Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-01
2001-08-14
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S229000, C540S230000, C540S310000
Reexamination Certificate
active
06274730
ABSTRACT:
SPECIFICATION
1. Technical Field
The present invention relates to a process for preparing halogenated &bgr;-lactam compounds containing a halogenated penam derivative or halogenated cephem derivative, which are synthetic intermediates for medicine. As an example of halogenated &bgr;-lactam compounds obtained by the invention, there is 6,6-dibromopenicillanic acid which is an intermediate for Sulbactam which is a kind of antibacterial agents (JP-A-72115/1980).
2. Background Art
A conventional process for preparing halogenated &bgr;-lactam derivatives of the formula (4) by using &bgr;-lactam amino compounds of the formula (1), as a starting material, is disclosed in, for example, Volkmann J. Org. Chem. 47, 3344 (1982).
A process for preparing halogenated &bgr;-lactam compounds without employing organic solvent is disclosed in Clayton J. Chem. Soc. C 2123 (1969).
In the former process, it is however essential to use a halogenated organic solvent such as methylene chloride or carbon tetrachloride. A large scale use of such a halogenated organic solvent is severely limited in view of safety and environmental pollution problems. The drawbacks of using carbon tetrachloride are its cost and its difficult handling properties. Therefore, a process for preparing halogenated &bgr;-lactam compounds in the system using no organic solvent, is highly desired. The latter process employing organic solvent is however impractical because of its remarkably low yield, namely, 34%.
An object of the present invention is to provide a process with which halogenated &bgr;-lactam compounds are prepared at high yield and efficiency, in an industrially useful, inexpensive and safe manner, by using water as a reaction solvent, not employing any organic solvent causing many problems in view of safety and environmental pollution.
DISCLOSURE OF THE INVENTION
The present invention provides a process for preparing halogenated &bgr;-lactam compounds, characterized in that a lactam amino compound of the formula (1) is reacted with nitrous acid or nitrite in a slurry dispersion state in water, under acid condition in the presence of halogen molecules, thereby obtaining a halogenated &bgr;-lactam compound of the formula (4)
wherein n is an integer of 0 to 2; A is the formula (2) or (3); R
1
and R
2
are the same or different and are hydrogen atom, halogen atom, C
1
-C
3
alkyl group, C
2
-C
4
alkenyl group, C
2
-C
4
alkynyl group, nucleophilic group, or CH
2
R
3
; and R
3
is halogen atom or nucleophilic group
wherein A is as defined above; X
1
is hydrogen atom or halogen atom; and X
2
is halogen atom.
The present invention was accomplished when it was discovered that halogenated &bgr;-lactam compounds of the formula (4) could be prepared efficiently on a large scale, by reacting &bgr;-lactam amino compounds of the formula (1) in a slurry dispersion state in water, after various reaction conditions were considered in order to avoid the use of organic solvents causing many problems in view of safety and environmental pollution, and establish a simple and inexpensive process by using water as a main solvent.
Halogen atoms present in substituent R
1
, R
2
or R
3
in the invention are chlorine, bromine and iodine. Examples of C
1
-C
3
alkyl group are methyl, ethyl and propyl. Examples of C
2
-C
4
alkenyl group are vinyl, propenyl, allyl and butenyl. Examples of C
2
~C
4
alkynyl group are ethynyl, propargyl and butynyl.
As nucleophilic groups represented by substituent R
1
, R
2
or R
3
in the invention, there are, for example, aliphatic acyloxy groups having 2 to 4 carbon atoms, such as acetyloxy group, propionyloxy group, 3-oxobutyryloxy group, 3-carboxypropionyloxy group and 4-carboxybutyryloxy group; aromatic acyloxy groups such as mandelyloxy group and 2-carboxybenzoyloxy group; carbamoyloxy group; hydroxy group; and mercapto group. Alternatively, these nucleophilic groups may be substituted with an alkyl group having 1 to 3 carbon atoms, or aliphatic acyl group having 1 to 3 carbon atoms. Suitable number of substituents is usually 1 or 2.
Further to the above examples of nucleophilic groups represented by substituent R
1
, R
2
or R
3
in the invention, there is a heterocycle bonded through S, that is, heterocyclic thio group. Herein, the heterocycle is a five- or six-member ring containing 1 to 4 heteroatoms selected from O, S or N. Examples of these heterocycles are pyridyl group, pyridazinyl group, pyrazolyl group, thiazolyl group, thiadiazolyl group, triazolyl group and tetrazolyl group. These heterocycles may have a substituent, such as a lower alkyl group having 1 to 3 carbon atoms.
Halogen atoms represented by X
1
and X
2
of halogenated &bgr;-lactam compounds of the formula (4) in the invention are chlorine, bromine and iodine.
In the present invention, acid condition is obtained by adding acid. Examples of acid used are sulfuric acid, hydrohalogenic acid and nitric acid. The amount of acid used to the compounds of the formula (1) is usually 1 to 20 equivalents, preferably 1.5 to 6 equivalents. Examples of halogen molecules used in the invention are bromine, iodine and chlorine. The amount of halogen molecules used to the compounds of the formula (1) is usually 1 to 16 equivalents, preferably 2 to 6 equivalents. Suitable nitrites are sodium nitrite and potassium nitrite. The amount of nitrous acid or nitrite used to the compounds of the formula (1) is usually 1 to 12 equivalents, preferably 2 to 6 equivalents.
The reaction of the invention is usually conducted at atmospheric pressure, but it may be conducted under increased pressure, if required. The reaction temperature is preferably about −10 to 15° C., most preferably −5 to 6° C.
In the present invention, a slurry formed by a compound of the formula (1) and water, or powder of a compound of the formula (1), is preferably added in portions over an adequate time. The reaction time depends on the reaction temperature, substrate concentration and reagent equivalent number, but suitable reaction time is usually about 6 to 36 hours, most desirably 12 to 24 hours.
In the present invention, desired high purity &bgr;-lactam compounds can be obtained efficiently by conducting the reaction within a sealed- or unsealed-type container, and filtering a deposited crystal after the reaction is completed. The crystal can also be purified by a usual purification method, such as recrystallization.
REFERENCES:
patent: 4276285 (1981-06-01), Barth
Ikeda, Chem. Pharm. Bull. 36(1) 218, 1988.*
J. Org. Chem. (1982), 47, pp. 3344-3345, Volkmann et al.
Asai Hiroaki
Kawahara Ichirou
Shimabayashi Akihiro
Yaguchi Shigetoshi
Arent Fox Plotkin Kintner Kahn PLLC.
Berch Mark L.
Otsuka Kagaku Kabushiki Kaisha
LandOfFree
Process for producing halogenated &bgr;-lactam compound does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for producing halogenated &bgr;-lactam compound, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing halogenated &bgr;-lactam compound will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2451166