Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
1999-09-09
2001-01-23
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S170000, C544S175000, C514S230800, C514S231200, C514S239500
Reexamination Certificate
active
06177564
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of a 1,4-oxazin-2-one derivative 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 N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one which is an intermediate in the preparation of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
U.S. Pat. No. 5,719,147 describes the preparation of benzyloxazinones by a two-step process starting from an optically pure glycine derivatives. Control of process parameters (e.g. reaction time, temperature, moisture content) is necessary to prevent racemisation in these steps. With reference to Example 59 in U.S. Pat. No. 5,719,147, N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one [3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone] is prepared in several steps as follows:
The optically pure (S)-(4-fluorophenyl)glycine is disclosed as having been prepared by means of a four-step asymmetric synthesis process which is based upon the procedure for the asymmetric synthesis of &agr;-amino acids described by D. A. Evans et al.,
J. Am. Chem. Soc.,
(1990) 112, 4011-4030. The complexity of this four-step process combined with the sensitive nature of the protection and double alkylation reactions to give the desired 1,4-oxazin-2-one, renders these prior art syntheses impracticable when attempted on anything other than a laboratory scale.
U.S. Pat. No. 5,668,280 describes an alternative procedure which utilizes racemic N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one as starting material and in a minimum of steps afforded product of high enantiomeric purity in high yield. Resolution of racemic N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one was achieved using (−)-3-bromocamphor-8-sulphonic acid (also referred to as (−)-3-BCS) in the presence of a racemising agent. While this is an effective method for obtaining substantially pure N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one, the use of (−)-3-BCS on a large scale is expensive. Furthermore, large quantities of (−)-3-BCS are not readily available.
It will be appreciated that chiral 3-(4-fluorophenyl)-1,4-oxazin-2-one derivatives are important intermediates for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one 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.
General processes and intermediates have been disclosed in the art for the preparation of 5-substituted oxazinones (see
J. Chem. Soc. Perkin Trans.,
1, 3587 (1994);
Tetrahedron,
51, 9179 (1995);
Tetrahedron Lett.,
36, 7081 (1995);
Bull. Chem. Soc. Jpn.,
65, 2359 (1992);
J. Org. Chem.,
57, 5462 (1992);
Tetrahedron Lett.,
37, 4001 (1996)). The oxazinones prepared by these published methods have substitution at the 5-position of the oxazinone ring. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of oxazinones which are unsubstituted at the 5-position of the oxazinone ring.
Accordingly, the subject invention provides a process for the preparation of N-benzyl-3(4-fluoro-phenyl)-1,4-oxazin-2-one via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of N-benzyl-3(4-fluorophenyl)-1,4-oxazin-2-one, and the useful intermediates obtained therein. 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 N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one of the formula:
The general process for the preparation of N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one is as follows:
An embodiment of the present invention concerns a process for the preparation of a compound of the structural formula 4:
which comprises:
a) treating 4-fluorobenzaldehyde of the structural formula 1:
with sodium metabisulfite in a solvent followed by reaction with sodium cyanide or potassium cyanide to give 1-cyano-1-(4-fluorophenyl)methanol of the structural formula 2:
b) followed by treating the compound of the structural formula 2 with N-benzylethanolamine of the structural formula 3:
to give the compound of structural formula 4.
Although numerous cyanide sources may be employed in this process, sodium cyanide and potassium cyanide are preferred, and sodium cyanide is most preferred. This process may be carried out in a solvent such as an alcohol, such as methanol, ethanol, isopropanol, n-propanol or water, or a mixture thereof. The preferred solvent system is methanol/water or isopropanol/water, and the most preferred solvent is methanol/water. The preferred temperature range for the reaction of 4-fluorobenzaldehyde with sodium metabisulfite and sodium cyanide is between about 10 and about 50° C., a more prefered reaction temperature range is between about 20 and about 40° C., and the most preferred temperature is about 30° C. The preferred temperature range for the reaction of the compound of structural formula 2 with N-benzyl-ethanolamine is between about 10 and about 50° C., a more prefered reaction temperature range is between about 20 and about 40° C., and the most preferred temperature range is about 30±2° C.
In the interest of efficiency, it is preferred that this reaction be conducted in situ without isolation of the compound of structural formula 4 following its preparation by the aforementioned process.
Another embodiment within the present invention concerns a process for the preparation of N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one of the structural formula 5:
which comprises:
treating the compound of the structural formula 4:
with a strong acid in a solvent. Optionally the free base of N-benzyl-3-(4-fluoro-phenyl)-1,4-oxazin-2-one may be formed by neutralization with a base.
Appropriate strong acids include: hydrochloric acid, including hydrogen chloride gas; methanesulfonic acid; trifluoroacetic acid; hydrogen bromide; hydrogen iodide; trifluoromethane-sulfonic acid; camphorsulfonic acid; sulfuric acid; phosphoric acid; and an arylsulfonic acid, such as benzenesulfonic acid, p-toluenesulfonic acid, and p-chlorobenzene-sulfonic acid. Preferred strong acids include: hydrochloric acid, including hydrogen chloride gas; methanesulfonic acid; trifluoroacetic acid; camphorsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid; and p-chlorobenzene-sulfonic acid. The most preferred strong acid is hydrochloric acid, including hydrogen chloride gas, and the most preferred strong acid is hydrogen chloride gas.
This process may be carried out in a suitable solvent such as an ether, for example, dioxane, or an ester, for example, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, sec-butyl acetate, n-butyl propionate, isobutyl propionate, ethyl butyrate, or n-propyl butyrate, water, or a mixture thereof. Dioxane, isopropyl acetate, isobutyl acetate, or isopropyl acetate/water are particularly preferred and isopropyl acetate/water is especially preferred. The preferred temperature range for the reaction is between about −10 and 50° C., a more prefered reaction temperature range is between about 30 and 45° C., and the most preferred temperature range is about 38±3° C. If desired, the free base may be formed by employing a weak base such as potassium bicarbonate, sodium bicarbonate, potassium carbonate or sodium
Bhupathy Mahadevan
Nelson Todd D.
Merck & Co. , Inc.
Patel Sudhaker
Rose David L.
Shah Mukund J.
Thies J. Eric
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