Chemistry of hydrocarbon compounds – Unsaturated compound synthesis – Triple-bond product
Reexamination Certificate
1999-06-28
2001-05-22
Johnson, Jerry D. (Department: 1764)
Chemistry of hydrocarbon compounds
Unsaturated compound synthesis
Triple-bond product
C585S534000
Reexamination Certificate
active
06235957
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to novel methods for the synthesis of cyclopropylacetylene which is an essential reagent in the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; a useful human immunodeficiency virus (HIV) reverse transcriptase inhibitor.
BACKGROUND OF THE INVENTION
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of formula (VI):
is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a reverse transcriptase inhibitor, economical and efficient synthetic processes for its production need to be developed.
Cyclopropylacetylene is an important reagent in the synthesis of compound (VI). Thompson et al,
Tetrahedron Letters
1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown below. As a reagent the cyclopropylacetylene was synthesized in a 65% yield by cyclization of 5-chloropentyne with n-butyllithium at 0°-80° C. in cyclohexane followed by quenching with ammonium chloride. The process generates a low yield of cyclopropylacetylene which is not feasible for the large commercial process of a difficult to handle reagent.
Thompson et al, PCT International Patent Application Number WO 9622955 Al describe an improved synthesis of cyclopropylacetylene useful in the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. Application WO 9622955 Al discloses methods which continue to be inefficient in the overall synthesis on a kilogram scale for which this invention makes significant improvements.
The majority of the cyclopropylacetylene preparations in the chemical literature teach the conversion of cyclopropylmethyl ketone to cyclopropylacetylene in a two or three step process on a bench top scale . The processes, via the following chemical scheme, teach the preparation of gem-dichloride first followed by subsequent heating to produce cyclopropylacetylene. The method will produce cyclopropylacetylene on small scale, <1 kilogram, but is not amenable for bulk production; thus an alternative needed to be developed.
The above methods for the synthesis of cyclopropylacetylene use multistep processes with incomplete conversions and low yields; such processes render the overall synthesis inefficient and yield cyclopropylacetylene of lower purity. Thus, it is desirable to discover new synthetic routes to cyclopropylacetylene on a large scale which improve upon these limitations and provide higher yields of desired cyclopropylacetylene.
The present invention provides for essentially a one step process wherein the premixing of the reducing agent, eg. PCl
5
, with the complexing agent, eg. quinoline, followed by addition of the cyclopropylmethylketone unexpectedly produces cyclopropylacetylene in high yield without quantitative generation of gem-dichlorides or vinylchlorides. Without premixing the reducing agent and the complexing agent, gem-dichlorides or vinylchlorides are produced as the major product. Additionally, the direct conversion of cyclopropylmethylketone to cyclopropylacetylene is affected by the chemical nature of the complexing agent. Furthermore, under harsh conditions, eg. higher refluxing temperatures, undesirable chlorination of the cyclopropyl ring occurs.
The present invention discloses a novel scalable procedure for the preparation of cyclopropylacetylene. The invention provides novel chemistry for the production of cyclopropylacetylene from cyclopropylmethylketone. The one pot reaction on a large scale occurs in high yield using convenient reaction conditions. The process provides a high solution yield (>90%) for the convenient reaction of a homogeneous mixture of phosphorous pentachloride and quinoline with cyclopropyl methyl ketone. Improvements over previously disclosed preparations of cyclopropylacetylene are the one pot reaction, scalability, essentially one step, operationally uncomplicated, isolation is uncomplicated, and produces a neat material in high purity. The final preparation of cyclopropylacetylene enables the manufacturer to circumvent the process step of dehydrohalogenation from cyclopropyl vinyl halide. Furthermore, the preparation of cyclopropylacetylene proceeds directly to high yields and suitable purities wherein the cyclopropylacetylene produced can be stored or used as a solution in an inert solvent.
None of the above-cited references describe the methods of the present invention for the synthesis of cyclopropylacetylene.
SUMMARY OF THE INVENTION
The present invention concerns an improved process suitable for the large scale preparation of substituted acetylenes, more specifically, cyclopropylacetylene. In the one pot process, phosphorous pentachloride and quinoline are premixed to form a “PCl
5
/quinoline” mixture upon which cyclopropyl methyl ketone is contacted with the “PCl
5
/quinoline” mixture to form cyclopropyl acetylene quantitatively. This improvement provides for high conversion of inexpensive, readily available starting materials directly to cyclopropylacetylene on an industrial scale; it enables a manufacturer to avoid the process step of dehydrohalogenation of cyclopropyl vinyl halides; and provides for high yields and suitable purities wherein the cyclopropylacetylene produced can be stored or used as a solution in an inert solvent.
DETAILED DESCRIPTION OF THE INVENTION
[1] In a first embodiment, the present invention provides a process for the preparation of a compound of formula (I),
wherein:
R
1
is selected from:
C
1-6
alkyl substituted with 1-3 R
4
,
C
2-6
alkenyl substituted with 0-1 R
4
,
C
3-7
cycloalkyl substituted with 0-2 R
5
,
phenyl substituted with 0-2 R
6
, and
C
3-6
carbocyclic ring substituted with 0-2 R
5
;
R
3
is H, methyl, ethyl, or propyl;
R
4
, at each occurrence, is selected from OR
7
, F, Cl, Br, I, NR
7
R
7a
, phenyl, and cyclopropyl;
R
5
, at each occurrence, is selected from D, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, F, Cl, Br, and I;
R
6
, at each occurrence, is selected from methyl, ethyl, propyl, methoxy, ethoxy, propoxy, F, Cl, Br, I, CN, and NR
7
R
7a
;
R
7
and R
7a
are independently selected from methyl, ethyl, propyl, and butyl;
said process comprising:
(1) contacting a reducing agent with a complexing agent in a suitable nonaqueous solvent at a temperature below 20° C.;
(2) contacting a compound of formula (II);
wherein R
2
is methyl, ethyl, propyl or butyl;
with the solution of step (1) while maintaining the temperature below 20° C. to form a compound of formula (I).
[2] In a preferred embodiment, the present invention provides a process for the preparation of cyclopropylacetylene said process comprising:
(1) contacting a reducing agent with a complexing agent in a suitable nonaqueous solvent at a
Dang Thuan D.
DuPont Pharmaceuticals Company
Johnson Jerry D.
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