Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-07-20
2003-04-29
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S283000, C514S266300
Reexamination Certificate
active
06555686
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the asymmetric synthesis of quinazolin-2-ones that are useful as inhibitors of HIV reverse transcriptase.
BACKGROUND OF THE INVENTION
Non-nucleoside reverse transcriptase inhibitors (NNRTI's) like those of Formulas Ia and Ib shown below:
are currently being clinically investigated. As a result, large quantities of these compounds are needed to satisfy clinical demands.
Tucker et al (
J. Med. Chem.
1994, 37, 2437-2444) describe the preparation of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones (i.e., NNRTI's) by the addition of aryl acetylides to N-protected quinazolinone precursors. A typical example is shown below.
Unfortunately, the addition of the aryl acetylide requires the quinazolinone precursor to be N-protected. An undesirable deprotection step is consequently required after acetylide addition. Other papers have described similar N-protected routes (see
J. Org. Chem.
1995, 60, 1590-1594;
Tetr. Lett.
1994, 35(37), 6811-6814).
It can be seen that preparation of NNRTI's is difficult. Thus, it is desirable to find efficient syntheses of NNRTI'S, specifically those of Formulas Ia and Ib.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel asymmetric processes for preparing quinoxazin-2-ones.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formulas Ia and Ib can be prepared from quinazolinone precursors of Formulas IIa and IIb:
via chiral moderated asymmetric addition of cyclopropylacetylene.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In an embodiment, the present invention provides a novel process for making a compound of Formula Ia or Formula Ib:
comprising: contacting a quinazolinone precursor of Formula IIa or IIb:
with cyclopropylacetylide in the presence of a chiral moderator and a base, wherein the chiral moderator is a compound selected from:
In another preferred embodiment, the chiral moderatoris a compound selected from:
In another preferred embodiment, the chiral moderator is a compound selected from:
In another preferred embodiment, the chiral moderator (CM) is selected from:
In another preferred embodiment, the chiral moderator is CM
1
.
In another preferred embodiment, the chiral moderator is CM
2
.
In another preferred embodiment, the chiral moderator is CM
3
.
In another preferred embodiment, cyclopropylacetylide is lithium cyclopropylacetylide (Li-CPA).
In another preferred embodiment, contacting is performed with tetrahydrofuran as a solvent.
In another preferred embodiment, the base is selected from lithium hexamethyldisilazide, n-BuLi, s-BuLi, t-BuLi, and n-HexLi.
In another preferred embodiment, the base is n-HexLi or n-BuLi.
In another preferred embodiment, the base is lithium hexamethyldisilazide (Li-HMDS).
In another preferred embodiment, contacting is performed with tetrahydrofuran as a solvent and lithium hexamethyldisilazide as a base.
In another preferred embodiment, contacting is performed by adding a solution, comprising: a quinazolinone precursor to a solution comprising chiral moderator, Li-CPA, and base.
In a more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA, chiral moderator and base to a solution comprising quinazolinone precursor.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA and base to a solution comprising chiral moderator and quinazolinone precursor.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: chiral moderator and quinazolinone precursor to a solution comprising Li-CPA and base.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA to a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base. Preferably LiHMDS is used as base for this route.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base to a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: deprotonated chiral modifier to a solution, comprising: quinazolinone precursor and LiHMDS and then adding a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to about 1 equivalent of LiHMDS to 3 to 3.6 equivalents of n-BuLi to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: quinazolinone precursor to a solution, comprising: a chiral modifier, cyclopropylacetylene, and LiHMDS and then adding a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are about 3 equivalents of chiral moderator to about 1 equivalent of cyclopropylacetylene to 1 to 1.5 equivalents of Li-CPA to about 4 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another embodiment, the quinazolinone precursor of Formula IIa or IIb:
is prepared by the process, comprising: dehydrating a compound of Formula IIIa or IIIb:
In another preferred embodiment, dehydrating is performed by heating a compound of Formula IIIa or IIIb in a solvent selected from toluene and xylenes and mesitylenes in the presence of a water scavenger.
In another preferred embodiment, dehydrating solvent is xylenes, the water scavenger is a Dean-Stark trap, and the reaction is conducted in the presence of benzene sulfonic acid.
In another embodiment, dehydrating solvent is mesitylene, with or without the water scavenger as a Dean-Stark trap.
In another preferred embodiment, the reaction solution resulting from dehydration is reduced in volume and used in the contacting reaction without further purification.
In another embodiment, the present invention provides a novel process for making a compound of Formula Ia or Formula Ib:
comprising: contacting a quinazolinone precursor of Formula IIa or IIb:
with cyclopropylacetylene in the presence of a chiral moderator and a base, wherein the chiral moderator is a compound that provides an enantiomeric excess of at least 30 to 100%.
In a preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 60 to 99%.
In another preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 80 to 99%.
In another preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 85 to 99%.
In anoth
Davulcu Akin H.
Dorow Roberta L.
Fortunak Joseph M.
Harris Gregory D.
Kauffman Goss S.
Bristol-Myers Squibb Pharma
Houghton Gregory C.
Shah Mukund J.
Truong Tamthom N.
VanAtten Mary K.
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