Process for producing 2-aminobenzophenone compound

Details Process for producing 2-aminobenzophenone compound Process for producing 2-aminobenzophenone compound

2001-01-22

2001-10-30

Richter, Johanni (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S315000, C564S321000, C564S328000

Reexamination Certificate

active

06310249

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing 2-aminobenzophenones which can be useful intermediates of cholesterol reducing agents (HMG-CoA reductase inhibitors), mental disorders agents and anti-inflammatory agents.
BACKGROUND ART
The quinoline compound represented by formula (3) is disclosed in JP-A-1-279866, EP-A-304063 and U.S. Pat. No. 5,011,930 as a useful cholesterol reducing agent (HMG-CoA reductase inhibitor), and the 2-aminobenzophenone represented by formula (2) (wherein X=4-F) is reported to be useful as its intermediate in Tetrahedron Letters, 1993, vol. 34, p.8267.
Likewise, the mental disorder agent represented by formula (4) and the anti-inflammatory agent represented by formula (5) are also synthesized via 2-aminobenzophenones. Therefore, establishment of an industrially advantageous process for their production is of great significance.
Some processes have been reported for production of 2-aminobenzophenones [review: Synthesis, 677 (1980)]. The process using anthranilic acid as the starting material which comprises formation of an acid chloride after protection of the amino group by a tosyl group and the Friedel-Crafts reaction followed by deprotection has been known long (Org. Synth. Coll. Vol. IV, 34 (1963), Scheme 1) and appreciated for the low raw material cost and the reliability. However, because of the use of concentrated sulfuric acid as the solvent essential for the last detosylation step, the process admittedly has a serious problem with waste liquor disposal from the industrial aspect. Conversely, this means that the production route is pretty fine only if this problem is solved.
wherein X is a hydrogen atom, a C
1-4
alkyl group or a halogen atom.
DISCLOSURE OF THE INVENTION
As a result of their extensive research to solve the above-mentioned problem, the present inventors found that heating in the presence of an excess of aluminum chloride subsequent to the Friedel-Crafts reaction facilitates detosylation as shown in Scheme 2 and have accomplished the present invention on the basis of the discovery. The process of the present invention also improves the total yield, for example to 64%, based on anthranilic acid having a tosyl-protected amino group, in the case of the compound (2) (X=4-F) which is an intermediate of the cholesterol reducing agent (HMG-CoA reductase inhibitor)represented by formula (3). A cutback in materials and a great improvement in production efficiency can be accomplished by conducting the three steps starting from the formation of the acid chloride in the same solvent continuously.
Namely, the present invention relates to a process for producing a 2-aminobenzophenone represented by formula (2) characterized by heating an arylsulfonamide represented by formula (1) in the presence of aluminum chloride.
The process of the present invention dispenses with the conventional need for concentrated sulfuric acid in detosylation and is advantageous in respect of waste liquor disposal. The process of the present invention also makes it possible to conduct the Friedel-Crafts reaction and detosylation without a break and contributes to a cutback in material and a great improvement in production efficiency in production of a medical intermediate represented by formula (2).
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the process of the present invention will be described.
As the reaction solvent used in the formation of the chloride of tosylanthranilic acid, although a halogenated aliphatic hydrocarbon such as dischloroethane could be used as disclosed in Org. Synth. Coll. Vol. IV mentioned above, it is advantageous in terms of efficiency to use a high-boiling substituted aromatic hydrocarbon (having a halogen atom or a nitro group as the substituent) such as ortho-dichlorobenzene so that the resulting phosphorus oxychloride can be distilled off at reduced pressure, leaving the solvent behind. The subsequent Friedel-Crafts reaction and detosylation reaction can be conducted directly in the solution of the acid chloride in the substituted aromatic hydrocarbon.
The formation of the acid chloride can be carried out at temperatures of from 0 to 100° C., but it is preferred to add phosphorus pentachloride at from 15 to 30° C. and then complete the reaction at elevated temperatures of from 70 to 90° C. The sequential Friedel-Crafts reaction and detosylation reaction are preferred to be carried out by adding aluminum chloride at from 15 to 30° C., continuing the reactions at from 40 to 60° C. and completing the reaction at elevated temperatures of from 70 to 90° C. Although from 1.1 to 1.2 times as many moles of aluminum chloride is sufficient for the Friedel-Crafts reaction, it is preferred to use from 2 to 4 times as many moles of aluminum chloride in order to proceed to the detosylation without a break. An excess of aluminum chloride, though not being influential in the reactions, would add to the burden of post-treatment. Conversely, shortage of aluminum chloride would be an obstacle to completion of the reactions.
In the meantime, it is advantageous in terms of efficiency to isolate and purify the 2-aminobenzophenone in the form of the methanesulfonate salt in case that contamination with the following by-product occurs.


REFERENCES:
patent: 3213139 (1965-10-01), Chase et al.
David A. Walsh. “The Synthesis of 2-Aminobenzophenone”. Synthesis, 1980; p 677-687.*
Theodora W. Greene. Protective Groups in Organic Synthesis; 1982; p 288, 293, and 331-334.

Affiliated with

Also associated with

Rating

Process for producing 2-aminobenzophenone 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 2-aminobenzophenone compound, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing 2-aminobenzophenone compound will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2580226