Chemistry of hydrocarbon compounds – Unsaturated compound synthesis – Triple-bond product
Reexamination Certificate
2000-10-27
2001-11-06
Geist, Gary (Department: 1623)
Chemistry of hydrocarbon compounds
Unsaturated compound synthesis
Triple-bond product
C562S506000
Reexamination Certificate
active
06313364
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of cyclopropaneacetylene (CPA) by a catalytic decarboxylation reaction.
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 enantiomeric 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 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 the 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-Homer 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, for example synthesizing CPA from 5-chloro-1-pentyne, are not efficient in a large-scale production of CPA, and often have problems with impurities in the final product. As a result, there is a need for an alternative practical way to prepare CPA.
Therefore, it is an object of the present invention to provide a more efficient way to produce CPA, which involves a novel catalytic decarboxylation process.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of cyclopropaneacetylene (CPA) by a two step process. In the first step, alpha-acetylenic acid (propiolic acid) is cycloalkylated with a 3-carbon containing bis-electrophile yielding the crystalline cyclopropaneacetylene carboxylic acid. In the second step, the latter intermediate, cyclopropaneacetylene carboxylic acid, is decarboxylated in the presence of a copper catalyst to yield CPA.
A process for the preparation of cyclopropaneacetylene (CPA) comprises the steps of: (a) alkylating propiolic acid with a 1,3-disubstituted propane in a first base and an aprotic solvent to produce a reaction mixture containing a 6-substituted 2-hexynoic acid; (b) intramolecular cycloalkylation of the 6-substituted 2-hexynoic acid by addition of a second base to produce a reaction mixture containing cyclopropaneacetylene carboxylic acid; and (c) decarboxylating the cyclopropaneacetylene carboxylic acid with a copper catalyst in polar aprotic solvent to give a cyclopropaneacetylene (CPA).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a process for the preparation of cyclopropaneacetylene (CPA) by a two-step process as shown below:
In the first step, about one equivalent of propiolic acid is mixed with at least one equivalent of the first base in aprotic solvents, preferably in a mixture of hexamethyl phosphoric triamide (HMPA) and THF, at a temperature between about −60° C. and about −80° C. The first base may be present in amounts between about 1.0 equivalent to about 3.0 equivalents relative to the amount of propiolic acid, preferably between about 2.0 and about 2.5 equivalents. Upon contact with the first base, the solution is allowed stand at temperature between about 0° C. to about −20° C., preferably at about −15° C., for time sufficient for the reaction to occur, generally from about 30 minutes to about an hour. After cooling the reaction mixture to about −50° C. to about −100° C., preferably about −70° C. to about −80° C., approximately one equivalent of 1,3-disubstituted propane, preferably 1-bromo-3-chloropropane, is added. The mixture is then allowed to stand at a temperature between about −10° C. and about −20° C. for about an hour before adding a second base to the reaction mixture, which is about one equivalent of a freshly prepared solution of lithium diisopropylamide (LDA). The resulting mixture is then allowed to stand at a temperature of between about −10° C. and about −20° C. for sufficient time to complete the reaction, generally from about an hour to about two hours. The reactions of above alkylation and cycloalkylation (step 1) occur at a temperature range of between about 0° C. and about −100° C. The mixture is then quenched with a sodium bicarbonate solution and washed with organic solvent, preferably diethyl ether. The pH of the aqueous layer is adjusted to about 1.0 with acid, preferably HCl, and then extracted with organic solvent, preferably diethylether. The combined extracts are dried and concentrated in usual fashion yielding crude cyclopropaneacetylene carboxylic acid. Pure cyclopropaneacetylene carboxylic acid can be obtained via crystallization from organic solvent, preferably from diethylether.
In the second step, the reaction is carried out in a polar aprotic solvent, preferably in dimethylformamide (DMF). In carrying out the reaction, cyclopropaneacetylene carboxylic acid produced in Step 1 is added to the solvent containing a catalytic amount of copper catalyst, preferably cuprous chloride. The mixture is then allowed to stand at a temperature of between about 50° C. and about 100° C. for a time sufficient to complete the reaction to form CPA, generally from about an hour to about two hours. After completion of the reaction, CPA is recovered from the reaction mixture by partitioning between water and organic solvent, preferably n-octane, to obtain the final compound CPA.
For the purpose of this invention, the aprotic solvent is selected from the group consisting of tetrahydrofuran (THF), 2,5-dimethyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, methyl-tert-butyl ether (MTBE), diethoxymethane, dimethoxyethane, cyclohexane, pentane, hexane, toluene, hexamethyl phosphoric triamide (HMPA), dimethylpropyleneurea (DMPU) and mixtures of thereof. The preferred aprotic solvent is the mixture of TH
Camara Valerie J.
Geist Gary
Merck & Co. , Inc.
Reyes Hector M
Walton Kenneth R.
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