (fr)
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Walther Jary
Christian Rogl
Wolfgang Skranc
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Dsm Fine Chemicals Austria Nfg Gmbh & Co Kg
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • the present invention relates to a process for preparing N-acetylaminoacetophenones and downstream products.
  • N-Acetylaminoacetophenones and their downstream products are valuable intermediates for preparing, for example, pharmaceuticals and agrochemicals.
  • N-acetylaminoacetophenones are known from the literature.
  • One variant is, for example, the oxidative cleavage of 2,3-dimethylindole (Journal of the Chemical Society, Perkin Transactions 2, (9), 1634-1640; 2001 ; Chemical Communications (Cambridge), (10), 869-870; 2000; Journal of Molecular Catalysis, 57(1 ), L9-L12; 1989; Journal of Molecular Catalysis, 32(3), 285-90; 1985) using various catalysts and solvents or the hydrogenation of 2-nitroacetophenone (Journal of Molecular Catalysis A: Chemical, 212(1-2), 127-130; 2004; Synthetic Communications, 33(17), 2985-2988; 2003; Journal of Organic Chemistry, 64(7), 2301-2303; 1999; Tetrahedron Letters, 35(23), 3965-6; 1994, etc.) and subsequent acetylation, once again using various catalysts and solvents.
  • a further method of preparation is the ozonolysis of 2,3-dimethylindole in ethyl acetate or acetic acid/water.
  • the work-up of the peroxides is carried out by hydrolysis in a basic medium.
  • the product is worked up by extraction with ether.
  • the disadvantages of the process are the low yields of from 10 to 57%, the basic hydrolysis of the peroxides which causes rearrangement of the peroxides and thus leads to phenolic by-products which are extremely toxic and the isolation of the product by extraction with ether since such an extraction cannot be carried out industrially because of the risk of explosion associated with ether solvents.
  • the present invention accordingly provides a process for preparing N-acetylaminoacetophenones of the formula (I)
  • R2 is CrC 4 -alkyl, C r C 6 -alkylsulfinyl, C r C 6 -alkylsulfonyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, halocycloalkyl, formyl-Ci-C 3 -alkyl
  • R3 is H, fluorine, chlorine, CrC 4 -alkyl or trifluoromethyl and
  • R4 is hydrogen, CrC ⁇ -alkyl, d-C ⁇ -alkoxy, C 3 -C
  • N-Acetylaminoacetophenones of the formula (I) are prepared by the process of the invention.
  • R1 is a CrC 6 -alkyl radical such as methyl, ethyl, propyl, isopropyl, n-, iso- and tert-butyl, pentyl and hexyl, or else Ci-C 6 -alkylsulfinyl, Ci-C 6 -alkylsulfonyl,
  • R2 is C r C 4 -alkyl, Ci-C 6 -alkylsulfinyl, C r C 6 -alkylsulfonyl, Ci-C 4 -alkoxy-C r C 4 -alkyl, halocycloalkyl or formyl-Ci-C 3 -alkyl, preferably a Ci-C 2 -alkyl radical and particularly preferably a methyl radical.
  • R3 is H, fluorine, chlorine, trifluoromethyl or Ci-C ⁇ alkyl, preferably H.
  • the compound of the formula (I) can be monosubstituted or multiply substituted by
  • the preparation according to the invention of the N-acetylaminoacetophenones of the formula (I) is effected by ozonolysis in a suitable solvent.
  • Solvents which are suitable for the process of the invention are CrC ⁇ -alcohols such as methanol, ethanol, n-propanol, butanol, glycol, etc., nitriles such as acetonitrile, benzonitrile, etc., C r C 4 -carboxylic acids or anhydrides thereof, e.g.
  • acetic acid, propionic acid, etc., acetic anhydride, etc. CrC 6 -alkyl acetates such as ethyl acetate, propyl acetate, butyl acetate, etc., chlorinated hydrocarbons such as dichloro- methane, dichloroethane, dichlorobenzene, etc., N-methylpyrrolidone, dimethylform- amide, dimethylacetamide, water or mixtures thereof in any ratios.
  • the ozonolysis is preferably carried out in a solvent mixture of CrC 4 -carboxylic acid and water, particularly preferably in a mixture of propionic acid and water.
  • the volume ratio of the two solvents is from 1 :100 to 100:1 , preferably 2:1.
  • the ozonization is carried out using an equivalent amount of ozone or using a certain excess of ozone up to about 2 equivalents at a temperature of from -8O 0 C to +4O 0 C, preferably from -40 0 C to + 4 0 C.
  • the ozone can be generated from pure oxygen or from industrial air (from 20 to 4% by volume of oxygen, balance inlet gases).
  • the ozonolysis can be carried out industrially in batch reactors, ozonolysis plants with circulation or in microreactors as described, for instance, in JP2004285001.
  • the reaction solution obtained in this way which contains the corresponding peroxides, is reduced in a customary manner.
  • customary reducing agents such as dimethyl sulfide, thiodiethanol, thiourea, sodium sulfite, sodium thiosulfate, Zn/acetic acid, decomposition of the peroxides by boiling in an acidic medium, catalytic decomposition of the peroxides by means of transition metal catalysts as described in WO 04054950 or by catalytic hydrogenation with or without pH regulation, metering- in of peroxide and/or temperature regulation.
  • Desired ⁇ /-acetylaminoacetophenone is subsequently isolated from the reaction solution if desired.
  • the isolation of the desired ⁇ /-acetylaminoacetophenone can be achieved by distilling off at least part of the solvent and subsequently crystallizing out the product in methanol at low temperatures or by admixing the mother liquor with nonpolar solvents such as pentane, heptane, hexane, special grades of petroleum spirit, petroleum ether, benzene, toluene, xylene, etc.
  • the product is then recovered from the mother liquor by filtration and drying.
  • the process of the invention enables ⁇ /-acetylaminoacetophenones of the formula (I) to be obtained in higher yields compared to the prior art (increases by more than 50%) and high purities of up to 99.9% (GC-% by area) in a simple and inexpensive way.
  • ⁇ /-acetylaminoacetophenones of the formula (I) prepared according to the invention can then, if desired, be converted in various downstream products such as substituted or unsubstituted 2-aminoacetophenones by removal of the ⁇ /-acetyl protective group by customary methods (e.g. lit.: Greene, Wutts; Protective Groups in Organic Synthesis, Wiley Interscience, Third Edition).
  • R2 is C- ⁇ -C 4 -alkyl, CrC ⁇ -alkylsulfinyl, CrC- ⁇ -alkylsulfonyl, CrC 4 -alkoxy-C r C 4 - alkyl, halocycloalkyl, formyl-Ci-C 3 -alkyl and R3 is H, fluorine, chlorine, C r C 4 -alkyl or trifluoromethyl, can be effected by removal of the ⁇ /-acetyl group in a strongly acidic medium.
  • the present invention therefore further provides a process for preparing 2-aminoacetophenones of the formula (III)
  • R2 is CrC 4 -alkyl, Ci-C 6 -alkylsulfinyl, C r C 6 -alkylsulfonyl, C r C 4 -alkoxy-Ci-C 4 - alkyl, halocycloalkyl, formyl-Ci-C 3 -alkyl and R3 is H 1 fluorine, chlorine, CrC 4 -alkyl or trifluoromethyl, wherein the N-acetyl group of the compound of the formula (I)
  • R2 is CrC 4 -alkyl, C r C 6 -alkylsulfinyl, C r C 6 -alkylsulfonyl, Ci-C 4 -alkoxy-C r C 4 -alkyl, halocycloalkyl, formyl-Ci-C 3 -alkyl
  • R3 is H, fluorine, chlorine, CrC 4 -alkyl or trifluoromethyl and
  • R4 is hydrogen, CrC 8 -alkyl, CrC 8 -alkoxy,
  • the ⁇ /-acetylaminoacetophenone used does not have to be isolated from the reaction solution but can be used directly as reaction solution for the removal of the N-acetyl group.
  • the removal of the N-acetyl group is carried out at a pH of 0-3.
  • Acids suitable for producing the strongly acidic medium are, for example, HCI, sulfuric acid or other mineral acids, toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid and other and organic acids.
  • the corresponding ⁇ /-acetylaminoacetophenone of the formula (I) is taken up in an acid/water mixture or in the pure acid and then boiled at reflux temperature.
  • the reaction mixture is cooled and a suitable base, for example dilute sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide solution, is added so that a pH of 7-14, preferably 8-12, is set.
  • a suitable base for example dilute sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide solution
  • the crude product can then be extracted by extraction with a suitable solvent.
  • the product can also be distilled directly from the mixture after neutralization with the alkali at a suitable boiling point and/or steam volatility.
  • the distillation can be carried out at atmospheric pressure or under reduced pressure. In the case of a steam distillation, steam at 100 0 C or superheated steam (temp. > 150 0 C) can be used.
  • Fine purification of the product can be carried out by means of fine distillation or by means of multiple recrystallization of the product.
  • the reaction solution was then warmed to room temperature and part of the solvent was subsequently distilled off (leaving 110 ml) and the product was crystallized out at 0 0 C.
  • the precipitated solid was filtered off with suction on a sintered glass filter (pore size 3) and washed with 25 ml of cyclohexane (technical grade) and subsequently dried under reduced pressure.
  • reaction solution was added dropwise to an ice-cooled methanolic thiodiethanol solution ⁇ 10.1 g [0.083 mol] of thiodiethanol in 100 ml of methanol ⁇ over a period of 1 hour.
  • reaction solution was then warmed to room temperature, part of the solvent was distilled off (leaving 110 ml) and the product was crystallized out at 0 0 C.
  • the precipitated solid was filtered off with suction on a sintered glass filter (pore size 3) and washed with 25 ml of cyclohexane.

Abstract

A process for preparing N-acetylaminoacetophenones of the formula (I) where R1 is a C1-C8-alkyl radical, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl, halocycloalkyl, formyl-C1-C3-alkyl or -C(=0)C(=0)R4, R2 is C1-C4-alkyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C4-alkoxy-C1-C4-alkyl, halocycloalkyl, formyl-C1-C3-alkyl, R3 is H, fluorine, chlorine, C1-C4-alkyl or trifluoromethyl and R4 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy, C3-C8-cycloalkyl, wherein an indole of the formula (II) where R2 and R3 are as defined above and R5 is H or a C1-C4-alkyl radical, C1-C8-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C4-alkoxy- C1-C4-alkyl, halocycloalkyl, formyl- C1-C3-alkyl, C(=0)C(=0)R4, where R4 is as defined above, is reacted with ozone in a suitable solvent from the group consisting of C1-C6-alcohols, nitriles, C1-C4-carboxylic acids or an anhydride thereof, C1-C6-alkyl acetates, chlorinated hydrocarbons, water and mixtures thereof and the peroxide solution obtained in this way is reduced and the desired N-acetylaminoacetophenone of the formula (I) is isolated, and also, if desired, conversion of the compound of the formula (I) into a compound of the formula (III) where R2 and R3 are as defined above.

Description

Process for preparing N-acetylaminoacetophenones and downstream products
The present invention relates to a process for preparing N-acetylaminoacetophenones and downstream products.
N-Acetylaminoacetophenones and their downstream products are valuable intermediates for preparing, for example, pharmaceuticals and agrochemicals.
A number of methods of preparing N-acetylaminoacetophenones are known from the literature. One variant is, for example, the oxidative cleavage of 2,3-dimethylindole (Journal of the Chemical Society, Perkin Transactions 2, (9), 1634-1640; 2001 ; Chemical Communications (Cambridge), (10), 869-870; 2000; Journal of Molecular Catalysis, 57(1 ), L9-L12; 1989; Journal of Molecular Catalysis, 32(3), 285-90; 1985) using various catalysts and solvents or the hydrogenation of 2-nitroacetophenone (Journal of Molecular Catalysis A: Chemical, 212(1-2), 127-130; 2004; Synthetic Communications, 33(17), 2985-2988; 2003; Journal of Organic Chemistry, 64(7), 2301-2303; 1999; Tetrahedron Letters, 35(23), 3965-6; 1994, etc.) and subsequent acetylation, once again using various catalysts and solvents. Disadvantages of these processes are the generally poor yield of product and the formation of undesirable by-products which makes complicated work-up and purification of the product necessary. Further disadvantages of these methods are the catalysts or catalytic systems used, which cannot be employed industrially since the ligands for the catalysts are not commercially available and, in addition, the catalysts used are toxic.
A further method of preparation is the ozonolysis of 2,3-dimethylindole in ethyl acetate or acetic acid/water. The work-up of the peroxides is carried out by hydrolysis in a basic medium. The product is worked up by extraction with ether. The disadvantages of the process are the low yields of from 10 to 57%, the basic hydrolysis of the peroxides which causes rearrangement of the peroxides and thus leads to phenolic by-products which are extremely toxic and the isolation of the product by extraction with ether since such an extraction cannot be carried out industrially because of the risk of explosion associated with ether solvents.
It is accordingly an object of the present invention to discover a process for preparing N-acetylaminoacetophenones and their downstream products, which makes it possible to prepare the desired compounds in yields which are higher than in the prior art and higher purities by a cheaper route.
The present invention accordingly provides a process for preparing N-acetylaminoacetophenones of the formula (I)
Figure imgf000004_0001
where R1 is a d-Cs-alkyl radical, Ci-Ce-alkylsulfinyl, CrC6-alkylsulfonyl, CrC4- alkoxy-CrC4-alkyl, halocycloalkyl, formyl-CrC3-alkyl or -C(=O)C(=O)R4, R2 is CrC4-alkyl, CrC6-alkylsulfinyl, CrC6-alkylsulfonyl, Ci-C4-alkoxy-Ci-C4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl, R3 is H, fluorine, chlorine, CrC4-alkyl or trifluoromethyl and R4 is hydrogen, CrCβ-alkyl, d-Cβ-alkoxy, C3-Cβ-cycloalkyl, wherein an indole of the formula (II)
Figure imgf000004_0002
where R2 and R3 are as defined above and R5 is H or a Ci-C4-alkyl radical, CrC6- alkylsulfinyl, Ci-C6-alkylsulfonyl, Ci-C4-alkoxy-C-ι-C4-alkyl, halocycloalkyl, formyl- CrC3-alkyl, C(=O)C(=O)R4, where R4 is hydrogen, CrCs-alkyl, Ci-C8-alkoxy or C3-Cβ-cycloalkyl, is reacted with ozone in a suitable solvent from the group consisting of d-Cβ-alcohols, nitriles, CrC4-carboxylic acids or an anhydride thereof, CrC6-alkyl acetates, chlorinated hydrocarbons, water and mixtures thereof and the peroxide solution obtained in this way is reduced to give the desired N-acetylaminoacetophenone of the formula (I).
N-Acetylaminoacetophenones of the formula (I) are prepared by the process of the invention.
In the formula (I), R1 is a CrC6-alkyl radical such as methyl, ethyl, propyl, isopropyl, n-, iso- and tert-butyl, pentyl and hexyl, or else Ci-C6-alkylsulfinyl, Ci-C6-alkylsulfonyl,
CrC4-alkoxy-Ci-C4-alkyl, halocycloalkyl, formyl-CrC3-alkyl or -C(=O)C(=O)R4 where R4 is hydrogen, Ci-Cs-alkyl, C-i-Cs-alkoxy or Ca-Cβ-cycloalkyl.
Preference is given to CrC4-alkyl radicals, and particular preference is given to the methyl radical.
R2 is CrC4-alkyl, Ci-C6-alkylsulfinyl, CrC6-alkylsulfonyl, Ci-C4-alkoxy-CrC4-alkyl, halocycloalkyl or formyl-Ci-C3-alkyl, preferably a Ci-C2-alkyl radical and particularly preferably a methyl radical.
R3 is H, fluorine, chlorine, trifluoromethyl or Ci-C^alkyl, preferably H.
The compound of the formula (I) can be monosubstituted or multiply substituted by
R3.
The preparation according to the invention of the N-acetylaminoacetophenones of the formula (I) is effected by ozonolysis in a suitable solvent.
Solvents which are suitable for the process of the invention are CrCβ-alcohols such as methanol, ethanol, n-propanol, butanol, glycol, etc., nitriles such as acetonitrile, benzonitrile, etc., CrC4-carboxylic acids or anhydrides thereof, e.g. acetic acid, propionic acid, etc., acetic anhydride, etc., CrC6-alkyl acetates such as ethyl acetate, propyl acetate, butyl acetate, etc., chlorinated hydrocarbons such as dichloro- methane, dichloroethane, dichlorobenzene, etc., N-methylpyrrolidone, dimethylform- amide, dimethylacetamide, water or mixtures thereof in any ratios. Preference is given to using CrC4-alcohols, CrC4-carboxylic acids and/or C1-C4- alkyl acetates, particularly preferably methanol and/or butyl acetate.
The ozonolysis is preferably carried out in a solvent mixture of CrC4-carboxylic acid and water, particularly preferably in a mixture of propionic acid and water. The volume ratio of the two solvents (carboxylic acid:water) is from 1 :100 to 100:1 , preferably 2:1.
The ozonization is carried out using an equivalent amount of ozone or using a certain excess of ozone up to about 2 equivalents at a temperature of from -8O0C to +4O0C, preferably from -400C to + 40C.
The ozone can be generated from pure oxygen or from industrial air (from 20 to 4% by volume of oxygen, balance inlet gases).
The ozonolysis can be carried out industrially in batch reactors, ozonolysis plants with circulation or in microreactors as described, for instance, in JP2004285001.
After the ozonolysis is complete, the reaction solution obtained in this way, which contains the corresponding peroxides, is reduced in a customary manner. This can be effected, for example, by addition of customary reducing agents such as dimethyl sulfide, thiodiethanol, thiourea, sodium sulfite, sodium thiosulfate, Zn/acetic acid, decomposition of the peroxides by boiling in an acidic medium, catalytic decomposition of the peroxides by means of transition metal catalysts as described in WO 04054950 or by catalytic hydrogenation with or without pH regulation, metering- in of peroxide and/or temperature regulation.
Desired Λ/-acetylaminoacetophenone is subsequently isolated from the reaction solution if desired. The isolation of the desired Λ/-acetylaminoacetophenone can be achieved by distilling off at least part of the solvent and subsequently crystallizing out the product in methanol at low temperatures or by admixing the mother liquor with nonpolar solvents such as pentane, heptane, hexane, special grades of petroleum spirit, petroleum ether, benzene, toluene, xylene, etc. The product is then recovered from the mother liquor by filtration and drying.
The process of the invention enables Λ/-acetylaminoacetophenones of the formula (I) to be obtained in higher yields compared to the prior art (increases by more than 50%) and high purities of up to 99.9% (GC-% by area) in a simple and inexpensive way.
The Λ/-acetylaminoacetophenones of the formula (I) prepared according to the invention can then, if desired, be converted in various downstream products such as substituted or unsubstituted 2-aminoacetophenones by removal of the Λ/-acetyl protective group by customary methods (e.g. lit.: Greene, Wutts; Protective Groups in Organic Synthesis, Wiley Interscience, Third Edition).
The conversion of the Λ/-acetylaminoacetophenones of the formula (I) into substituted or unsubstituted 2-aminoacetophenones of the formula (III)
Figure imgf000007_0001
where R2 is C-ι-C4-alkyl, CrCβ-alkylsulfinyl, CrC-β-alkylsulfonyl, CrC4-alkoxy-CrC4- alkyl, halocycloalkyl, formyl-Ci-C3-alkyl and R3 is H, fluorine, chlorine, CrC4-alkyl or trifluoromethyl, can be effected by removal of the Λ/-acetyl group in a strongly acidic medium. The present invention therefore further provides a process for preparing 2-aminoacetophenones of the formula (III)
Figure imgf000008_0001
where R2 is CrC4-alkyl, Ci-C6-alkylsulfinyl, CrC6-alkylsulfonyl, CrC4-alkoxy-Ci-C4- alkyl, halocycloalkyl, formyl-Ci-C3-alkyl and R3 is H1 fluorine, chlorine, CrC4-alkyl or trifluoromethyl, wherein the N-acetyl group of the compound of the formula (I)
Figure imgf000008_0002
where R1 is a CrC8-alkyl radical, CrC6-alkylsulfinyl, Ci-C6-alkylsulfonyl, C1-C4- alkoxy-CrC4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl or -C(=O)C(=O)R4, R2 is CrC4-alkyl, CrC6-alkylsulfinyl, CrC6-alkylsulfonyl, Ci-C4-alkoxy-CrC4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl, R3 is H, fluorine, chlorine, CrC4-alkyl or trifluoromethyl and R4 is hydrogen, CrC8-alkyl, CrC8-alkoxy, Ca-Ca-cycloalkyl, is removed at reflux temperature in a strongly acidic medium.
The Λ/-acetylaminoacetophenone used does not have to be isolated from the reaction solution but can be used directly as reaction solution for the removal of the N-acetyl group.
The removal of the N-acetyl group is carried out at a pH of 0-3. Acids suitable for producing the strongly acidic medium are, for example, HCI, sulfuric acid or other mineral acids, toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid and other and organic acids. The corresponding Λ/-acetylaminoacetophenone of the formula (I) is taken up in an acid/water mixture or in the pure acid and then boiled at reflux temperature.
To isolate the desired compound of the formula (III), the reaction mixture is cooled and a suitable base, for example dilute sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or magnesium hydroxide solution, is added so that a pH of 7-14, preferably 8-12, is set. The crude product can then be extracted by extraction with a suitable solvent. The product can also be distilled directly from the mixture after neutralization with the alkali at a suitable boiling point and/or steam volatility. The distillation can be carried out at atmospheric pressure or under reduced pressure. In the case of a steam distillation, steam at 1000C or superheated steam (temp. > 1500C) can be used.
Fine purification of the product can be carried out by means of fine distillation or by means of multiple recrystallization of the product.
Example 1) Preparation of 2-(Λ/-acetylamino)acetophenone bv ozonolvsis
7.25 g [0.05 mol] of 2,3-dimethylindole were taken up in 180 ml of methanol and 20 ml of butyl acetate. The solution was placed in a double-walled vessel and cooled to -200C. After a constant ozone/oxygen stream of 38 g/standard m3 had been established, the ozonolysis was commenced. After the ozonolysis was complete, the reaction solution was added dropwise to an ice-cooled methanolic dimethyl sulfide solution {3.4 g (4.1 ml), [0.055 mol] of dimethyl sulfide in 100 ml of methanol} over a period of 1 hour. The reaction solution was then warmed to room temperature and the solvent was subsequently distilled off. The residue was taken up in 100 ml of methanol and the product was crystallized out at 0°C.
Yield: 5.31 g (60% of theory), 99.8% (GC-% by area), sand-colored to light-brown powder 1H-NMR: 300 MHz (CDCI3); 2.22 (s, 3H); 2.65 (s, 3H); 7.12 (t, 1 H); 7.56 {t, 1 H); 7.83 (of, 1 H); 8.65 (of, 1 H)
13C-NMR: 75.47 MHz (CDCI3); 25.51 ; 28.59; 120.6; 121.6; 122.2; 131.6; 135.1 ; 169.5; 202.8
GC-MS (m/e): 177 [M+], 162, 144, 135, 120 (100%), 106, 92, 77, 65, 51 , 43
Example 2)
17.O g [0.117 mol] of 2,3-dimethylindole were taken up in 180 ml of methanol and 20 ml of butyl acetate. The solution was placed in a double-walled vessel and cooled to -2O0C. After a constant ozone/oxygen stream of 36 g/standard m3 had been established, the ozonolysis was commenced. After the ozonolysis was complete, the reaction solution was added dropwise to an ice-cooled methanolic thiodiethanol solution {15.7 g [0.128 mol] of thiodiethanol in 100 ml of methanol} over a period of 1 hour. The reaction solution was then warmed to room temperature and part of the solvent was subsequently distilled off (leaving 110 ml) and the product was crystallized out at 00C. The precipitated solid was filtered off with suction on a sintered glass filter (pore size 3) and washed with 25 ml of cyclohexane (technical grade) and subsequently dried under reduced pressure.
Yield: 9 g (50% of theory), 99.8% (GC-% by area), sand-colored, light-brown powder
1H-NMR: 300 MHz (CDCI3); 2.22 (s, 3H); 2.65 (s, 3H); 7.12 (., 1 H); 7.56 {t, 1 H); 7.83 (d, 1 H); 8.65 (d, 1 H)
13C-NMR: 75.47 MHz (CDCI3); 25.51 ; 28.59; 120.6; 121.6; 122.2; 131.6; 135.1 ; 169.5; 202.8
GC-MS (m/e): 177 [M+], 162, 144, 135, 120 (100%), 106, 92, 77, 65, 51 , 43 Example 3: 10.0 g [0.0689 mol] of 2,3-dimethylindole were taken up in 200 ml of methanol. The solution was placed in a double-walled vessel and cooled to -2O0C. After a constant ozone/oxygen stream of 36 g/standard m3 had been established, the ozonolysis was commenced. After the ozonolysis was complete, the reaction solution was added dropwise to an ice-cooled methanolic thiodiethanol solution {10.1 g [0.083 mol] of thiodiethanol in 100 ml of methanol} over a period of 1 hour.
The reaction solution was then warmed to room temperature, part of the solvent was distilled off (leaving 110 ml) and the product was crystallized out at 00C. The precipitated solid was filtered off with suction on a sintered glass filter (pore size 3) and washed with 25 ml of cyclohexane.
Yield: 7.3 g (60% of theory), 99.5% (GC-% by area), sand-colored, light-brown powder
1H-NMR: 300 MHz (CDCI3); 2.22 (s, 3H); 2.65 (s, 3H); 7.12 (t, 1 H); 7.56 (., 1 H); 7.83 (d, 1 H); 8.65 (of, 1 H)
13C-NMR: 75.47 MHz (CDCI3); 25.51 ; 28.59; 120.6; 121.6; 122.2; 131.6; 135.1 ; 169.5; 202.8
GC-MS (m/e): 177 [M+], 162, 144, 135, 120 (100%), 106, 92, 77, 65, 51 , 43
Example 4: Preparation of 2-aminoacetophenone from 2-(Λ/-acetylamino)acetophe- none
5 g of 2-(Λ/-acetylamino)acetophenone were taken up in 100 ml of 1.2N hydrochloric acid and stirred at reflux temperature for 6 hours. After cooling to room temperature, the pH was set to 10 by means of 40% strength sodium hydroxide and the reaction mixture was stirred with 100 ml of MTBE (MTBE = methyl tert-butyl ether). The organic phase was dried over sodium sulfate and evaporated on a rotary evaporator. This gave a light-brown oil. Yield: 2.7 g (69% of theory), reddish brown oil
1H-NMR: 300 MHz (CDCI3); 2.55 (s, 3H); 6.3 φrs, 2H); 6.28 (m, 2H); 7.24 {t, 1 H); 7.68 (f, 1 H)
13C-NMR: 75.47 MHz (CDCI3); 28, 115, 117, 132, 134, 170 GC-MS (m/e): 135 [M+], 120 (100%), 106, 92, 85, 77, 65, 52, 39

Claims

Claims:
1. A process for preparing N-acetylaminoacetophenones of the formula (I)
Figure imgf000013_0001
where R1 is a CrC8-alkyl radical, CrC6-alkylsulfinyl, Ci-C6-alkylsulfonyl, Ci-C4- alkoxy-CrC4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl or -C(=O)C(=O)R4, R2 is Ci-C4-alkyl, d-Ce-alkylsulfinyl, Ci-C6-alkylsulfonyl, Ci-C4-alkoxy-CrC4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl, R3 is H, fluorine, chlorine, CrC4-alkyl or trifluoro- methyl and R4 is hydrogen, C-i-Cβ-alkyl, C-i-Cβ-alkoxy, C3-C8-cycloalkyl, wherein an indole of the formula (II)
Figure imgf000013_0002
where R2 and R3 are as defined above and R5 is H or a CrC4-alkyl radical, d- Cβ-alkylsulfinyl, Ci-Cβ-alkylsulfonyl, Ci-C4-alkoxy-CrC4-alkyl, halocycloalkyl, for- myl-Ci-C3-alkyl, C(=O)C(=O)R4, where R4 is hydrogen, d-Cs-alkyl, Ci-C8-alkoxy or C3-C8-cycloalkyl, is reacted with ozone in a suitable solvent from the group consisting of CrCβ-alcohols, nitriles, CrC4-carboxylic acids or an anhydride thereof, CrC-6-alkyl acetates, chlorinated hydrocarbons, water and mixtures thereof and the peroxide solution obtained in this way is reduced to give the desired N-acetylaminoacetophenone of the formula (I).
2. The process as claimed in claim 1 , wherein methanol, ethanol, n-propanol, bu- tanol, glycol, acetonitrile, benzonitrile, acetic acid, propionic acid, acetic anhydride, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, dichloroethane or water or a mixture thereof is used as solvent.
3. The process as claimed in claim 1, wherein a mixture of a CrC6-alcohol and a Ci-Cβ-alkyl acetate is used as solvent.
4. The process as claimed in claim 1 , wherein the reaction is carried out at a temperature of from -8O0C to +400C.
5. The process as claimed in claim 1 , wherein the reduction of the peroxides is effected by addition of reducing agents selected from the group consisting of dimethyl sulfide, thiodiethanol, thiourea, sodium sulfite, sodium thiosulfate, Zn/acetic acid, by decomposition of the peroxides by boiling in an acidic medium, by catalytic decomposition of the peroxides by means of transition metal catalysts or by catalytic hydrogenation with or without pH regulation, metering-in of peroxide and/or temperature regulation.
6. The process as claimed in claim 1 , wherein the isolation of the N-acetylaminoacetophenone of the formula (I) is achieved by distilling off at least part of the solvent and subsequently crystallizing out the product in methanol at low temperatures or by admixing the mother liquor with nonpolar solvents selected from the group consisting of pentane, heptane, hexane, special grades of petroleum spirit, petroleum ether, benzene, toluene and xylene and subsequently filtering off and drying the product.
7. The process as claimed in claim 1 , wherein the N-acetylaminoacetophenone of the formula (I) is converted by removal of the N-acetyl protective group in a strongly acidic medium at reflux temperature into a compound of the formula (III)
Figure imgf000015_0001
where R2 is CrC4-alkyl, CrC6-alkylsulfinyl, Ci-C6-alkylsulfonyl, Ci-C4-alkoxy-Cr C4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl and R3 is H, fluorine, chlorine, C1-C4- alkyl or trifluoromethyl
8. A process for preparing 2-aminoacetophenones of the formula (III)
Figure imgf000015_0002
where R2 is Ci-C4-alkyl, Ci-C6-alkylsulfinyl, CrC6-alkylsulfonyl, Ci-C4-alkoxy-Cr C4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl and R3 is H, fluorine, chlorine, C1-C4- alkyl or trifluoromethyl, wherein the N-acetyl group of the compound of the formula
(I)
Figure imgf000015_0003
where R1 is a Ci-C8-alkyl radical, Ci-Cβ-alkylsulfinyl, Ci-Cβ-alkylsulfonyl, C1-C4- alkoxy-CrC4-alkyl, halocycloalkyl, formyl-Ci-C3-alkyl or -C(=O)C(=O)R4, R2 is CrC-4-alkyl, CrC6-alkylsulfinyl, CrC6-alkylsulfonyl, CrC4-alkoxy-CrC4-alkyl, halocycloalkyl, formyl-CrC3-alkyl, R3 is H, fluorine, chlorine, CrC4-alkyl or trifluoro- methyl and R4 is hydrogen, CrC8-alkyl, Ci-C8-alkoxy, C3-C8-cycloalkyl, is removed at reflux temperature in a strongly acidic medium.
9. The process as claimed in claim 7 or 8, wherein the removal of the N-acetyl group is carried out at a pH of 0-3.
10. The process as claimed in claim 7 or 8, wherein the compound of the formula (III) is isolated by adding a base to the reaction mixture after removal of the N-acetyl group so that a pH of 7-14 is set and subsequently separating off the compound of the formula (III) by extraction or distillation.
PCT/EP2006/008630 2005-09-30 2006-09-05 Process for preparing n-acetylaminoacetophenones and downstream products WO2007039034A1 (en)

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Citations (1)

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EP0549039B1 (en) * 1991-12-20 1995-08-09 MERCK SHARP & DOHME LTD. 3-Phenylureido-1,4-Benzodiazepinones and their use as cholecystokinin or gastrin antagonists
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