A-Chloropropionaldehyde

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

The oxidation of the crude /3-chloropropionaldehyde is carried out in a 200-cc. flask fitted with a cork stopper held by a clamp about 2 cm. %bove the opening of the neck. The stopper carries a mechanical stirrer, a separatory funnel, a thermometer and a glass delivery tube about 10 mm. in diameter which is connected to a water pump. The space between the stopper and the flask is closed by winding a strip of asbestos paper around it (Note 3). 

Chloropropionaldehyde is a very unstable substance which polymerizes rapidly especially in the presence of traces of hydrochloric acid. The crude material must be oxidized without delay as standing before oxidation will cause a lowering of the yield. 

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]. 

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°. 

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. 

Problem 15.2 Give structural formulas for (a) methyl isobutyl ketone, (b) phenylacetaldehyde, (c) 2-methyl-3-pentanone, (d) 3-hexenal, (e) /i-chloropropionaldehyde. ... 

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... 

There are many examples of reaction (a) e.g., arenediazonium chlorides add to acrylic and methacrylic acids esters, and nitriles giving / -aryl-chloro-propionic acids, esters, and nitriles 242-244 and <%,/ -unsaturated aldehydes afford 3-aryl-2-chloropropionaldehyde and the analogous 2-bromo aldehydes.245,246 Butadiene undergoes 1,4-addition.247-249 Phenylacetylene and a benzenediazonium chloride solution that has been neutralized with sodium carbonate solution gives, at 25-30°, a 46.5% yield of <%-chlorostilbene.250... 

In chlorination of aldehydes the nature of the product (a-chloro aldehyde or carboxylic acid) depends both on the concentration of the added acid and on the nature of its anion 628 In 0.5N-hydrochloric acid at 10-15° chlorination of propionaldehyde gives 98% of propionic acid but in 4.5-6.3N-hydrochloric acid gives 90-92% of 2-chloropropionaldehyde. The concentration of acid is held constant by addition of water during the chlorination. 

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). 

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