Process for the synthesis of...

Organic compounds -- part of the class 532-570 series – Organic compounds – Halogen containing

Reexamination Certificate

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C570S206000

Reexamination Certificate

active

06255545

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of 3,5-bis(trifluoromethyl)bromobenzene (CAS 328-70-1) which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The preparation of 3,5-bis(trifluoromethyl)bromobenzene by bromination of 1,3-bis(trifluoromethyl)benzene has been described various references. See for example: (a) Porwisiak, J; Schlosser, M.
Chem. Ber.,
129(2), 233 (1996); (b) Kunshenko, B. V.; Omarov, V. O.; Muratov, N. N.; Mikhailevskii, S. M.; Yagupol'skii, L. M.
Zh. Org. Khim.,
27(1), 125 (1991); (c) Larionova, Y. A.; Ponomarev, A. I.; Klebanskii, A. L.; Zaitsev, N. B.; Kol'tsov, A. I.; Motsarev, G. V.; Rozenberg, V. R.
Zh. Prikl. Khim.,
46(9), 2012 (1973); (d) Furumata, T. (Central Glass Company, Ltd.) JP 9067297-A2 [J09067297] 97.03.11; Filing Date Aug. 28, 1995; (e) Suzuki, H. (Nissan Chemical Industries, Ltd., Japan) JP 9169673-A2 [J09169673] 97.06.30 Heisei; Filing Date Dec. 22, 1995. These references describe the preparation of 3,5-bis(trifluoromethyl)bromobenzene by brominating 1,3-bis(trifluoromethyl)benzene utilizing either N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin (DBH) in sulfuric acid or trifluoroacetic acid. The yields are quoted in the 90% range with isomeric and bis-brominated byproducts amounting to 5-10%. Efforts to repeat the procedures using methods with sulfuric acid as disclosed therein led to inconsistent yields of the desired product.
The general processes disclosed in the art for the preparation of 3,5-bis(trifluoromethyl)bromobenzene result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 3,5-bis(trifluoromethyl)bromobenzene in relatively higher yield.
In accordance with the present invention, the use of acetic acid and/or a faster rate of stirring for the bromination of 1,3-bis(trifluoromethyl)benzene in sulfuric acid results in a more selective bromination of the starting material with higher yields of the product and lower amounts of bis-brominated byproducts.
It will be appreciated that 3,5-bis(trifluoromethyl)bromobenzene is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of 3,5-bis-(trifluoromethyl)bromobenzene which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of 3,5-bis(trifluoromethyl)bromobenzene. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of 3,5-bis(trifluoromethyl)bromobenzene of the formula:
The general process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene is as follows:
In a highly preferred embodiment, the present invention is directed to the preparation of 3,5-bis(trifluoromethyl)bromobenzene by the reaction of 1,3-bis-(trifluoromethyl)benzene with 1,3-dibromo-5,5-dimethylhydantoin in a mixture comprising glacial acetic acid and 96% sulfuric acid.
In accordance with the present invention, the use of acetic acid and/or a high rate of mixing in this reaction system increases solubilization of the starting material and results in less sensitivity to stirring parameters, as well as increased regioselectivity with respect to the position of bromination.
An embodiment of the present invention concerns a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene of the formula:
which comprises:
treating a reaction mixture which comprises sulfuric acid, acetic acid, and 1,3-bis(trifluoromethyl)benzene of the formula:
with a brominating agent to give 3,5-bis(trifluoromethyl)bromobenzene.
A preferred embodiment within the present invention concerns a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene of the formula:
which comprises:
treating a reaction mixture which comprises concentrated sulfuric acid, glacial acetic acid, and 1,3-bis(trifluoromethyl)benzene of the formula:
with a brominating agent selected from: N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin, to give 3,5-bis(trifluoromethyl)bromobenzene.
Although numerous brominating agents may be employed in this process, N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin (DBH) are preferred, and 1,3-dibromo-5,5-dimethylhydantoin is more preferred.
This process is carried out in a solvent which comprises sulfuric acid and acetic acid, and which may additionally comprise water. The preferred solvent system is a mixture of sulfuric acid and acetic acid, and a more preferred solvent system is a mixture of concentrated sulfuric acid and glacial acetic acid. In the present invention it is preferred that the ratio of sulfuric acid:acetic acid is approximately 5:1 to 7:1 (v:v), and it is more preferred that the ratio of sulfuric acid:acetic acid is approximately 6:1 (v:v). In the present invention it is preferred that the sulfuric acid is added to the acetic acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stirring).
In the present invention it is preferred that the ratio of the sulfuric acid/acetic acid to the 1,3-bis(trifluoromethyl)benzene substrate is approximately 2:1 to 1:2 (v:v). In the present invention it is more preferred that the ratio of the sulfuric acid/acetic acid to the 1,3-bis(trifluoromethyl)benzene substrate is approximately 1.5:1 (v:v). In the present invention it is preferred that the 1,3-bis(trifluoromethyl)benzene is added to the sulfuric acid:acetic acid at a controlled rate with cooling and rapidly mixing (such as with mechanical stirring).
In the present invention it is preferred that the reaction mixture is rapidly mixed (such as with mechanical stirring) and cooled upon treatment with the brominating agent. In the present invention it is preferred that the brominating agent is added to rapidly mixed reaction mixture which comprises sulfuric acid, acetic acid, and 1,3-bis(trifluoromethyl)benzene. In the present invention it is also preferred that the brominating agent is added to the reaction mixture in a controlled manner as individual portions.
The preferred temperature range following addition of the brominating agent is between about 10 and 70° C., a more prefered reaction temperature range is between about 40 and 50° C., and the most preferred temperature is about 45° C.
In a preferred embodiment, 1,3-bis(trifluoromethyl)benzene is brominated with N,N′-dibromo-5,5-dimethylhydantoin in sulfuric acid/acetic acid at 45° C. The reaction mixture is then diluted into cold water, and the phases are separated, washed with aqueous sodium hydroxide (preferably 5 N sodium hydroxide) and allowed to separate to produce 3,5-bis(trifluoromethyl)bromobenzene.
The product may contain approximately 2.6% isomeric impurities (which typically include 1,2-dibromo-3,5-bis(trifluoromethyl)benzene, 1,4-dibromo-3,5-bis(trifluoromethyl)bromobenzene, as well as small amounts of 2,4bis(trifluoromethyl)bromobenzene, 2,6-bis(trifluorome

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