Cyclopropylcarbonyl chloride

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

Preparation of 2-Cyclopropylcarbony/amido-5-Chlorobenzophenone To 400.5 g (1.73 mols) of 2-amino-5-chlorobenzophenone dissolved in 220 g (2.18 mols) of triethylamine and 3.5 liters of tetrahydrofuran is added cautiously 181 g (1.73 mols) of cyclopropane-carboxylic acid chloride. The reaction is refluxed 2 /2 hours and allowed to cool to room temperature. The solvent is then removed under vacuum to obtain 2-cyclopropylcarbonyl-amido-5-chlorobenzophenone as a residue which is dissolved in 1 liter of methylene chloride, washed twice with 5% hydrochloric acid, and then twice with 10% potassium hydroxide. The methylene chloride solution is then dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The residue is recrystallized from 1,500 ml of methanol, charcoal-treating the hot solution to give 356 g of 2-cyclopropylcarbonylamido-5-chlorobenzophenone, MP 105° to 105.5°C (69% yield). 

Epoxycyclobutanes 5 afforded cyclopropyl aldehydes and ketones 6 in good to excellent yields when treated with sulfuric acid or hydrogen chloride. The use of aluminum trichloride as the acidic reagent generally leads to mixtures of cyclopropylcarbonyl compounds and cyclobutanones. 

A few imines have been prepared by special methods. The reaction between benzyl azide and 1-phenylcyclopropaneearbaldehyde yielded the corresponding V-benzylimine. Similarly, reaction of 2-azido-V-(cyclopropylcarbonyl)-V-methylbenzenecarboxamide with an equimolar amount of triphenylphosphane occurred spontaneously at room temperature to give a quinazolinone in essentially quantitative yield. Treatment of tricyclo[4.4.1.0 ]undeca-3,7,9-triene-2,5-dione with bis(trimethylsilyl)carbodiimide in the presence of titanium(IV) chloride afforded V,V -dicyanotricyclo[4.4.1.0 ]undeca-3,7,9-triene-2,5-diimine in excellent yield. ... 

The key intermediates for the synthesis of mebendazole (14), flubendazole (15) and ciclobendazole (16) are 4-benzoyl-2-nitrohalobenzene (94a), 4-(4-fluoroben-zoyl)-2-nitrohalobenzene (94b) and 4-cyclopropylcarbonyl-2-nitrofluorobenzene (94c), respectively, which are prepared by Fridel-Crafts reaction of an acid chloride with the appropriate aromatic compounds. These substituted halobenzenes (94a-c) are converted into 14-16 as shown in scheme 4 [137-139]. 

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