Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-08
2002-06-11
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S106000, C544S177000
Reexamination Certificate
active
06403793
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine 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 (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of (2R, 2-alpha-R)-4-benzyl-2-[1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy-1,4-oxazin-3-one result in relatively low and inconsistent yields of the desired product (see U.S. Pat. No. 5,719,147). In contrast to the previously known processes, the present invention provides more practical and economical methodology for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy-3-(4-fluorophenyl)-1,4-oxazine in relatively high yield and purity.
It will be appreciated that (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoro-methyl) phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine 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 (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis (trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine 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 (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine via a very simple, short, relatively inexpensive and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine. 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 psychiatric disorders, inflammatory diseases, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula:
An embodiment of the general process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula:
comprises:
(1) contacting a compound of the formula:
with an oxidizing agent to give a compound of the formula:
(2) activating such compound with an activating agent and contacting the activated compound with ethanolamine to give a compound of the formula:
(3) condensing such compound with glyoxal and 4-fluoroboronic acid to give a compound of the formula:
(4) intramolecular coupling of such activated compound to give a compound of the formula:
(5) quarternizing the amino group of such compound to give a compound of the formula:
(wherein X
−
is a counterion)
(6) hydrolysis of such compound to give a compound of the formula:
and (7) hydrogenation of such compound to give the compound of the formula:
A specific embodiment of the process for the preparation of (2R, 2-alpha-R, 3 a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula:
comprises:
(1) contacting a compound of the formula:
with an oxidizing agent selected from osmium tetroxide/N-methyl morpholine to give a compound of the formula:
(2) activating such compound with an activating agent selected from methanesulfonyl chloride and contacting the activated compound with ethanolamine to give a compound of the formula:
(3) condensing such compound with glyoxal and 4-fluoroboronic acid to give a compound of the formula:
(4) intramolecular coupling of such activated compound under Mitsunobu conditions to give a compound of the formula:
(5) quarternizing the amino group of such compound with a benzyl halide to give a compound of the formula:
(wherein X
−
is a counterion)
(6) hydrolysis of such compound with an inorganic base to give a compound of the formula:
and (7) catalytic hydrogenation of such compound with a palladium catalyst to give the compound of the formula:
Another embodiment of the present invention concerns a process for the preparation of a compound of the formula:
which comprises hydrogenation of a compound of the formula:
to give the compound of the formula:
In this embodiment it is preferred that the hydrogenation is catalytic hydrogenation. It is preferred that the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman's catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C
1
-C
4
primary, secondary and tertiary alcohols, and water. Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise ethanol or methanol and mixtures thereof with water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10° C. to about 50° C., wherein the most preferred temperature is about 20-25° C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
Another embodiment of the process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-5 oxazine of the formula:
comprises the processes as outlined in the following Scheme.
Another embodiment of the present invention is directed to the processes as outlined in the following Schemes.
As depicted in Scheme 1, a retrosynthetic analysis of 1 indicates a possible disconnection at the acetal center leading to 3,5-bis(trifluoromethyl)-sec-phenethyl alcohol 3 and the activated morpholine 2. Unfortunately, this glycosidation-type approach fails because either facile elimination of the leaving group (LG) or substitution from the &bgr;-face resulted in the undesired trans stereochemistry, presumably due to steric blocking by the adjacent 4-fluorophenyl group. Alternatively, vinyl ether 4 is a desirable intermediate because diastereoselective hydrogenation of the vinyl ether provides (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)-mopholine (Hale, et al.,
J. Med. Chem
. 1998, 41, 4607.) Importantly, 4 is retrosynthetically transformed to the bicyclic quaternary ammonium salt 5 by a regioselective Hofmann elimination. The critical cis-stereochemistry in 5 is set by an intramolecular displacement of the lactol hydroxyl group of 6, thus overcoming the bias towards the trans arrangement. Lactol 6 is derived from chiral aminodiol 7 using a Mannich boronic acid condensation. It was imperative to the success of this strategy that the single stereocenter of aminodiol 7 co
Pye Philip J.
Rossen Kai
Higel Floyd D.
Merck & Co. , Inc.
Saeed Kamal
Thies J. Eric
Winokur Melvin
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