D-Thyroxine monosodium salt

Originator

Choloxin,Knoll

Uses

D-Thyroxine sodium salt (CAS# 137-53-1) is a persistent and bioaccumulative pharmaceutical, and the sodium salt form of D-Thyroxine (T425605), a hormone involved in the maintenance of metabolic homeostasis.

Uses

Antihyperlipidemic.

Manufacturing Process

The synthesis of dextrothyroxine includes 10 steps:
1. 3-Iodo-5-nitro-4- [4-methoxy-phenoxy]benzaldehyde
2. 2-Methyl-4-[3-iodo-5-nitro-(4-methoxy-phenoxy)-benzylidene]-4-H-oxazol5-one
40 g above prepared derivate was heated with 12 g acetic acid and 10 g dry sodium acetate in 70 ml acetic anhydride for 2.5 hours at 100°C. On cooling the oxazolone precipitated. It was filtered off, washed with CCl4 and water; next it was recrystallized from benzene. Yield 35 g. MP: 205°-206°C.
3. Methyl ester 3-iodo-5-nitro-4- [4-methoxy-phenoxy]-αacetylaminocinnamonic acid
20 g the product from an item 2 was stirred with a solution of 1.2 g sodium in 200 ml methanol at 20°C. Soon the desirable ester began to fall. It was filtered off after adding of 5 ml 95% acetic acid and recrystallized from 95% acetic acid. Yield 18 g; MP: 216°C.
4. Methyl ester 3-iodo-5-amino-4- [4-methoxy-phenoxy]-αacetylaminocinnamonic acid
25 g Raney nickel was added to the suspension of 67 g above nitro ester in 450 ml methanol. Whereupon about 8.55 L hydrogen was passed (2 hours), the hydrogenation product crystallized. It was filtered off. The catalyst was removed by dissolving in tetrahydrofuran and repeated filtration. The solvent was removed in vacuum. Yield 38 g; MP: 184°C (recrystallized from methanol).
5. Methyl ester 3,5-diiodo-4- [4-methoxy-phenoxy]-α-acetylaminocinnamonic acid
5 g the product from item 4 in 20 ml 95% acetic acid and 30 ml conc. H2SO4 was dropwise added to the solution of 1.1 g sodium nitrite in 15 ml conc. H2SO4 and 30 ml conc. acetic acid. After 30 minutes the solution of diazonium salt was added to the mixture of 3.5 g KI, 5.2 g I2 and 2.0 g urea in 250 ml water and 30 ml CHCl3.
The excessive iodine was removed with NaHSO3, an organic layer was separated and distilled off to dryness. The residue was recrystallized from acetic acid to yield 3.9 the desired product. MP: 209°C.
150 ml acetaldehyde was dropwise added to 150 ml HI (d 1.70) by ice cooling. Then 0.1 g FeSO4 and 18 g red phosphorous was added to 27 g diiodo-derivate from the step 5. The mixture was heated to reflux about 20 minutes. Simultaneously methyl iodide was distilled off. Red phosphorous was filtered off. The clear filtrate was distilled to dryness. The residue was dissolved in 150 ml of hot water and 100 ml 2 N HCl. The conc. NH3 was added. Precipitated product was washed with water, methanol and acetone and dried. Yield 20.7 g (86%). MP: 256°C (decomp.).
7. DL-N-Formyl-3,5-diiodothyronine
100 g DL-3,5-Diiodothyronine was added to the mixture of 100 ml dry formic acid and 50 ml acetic anhydride by stirring at ambient temperature to give the clean solution. Soon DL-N-formyl-3,5-diiodothyronone begun to crystallize. Yield 95 g. MP: 225°-230°C.
8. (-)-D-N-Formyl-3,5-diiodothyronine
The above prepared DL-N-formyl-3,5-diiodothyronine was in 1500 ml of dry isopropanol heated on a steam bath heated and the hot solution of 300 g dry brucine in 1500 ml dry isopropanol was added. On cooling (+/-)-D- N-formyl3,5-diiodothyronone-brucine salt precipitated during 3 hours. 290 g this salt was recrystallized from a mixture of 1 L dimethylformamide and 2.5 L
isopropanol. MP: 271°C. It was dropped into 750 ml 2 N NH3, four times with methylene chloride extracted for brucine removing. Water-basic solution was acidified to pH 2 with conc. HCl. (-)-D-N-Formyl-3,5-diiodothyronine precipitated on cooling. Yield 140 g (96.5 %). MP: 186°C.
9. (-)-D-3,5-Diiodothyronine
It was prepared from 100 g (-)-D-N-formyl-3,5-diiodothyronine and mixture of 1 L 48% HBr and water (1:2). Yield 80.5 g MP: 252°C (decomp.). [α]D20: - 25.0° (c=5, in 1 N HCL/95% ethanol 1:2)
10. (-)-D-3,5,3',5'-Tetraiodothyronine (dextrothyroxine)
9 g (-)-D-3,5-diiodothyronine was dissolved in 80 ml 40% methylamine by stirring at room temperature. 34 ml 1 N iodine/KI was added slowly to this solution. After 1.5 hours stirring, 150 ml NaCl solution was added and a sodium salt precipitated. It was dissolved in mixture of 200 ml methanol and 20 ml 2 N HCl, and heated with an animal coal. The coal was filtered off and neutralized with solution sodium acetate to pH 6. The precipitated was filtered off, washed with methanol and acetone and dried. Yield of desired product 6.2 g; MP: 235°C; [α]D25:- 14.6° (c=5, in 1 N HCl/95% ethanol 1:2).

brand name

Choloxin (Abbott).

Therapeutic Function

Thyroid hormone, Anticholesteremic

General Description

Dextrothyroxine sodium,O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-D-tyrosinemonosodium salt hydrate, sodium D-3,3 ,5,5 -tetraiodothyronine(Choloxin), occurs as a light yellow to buffpowder. It is stable in dry air but discolors on exposure tolight; hence, it should be stored in light-resistant containers.It is very slightly soluble in water, slightly soluble in alcohol,and insoluble in acetone, chloroform, and ether.The hormones secreted by the thyroid gland have markedhypocholesterolemic activity along with their other wellknownactions. The finding that not all active thyroid principlespossessed the same degree of physiological actionsled to a search for congeners that would cause a decrease inserum cholesterol levels without other effects such as anginapectoris, palpitation, and congestive failure. D-Thyroxineresulted from this search. At the dosage required, however,L-thyroxine contamination must be minimal; otherwise, itwill exert its characteristic actions. One route to opticallypure (at least 99% pure) D-thyroxine is the use of an L-aminoacid oxidase from snake venom, which acts only on theL-isomer and makes separation possible.

Clinical Use

D-Thyroxine monosodium salt potentiates the action of anticoagulants suchas warfarin or dicumarol; thus, the dosage of the anticoagulantsused concurrently should be reduced by one third andthen, if necessary, further modified to maintain the prothrombintime within the desired limits.