Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1997-04-07
1999-06-29
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
560 39, C07C22900
Patent
active
059170875
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to improvements in a process for producing sodium l-thyroxine, which is a thyroid hormone used to treat conditions such as myoedema, cretinism and obesity.
Sodium-l-thyroxine (which is the sodium salt of O-(4-hydroxy-3,5-diiodo-phenyl)-3,5-diiodo-l-tyrosine) can be produced in a six step synthesis as described in U.S. Pat. No. 2,889,363 and U.S. Pat. No. 2,889,364 (Baxter). This process starts from the naturally occurring amino acid l-tyrosine, which is iodinated in a first step to form 3,5-diiodo-l-tyrosine. The amino group is protected by acetylation in a second step and then the acid group is converted into the ethyl ester in a third step. The fourth step in this synthesis is the oxidative coupling (using oxygen and a manganese salt catalyst) of the protected iodinated tyrosine product to form a biphenyl ether moiety. Acid hydrolysis of this biphenyl ether moiety in a fifth step yields l-thyroxine, as a free base, which is converted into its sodium salt in a sixth step. The present invention relates to improvements in the preceding process.
Modern standards of pollution control, safety and environmental protection have changed over the years and it has been found that this six step synthesis, in particular the step four coupling, does not always meet modern standards. For example, pure oxygen used in an open, unpressurised system in the presence of flammable solvents is a fire or explosion hazard. Use of a pressurised closed system would be preferred to obtain greater effluent control to reduce or eliminate environmental pollution. A closed system would more readily meet modern safety standards, and reduce risk of fire. However, if the fourth step oxidative coupling reaction is performed in a closed system at increased pressure using only pure oxygen and a manganese salt, the reaction does not proceed well on a large scale even when the pressure is increased, for example to 20 atmospheres. Instead, side reactions predominate and little of the desired product is produced. An aspect of the present invention relates to a means for performing the above desired coupling reaction in reasonable yield in a closed system with all the advantages mentioned above.
At atmospheric pressure it is known the oxidative coupling step (step four) is more efficient with oxygen used as the oxidising agent than air. For example, see U.S. Pat. No. 2,589,364 (Baxter), column 4,lines 1-13,table IV--in which oxygen produces a yield of 20.8% compared to the yield with air of 4.8%. Surprisingly, it has been found that comparable or better yields are obtained in the desired coupling and the reaction time is reduced if an organic amine additive is present in the reaction mixture, the coupling is performed at a pressure of about 20 atmospheres and optionally an inert diluent is added to the oxygen. Under these conditions some or all of the disadvantages (described herein) present in the prior art process are avoided.
Broadly the invention comprises the oxidative coupling of a diiodo-1-tyrosine to form a biphenyl ether derivative, catalysed by a manganese salt in which the amine and acid functionality of the diiodo-1-tyrosine have been protected by suitable protecting groups, characterised in that the reaction is performed at a pressure of about 20 atmospheres in presence of an organic amine additive using a gaseous oxidant comprising oxygen and optionally an inert diluent.
Preferably, the inert diluent is nitrogen, and the oxidising gas mixture comprises from about 10% to 40% by volume of oxygen, more preferably from about 21% to about 38% by volume of oxygen, most preferably the gas mixture is air.
Suitably the organic amine additive may be a primary amine of formula R.sub.1 NH.sub.2 in which R.sub.1 comprises an optionally substituted C.sub.1-10 alkyl chain which may be straight or branched, a secondary amine of formula R.sub.2 R.sub.3 NH in which R.sub.2 and R.sub.3 independently represent an optionally substituted C.sub.1-6 alkyl chain which may be straight or branched or R.sub.2 and R.sub.3 together
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Killos Paul J.
Knoll Aktiengesellschaft
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