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Process for prepn. of cyclopropylacetylene

A technology of cyclopropyl acetylene and cyclopropyl ethylene, applied in the field of cyclopropyl acetylene synthesis, can solve the problems of infeasible purity of the total synthesis method, difficult to operate reagents, incomplete conversion and the like

Inactive Publication Date: 2000-08-30
DU PONT PHARMA CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The aforementioned synthesis of cyclopropylacetylene uses toxic, difficult-to-handle reagents, relatively expensive starting materials, incomplete conversions, and low yields, all of which make total synthesis impractical and yield cyclopropylacetylene of low purity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0074] Cyclopropanecarbaldehyde (100 g, 1.43 mol, 1 eq), malonic acid (297 g, 2.85 mol, 2 eq) and pyridine (565 g, 7.15 mol, 5 eq) were placed in a suitable vessel equipped with a reflux condenser and stirring Stir together. The suspension was vigorously stirred and warmed to about 50°C, during which time the malonic acid gradually dissolved. Then piperidine (15ml, 15mmol, 1mol%) was added and the reaction mixture was heated to 80-85°C (internal temperature). After maintaining this temperature for about 1.5 hours, the reaction mixture was heated so as to maintain reflux (about 115°C) for 3 hours. The reaction mixture was then cooled to 0°C and 500 ml of cold water was added, followed by the slow addition of 680 ml of concentrated aqueous hydrochloric acid with vigorous stirring. Gradually pale yellow crystals formed, which were isolated by filtration and washed several times with cold water. The yield of the first batch was 68 g (43%) of 3-cyclopropylacrylic acid after dryi...

Embodiment 23

[0075] A solution of cyclopropanecarbaldehyde (7.0 g, 100 mmol) in 50 ml of toluene was treated with 11.5 g (110 mmol) of malonic acid. The stirred suspension was treated with 0.87 g (10 mmol, 10 mol%) morpholine and then 3.95 g (50 mmol, 50 mol%) piperidine. The mixture was then heated to reflux to remove residual water. Water was separated from the reaction mixture for about 1 hour, during which time a little more water than theoretical (2 ml) was separated. The reaction mixture was a clear, pale yellow solution. The reactant was then cooled to room temperature, washed with 50 ml of 10% aqueous hydrochloric acid, and washed twice with 50 ml of water. The toluene solution was concentrated to about a quarter volume, diluted with 40 mL of n-heptane and cooled to about 5°C with stirring. The product precipitated out of solution as fine pale yellow needles. The product was collected by filtration and dried to constant weight. Yield about 8.5 g (76%). A second crop (1.7 g) w...

Embodiment 3

[0076] The cyclopropylacrylic acid obtained in step 1 (30g, 268mmol, 1 equivalent, prepared in Example 1) and lithium acetate dihydrate (2.73g, 26.8mmol, 0.1 equivalent) were dissolved in 300ml of acetonitrile and water (9ml). This solution was stirred at room temperature for about 5 minutes, then treated with N-bromosuccinimide (57.2 g, 321 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 45 minutes; then quenched with 100 mL of water and extracted with hexane (3 x 300 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The desired product was obtained by 1 H NMR and GC analysis determined a mixture of stereochemical isomers (colorless liquid, 32 g, 82% yield; bp 45°C / ~20 mmHg). The preparation of embodiment 4 cyclopropylacetylene:

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Abstract

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. In the process, cyclopropane carboxaldehyde is condensed with malonic acid to form 3-cyclopropylacrylic acid; 3-cyclopropylacrylic acid is halogenated to form (E,Z)-1-halo-2-cyclopropylethylene; and (E,Z)-1-halo-2-cyclopropylethylene is dehydrohalogenated to form cyclopropyl acetylene. This improvement provides for high conversion of inexpensive, readily available starting materials into cyclopropylacetylene, high overall yields and can be conducted on an industrial scale.

Description

field of invention [0001] The present invention relates to a novel method for the synthesis of cyclopropylacetylene, a useful human immunodeficiency virus (HIV) reverse transcriptase inhibitor (S)-6-chloro-4-cyclopropylethynyl-4- An essential reagent for the asymmetric synthesis of trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. Background of the invention [0002] Reverse transcription is a general feature of retroviral replication. Viral replication requires a virally encoded reverse transcriptase to generate a DNA copy of the viral sequence through reverse transcription of the viral RNA chromosome. Thus, reverse transcriptase is a clinically relevant target for chemotherapy of retroviral infections because inhibition of virally encoded reverse transcriptase can interrupt viral replication. [0003] Many compounds are effective in the treatment of human immunodeficiency virus (HIV), a retrovirus that causes the gradual destruction of the human immune system and lead...

Claims

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Application Information

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IPC IPC(8): B01J31/02B01J31/04C07B61/00C07C1/30C07C5/42C07C13/04C07C17/093C07C22/00C07C51/353C07C51/38
CPCC07C51/353C07C1/30C07C13/04C07C51/38C07C2101/02C07C17/093C07C2101/04C07C2601/02C07C2601/04C07C22/00C07C57/26
Inventor J·M·福图纳克Z·王J·尹
Owner DU PONT PHARMA CO