METHODS FOR THE SYNTHESIS OF THYROXINE AND TRIIODOTHYEONINE P. M. Kochergin, R. M. Palei, A. N. Kravchenko, and E. V. Popova UDC 615.357:577.175.443.444].012.1[048.8]

Thyroxine (I, T~, tetraiodothyronine, L-~-amine-~-[3,5-diiodo-4-(3',5'-diiodo-4'-hydroxyphenoxy)phenyl]propionic acid) and triiodothyronine (II, T 3, L-~-amino-$-[3,5-diiodo-4-(3'iodo-4'-hydroxyphenoxy)phenyl]propionic acid)* are hormones produced by the thyroid glands of humans and animals. They are responsible for vitally important functions in the human body: they regulate energy processes, tissue oxygen utilization, growth, and tissue differentiation; they affect the states of the nervous and cardiovascular systems. Deficient or excess secretion of I and II result in a number of severe diseases, the thyroid hormones I and II have consequently found wide medical use [7, 23, 27, 28, 40, 59, 69, 70]. The similarity in structure results in similarities in biological actions, with the difference that II is 3-5 times more active than I [7, 13, 63]. Apart from their therapeutic uses, I and II have recently become useful as starting material for the preparation of diagnostic reagents, in radioimmunoassay kits [44, 80], and in immunoenzyme assay kits [3, 4, 8, 61], which allow easy and rapid assessment of the functional state of the thyroid gland in patients. The biological actions of I and II have been reviewed in detail [2, 7, 23, 27, 28, 40, 59,. 69, 70], though the methods of their synthesis have not yet been considered systematically. The only review available describes the chemistry of I, covering data up to 1950 [51]. The aim of the present review is to attempt to generalize the various experimental and clinical data on the synthesis of I and II, as methods for their synthesis is important for the industrial production of thyroid hormones.



i~ I

i ,r-"

NH z

i~ Z
3 5 Z 6 I .N]"[Z I


3' 2' 5' 6 '~

JqHz I

I l~ I




NHz I 1 ~ NH7




~I]le alternative names for these hormones, L-~-[3,5-diiodo-4-(3',5'-diiodo-4'-hydroxyphenoxy)phenyl]alanine (I) and L-6-[3,5-diiodo-A-(3'-iodo-4'-hydroxyphenoxy)phenyl]alanine (II), are often found in the literature. S. Ordzhonikidze Science Research Chemicopharmaceutical Institute, Moscow. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 6, pp. 43-49, June, 1990. Original article submitted June 29, 1989.



9 1991 Plenum Publishing Corporation

Scheme 1 2I' /F Iz [o] Iz Iz 2Z X Scheme 2 I + ~r I ~ I .CI~ -~ I 2Z~ 0 PhCONHCHzCOOH _~CH]'-/>'.Ph o H20 = I I MeO~ o~CH= I "-7.~r I ~ O NHz 0 NO Z ~ H+ XlZ I 2~ I IO ~ O ~ M e T = N I C [ I Ou--q~ Meo J 5Z7 O GN Sr. 59. 69]. and designated it thyroxine. though he mistakenly suggested it to be an iodinated indole derivative [59. 69]. with a high (up to 75%) content of iodine. ~8. In 1914. The chemical structure of I was determined in 1926-1927 by Harington and Barger [47. Kendall extracted a pure compound from the thyroid gland. 431 . English and German investigators exctracted a substance (iodothyrine). using acid and alkaline hydrolysis of the thyroid gland [59].'~"+~HCOPh MeO-</~\~-O~ ~3H=CCOOEt 'CCOOH n ~woPh I)-~J I f HI m H O .~ O~CIi2CI HCOOH I NHZ + D-I D-7 J%eparation~ ~-I into enatiomers The importance of the thyroid hormones and their major role in the etiology of the endocrine disease hypothyroidism were already known at the end of the last century.

~ E 7 "r -~ enantiomers I(. 3. however. I and II themselves are used for clinical purposes. 2'. be noted that XI is used as a therapeutic agent for the treatment of endocrine diseases [7]. ----.II was extracted from human blood and bull thyroid gland in 1951-1953 by Gross and PittRivers [45. and as a racemate (L-. 69. in atherosclerosis. h ~ a n and animal blood and thyroid glands are now known to contain seven other iodinated thyronine (III) and tyrosine (IV) derivatives: 3. and 3.Z~ I I HCfX~. as are their sodium salts and hydrochlorides. as thyroid hormones.XX V// H~ CH=Q. I and II are optically active substances. [71-77]. which is widely distributed in the animal and plant worlds. As a-amino acids.3'. ~l-lCHO HIO H) xxx.5-diiodotyrosine (XI).7 times more active than DL-II. D-. These two groups independently determined its structure. PhCO RCONHCH~H~EO O CHi~ ~ xx~ I ~ M e .3'-diiodothyronine (VIII).OOOMe------RO-<~ ~}-O-~' "2-CH= C-COOMe NO7. They can therefore exist as two enantiomers: the levorotatory and the dextrorotatory.and tri-iodo derivatives of the amino acid thyronine (III. as each contains an asymmetric carbon atom. as D-I has anticholesterolemic properties [63]. The natural compounds I and II are Lenantiomers. 3. crystalline substances. L-II is 14 times more active than D-II. 69]. but in other diseases.5'-triodothyronine (V). and by Roche et al. and 1.C~O ~--~ O "~_ ' 9 C Separation into CH~ HCOOH ~ L . The latter is because the L enantiomers have significantly greater activity in comparison with the D enantiomers and the racemates. I and II are stable. 75]. but is thus far excluded from general use because of its low activity. D-I (dextrothyroxine) and its sodium salt also have clinical uses. Scheme 3 I I MOz NOz 2XZZ I O=r-O. 3-iodotyrosine (X). 76]. Compounds V-XI are generally not considered to be hormones [40.5-diiodothyronine (VI). Y). respectively). and biological roles have not yet been discovered for most of them. 69. 74. Apart from I and II. It is known only that X and XI are intermediates in the biosynthesis of I and II. for example. Ph I -------RO 0 . In structural terms. and DL-forms. D-~ i(~) D-~ D-I H20 DL- L-2X~ L-I 432 . and form salts with both alkalis and with mineral acids. 46. which does not occur in nature: thyronine is in turn a derivative of the amino acid tyrosine (IV). and have the same configuration as L-IV [41.HO A. 72. 60. ~ R=Me. It should. I and II are tetra. 1 ~OR XXVI// ~{Z t NHCOR Ro I-I* o XX// -CO?Me SO - m= 1 L I ooR j o_ o_ o-oooMo I . 46. according to [13]. Thus. 69]. in the L-forms. 3iodothyronine (IX).6'-diiodothyronine (VII). and carried out the first syntheses [45. they are amphoteric. solid.

L-I and D-I were obtained by hydrolysis of the formyl group and subsequent iodination of the resulting compounds L-XXIII and D-XXIII ~see Scheme 3). including a number of preparations for pediatric use. which enter the blood. and consists of a number of steps [40. This syntesis of I was improved by Nahm and Siedel [64]. These authors noted that the separation of DL-I into optical enantiomers was difficult. However. The pharmaceutical industry has great experience in the extraction of natural hormones from animal materials [25. and others). XXIII). I has also been synthesized from XI in vitro: by the oxidation of XI with air oxygen in weakly alkaline conditions in the presence of an Mn30 . catalyst [9. 79]. to form 3-iodo.3-triiodo-5-nitrobenzene (XIV). this is not a good route for the preparation I and II. with the removal of an a-alanine fragment. 69] (Scheme i). These methods have not been used industrially.5-diiodothyronine (DL-XDL\I) using brucine (dimethoxystrychnine) [22. was carried out in 1927 by Harington and Barger [48]. Hungary. has been used for several decades in the therapy of endocrine diseases with altered thyroid function. 41. which iodinates tyrosine (IV) bound to the protein thyroglobulin. This is a defatted and dried thyroid gland extract from slaughter animals. which reacts with the initial substrate XI to form I. containing I and II in the ratio 4-5:1 [6. 433 . DL-I was resolved to its optical enantiomers using a-phenylethylamine [49]. FRG. requiring rather complex separation into enantiomers. from which. which is then transformed to pyruvic acid and ammonia. ii. 69]. 59. These workers started with 4-methoxyphenol (XIII) and 1. the large number of stages. A hormonal preparation of natural origin. and have been scaled up for industrial production in several countries (USA. 64]. I was produced in the form of a racemate (Scheme 2). this simple one-step synthesis of I from the readily available XI has not found use for therapeutic preparations. producing I with a yield of 23-36% [53. The first synthesis of I. It has been suggested that this oxidative reaction has a radical-mediated mechanism.5-diiodotyrosines (X and XI). which remain bound to thyroglobulin.and 3. 69]: partial oxidation of XI produces diiodoarylpyruvic acid [XII]. 26]. 59. GDR. 23. This route for biosynthesis has also been demonstrated chemically: by oxidation with air oxygen of a mixture of XI and XIII in aqueous buffer (pH 7. Other possible mechanisms of the biosynthesis of I and II have also been considered [40. 49. Belgium. 62] (see Scheme I). because of its low yield and the loss of optical activity. in the form of a-aminoacrylic acid. via a series of reactions through compounds XV-XXIII. The use of this preparation is now declining because of the synthetic production of I and II.6).2. This material appeared to be biologically identical to the natural hormone extracted from the thyroid gland. Preparative methods for the synthesis of I and II are described below. They therefore suggested that this operation should be carried out at the stage of N-formyl-3. which confirmed its structure. As a result. Iodides are oxidized by peroxidase to free iodine. becuase of their low concentrations in the thyroid and the complexity of their extraction and purification [50. Such methods have been developed. X and XI residues react together to form I and II. 69]. The synthetics also allow I and II to be used together in different combinations. The availability of synthetic I and II resulted in the possibility of developing state of the art therapeutic preparations with strictly controlled dosing levels. 25-28. This process is regulated by the hormone thyrotropin. 65-69. and the production of racemic mixtures (I. and with potassium iodide [7]. 7. by the replacement of XIV with 3-iodo-4-hydroxy-5-nitrobenzaldehyde (XXIV) using Scheme 3 (via compounds XXV-XXXI). The first step is the concentration of inorganic iodides from the blood into the thyroid gland. Reduction of L-I to thyronine (III) showed that this hormone has the same configuration as the natural configuration as the amino acid tyrosine (IV) [41]. Proteolysis of thyroglobulin-bound I and II results in the formation of the free hormones. 50. thyroidin. II being produced by deiodination of I (see Scheme i).The biosynthesis of I and II takes place in the thyroid gland. Switzerland. However. investigators have turned their attention to the development of synthetic methods for the production of I and II. since they are based on the use of starting compounds of low availability.

18. using the Sandmeier reaction produced the ethyl eser of N-acetyl-3.7 I ~/-C~I~HC . scheme 4 was successful]y used for its synthesis. Subsequent acetylation of XXXII and esterification of XXXIII produced the ethyl ester of N-acetyl-3. J~Iz /-J~rO z r NO 2 ~OMe XXXIII J~O~ 3 ~ci I J~Oz xxx/v ~ ~Oz x~Y~' In-~OC~OH ~ -J ------"=. or by enzymatic synthesis [29-31]. 13. resulting in the formation of L-diiodothryonine (XXIII). A patented procedure I15] uses N-iodoacetamide as iodinating agent.. or 8-15% in terms of the initial L-IV {Scheme 5) [i0.5-diiodo-4'-methoxythyronine (XXXIX). H B r ~OH I xxx/x I I. 3. 434 . with iodination of XXIII with iodine (2 moles) in the presence of potassium iodide and ethylamine. The yield of L-II ranged from 50-95% in terms of LXXIII. followed by replacement of the diazo group of YXKXVIII with iodine.-. The widely available L-tyrosine (IV) was used as starting material. 15. from which the diamine (XXXVII) was produced by hydrogenation. using a mixture of nitric and sulfuric acids. this was prepared by hydrolysis of keratin-containing waste products of meat factories. I I I In 1949 Hems et al. 13. XXXI// -----. After the discovery of II. 18.2~HCOOEt ~ H~SO4 ------ %~-I z ~'XXVII XXXI/I.~ HIor. producing L-I with a yield of 26% in terms of IV (Scheme 4). All the protecting groups were removed by heating this compound with concentrated HI or HBr. 12. and the reaction takes place in anhydrous methanol in the presence of triethylamine. 24]. 24].NO?.5-dinitrotyrosine (XXXIV). Diazotization of XXXVII. Treatment of EXD(IV with p-toluolsulfochloride and p-methoxyphenol in anhydrous pyridine without extraction of the intermediate tosylate (XXXV) resulted in the synthesis of the corresponding diphenyl ester (XXXVI). by iodination of L-XXIII with an equimolar quantity of iodine in the presence of potassium iodide in aqueous ammonia or primary or secondary amines [i0.MeO ~ /_ CH. x/~"CH~"~COOEtl " ~'~ L .HO-(' ")-CT'I"LQHCOOEt----Z-"~ITs"O-~. 12. [42] described a new stereospecific synthesis of I. -/ .5-dinitrotyrosine (XXXII)was prepared by nitration of IV.N'Oz = lv~O_~~CHzOI~COEt _ _ PIC HZ ~. The Harington-Barger scheme was then followed.Scheme 4 z ~ .

and patents.6-diiodophenols [32. the synthesis of I and II using schemes 4 and 5 has industrial value. and DL-II was synthesized by iodination of D-XXIII by N-potassium-iodo-ptoluolsulfonamide [16. 17. This resulted in the proposal of a second stereospecific synthesis of L-I and L-II from L-IV through L-XI [15. followed by addition of sodium bromide resulted in the synthesis of 4. and the low yields of I and II (8-26% in terms of the initial compound IV). Despite these disadvantages. and of methods of extraction and purification of the final products I and II. compound II is formed as an admixture. with methods including preparative chromatography [12.. These syntheses of I and II have a number of disadvantages. describing a number of modifications both of individual stages. 37.g. as are 435 . the ethyl ester of N-acetyl-3.5-diiodothyronine (XXIII). 51]. A proportion of XXIII also remains unreacted. e. it has a significant disadvantage.g.5-diiodotyrosine (XI). 33]. with subsequent acylation with XI and esterification with XLII. 37.6-diiodophenols do react with diaryliodonium iodides (or bromides) with the formation of the respective diphenyl esters. A number of authors [32. 20. while I is always present in preparations of it. 2. This was iodinated to produce L-I and L-II with yields of 25% in terms of the starting compound IV II0. It should also be noted that the iodination of XXIII produces heterogeneous products. 35].4'-dimethoxydiphenyliodonium iodide and the respective bromide (XLI) [14.13p _+_ I D-II was synthesized by a route analogous to that used for L-II. 69]. by the iodination of D-XXIII with iodine. e. though these attempts were unsuccessful. This substance may be explosive. 52] (Scheme 6). 41. 13. As a result. [i0. During preparation of I. 64]. 38. The reaction of XLIII with XLI produces the ester XXXIX. purification of I and II must be carried out carefully. Heating XXX IX with HI or HBr produces 3. 18. which is probably explained by the difficulty in forming diphenyl esters using 2. 38] have tried to prepare XXIII from 3. [24]. Although slowly. 19]. 21] (Scheme 6). the use of anhydrous pyridine and concentrated HI or HBr.5-dinitrotyrosine (XXXII) bv Scheme 4. Attention should be brought to a number of later papers.~ K1 MeCONHI L-II l o ~ o x" Scheme 6 ~o -• 2Z "NaI04 m or mffr I 2X/ X=l. the main ones being the nitration of IV to XXXII and the substitution of the two amino groups with iodine by the Sandmeier reaction. The entire synthesis of I and II consists of seven steps.5-diiodotyrosine (XLIII) was obgtained by iodination of IV with iodine or with iodine-chlorine [i. Treatment of anisole (XL) with sodium iodate and potassium iodide or a mixture of iodine pentoxide.Scheme 5 L-XXIll I.. Although this synthesis of I and II is two steps shorter compared with the synthesis via 3. namely the preparation of iodonium iodide {or bromide) (XLI). 12-15. The second component.

The authors who first synthesized this amino acid [48] attempted to iodinate it. 69. and to attempt to produce compounds more active than I and II. 73. 76. the substitution of the ~-alanine side chain with fragments of other amino acids. the reaction also took place in ring B.and 3'. since iodination occurred on the more distal benzene ring B.groups. When 3-iodothyronine (IX) was iodinated. the introduction of alkyl radicals at the 5' position. a number of papers appeared in the literature discussing the synthesis of different derivatives of these hormones. 69]. and the long reaction time required (24-80 h) should also be noted.and 3. The iodination of III was later studied in more detail by Roche et al.and m-tyrosines and other compounds [34. I. [72. with the formation of 3. ]/ ~E I I/ ~Z I I Other studies included the substitution of iodine atoms in compounds I and II for atoms of other halogens. the positioning of iodine atoms in other positions of benzene rings A and B. 54-58. The low yields of XLI (12-47%) and XXXIX (50-60%). A number of authors [40. They also failed to obtain I and II.5'-diiodothyronine (XLIV. Further iodination of V and VIII was not discussed.5'-triiodothyronines VIII and V {73. Finally.Scheme 7 z I IzI I 1 Scheme 8 I I ~ I Iz 1 other iodinated compounds [5]. and of compounds of similar structure [40. The biological investigation of these compounds showed that they were either inactive er had weak thyroid activity. 36. and the synthesis of analogs of I and II based on o. XLV) (Scheme 7). 43. but did not obtain compound I.3'. NH2. The basic aim of these studies was to determine the relationship between the structure and the biological actions of the compounds. after the structures of I and II were established and methods for their synthesis were developed. 75] (Scheme 8). 69] synthesized derivatives of I and II containing OH-. their methods of synthesis are not reviewed here. 77]. and COOH. the replacement of the bridging oxygen atom with sulfur.3'-diiodo. Iodination of thryonine (III) may be an attractive route for the synthesis of I and II. 78]. 436 . I/~ I. with the formation of 3'-iodo. Since attempts to synthesize different derivatives of 1 and 7I have not produced useful therapeutic preparations. and their great medical value for the treatment of a number of diseases were recorded. even adding a third iodinated benzene ring (compounds XLVI and XLVII) [39]. 40.

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