Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-06-08
2002-03-05
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S426000, C568S492000
Reexamination Certificate
active
06353140
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to a process for the purification of cyclopropanecarboxaldehdye (CPCA) which contains crotonaldehyde impurity by chemical treatment. More specifically, this invention pertains to a CPCA purification process wherein CPCA containing crotonaldehyde impurity is treated with a base at elevated temperature to convert the crotonaldehyde to one or more higher boiling compounds. CPCA substantially free of crotonaldehyde may be recovered by distillation. Alternatively, CPCA containing crotonaldehyde impurity may be treated with a base at elevated temperature to convert the crotonaldehyde to one or more higher boiling compounds followed by conversion of the CPCA to another compound which subsequently is separated from the higher boiling compounds.
BACKGROUND OF THE INVENTION
CPCA, 2,5-dihydrofuran (2,5-DHF), and 2,3-dihydrofuran (2,3-DHF) are important synthetic building blocks for organic chemical synthesis. CPCA is useful for introduction of the cyclopropane group into chemical compounds useful as human and veterinary drugs and pesticides. See, for example, U.S. Pat. No. 4,275,238, and European Patent Publications EP 237,955 A2, and EP 430,847 A1. CPCA is especially useful in the synthesis of cyclopropylacetylene which is an essential reagent in the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, a useful human immunodeficiency virus (HIV) reverse transcriptase inhibitor [U.S. Pat. Nos. 5,955,627, 6,049,019, and 6,072,094; Wang, et al.,
J. Org. Chem
., 65, 1889 (2000)]. 2,3-DHF is useful in the production of CPCA and for protection of alcohols and carboxylic acids [e.g., WO 99/00377; Mattson and Rapoport,
J. Org. Chem
., 61, 6071 (1996)]. 2,5-DHF is useful for the production of 2,3-DHF and tetrahydrofuran (e.g., U.S. Pat. No. 4,962,210).
CPCA is derived from 1,3-butadiene by a sequence of four reactions. Monoepoxidation of 1,3-butadiene produces 3,4-epoxy-1-butene (EPB) as described in U.S. Pat. Nos. 4,897,498 and 4,950,773. This epoxide is isomerized to 2,5-DHF (U.S. Pat. Nos. 5,082,956 and 5,315,019) which is isomerized to 2,3-DHF (U.S. Pat. Nos. 5,254,701 and 5,536,851). Finally, 2,3-DHF is isomerized to CPCA (C. L. Wilson,
J. Amer. Chem. Soc
., 69, 3002 (1947) and U.S. Pat. No. 5,502,257).
Production of CPCA, 2,5-DHF, and 2,3-DHF often results in the co-production of low levels of the unwanted side-product crotonaldehyde (CH
3
CH═CHCHO). This material is isomeric with EPB, 2,5-DHF, 2,3-DHF and CPCA. For some purposes the mixture of crotonaldehyde with CPCA, 2,5-DHF or 2,3-DHF can be used in the next process step. However, it is often necessary to produce CPCA essentially free of crotonaldehyde. In mixtures with 2,5-DHF (bp 66° C.) and/or 2,3-DHF (bp 55° C.), crotonaldehyde (bp 104° C.) can be removed by fractional distillation due to its significantly higher boiling point. However, CPCA (bp 100° C.) is virtually impossible to separate from crotonaldehyde by fractional distillation due to its similar boiling point. As aldehydes, CPCA and crotonaldehyde have similar chemical reactivities thereby reducing the possibilities for using CPCA/crotonaldehyde mixtures in the production of CPCA derivatives. Purification of CPCA, therefore, presents an especially important and difficult problem.
U.S. Pat. No. 5,471,003 describes a process for the purification of CPCA contaminated with crotonaldehyde by the selective hydrogenation of the crotonaldehyde to butyraldehyde followed by distillation to separate the butyraldehyde from the cyclopropanecarboxaldehyde. However this distillation is difficult, especially when water is present in the mixture. For these reasons there is a need for an effective and easily practiced process to remove crotonaldehyde from CPCA.
McCombs, U.S. Pat. No. 6,103,943 describes a process for the production of 3-buten-1-ol by the reduction of 3,4-epoxy-1-butene. The process also produces crotonaldehyde as an impurity. The conversion of crotonaldehyde in the mixture to a high-boiling imine with a stoichiometric amount of a primary or secondary amine permits isolation of pure 3-buten-1-ol by distillation. The McCombs patent also mentions the conversion of crotonaldehyde to its dimer by the addition of an alkali metal hydroxide or carbonate to the crude 3-buten-1-ol product mixture.
SUMMARY OF THE INVENTION
It has been discovered that crotonaldehyde present as an impurity in CPCA reacts selectively upon treatment with base to form higher boiling materials or derivatives. The present invention, therefore, provides a process which comprises contacting a mixture comprising CPCA and crotonaldehyde with a base selected from secondary amines, alkali metal hydroxides, alkali metal carbonates, alkaline earth hydroxides, alkaline earth carbonates and basic ion exchange resins at elevated temperature whereby crotonaldehyde is converted to high boiling materials or derivatives, i.e., derivatives having a boiling point significantly above the boiling point of CPCA, provided that the CPCA remains substantially unconverted. That is, the base converts the crotonaldehyde to high boilers preferentially to the CPCA. For example, less than about 15% of the CPCA is converted to other materials; preferably, less than about 10% and more preferably less than about 5% of the CPCA is converted. The present invention includes an economical and effective means for the purification of CPCA contaminated with crotonaldehyde by the selective conversion of the crotonaldehyde to one or more higher boiling materials followed by distillation. This second embodiment concerns a process for the purification of CPCA containing crotonaldehyde impurity which comprises the steps of:
(1) contacting a mixture comprising CPCA and crotonaldehyde with a base selected from secondary amines, alkali metal hydroxides, alkali metal carbonates, alkaline earth hydroxides, alkaline earth carbonates and basic ion exchange resins at elevated temperature; and
(2) distilling the mixture resulting from step (1) to recover CPCA substantially free of crotonaldehyde as a distillate. In the process for the purification of CPCA containing crotonaldehyde as an impurity, all, or essentially all, of the crotonaldehyde reacts selectively with itself to form crotonaldehyde derivatives having boiling points significantly higher than the boiling point of CPCA. Thus, CPCA can be separated readily from the crotonaldehyde derivatives to recover CPCA substantially free of crotonaldehyde.
In another embodiment of the present invention, a mixture comprising CPCA and crotonaldehyde is treated with a base at elevated temperature to convert the crotonaldehyde to high boiling materials or derivatives, then converting the CPCA to a CPCA-derivative, i.e., another compound derived directly or indirectly from CPCA, and distilling or crystallizing a mixture of the CPCA-derivative and high boiling crotonaldehyde derivatives to recover the CPCA-derivative substantially free of crotonaldehyde as a distillate or solid. This third embodiment of the invention is directed to a process for the preparation and recovery of a CPCA-derivative wherein CPCA containing crotonaldehyde impurity is used as a reactant which comprises the steps of:
(i) contacting a mixture comprising CPCA and crotonaldehyde with a base selected from secondary amines, alkali metal hydroxides, alkali metal carbonates, alkaline earth hydroxides, alkaline earth carbonates and basic ion exchange resins at elevated temperature whereby crotonaldehyde is converted to one or more high boiling derivatives, provided that the CPCA remains substantially unconverted; and
(ii) reacting the CPCA-containing mixture of step (i) with a reactant which reacts with CPCA to form a CPCA derivative but does not react, or does not react significantly, with the high boiling crotonaldehyde derivatives of step (i).
The CPCA derivative produced in step (ii) may be separated from the high boiling crotonaldehyde derivative by distillation or crystallization. The reaction contemplated by step (ii) no
Falling Stephen Neal
Large Shannon Eugene
Maleski Robert Joseph
Blake Michael J.
Eastman Chemical Company
Graves Bernard J.
Padmanabhan Sreeni
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