Method for producing oxindoles

Details Method for producing oxindoles Method for producing oxindoles

2002-06-26

2004-03-16

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06706890

ABSTRACT:

Oxindoles are valuable intermediates in the synthesis of pharmaceutical products, such as cardiac drugs or tyrosine kinase inhibitors which regulate skin growth.
J. Chem. Educ. 1993, 70 (4), p. 332 discloses that 2-oxindoles are prepared by a two-step reaction, the first step of which comprises reacting isatin with hydrazine hydrate in anhydrous methanol to give the intermediate isatin hydrazone and isolating and purifying the intermediate. In the second step, the purified and dried intermediate is subjected to a Wolf-Kishner reduction in an anhydrous ethanol solution in the presence of a strong base such as sodium ethoxide. The yields achieved by this preparation method are up to about 69%. However, the disadvantage of this variant is the necessity of isolating, purifying and drying the intermediate before the reduction step can take place. A further disadvantage is the use of expensive, anhydrous ethanol as solvent because of the readiness of sodium ethoxide to react with water. A further preparation variant is described by Synth. Commun. 1994, 24 (20), p. 2835-41. In this variant, isatin is first dissolved in pure hydrazine and then reacted with pure hydrazine under reflux to give 2-oxindole in yields of up to 76%. However, this method requires a large quantity of pure hydrazine which serves as solvent and as reagent. When pure hydrazine is used, there is known to be a risk of explosion on heating or on reaction with oxidizing agents, so that particular safety measures have to be taken. An improvement suggested by U.S. Pat. No. 5,973,165 comprises preparing 2-oxindoles by reacting isatin with hydrazine hydrate in the presence of a weak base as catalyst and in a polar solvent. In order to obtain the desired end product in pure form, after the end of the reaction, 2-oxindole (purity about 97%) is first extracted, the extract is dried and then dissolved in a suitable solvent, and activated carbon is then added to the solution to decolorize it. After filtering off the activated carbon, 2-oxindole is crystallized out of the solution and obtained in a purity of 99.5%. The yields which are obtained by this process according to Example 1 are around 85%, but otherwise from 52 to 72%.
It is an object of the present invention to provide a process which facilitates the preparation of oxindoles in high yields and purity while avoiding complicated purification steps.
The invention accordingly provides a process for preparing 2-oxindoles of the formula (II)
where R is H, CH
3
, phenyl or benzyl, R
1
is H, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyl, phenoxy, halogen, amino, nitro or hydroxy, by reacting the corresponding isatins of the formula (I)
in a polar solvent with hydrazine hydrate in the presence of a tertiary amine catalyst, characterized in that the isatin is converted to the corresponding isatin hydrazone at a temperature of from 15 to 185° C. which is directly reacted further by adding a diazabicyclooctane and/or diazabicycloundecane and/or ethyldiisopropylamine catalyst a temperatures of from 100 to 185° C. while distilling off the water of reaction formed to give the corresponding 2-oxindole of the formula which is then isolated by distilling off the solvent and crystallizing out of the reaction mixture.
The process according to the invention converts an isatin of the formula (I) to the corresponding 2-oxindoles of the formula (II). The isatins used as starting compound may be substituted in the nitrogen atom by H, CH
3
, phenyl or benzyl. Preference is given to the nitrogen atom being substituted by H. The starting compounds may also be substituted in positions 4, 5, 6 or 7 by H, C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, phenyl, phenoxy, halogen, amino, nitro or hydroxy. Preference is given to the H or OCH
3
substituents, and particular preference to H. The appropriate isatin is dissolved in a polar solvent as an initial charge. Useful solvents include alcohols having a boiling point above about 100° C. Examples thereof include C
4
-C
10
-alcohols such as butanol, hexanol, 2-ethylhexanol, etc. Preference is given to using hexanol or 2-ethylhexanol, more preferably 2-ethylhexanol. From a molar deficiency to a molar excess of hydrazine hydrate is then added. The quantity of hydrazine hydrate used is generally in a range from about 5% molar deficiency to a 5% molar excess. Preference is given to from a 3% molar deficiency to a 1% molar excess, and particular preference to from a 1% molar deficiency to an equimolar quantity. After the hydrazine hydrate is added, the reaction mixture is held at the reaction temperature to form the isatin hydrazone for from about 10 to 120 minutes, preferably from 30 to 100 minutes and more preferably from 40 to 80 minutes. The reaction temperatures is from 15 to 185° C., preferably from 20 to 100° C. and more preferably from 30 to 60° C.
The isatin hydrazone formed is not isolated from the reaction mixture, but is instead further processed directly. To this end, a tertiary amine catalyst is added. Examples of useful tertiary amines include diazabicyclo compounds such as diazabicyclooctane (DABCO) or diazabicycloundecene (DBU), or trialkylamines such as ethyldiisopropylamine. Preference is given to using DABCO as catalyst. The catalyst in the process according to the invention is added in a quantity of from 5 to 40 mol % based on the starting compound isatin. Preference is given to adding a catalyst quantity of from 10 to 30 mol %, more preferably from 15 to 25 mol %. The reaction temperature for this step is from 100 to 185° C., preferably from 120 to 160° C. and more preferably from 125 to 145° C. This results in nitrogen elimination. At the same time, the water of reaction resulting from the hydrazone formation is distilled off under atmospheric pressure and the reaction solution held at the reaction temperature until complete conversion. If desired, the water of reaction may already be withdrawn from the reaction mixture before the catalyst is added, for example by means of azeotropic distillation. A portion of the solvent is then distilled off to isolate the corresponding 2-oxindole. Preference is given to removing from about 50 to 90%, more preferably from about 60 to 80% of the solvent from the reaction mixture. The remaining reaction solution is slowly cooled to a temperature of from 0° C. to room temperature with stirring to crystallize the 2-oxindole. If desired, an ether such as methyl tert-butyl ether (MTSE) or diisopropyl ether (DIPE) may also be added before crystallization. The quantity added may be up to twice the quantity of the solvent remaining. The product is then filtered off, washed with the cold solvent, preferably that used in the reaction or the ether added before the crystallization, and dried.
The process according to the invention provides 2-oxindoles in high yields and high purity without requiring any complicated purification steps. Preference is given to using the process according to the invention for preparing unsubstituted 2-oxindole, which is obtained in a purity of up to 99.9 area % by GC.


REFERENCES:
patent: 5973165 (1999-10-01), Kuo et al.
Database HCA “Online!”, Chemical Abstracts Service, Columbus, Ohio, U.S.: Abstract No. 123:285775 XP002167820 (1995).

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