Ethyl atropate

Synthesis The reaction of buta-1,3-dienyl-dimethylamine 3 with ethyl atropate 4 yields tilidine as a cis/trans mixture (trans cis = 2 3). Most of the analgesically inactive cis isomer is separated as a zinc complex and the trans isomer is isolated as the hydrochloride. The cis isomer can be epimerized to the trans form by treating the epimeric mixture with acid (Satzinger (Godecke), 1965 Sallay (Warner-Lambert), 1969, Satzinger, 1972 Satzinger et al., 1978 Overman et al., 1979 Kleemann et al. 1999). 

Tilidine is the minor component of the product of cycloaddition of trans 1-dimethylamino-l,3-butadiene (21a, R = NMe2) to ethyl atropate, a reaction with favored cis stereochemistry. When the butadiene 21a (R = NHC02CH2CC13) was employed, the trans isomer was obtained exclusively and was converted to tilidine in two steps (Zn dust-HAc followed by CH20-NaBH4).(35) Stereochemistry in the series was established by spectroscopic methods, X-ray crystallography, and chemical transformations. t-l-Dimethyl-amino-r-3-propionyloxy-3-phenylcyclohexane, a saturated reversed-ester analog of tilidine, was only feebly active in the MHP test.(62)... 

Diels-Alder reaction with ethyl atropate (2). The diene reacts with 2 to form a single cycloadduct 3. In contrast, when the —CH2CQ3 group is replaced by benzyl, the addition yields two crystalline adducts 4 and 5. In general l-(acylamino)-l,3-dienes show favored cndo-stereoselectivity, whereas l-(dialkylamino)-l,3-dienes show favored ejto-stereoselectivity. ... 

Tilidine synthesis is impressively simple. [112] The cyclohexene system is constructed by a Diels-Alder reaction of an enamine, derived from croton-aldehyde, and ethyl atropate. 

A highly stereoselective tilidine synthesis was published by Larry Overman. [113] The Diels-Alder reaction of a related carbamate with ethyl atropate... 

The synthesis of ethyl atropate was adapted from the procedure of Amos and Davey. Freshly distilled diethyl oxalate (Eastman, 109.5 g) and ethyl phenylacetate (Eastman, 162.9 g) are successively added to 51.5 g of sodium ethoxide (freshly prepared from Na metal and ethanol) in 300 ml of benzene. After standing overnight, the sodium salt of diethyl phenyloxaloacetate separates from the solvent. This product is washed with ether and acidified with concentrated H2SO4 to yield diethyl phenyloxaloacetate. At this stage, 90 ml of 38% aqueous formaldehyde and 300 ml of H2O are added at 15°. Then, 81 g of K2CO3 in 150 ml of water are added over a period of 30 min. After standing for about 4 hr, the reaction mixture is extracted with ether to yield 116 g of ethyl atropate, b.p. 76°-77° (1-2 mm). 

L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-L-phenylalanine methyl ester trihydrochloride Angiotensin amide Atropic acid ethyl ester Tilidine HCI Atropine... 

A solution of 194 grams (2 mols) of fresh-distilled l-(dimethylamino)-l,3-butadiene is combined at room temperature in a 1 liter round-bottom flask with 352 grams (2 mols) atropic acid ethyl ester. After being stirred for about 10 minutes, the reaction mixture gradually becomes exothermic. By cooling with ice water, the contents of the flask are kept at a temperature of 40° to 60°C. After the reaction has ceased, the mixture is kept overnight (about 8 to... 

The insolubilized DIOP catalyst (34) was found to be rather ineffective for the asymmetric hydrogenation of oleflnic substrates the hydrogenation of a-ethyl-styrene proceeded readily but gave (-)-R-2-phenylbutane with an optical purity of only 1.5%. Methyl atropate was hydrogenated to (+)-S-methylhydratropate (2.5% ee). The soluble DIOP catalyst gave 15 and 17% ee, respectively, for the same reductions. The optical purity of the products was lower when recovered insolubilized catalyst was used. There was no reduction of a-acetamidocinnamic acid in ethanol-benzene with the insolubilized catalyst, presumably due to the hydrophobic nature of the polymer support causing it to shrink in hydroxylic solvents. 

Several syntheses from acetophenone have definitely established structure III for atropic acid. In the first instance the ethyl ether (IV) of atrolactic acid was synthesized and the atropic acid was derived from this by splitting the ether and dehydrating (HCl) the resulting atrolactic acid (83). The synthesis of atrolactic acid ethyl ether involved the conversion of acetophenone to a,a-dichloroethylbenzene (PCh), thence to a-ethoxy-a-cyanoethylbenzene (alcoholic KCN) followed by hydrolysis (Ba(OH)s) to IV. This may be illustrated by the following reaction sequence ... 

Atropic acid ethyl ester Hydrogen chloride... 

The atropic ester typically is produced by condensation of ethyl phenyl-acetate and formaldehyde. The condensation reaction can be performed in the presence of ethyl oxalate to obtain the product in higher yield. A more modern approach is the Pd-catalysed alkoxylcarbonylation of phenylacetylene. 

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