715. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from L-tyrosine

Chalmers, Jane; Dickson, G. T.; Elks, J.; Hems, B. A.

doi:10.1039/jr9490003424

Cited by 78 publications

(45 citation statements)

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“…32 Lactam 33 was reduced to the aniline and then converted to lactam 34 via a Sandmeyer iodination reaction (Scheme 2). 33 Treatment of 34 with FSO 2 CF 2 CO 2 CH 3 and CuI in DMF yielded 35. 34 Compounds 34 and 35 were reduced with diborane to yield THIQs 13b and 12b, respectively.…”

Section: Chemistrymentioning

confidence: 99%

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

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Abstract3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α 2 -adrenoceptor. Fluorination of the methyl group lowers the pK a of the THIQ amine from 9.53 (CH 3 ) to 7.88 (CH 2 F), 6.42 (CHF 2 ), and 4.88 (CF 3 ). This decrease in pK a results in a reduction in affinity for the α 2 -adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often non-selective due to significant affinity for the α 2 -adrenoceptor, while the latter were devoid of α 2 -adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pK a properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the "Goldilocks Effect" analogy, the 3-fluoromethylTHIQs are too potent (too hot) at the α 2 -adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α 2 -adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.

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Section: Chemistrymentioning

confidence: 99%

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

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“…[89] The first of the methods described here for the production of thyroxine is the so-called Glaxo synthesis. [90] (L)-Tyrosine serves as the starting material. Dinitration and N-protection of the amino acid function lead to an important intermediate.…”

Section: Industrial Synthesismentioning

confidence: 99%

Hormones

Schaefer¹

2014

Natural Products in the Chemical Industry

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“…159..5161.5°. When the cold solution of diazotized 4-amino-7-nitrometan~econine from 3 g of the amine was poured into a mixture of water, chloroform, urea, potassiunl iodide, and iodine in the more elaborate procedure used in previous examples (8,15), the total yield of once-crystallized product was only 76y0. Three more recrystallizations of the first fraction of this material from ethanol gave the analytical sample, m.p.…”

Section: -Iodo-7-witrometanzeconine (Iid)mentioning

confidence: 99%

“…The method resembled that used by Chalmers, Dickson, Elks, and Hems in the synthesis of a precursor of thyroxine (8). Sodium nitrite (0.42 g) was warmed with concentrated sulfuric acid (8 ml).…”

Section: -Iodo-7-witrometanzeconine (Iid)mentioning

confidence: 99%

“…When sulfuric acid was used in the diazotization of IIe (in an attempt to avoid nucleophilic displacement of the nitro group) a diazonium salt was obtained whose resistance to thermal decom&tion and to reduction has been recorded (1). The idea of using the poorly nucleophilic m-alent anions, nitrate and perchlorate, in place of sulfate, seemed most u n a t t r a c t i~e .~ Fortunately, the diazonium sulfate prepared by the method of Hodgson and Walker (7,8) was found to react under suitable conditions (8) with cuprous chloride, cuprous bromide, or potassium iodide to give good yields of the activated aromatic halides 4-chloro-7-nitrometameconine (IIb), 4-bromo-7-nitrometameconine (IIc), and 4-iodo-7-nitrometameconine (IId) , respectively.…”

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A Series of Model Compounds for the Study of Aromatic Reactions

Safe¹,

Moir²

1965

Can. J. Chem.

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A series of halogenated phthalides \vas prepared in xhich there \vas a systematic variation in the identity, position, and degree of activation of the halogen, and in the activation of the methylerle group. A study was made of the selective reductive removal of halogen in the presence of another halogen, or of a nitro group.i\Ietameconine (Ia) is admirably adapted to the study of competitive reactions. A rapid survey of its possibilities has shown that in several well-ltno\vn aroinatic reactions it could be used to drive currently favored theories into difficulties that were not easily resolved (1). The new colnpounds described in this paper formed a weapon that has since been used in a much Inore intensive attack upon two of these reactions.One of these was the copper-catalyzed removal of halogen by aqueous hydroxide ion. Our previous work (1-6) had provided a set of compounds superbly suited to the study, a s she\\-n by the large number of new observations recorded in the next paper. RIore coinpounds needed in the investigation were provided in the present work. In particular, the synthesis of IIb, 116, and IId was saved froin triviality by two difficulties that had to be overcome. I t was pointed out previously (1) that the nitro group in 4-amino-7-nitrometameconine (IIe) was very easily extruded on diazotization. For example, when IIe was diazotized in dilute aqueous hydrochloric acid, reduction of the diazonium solution gave 7-chloron~etan~econine (IIIa), and treatment of the diazonium solution wit11 potassiulll iodide gave 4-iodo-7-chlorometan~econine (IIId) (1). The same diazonium solution has now been sho\vn to give 4,7-dichlorometameconine (IIIb) with cuprous chloride. Hou~ever, cuprous bromide gave a mixture of compounds instead of pure 1116. Thus the diazonium cation IIIe was conventional in its relative reactivities towards chloride, bromide, and iodide under the conditions used.

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715. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from L-tyrosine

Cited by 78 publications

References 0 publications

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

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A Series of Model Compounds for the Study of Aromatic Reactions

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715. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from L-tyrosine

Cited by 78 publications

References 0 publications

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Hormones

A Series of Model Compounds for the Study of Aromatic Reactions

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Product

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About

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination