ChemicalBook CAS DataBase List L-Thyroxine

L-Thyroxine synthesis

8synthesis methods

Product Name:L-Thyroxine
CAS Number:51-48-9
Molecular formula:C15H11I4NO4
Molecular Weight:776.87

Levothyroxine, L-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl] alanine (25.1.10), is synthesized in a multi-stage synthesis from 4-hydroxy-3-iodo- 5-nitrobenzaldehyde. Reacting this with benzenesulfochloride in pyridine gives the corresponding benzenesulfonate 25.1.1, the benzenesulfonyl group of which is easily replaced with a 4-methoxyphenyloxy- group upon reaction with 4-methoxyphenol. The resulting 3-iodo-4-(4-methoxyphenoxy)benzaldehyde (25.1.2) is reacted further with N-acetylglycine in the presence of sodium acetate in a Knoevenagel reaction, in which the resulting ylidene compound cyclizes to an oxazolone derivative 25.1.3. The oxazolone ring of this compound is opened upon reaction with sodium methoxide, forming the desired cinnamic acid derivative 25.1.4. The nitro group of this product is reduced to an amino group by hydrogen in the presence of a Raney nickel catalyst, forming the corresponding amine, and subsequent diazotation and replacement of the diazo group of which with iodine gives the methyl ester of α-acetamido-3,5-diiodo-4-(4-methoxyphenoxy)crotonic acid (25.1.6). The resulting compound undergoes simultaneous reaction with hydrogen iodide and phosphorous in acetic acid, in which the double bond in the crotonic acid is reduced, and the methoxy protection is removed from the phenol ring. During this, a simultaneous hydrolysis of the acetyl group on the nitrogen atom also takes place, forming D,L-3,5-diiodothyronine (25.1.7). The amino group in this product is once again protected by the reaction with formic acid in the presence of acetic anhydride, which gives D,L-N-formyl-3,5-diiodothyronine. Separation of isomers in the resulting racemic mixture is accomplished using brucine, giving D-(+)-N-formyl-3, 5-diiodothyronine L-(+)-N-formyl-3,5-diiodothyronine (25.1.8). The protecting formyl group is hydrolyzed using hydrobromic acid, giving L-(+)-3,5-diiodothyronine (25.1.9), which undergoes direct iodination using iodine in the presence of potassium iodide in aqueous methylamine, to give the desired levothyroxine.

70-40-6
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51-48-9
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Yield:51-48-9 91.2%

Reaction Conditions:

Stage #1: 3,3′-diiodothyroninewith methylamine in methanol at 25 - 30;
Stage #2: with iodine in methanol at -8 - 0;
Stage #3: with potassium dihydrogenphosphate;sodium hydrogensulfite in methanol at 15 - 20;

Steps:

3 Example-3 Preparation of Levothyroxine

RBF was charged with lOOgms of 3,5-Diiodothyronine and l000ml of methanolic monomethylamine at 25-30°C and stined for 15-20mm to get clear solution. The reaction mixture was then cooled to -8 to 0°C, and added with Iodine solution at -8 to 0°C overperiod of 2hrs and maintained for 30-45mm at -8 to 0°C.The temperature of the reaction mixture was slowly brought to 15-20°C and charged with lOOgms of sodium bisulphite followed by 300gms of Potassium dihydrogen phosphate.The temperature of the reaction mixture was adjusted to 25-30°C and maintained for 30 - 45mm at 25-30°C. The resultant mixture was filtered and washed with 200m1 of water followed by 200m1 of acetonitrile,dried under vacuum for 12-l5hrs at 55-60°C to get l3Ogms of Levothyroxine with purity NLT 98.5% and yield of 84.5-91.2%.

References:

WO2015/11573,2015,A1 Location in patent:Page/Page column 7

55-03-8
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51-48-9
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References

300-30-1
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51-49-0
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1027-28-7
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300-39-0 Synthesis

300-39-0
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References

L-Thyroxine Related Search:

Inositol Tris(hydroxymethyl)aminomethane PHENYL VALERATE L-Tyrosine L-Alanine Glycine 6-Aminocaproic acid 3,5-Diiodo-L-tyrosine dihydrate 3,5-Diiodo-DL-tyrosine