An Examination of Synthetic Routes to Papaverine, and, Synthetic Studies in 1:4 Oxazine Chemistry

Dawson, William (1951) An Examination of Synthetic Routes to Papaverine, and, Synthetic Studies in 1:4 Oxazine Chemistry. PhD thesis, University of Glasgow.

Abstract

Part I - An Examination of Synthetic Routes to Papaverine. In an attempt to establish a new synthesis of the alkaloid papaverine, four possible routes were examined. 3:4-Dimethoxyphenylacetyl chloride was condensed with ethyl aminoacetate giving ethyl 3:4-dimethoxyphenylacetamido-acetate, which on hydrolysis formed the free acid. Condensation of this acid and 3:4-dimethoxybenzaldehyde led to the formation of 2-(3:4-dimethoxybenzyl)-4-(3:4-dimethoxybenzal)-oxazol-5-one which underwent ring opening with sodium carbonate to alpha-(3:4-dimethoxyphenylacetamido)-3:4-dimethoxy-cinnamic acid. Decarboxylation of the acid gave beta-(3:4-dimethoxyphenylacetamido)-3:4-dimethoxystyrene (I). The structure of this material was confirmed by hydrogenation to homoveratroyl-homoveratrylamine. All attempts to ring close this substance with the elimination of the elements of water to papaverine failed. The theoretical aspects of this failure are discussed. Using opianic acid, a possible synthetic route was investigated. The acid condensed with nitromethane giving nitromethyhmeconin, reduction of which formed aminomethyl-meconin hydrochloride. Acylation with 3:4-dimethoxyphenyl-acetyl chloride led to the formation of the desired 3:4-dimethoxyphenylacetamido-methylmeconin (II). It was however found impossible to eliminate the lactone ring and convert this compound either to papaverine or an isoquinoline derivative. An examination of the ring closure of 2-(alpha-bromophenyl-acetamido)-l-phenyl-ethane (III) was made in the hope that during this reaction the excess hydrogen atoms of the heterocyclic ring formed, would be removed by reductive dehalogenation. Instead of the expected product, 1-benzyl-isoquinoline however, 1-benzyl-3:4-dihydroisoquinoline was produced. When the reaction was examined using 2-(alpha-chloro-3:4-dimethoxyphenylacetamido)-1-(3:4-dimethoxy-phenyl)-ethane, no evidence of reductive dehalogenation was found. An approach to a papaverine synthesis was made through dihomoveratramide (IV) by treatment of this substance with phosphorus oxychloride to form 3-chloro papaverine. The diamide was found to be unstable to the action of this reagent and gave homoveratramide. An alternative synthesis of 3-hydroxy-isoquinolines was established. Methyl 2-acetyl-4:5-dimethoxyphenylacetate with ammonia gave 6:7-dimethoxy-3-hydroxy-1-methyl-isoquinoline and similarily methyl 2-benzoyl-4:5-dimethoxyphenylacetate formed 6:7-dimethoxy-3-hydroxy-1-phenyl-isoquinoline. When the reaction was examined using methyl 4:5-dimethoxy-2-phenylacetyl-phenylacetate, the product isolated was 6:7-dimethoxy-2-hydroxy-3-phenyl-1:4-naphthoquinone. Methyl 4:5-dimethoxy-2- (3: 4-dimethoxyphenylacetyl) -phenylacetate also formed 6:7-dimethoxy-3-( 3:4-dimethoxyphenyl)-2-hydroxy -1:4-naphthoquionoe. In conjunction with this work, the Schiff's base formed by the condensation of 2-(3:4-dimethoxyphenyl)-2- methoxy-ethylamine and 3:4-dimethoxybenzaldehyde was shown to rearrange giving 1:2-dihydro-6:7-dimethoxy-l-(3:4-dimeth- oxyphenyl) -isoquinoline. Part II - Synthetic Studies in 1:4-Oxazine Chemistry In an extension of the synthetic route to 5-hydroxy-l:4-oxazines discovered by Newbold, Spring and Sweeny (J. 1950, 909. ), the synthesis of phenyl substituted 5-hydroxy-1:4-oxazines was successfully carried out by this method. At the same time various condensations of difunctional compounds to 1:4-oxazines were examined. Bromoacetal was condensed with ethanolamine forming 2-amino-ethoxy-acetaldehyde diethylacetal which was converted into dihydro-1:4-oxazine. 2-Amino-1-hydroxy-propane in a similar manner gave (2-amino-1-methyl-ethoxy)-acetaldehyde diethylacetal which was converted to 2-methyl-dihydro-1:4-oxazine. The extension of this reaction to fully unsaturated l:4-oxazines was examined.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1951
• Depositing User: Enlighten Team
• Unique ID: glathesis:1951-78871
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 14:44
• Last Modified: 30 Jan 2020 14:44
• URI: https://theses.gla.ac.uk/id/eprint/78871