2.5- dimethoxybenzoyl chloride

To a stirred suspension of 6-aminopenicillanic acid (540 g) in dry alcohol-free chloroform (3.75 liters) was added dry triethylamine (697 ml), and the mixture stirred for 10 minutes at room temperature. It was then cooled in a bath of crushed Ice while a solution of 2,6-dimethoxybenzoyl chloride (500 g) in dry alcohol-free chloroform (3.75 liters) was added in a steady stream over 20 minutes. When all the acid chloride had been added the cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was stirred vigorously and sufficient dilute hydrochloride acid (2.3 liters of 0.87 N) was added to give an aqueous layer of pH 2.5. The mixture was filtered, the layers separated, and only the chloroform layer was retained. 

Dimethoxybenzoylimidazolium chloride also reacts rather slowly because of steric hindrance and electronic deactivation of the carbonyl group by the two methoxy groups. The synthesis of 2,6-dimethoxybenzoyl chloride was carried out in chloroform at 90 °C in a bomb tube to give a yield of 60% after 3 h.[41... 

Dimethoxybenzoyl chloride was purchased from the Aldrich Chemical Company, Inc. and was used without purification. 

Ethyl acetoacetate was acylated with 3,4,5-trifluoro-2,6-dimethoxybenzoyl chloride to give ethyl 3-oxo-2(3,4,5-trifluoro-2,6-dimethoxybenzoyl)butyrate (01IZV1090), preparated as in (01MC76). The compound was used for the synthesis of 6,7,8-trifluoro-5-hydroxy-2-methylchromone (Scheme 168). 

The official compound may be prepared by condensing the fermentation-produced 6-APA in an appropriate solvent with 2, 6-dimethoxybenzoyl chloride and the resulting methicillin is subsequently precipitated as its corresponding sodium salt by the addition of sodium acetate. 

DITHIANES (SCHEME I). The dithiane benzamides were synthesized from the commercially available (Aldrich Chemical Co.) ethyl 1,3-dithiane-2-carboxylate. Treatment (2-4) with a base (e.g. lithium diisopropylamide) followed by methyl iodide or ethyl iodide gave the substituted dithiane esters 1. For the synthesis of isoxazoles, the esters were treated with acetonitrile and base to give the keto nitrile 2. Treatment with hydroxylamine gave the desired amino-isoxazolyldithiane 3. Condensation with 2,6-dimethoxybenzoyl chloride yielded dithianes 4a-c. Overall yields for these compounds were good. 

The dithianethiadiazolylbenzamides were synthesized from the dithiane esters, 1, by hydrolysis of the esters followed by treatment of the acids with phosphorous oxychloride and then thiosemi-carbazide, yielding the aminothiadiazolyldiathianes 5. Condensation of the amino group of 5 with 2,6-dimethoxybenzoyl chloride gave the benzamides 6a-c in high yield. 

Bis(hydroxymethyl)propionic acid was also used to make the diether analog (Scheme IV). Treatment of the acid with methanol and boron trifluoride etherate gave the corresponding ester. The diol was then converted to the ether by alkylation with sodium hydride and methyl iodide. The dimethoxy ester was transformed to the isoxazole amine by reaction with the anion of acetonitrile (as in Scheme I) to yield the ketonitrile and then cyclization with hydroxylamine to give the isoxazole amine 17. Reaction with 2,6-dimethoxybenzoyl chloride gave the benzamide 18. 

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