Halogenating agent and process for halogenating hydroxyl group

Details Halogenating agent and process for halogenating hydroxyl group Halogenating agent and process for halogenating hydroxyl group

1999-10-13

2001-02-27

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S354000, C540S217000, C546S326000, C546S327000, C554S150000, C560S022000, C564S278000, C568S929000, C570S181000, C570S185000, C570S187000

Reexamination Certificate

active

06194567

ABSTRACT:

TECHNICAL FIELD
The invention relates to a novel halogenating agent and method of halogenating hydroxyl group.
BACKGROUND ART
The novel halogenating agent and halogenating method of the invention enable high purity and high yield production of halogenated aromatic compounds, halogenated heterocyclic compounds and halogenated cholesterol derivatives, each being useful for an intermediate for medicine and agricultural chemical, and also 7-acylamide-3-halocephem derivative useful for general cephem antibiotics used by oral administration.
As a method of halogenating hydroxyl group, it has been conventionally proposed to employ for example dimethyl haloiminium compound and diphenyl haloiminium compound, as a halogenating agent.
More specifically, Journal of Synthetic Organic Chemistry, 1980, 746 discloses a method in which dimethylformamide is reacted with oxalyl dichloride to obtain dimethyl chloroiminium compound, and hydroxyl group bonded to a straight-chain alkyl group is chlorinated by using the above chloroiminium compound. With this method, a 90% yield is achieved, however, such a high yield is not always obtained. Also, the purity of the resulting halogenide is about 80% at the most, and the reaction time is extremely long, namely, 24 hours.
Journal of the Pharmaceutical Society of Japan 85(6), 544-546 (1965) describes a method in which dimethylformamide is reacted with thionyl chloride to form dimethyl chloroiminium compound, and phenolic hydroxyl group is chlorinated by using this compound. This method, however, has the drawbacks that it is not applicable to a compound which has on its benzene ring a substituent liable to be chlorinated, except for hydroxyl group, and that since the reaction system becomes strongly acidic condition, application is limited to one which can be separated outside of the system, as a crystal, immediately after the termination of the reaction, thus being impractical.
Dimethyl haloiminium compound is also used in preparing N-acyl-4-chloro-1,2-dihydropyridine which is an intermediate for alkaloid [J. Org. Chem. (1993) 58, 7732-7739]. This method is, however, impractical because the reaction time is markedly long, namely, three days.
Further, it has been proposed to use dimethyl haloiminium compound in producing a 3-halogenated cephem derivative which is an intermediate for cephalosporin antibiotic used by oral administration (JP-A-116095/1974) With this method, however, the yield is as low as about 60% because the 7-position acyl group is also chlorinated, in addition to the desired 3-position hydroxyl group.
In the meantime, it is known a method with which the hydroxyl group bonded to a straight-chain alkyl group, the hydroxyl group bonded to a straight-chain alkenyl group, and the hydroxyl group of cholesterol, are chlorinated by using diphenyl chloroiminium chloride [Chemistry Letters, pp1173-1174 (1984)]. This method, however, fails to overcome the drawbacks that the reaction time is long, the purity of the resulting halogenide is low, and high yield is not ensured. Furthermore, this method is unsatisfactory for industrial production because the yield does not exceed 90% when chlorinating cholesterol or the compounds containing a double bond or ether linkage within the straight-chain molecules.
An object of the invention is to overcome the drawbacks of long reaction time, unstable yield, low purity, and the formation of by-product obtained by halogenation of other than the desired hydroxyl group, which drawbacks being common to the methods of halogenating hydroxyl group by using dimethyl haloiminium compound or diphenyl haloiminium compound.
DISCLOSURE OF THE INVENTION
The invention relates to halogenating agents of the following formula (1), and a method of halogenating hydroxyl group
wherein R
1
and R
2
, which may be the same or different, each is ethyl, propyl, isopropyl, butyl, isobutyl or allyl; X is chlorine atom or bromine atom; and Y is chlorine ion, bromine ion, dichlorophosphate ion, dibromophosphate ion, chlorosulfonate ion, bromosulfonate ion, chlorooxalate ion or bromooxalate ion.
In accordance with the invention, compounds obtained by halogenation of hydroxyl group can be produced at high yield and high purity in a short period of time.
After the present inventor conducted intensive research to solve the problems in the prior art, it has been found to overcome a variety of drawbacks acknowledged in the case of using dimethyl haloiminium compound by conducting halogenation of hydroxyl group by using a specific dialkylhaloiminium compound, namely, the compound in which alkyl part has 2 to 4 carbon atoms, thereby enabling to produce the desired halogenide at high yield and high purity in a short period of time.
More specifically, when the halogenating agent of the invention is used, only hydroxyl group is selectively halogenated, irrespective of the structure of a hydroxyl group containing compound and the kind of a substituent other than hydroxyl group. For example, in the reaction with 3-hydroxycephem compound described in JP-A-116095/1974, the acyl group at the 7-position and lactam part are not halogenated, and only the hydroxyl group at the 3-position is selectively halogenated. Therefore, the desired halogenide can be produced at high yield and high purity, and the reaction time is short.
It has also been found by the inventor that the combined use of a dimethyl haloiminium compound and a specific organic sulfur compound can also overcome the drawbacks of dimethyl haloiminium compound and only hydroxyl group is selectively halogenated, thus enabling to produce the desired halogenide at high yield and high purity in a short period of time.
Description will be made of the respective groups indicated in the present specification.
Examples of halogen atom are chlorine atom and bromine atom.
Examples of C
1
-C
4
alkyl group are straight-chain or branched-chain alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
Examples of C
2
-C
8
alkenyl group are straight-chain or branched-chain alkenyl groups, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, isobutenyl, isopentenyl, octenyl and isoprenyl.
Examples of monocyclic or polycyclic aromatic hydrocarbon group are phenyl group, naphthalene group and anthracene group. Examples of monocyclic or polycyclic heterocyclic hydrocarbon group are furyl group, pyrrolyl group, thienyl group, oxazolyl group, imidazolyl group, thiazolyl group, pyridyl group, pyrazyl group, pyridazyl group, morpholinyl group, quinolyl group, isoquinolyl group, indole group, indolizyl group, penicillin residue and cephalosporin residue. Examples of steroid residue are androsterone residue, testosterone residue and cholesterol residue.
Examples of C
1
-C
15
alkyl group are straight-chain, branched-chain or cyclic alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, hexyl, cyclohexyl and pentadecanyl.
Examples of substituted oxycarbonyl group are bromobutoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl and allyloxycarbonyl.
Examples of acyl group are formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, toluoyl and naphthoyl.
Exemplary of the protected amino group are amido groups such as phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, thienylacetamido, phenylacetoxyacetamido, &agr;-oxophenylacetamido, benzamido, p-methylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, phenylglycylamido, phenylglycylamido having protected amino, p-hydroxyphenylglycylamido, p-hydroxyphenylglycylamido having protected amino and/or protected hydroxyl, etc.; imido groups such as phthalimido, nitrophthalimido, etc., in addition to the groups disclosed in Theodora W. Greene, 1981, “Protec

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