Purification of carboxaldehyde

Details Purification of carboxaldehyde Purification of carboxaldehyde

2000-10-10

2002-03-12

Geist, Gary (Department: 1623)

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

Organic compounds

Oxygen containing

C568S425000, C514S011400

Reexamination Certificate

active

06355843

ABSTRACT:

This invention relates to the removal of impurities from 4′-chloro-4-biphenylcarboxaldehyde, a raw material used in the manufacture of ND
DISACC
-4-(4-chlorophenyl) benzyl)A82846B, a glycopeptide antibiotic used to combat vancomycin resistant infections. A82846B is a fermentation product isolated from the culture broth of
Amycolatopsis orientalis
, which produces a mixture of closely related co-fermentation factors, A82846B being identified as the major antibacterial agent in the mixture. A82846B is reductively alkylated with 4′-chloro-4-biphenylcarboxaldehyde to form ND
DISACC
-4-(4-chlorophenyl)benzyl) A82846B. By reducing the impurity level of the aldehyde raw material, there is seen an increase in overall yield, purity, and safety of the final antibiotic product.
The present invention provides an improved process for the removal of impurity from the synthesized 4′-chloro-4-biphenylcarboxaldehyde. The invention further provides a process for purifying 4′-chloro-4-biphenylcarboxaldehyde which comprises reacting 4′-chloro-4-biphenylcarboxaldehyde with sodium bisulfite in an aqueous/acetonitrile solution having an acetonitrile concentration sufficient to cause the bisulfite adduct to precipitate, isolating the bisulfite adduct precipitate from the solution, mixing the isolated bisulfite adduct in an aqueous/acetonitrile solution having a water concentration sufficient to cause the regenerated aldehyde to precipitate, and converting the bisulfite adduct to 4′-chloro-4-biphenylcarboxaldehyde.
The bisulfite adduct is represented by the formula:
and shall be referred to herein as the bisulfite adduct.
This type of aldehyde purification is historically performed in an aqueous/alcohol solution, see Horning, E. C.,
Organic Synthesis
, Collective Vol. 3, 438-440 (1955). Aqueous alcohol can be used as solvent in the present invention, but filtration of the novel bisulfite adduct and regenerated aldehyde is difficult and not commercially viable. In an improved embodiment of the present invention, aqueous acetonitrile is used. Use of this solvent allows better yields and purity of the purified aldehyde.
When reacting 4′-chloro-4-biphenylcarboxaldehyde with sodium bisulfite, the ratio of sodium bisulfite to 4′-chloro-4-biphenylcarboxaldehyde is not critical. The ratio can range from 1:1 to 10:1 sodium bisulfite to 4′-chloro-4-biphenylcarboxaldehyde. A preferred ratio for this reaction is from about 1:1 to about 1.3:1 sodium bisulfite to 4′-chloro-4-biphenylcarboxaldehyde. The solvent is not critical, so long as the bisulfite adduct precipitates. Aqueous methanol can be used, but aqueous acetonitrile has been found to be preferred. In this preferred embodiment, the ratio of acetonitrile to water during this reaction can range from about 2:1 to about 13:1 acetonitrile to water. A preferred range would be from about 5:1 to 7:1 acetonitrile to water. The temperature for this reaction is not critical and can range from about 0° C. to about 100° C. The reactants are typically mixed at about 45° C. to about 55° C. and then cooled to about 15° C. to about 25° C.
When mixing the isolated bisulfite adduct in an solution and converting the bisulfite adduct to 4′-chloro-4-biphenylcarboxaldehyde, the solvent is not critical, so long as the regenerated aldehyde precipitates. Aqueous methanol can be used, but aqueous acetonitrile has been found to be preferred. In this preferred embodiment, the ratio of acetonitrile to water during this reaction can range from about 1:1 to about 1:5 acetonitrile to water. A preferred range would be from about 1:3 to about 1:5 acetonitrile to water. The reaction typically is done at ambient temperature from about 15° C. to about 25° C. The pH of the solution during the reaction can range either acidic, 0-3, or basic, 10-14. A preferred pH range would be from about 12 to about 14.
Examples 1 and 2 show a better yield of aldehyde when the conversion of bisulfite adduct to 4′-chloro-4-biphenylcarboxaldehyde is done in a aqueous/acetonitrile solution under basic conditions. Examples 2 and 3 monitor the impurity 4,4′-dichlorobiphenyl, referred to hereafter as 4,4′-DCBP, a polychlorinated biphenyl by definition. Example 3 shows a complete removal of 4,4′-DCBP in the aqueous/acetonitrile under basic conditions.


REFERENCES:
patent: 4065505 (1977-12-01), Kim et al.
patent: 4075248 (1978-02-01), Marshall et al.
patent: 4162269 (1979-07-01), Mizutani et al.
patent: 5840684 (1998-11-01), Cooper et al.
Allen et al, Synergic Aldehyd, Organic Synthesis Colle3ction, vol. 4, pp. 866, 1963.

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