Synthesis of cyclopropaneacetylene by a one-pot process

Details Synthesis of cyclopropaneacetylene by a one-pot process Synthesis of cyclopropaneacetylene by a one-pot process

2000-10-27

2003-04-22

Norton, Nadine G. (Department: 1764)

Chemistry of hydrocarbon compounds

Alicyclic compound synthesis

From nonhydrocarbon

C585S538000, C585S359000, C585S357000, C585S325000

Reexamination Certificate

active

06552239

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of cyclopropaneacetylene (CPA) by a one-pot process.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome, AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replications is reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothylmidine or AZT.
Cyclopropaneacetylene (CPA) is a key raw material for the preparation of an inhibitor of HIV reverse transcriptase, which is known as DMP-266 having a chemical name of (−)6-chloro-4-cyclopropylenthynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxanzin-2-one.
The synthesis of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021, and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiometric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et. al.,
Tetrahedron Letters
1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
In addition, various aspects of the synthesis of DMP-266 have been disclosed in the United States Patents. U.S. Pat. No. 5,663,467 discloses a synthesis of CPA involving cyclization of 5-halo-1-pentyne in base. U.S. Pat. No. 5,856,492 discloses a synthesis of a chiral mediator, and U.S. Pat. No. 5,922,864 discloses an efficient method to prepare DMP-266 by a cyclization reaction. A process for making chiral alcohol is published on Jul. 16, 1998 in PCT Publication No. WO 98/30543.
Several methods have been described in published literature for preparation of cyclopropaneacetylene. C. E. Hudson and N. L. Bauld,
J. Am. Chem. Soc
. 94:4, p. 1158 (1972); J. Salaun,
J. Org. Chem
. 41:7, p. 1237 (1976); and W. Schoberth and M. Hanack,
Synthesis
p. 703 (1972), disclose methods for the preparation of cyclopropylacetylene by dehydrohalogenating 1-cyclopropyl-1,1-dichloroethane. Miltzer, H. C. et al.,
Synthesis
, 998 (1993) disclose a method for preparation of cyclopropylalkenes by halogenating an enolether, reacting the alkyl 1,2-dihaloether with propargyl magnesium bromide, and cyclizing to give a 2-alkoxy-1-ethynylcyclopropane. F. A. Carey and A. S. Court,
J. Org. Chem
., Vol. 37, No. 12, p. 1926 (1972) disclose the use of a modified Wittig-Horner olefin synthesis for organic transformations. D. J. Peterson,
J. Org. Chem
., Vol. 20C, No. 33, p. 780 (1968) describes the application of olefination to make vinyl sulfides and H. Takeshita and T. Hatsui,
J. Org. Chem
. Vol. 43, No. 15, p. 3083 (1978) disclose the use of potassium 3-aminopropylamide in base-catalyzed prototropic reactions.
However, the currently available ways to prepare CPA can result in poor yield and often have problems with impurities in the final product. Ohira, S.,
Synth. Comm
., 1989, 561-564 and Müller, S. et al.,
Synlett
, 1996, 521-522 describe an in-situ preparation of dimethyldiazomethylphosphonate and its use for the conversion of aldehydes into terminal acetylenes. The precursor for the in situ preparation of the dimethyldiazomethylphosphonate is dimethyl (1-diazo-2-oxopropyl)phosphonate. This reagent in turn is prepared from commercially available dimethyl (2-oxopropyl)phosphonate. The latter reaction is typically performed using a sulfonyl azide derivative as diazo transfer reagent followed by a difficult chromatographic purification of the dimethyl (1-diazo-2-oxopropyl)phosphonate product. Without purification, the crude dimethyl (1-diazo-2-oxopropyl)phosphonate product converts cyclopropanecarboxaldehyde to CPA in poor yield due to a reaction of the intermediate dimethyldiazomethylphosphonate with the sulfonamide by-product corresponding to the diazo transfer reagents. As a result of this need for purification, published methods are not suitable for a practical one-pot synthesis of CPA from cyclopropanecarboxaldehyde.
In view of above, there is a need for an alternative practical way to prepare CPA, and thus the objective of the present invention is to provide an efficient and practical way to produce CPA by a one-pot process.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of cyclopropaneacetylene comprising the steps of: (a) reacting a ketophosphonate compound of Formula I,
with a diazo-transfer reagent, [(R)
2
N]
3
P
+
N
3
X
−
, wherein R is C
1
-C
5
alkyl, in the presence of a catalytic amount of a first non-nucleophilic base in an aprotic solvent to generate a reaction mixture containing ketodiazophosphonate compound of Formula II;
wherein R
1
and R
2
substituents in Formulae I and II independently are: C
1
-C
6
alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of: Cl, F, Br, I, (C
1
-C
4
)-alkyl, —O—(C
1
-C
4
)-alkyl, —NO
2
, —OH, CF
3
, (C
1
-C
4
)-alkoxy, S(O)
x
—(C
1
-C
4
)-alkyl, —N(R)
2
, —COOR, and CON(R)
2
, wherein R is H, (C
1
-C
6
)-alkyl, phenyl, or (C
1
-C
6
)-alkylphenyl, and X is 0, 1, or 2; and (b) reacting the reaction mixture containing the ketodiazophosphonate compound of Formula II with cyclopropanecarboxaldehyde using a second non-nucleophilic base and a protic solvent to yield the cyclopropaneacetylene.


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H. Takeshita et al., “Sensitized Photoreduction of Dioxetanes to cis-1,2

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