Chloropropionaldehyde Acetal

To 340 g. (6 moles) of dry, powdered potassium hydroxide (Note 1) in a 500-cc. short-neck round-bottom flask (Note 2) is added 167 g. (1 mole) of /3-chloropropionaldehyde acetal (p. 26). The mixture is shaken vigorously and attached at once to a 3-bulb Glinsky, or other suitable column, connected to a water condenser set for distillation. The flask is heated in an oil bath at 210-2200 until nothing more distils (Note 3). The distillate is transferred to a separatory funnel and the lower aqueous layer is removed. The acrolein acetal is dried over 10 g. of potassium carbonate, filtered and distilled from a modified Claisen flask (Org. Syn. 1, 40). The yield is 98 g. (75 per cent of the theoretical, amount) of a product which boils at 122-126°. 

Acrolein acetal has always been prepared by treatment of /3-chloropropionaldehyde acetal with dry, powdered ix>tassium hydroxide.1... 

Chloropropionaldehyde acetal has been prepared by the action of acrolein on alcoholic hydrogen chloride alone,1 or in the presence of calcium chloride.2... 

Chloropropionaldehyde diethyl acetal Pipoxolan HCI a-Chloropropionyl chloride Carticaine... 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Cupric chloride, if present in concentrations above ca. 0.5 M, may cause side reactions to occur in the olefin aiylation reaction similar to those that occur with cupric chloride in the vinyl acetate synthesis mentioned above. The side reaction produces 2-arylethyl chlorides and these products may be made the major ones if cupric chloride is present to the extent of about 2M in 10% aqueous acetic acid solution 29>. The mixed solvent is required to obtain the necessary solubility of the cupric chloride. This is a general reaction useful for producing a variety of 2-arylalkyl halides. For example, 3-phenyl-2-chloropropionaldehyde is obtained in 63% yield by the reaction of phenylpalladium chloride , cupric chloride and acrolein. 

Acetalization. /5-Chloropropionaldehyde diethyl acetal can be prepared from acrolein in 88% yield by reaction of ethanol in the presence of hydrogen chloride dissolved in ether and with a 4 A molecular sieve as water scavenger.2 In the absence of a molecular sieve the yield drops to 65%. If ethanolic hydrogen chloride is used the yield is 34%.3... 

Furan dicarboxylic acid, 6, was prepared by a five-step procedure. Cold acrolein was added slowly to a stirred solution of HCl-saturated absolute ethanol at about 0° to form 3-chloropropionaldehyde diethyl acetal,(6). 

Chloropropionaldehyde diethyl acetal, purified by fractional distillation under reduced pressure (12-20 torr), was refluxed for 24 hrs. with potassium cyanide and potassium iodide in a mixture of water and ethanol giving 4,4-diethoxybutyronitrile, in 59% yield.An attempt was also made to prepare the nitrile by treating 3-chloropropionaldehyde diethyl acetal with sodium cyanide in dimethyl sulfoxide at about 150° over the course of about one hour. After stirring overnight, the reaction solution... 

Chloropropionaldehyde Diethyl Acetal. According to the literature procedure,200 g of absolute ethanol was saturated with dry hydrogen chloride (bubbled through concentrated sulfuric acid) in a 500 ml, threenecked flask, in an ice-water bath. The ethanolic solution was then transferred to a 3-liter, 3-necked flask fitted with an inlet tube, a bubbler, and a magnetic stirrer. The flask was cooled in an ice-water bath. The three-necked flask was also fitted with an efficient condenser which was connected to an exhaust bubbler. To the cold, acidified ethanol was added 112 g (2 moles) of cold acrolein from the liquid addition flask over the course of 1-2 hrs. This solution was then quickly transferred to a 2-liter separatory funnel which was sealed and placed in a refrigerator. After approximately 15 minutes, two layers had separated. The lower layer of acetal was collected and neutralized by the slow addition of powdered sodium bicarbonate. This supension was then filtered and the filtrate was washed with two 50 ml portions of ice-water and dried over 20-30 g of anhydrous potassium carbonate for 10-15 hr. The solution was finally filtered and distilled under reduced pressure, b.p. 96-136 , 12-20 torr (lit. 58-62 ,... 

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