Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-09-30
2002-03-19
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C560S124000, C562S506000, C585S359000, C585S534000, C585S538000
Reexamination Certificate
active
06359164
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to novel methods for the preparation 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 with superior anti-retroviral activity. In the process, for example, cyclopropane carboxaldehyde is alkylated to form 1,1,1-trichloro-2-cyclopropyl-ethanol; which in turn undergoes elimination to form 1,1-dichloro-2-cyclopropyl-ethene; which in turn undergoes elimination to form cyclopropylacetylene.
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):
generically known as efavirenz (SUSTIVA™), is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of SUSTIVA™ 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). Cyclopropylacetylene is also the most expensive raw material, of which availablity is difficult to obtain.
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 cyclopropyl acetylene 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 A1 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 A1 discloses methods which continue to be inefficient in the overall synthesis on a kilogram scale for which this invention makes significant improvements.
The chemical literature shows the majority of the cyclopropylacetylene preparations involve the conversion of cyclopropylmethyl ketone to cyclopropylacetylene via the following chemical scheme. The method will produce cyclopropylacetylene on small scale, <1 kilogram, but is not amenable for bulk production, thus an alternative was developed.
In addition to conversion of cyclopropylmethyl ketone to cyclopropylacetylene, Corey-Fuchs, Horner-Emomons and Gillbert-Seyferth reactions are the most frequently used methods for the conversion of aldehydes to terminal alkynes via a one-carbon homologation. The requirements of phosphorous reagents to promote these reactions, however, limit their industrial attractiveness and efficiency of these applications due to the problems of toxicity and volume of waste streams generated.
The above methods for, the synthesis of cyclopropyl-acetylene use combinations of toxic, difficult to handle reagents, relatively expensive materials, incomplete conversions and/or low yields which 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 high yields of desired cyclopropylacetylene.
The present invention discloses a novel, scalable, and efficient process for the preparation of substituted acetylenes, more specifically cyclopropylacetylene, via a one carbon homologation of substituted aldehydes. Improvements over previously disclosed preparations of cyclopropyl acetylene are in the low economic price and availability of the starting materials; the convenience and high yields for the chemistry; the efficiency of the process; the ease in handling of the 1,1-dichlorovinyl intermediates; and the ability to store without degradation the 1,1-dichlorovinyl intermediates. The invention provides novel chemistry for the production of cyclopropylacetylene from cyclopropane carboxaldehyde. The process provides a high yield for the convenient reaction of cyclopropane carboxaldehyde with trichloroacetic acid followed by zinc to give 1,1-dichloro-2-cyclopropylethene. The intermediate, 1,1-dichloro-2-cyclopropylethene, is a very stable liquid, easily purified by distillation, and produced in high yield. The subsequent dehalogenation of 1,1-dichloro-2-cyclopropylethene to cyclopropylacetylene proceeds in high yields and with suitable purities so that the cyclopropyl acetylene produced and isolated 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 cyclopropyl acetylene. None of the above-cited references describe the unexpected benefit that 2-substituted 1,1-dichloroethenes contribute to the overall efficiency of the invention.
SUMMARY OF THE INVENTION
The present invention concerns an improved process suitable for the large scale preparation of cyclopropyl acetylene. In the process, cyclopropane carboxaldehyde is condensed with an alkylating/halogenating agent, such as trichloroacetic acid, to form 1,1,1-trichloro-2-cyclopropyl-ethanol in situ; 1,1,1-trichloro-2-cyclopropylethanol is optionally protected in situ to form 1,1,1-trichloro-2-cyclopropyl-2-ethanylacetate; the 1,1,1-trichloro-2-cyclopropylethanol and/or 1,1,1-trichloro-2-cyclopropyl-2-ethanylacetate is reduced to form 1,1-trichloro-2-cyclopropyl ethene, which is easily isolated; and 1,1-trichloro-2-cyclopropylethene is dehalogenated to form cyclopropyl acetylene. This improvement provides for high conversion of inexpensive, readily available starting materials into cyclopropyl acetylene, with high overall yields, easily handled intermediates, and can be conducted on an industrial scale.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention provides a process for the preparation of a compound of formula (III);
wherein:
R
1
is selected from:
C
1-8
alkyl substituted with 0-3 R
4
,
C
3-10
cycloalkyl substituted with 0-2 R
5
, and
aryl substituted with 0-2 R
6
;
R
4
, at each occurrence, is selected from methyl, ethyl, propyl, butyl, OR
7
, NR
7
R
7a
, phenyl, and cyclopropyl;
R
5
, at each occurrence, is selected from D, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy;
R
6
, at each occurrence, is selected from methyl, ethyl, propyl, methoxy, ethoxy, propoxy, F, Cl, B, I, CN, and NR
7
R
7a
;
R
7
and R
7a
are independently selected from methyl, ethyl, propyl, and butyl;
said process comprising:
(1a) contacting an aldehyde of formula R
1
-CHO with trichloroacetic acid or tribromoacetic acid, in the presence of a base catalyst;
(1b) contacting the solution of (1a) with zinc in the presence of a suitable acid to form a compound of formula (II);
wherein R
2
is Cl or Br; and
(2)
Fortunak Joseph M.
Wang Zhe
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