WO1996011904A1 - Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine - Google Patents

Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine Download PDF

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Publication number
WO1996011904A1
WO1996011904A1 PCT/EP1995/004017 EP9504017W WO9611904A1 WO 1996011904 A1 WO1996011904 A1 WO 1996011904A1 EP 9504017 W EP9504017 W EP 9504017W WO 9611904 A1 WO9611904 A1 WO 9611904A1
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Prior art keywords
thyroxine
formula
tyrosine
compound
hydrochloride salt
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PCT/EP1995/004017
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French (fr)
Inventor
Paul Frederick Coe
Andrew Timothy Turner
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Knoll Aktiengesellschaft
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Priority to US08/817,325 priority Critical patent/US5917087A/en
Priority to DE69516529T priority patent/DE69516529T2/en
Priority to AU38413/95A priority patent/AU3841395A/en
Priority to AT95936478T priority patent/ATE192137T1/en
Priority to CA2202094A priority patent/CA2202094C/en
Priority to EP95936478A priority patent/EP0785921B1/en
Priority to DK95936478T priority patent/DK0785921T3/en
Publication of WO1996011904A1 publication Critical patent/WO1996011904A1/en
Priority to GR20000400963T priority patent/GR3033346T3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to improvements in a process for producing sodium 1-thyroxine, which is a thyroid hormone used to treat conditions such as myoedema, cretinism and obesity.
  • Sodium-1-thyroxine (which is the sodium salt of O- (4-hydroxy-3,5-diiodo-phenyl)-3,5-diiodo-1-tyrosine) can be produced in a six step synthesis as described in US
  • step four coupling does not always meet modern standards.
  • 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.
  • 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.
  • step four At atmospheric pressure it is known the oxidative coupling step (step four) is more efficient with oxygen used as the oxidising agent than air.
  • oxygen used as the oxidising agent than air.
  • step four see US 2589364 (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%.
  • 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.
  • 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.
  • the inert diluent is nitrogen
  • 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.
  • the organic amine additive may be a primary amine of formula R 1 NH 2 in which R 1 comprises an optionally substituted C 1-10 alkyl chain which may be straight or branched, a secondary amine of formula R 2 R 3 NH in which R 2 and R 3 independently represent an optionally substituted C 1-6 alkyl chain which may be straight or branched or R 2 and R 3 together with the nitrogen to which they are attached form a cyclic amine, or a tertiary amine of formula R 4 R 5 R 6 N in which R 4 , R 5 and R 6 independently represent an optionally substituted C 1-6 alkyl chain which may be straight or branched.
  • the organic amine additive is selected from 2-aminoethylbenzene, benzylamine, n-butylamine, cyclohexylamine, diisopropylamine, n-hexylamine, n-dodecaneamine, piperidine, morpholine, triethylamine, tributylamine and ethyl 3,5-diiodo-1-tyrosinate. More preferably the amine is selected from piperidine, morpholine, triethylamine and tributylamine. Urea or ammonia do not affect the desired coupling reaction.
  • the organic amine additive is present in an amount ranging from 1.2 to 5 molar equivalents with respect to the amount of manganese salt used.
  • the organic amine additive is present in an amount ranging from 1.5 to 4 molar equivalents and more preferably in an amount ranging from 1.8 to 3.8 molar equivalents with respect to the amount of manganese salt used.
  • the manganese salt is present in an amount ranging from 0.25-5% by weight of the protected diiodo-1-tyrosine used, preferably 0.5-3% and more preferably
  • the amino group of the diiodo-1-tyrosine may be protected by acylation, the acid group of the diiodo-1-tyrosine may be protected by esterification.
  • a further aspect of the invention is the isolation of sodium 1-thyroxine from step 6 using as a starting material a thyroxine hydrochloride salt crystallised from the fifth step rather than a thyroxine free base produced from step 5.
  • a thyroxine hydrochloride salt crystallised from the fifth step rather than a thyroxine free base produced from step 5.
  • 3,5-Diiodothyronine (T 2 ), liothyronine (T 3 ) and the d-enantiomer of thyroxine (d-T 4 ) are all undesirable by products which may be formed during the synthesis of 1-thyroxine.
  • T 2 , T 3 and d-T 4 are biologically active and therefore it is desirable to produce an 1-thyroxine product which is substantially free of these compounds.
  • the hydrochloride salt formed contains fewer impurities of T 2 , T3 and d-T 4 than the free thyroxine base produced from that step. If the hydrochloride salt is the starting material for conversion into sodium 1-thyroxine (step 6), sodium 1-thyroxine is generated in greater yield and/or with fewer impurities than if the free thyroxine base is used as the starting material in step 6.
  • the hydrochloride salt of 1-thyroxine is a very useful intermediate in the process of the present invention and is believed to be novel.
  • Another aspect of the present invention comprises the hydrochloride salt of 1-thyroxine in solid form.
  • the present invention also includes the use of the hydrochloride salt of 1-thyroxine in solid form in a process for producing sodium 1-thyroxine.
  • a still further aspect of the invention is a process for the synthesis of 1-thyroxine comprising the following steps:-
  • step 2 Protection of the amino group of the 3,5-diiodo-1- tyrosine product from step 1 with a suitable protecting group.
  • step 3 Protection of the carboxy group of the product of step 2 with a suitable protecting group.
  • step 4 Oxidative coupling of the protected 3,5-diiodo tyrosine produced from step 3 using oxygen as an oxidising agent in the presence of a manganese salt catalyst and an organic amine additive, the oxygen being diluted in a gas mixture with an inert gas diluent, the oxygen being present in an amount from 10% to 40%, by volume of the gas mixture.
  • step 4 Hydrolysis of the reaction product of step 4 with a mixture including hydrochloric acid to form the hydrochloride salt of 1-thyroxine, which is separated.
  • a preferred process of the invention comprises the following steps:
  • the vessel was pressurised within a range of (x) atmospheres with a gas (xi), and the reaction mixture was stirred at a temperature of (xii) for a period of (xiii) with the pressure maintained.
  • the pH of the mixture was monitored periodically falling to a final pH of (xiv).
  • the mixture was cooled to below 30°C and the pressure was released.
  • the product was collected by filtration and washed with 50% aqueous ethanol, dilute hydrochloric acid and water before being used in the fifth stage of the process. Yield (xv).
  • Step 5 Improvements to step 5 (hydrolysis of the product of step 4) will now be illustrated with reference to the following non-limiting Examples 7 to 15 and Table 2:
  • a comparative example E was prepared as above except that NaOH was added after washing the solid to generate 1-thyroxine (as a free base) which was isolated. Impurities were also characterised by hplc.
  • step 6 Improvements in the yield and purity of the sodium salt of 1-thyroxine generated in step 6 are illustrated in Table 3.
  • the product of step 5 (free base or HCl salt) was treated with sodium carbonate in a n-propanol solvent to generate sodium 1-thyroxine which was isolated by filtration.
  • Table 3 shows that if the starting material of step 6 is a hydrochloride salt of 1-thyroxine, (Examples 16 to 19), then sodium 1-thyroxine is generated in higher yield and/or with less impurities than if the free thyroxine base is used as the starting material as in the prior art process (as in comparative examples F and G).
  • the impurities were characterised by hplc.

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  • Organic Chemistry (AREA)
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Abstract

Improvements to a six-stage process for production of sodium 1-thyroxine from 1-tyrosine [described in US 2889363 and US 2889364 (Baxter)] are described, the improvements comprising the oxidative coupling of a diido-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 the presence of an organic amine additive using a gaseous oxidant comprising oxygen and optionally an inert diluent. The process optionally further comprises acid hydrolysis of the biphenyl ether derivative with hydrochloric acid to form a 1-thyroxine hydrochloride salt and generation of sodium-1-thyroxine from the 1-thyroxine hydrochloride salt.

Description

PROCESS FOR PRODUCING SODIUM 1-THYROXINE COMPRISING THE OXIDATIVE
COUPLING OF A DIIDO-1-TYROSINE CATALYSED BY A MANGANESE
SALT IN THE PRESENCE OF AN AMINE
The present invention relates to improvements in a process for producing sodium 1-thyroxine, which is a thyroid hormone used to treat conditions such as myoedema, cretinism and obesity.
Sodium-1-thyroxine (which is the sodium salt of O- (4-hydroxy-3,5-diiodo-phenyl)-3,5-diiodo-1-tyrosine) can be produced in a six step synthesis as described in US
2889363 and US 2889364 (Baxter). This process starts from the naturally occurring amino acid 1-tyrosine, which is iodinated in a first step to form 3,5-diiodo-1-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 1-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 US 2589364 (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 R1NH2 in which R1 comprises an optionally substituted C1-10 alkyl chain which may be straight or branched, a secondary amine of formula R2R3NH in which R2 and R3 independently represent an optionally substituted C1-6 alkyl chain which may be straight or branched or R2 and R3 together with the nitrogen to which they are attached form a cyclic amine, or a tertiary amine of formula R4R5R6N in which R4, R5 and R6 independently represent an optionally substituted C1-6 alkyl chain which may be straight or branched. Preferably the organic amine additive is selected from 2-aminoethylbenzene, benzylamine, n-butylamine, cyclohexylamine, diisopropylamine, n-hexylamine, n-dodecaneamine, piperidine, morpholine, triethylamine, tributylamine and ethyl 3,5-diiodo-1-tyrosinate. More preferably the amine is selected from piperidine, morpholine, triethylamine and tributylamine. Urea or ammonia do not affect the desired coupling reaction.
Suitably the organic amine additive is present in an amount ranging from 1.2 to 5 molar equivalents with respect to the amount of manganese salt used. Preferably the organic amine additive is present in an amount ranging from 1.5 to 4 molar equivalents and more preferably in an amount ranging from 1.8 to 3.8 molar equivalents with respect to the amount of manganese salt used.
Suitably the manganese salt is present in an amount ranging from 0.25-5% by weight of the protected diiodo-1-tyrosine used, preferably 0.5-3% and more preferably
0.75-1.5% by weight of the protected diiodo-1-tyrosine used.
Surprisingly, it has been found that if air or oxygen is used in the desired coupling step at a pressure of 20 atmospheres in the presence of an organic amine additive, the yield of the coupling reaction is comparable at 35 to 45% to that obtained when oxygen is used at atmospheric pressure. A further unexpected effect is that the reaction time for the pressurised coupling in air or oxygen in the presence of an organic amine additive, is significantly reduced to 20 hours compared to 96 hours required with oxygen at atmospheric pressure. This effect is of commercial importance as it allows more efficient use of capital intensive plant equipment which results in significant cost savings compared to the current process. Air is preferred to oxygen because it is readily available, cheap and safer to use.
The amino group of the diiodo-1-tyrosine may be protected by acylation, the acid group of the diiodo-1-tyrosine may be protected by esterification.
A further aspect of the invention is the isolation of sodium 1-thyroxine from step 6 using as a starting material a thyroxine hydrochloride salt crystallised from the fifth step rather than a thyroxine free base produced from step 5. 3,5-Diiodothyronine (T2), liothyronine (T3) and the d-enantiomer of thyroxine (d-T4) are all undesirable by products which may be formed during the synthesis of 1-thyroxine. T2, T3 and d-T4 are biologically active and therefore it is desirable to produce an 1-thyroxine product which is substantially free of these compounds. Surprisingly, it has been discovered that if hydrochloric acid is used in the hydrolysis step five of the synthesis of thyroxine, described above, the hydrochloride salt formed contains fewer impurities of T2, T3 and d-T4 than the free thyroxine base produced from that step. If the hydrochloride salt is the starting material for conversion into sodium 1-thyroxine (step 6), sodium 1-thyroxine is generated in greater yield and/or with fewer impurities than if the free thyroxine base is used as the starting material in step 6.
The hydrochloride salt of 1-thyroxine is a very useful intermediate in the process of the present invention and is believed to be novel. Another aspect of the present invention comprises the hydrochloride salt of 1-thyroxine in solid form. The present invention also includes the use of the hydrochloride salt of 1-thyroxine in solid form in a process for producing sodium 1-thyroxine.
Broadly, a still further aspect of the invention is a process for the synthesis of 1-thyroxine comprising the following steps:-
1: Iodination of 1-tyrosine to 3,5-diiodo-1-tyrosine.
2: Protection of the amino group of the 3,5-diiodo-1- tyrosine product from step 1 with a suitable protecting group. 3: Protection of the carboxy group of the product of step 2 with a suitable protecting group.
4: Oxidative coupling of the protected 3,5-diiodo tyrosine produced from step 3 using oxygen as an oxidising agent in the presence of a manganese salt catalyst and an organic amine additive, the oxygen being diluted in a gas mixture with an inert gas diluent, the oxygen being present in an amount from 10% to 40%, by volume of the gas mixture. 5: Hydrolysis of the reaction product of step 4 with a mixture including hydrochloric acid to form the hydrochloride salt of 1-thyroxine, which is separated.
6: Formation of the sodium salt from the hydrochloride salt of 1-thyroxine produced from step 5.
A preferred process of the invention comprises the following steps:
1: Iodination of the amino acid 1-tyrosine of formula I
Figure imgf000008_0001
for example by treatment with NaI/NaIO3 in acetic acid followed by NaHSO3 to remove any excess I2 to give a compound of formula II
Figure imgf000009_0001
2: Acetylation of a compound of formula II with acetic anhydride and a base (eg NaOH) followed by a solution of NaOH/EtOH and finally HCl and to give a compound of formula III
Figure imgf000009_0002
3: Esterification of compound of formula III with ethanol in sulphuric acid to give a compound of formula IV
Figure imgf000009_0003
4: Oxidative coupling of a compound of formula IV using air under pressure of 20 atmospheres with MnSO4 and H3BO4, in ethanol with a piperidine additive to form a compound of formula V
Figure imgf000010_0001
5: Hydrolysis of a compound of formula V with HCl acid and acetic acid followed by NaHSO3 to produce the hydrochloride salt of formula VI
Figure imgf000010_0002
6: Reaction of the HCl salt of formula VI with Na2CO3 in a n-propanol solvent to form sodium 1-thyroxine of formula VII
Figure imgf000010_0003
Examples 1-6 and comparative examples A, B,C and D
(Step 4)
Improvements to the fourth oxidation step are described below in more detail with reference to the following non-limiting examples 1 to 6 which are compared with control Examples A, B, C and D performed at lower pressures. The description of the process below should be read in conjunction with Tables la and lb.
Ethyl N-acetyl-3,5-diiodo-1-tyrosine (i), boric acid (ii), piperidine (iii), water (iv) and ethanol (v) were charged to a preparation vessel. Caustic soda liquor (vi) of specific gravity 1.5 was added to the vessel until the initial pH of the reaction mixture was (vii). The mixture was then transferred to a pressure vessel and heated to a temperature of (viii). Water, ethanol and an aqueous solution of MnSO4.H2O (ix) were charged to the pressure vessel. The vessel was pressurised within a range of (x) atmospheres with a gas (xi), and the reaction mixture was stirred at a temperature of (xii) for a period of (xiii) with the pressure maintained. The pH of the mixture was monitored periodically falling to a final pH of (xiv). The mixture was cooled to below 30°C and the pressure was released. The product was collected by filtration and washed with 50% aqueous ethanol, dilute hydrochloric acid and water before being used in the fifth stage of the process. Yield (xv).
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Examples 7 to 15 and comparative example E
(Step 5) Improvements to step 5 (hydrolysis of the product of step 4) will now be illustrated with reference to the following non-limiting Examples 7 to 15 and Table 2:
The product that was obtained from step 4 (in a method similar to that described above) in an amount of (a), was heated under reflux with acetic acid (b), hydrochloric acid (c) and water (d) at a temperature of (e) for a period of (f). The reaction mixture was cooled to (g) and sodium bisulphite solution was added to remove free I2. The solid product was isolated by filtration, washed with water and dried. Yield (h) of the thyroxine hydrochloride salt. The impurities T2 (j), T3 (k) and d-T4 (1) were characterised by high performance liquid chromatography (hplc).
A comparative example E was prepared as above except that NaOH was added after washing the solid to generate 1-thyroxine (as a free base) which was isolated. Impurities were also characterised by hplc.
Figure imgf000015_0001
Examples 16 to 19 and comparative examples F and G
(Step 6)
Improvements in the yield and purity of the sodium salt of 1-thyroxine generated in step 6 are illustrated in Table 3. The product of step 5 (free base or HCl salt) was treated with sodium carbonate in a n-propanol solvent to generate sodium 1-thyroxine which was isolated by filtration. Table 3 shows that if the starting material of step 6 is a hydrochloride salt of 1-thyroxine, (Examples 16 to 19), then sodium 1-thyroxine is generated in higher yield and/or with less impurities than if the free thyroxine base is used as the starting material as in the prior art process (as in comparative examples F and G). The impurities were characterised by hplc.
Figure imgf000017_0001

Claims

1. A process comprising the oxidative coupling of a diiodo-1-thyrosine to form a biphenyl ether derivative, catalysed by a manganese salt in which the amine and acid functionality of the diiodo-1-thyrosine have been protected by suitable protecting groups, characterised in that the reaction is performed at a pressure of about 20 atmospheres in the presence of an organic amine additive using a gaseous oxidant comprising oxygen and optionally an inert diluent.
2. A process as claimed in claim 1 further comprising acid hydrolysis of the biphenyl ether derivative with hydrochloric acid to form a 1-thyroxine hydrochloride salt and generation of sodium-1-thyroxine from the 1-thyroxine hydrochloride salt.
3. A process as claimed in either preceding claim comprising the following steps:
(a) iodination of 1-tyrosine to 3,5-diiodo-1-tyrosine.
(b) protection of the amino group of the 3,5-diiodo-1- tyrosine product from step (a) with a suitable protecting group.
(c) protection of the carboxy group of the product of step (b) with a suitable protecting group.
(d) oxidative coupling of the protected 3,5-diiodo tyrosine produced from step (c) using oxygen as an oxidising agent in the presence of a manganese salt catalyst and an organic amine additive, the oxygen being diluted in a gas mixture with an inert gas diluent, the oxygen being present in an amount from 10% to 40%, by volume of the gas mixture.
(e) hydrolysis of the reaction product of step (d) with a mixture including hydrochloric acid to form the hydrochloride salt of 1-thyroxine, which is separated.
(f) formation of the sodium salt from the hydrochloride salt of 1-thyroxine produced from step (e).
4. A process as claimed in any preceding claim comprising the following steps:
(a) iodination of the amino acid 1-tyrosine of formula I
Figure imgf000019_0001
followed by removal of any excess I2, to give a compound of formula II
Figure imgf000019_0002
(b) acetylation of a compound of formula II with acetic anhydride and a base to give a compound of formula III
Figure imgf000020_0001
(c) esterification of compound of formula III with ethanol in sulphuric acid to give a compound of formula IV
Figure imgf000020_0002
(d) oxidative coupling of a compound of formula IV using air under pressure of 20 atmospheres with MnSO4 and H3BO4, in ethanol with a piperidine additive to form a compound of formula V
Figure imgf000020_0003
(e) hydrolysis of a compound of formula V with hydrochloric acid to produce the hydrochloride salt of formula VI
Figure imgf000021_0001
(f) reaction of the hydrochloric salt of formula VI with a sodium base to form sodium 1-thyroxine of formula VII
Figure imgf000021_0002
5. A process as claimed in any preceding claim with reference to the examples described herein.
6. The hydrochloride salt of 1-thyroxine in solid form.
7. The use of the hydrochloride salt of 1-thyroxine in solid form in a process for producing sodium 1-thyroxine.
PCT/EP1995/004017 1994-10-14 1995-10-12 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine WO1996011904A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US08/817,325 US5917087A (en) 1994-10-14 1995-10-12 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine
DE69516529T DE69516529T2 (en) 1994-10-14 1995-10-12 METHOD FOR PRODUCING SODIUM-1-THYROXIN BY OXIDATIVE COUPLING OF DIIODO-L-THYROSINE, CATALYZED BY A MANGANE SALT AND IN THE PRESENCE OF AN AMINE
AU38413/95A AU3841395A (en) 1994-10-14 1995-10-12 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine
AT95936478T ATE192137T1 (en) 1994-10-14 1995-10-12 METHOD FOR PRODUCING SODIUM-1-THYROXINE BY OXIDATIVE COUPLING OF DIIODO-L-THYROSINE CATALYSED BY A MANGANEOUS SALT AND IN THE PRESENCE OF AN AMINE
CA2202094A CA2202094C (en) 1994-10-14 1995-10-12 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine
EP95936478A EP0785921B1 (en) 1994-10-14 1995-10-12 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine
DK95936478T DK0785921T3 (en) 1994-10-14 1995-10-12 Process for the preparation of sodium L-thyroxine comprising oxidative coupling of a diiodo-L-tyrosine catalyzed by a
GR20000400963T GR3033346T3 (en) 1994-10-14 2000-04-27 Process for producing sodium 1-thyroxine comprising the oxidative coupling of a diido-1-tyrosine catalysed by a manganese salt in the presence of an amine

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GB9420705.7 1994-10-14
GB9420705A GB9420705D0 (en) 1994-10-14 1994-10-14 Process

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US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6677473B1 (en) 1999-11-19 2004-01-13 Corvas International Inc Plasminogen activator inhibitor antagonists
WO2011073409A1 (en) 2009-12-18 2011-06-23 Bracco Imaging Spa Process for the preparation of thyroid hormones and salts thereof

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PL369972A1 (en) * 2002-01-07 2005-05-02 Abbott Gmbh & Co.Kg Crystallization of amino acids using ultrasonic agitation
US20060008512A1 (en) * 2004-07-07 2006-01-12 Hooge Danny M Composition and methods for improved animal performance
CN102199103B (en) * 2011-03-24 2013-12-25 常州工程职业技术学院 Improved method for synthesizing L-thyroxine sodium
WO2015011573A1 (en) * 2013-07-24 2015-01-29 Azico Pharmaceuticals Private Limited Novel process for the preparation of levothyroxine sodium
NL2017110B1 (en) 2016-07-05 2018-01-12 Emp Levo Gmbh Methods for the preparation of a levothyroxine solution

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6677473B1 (en) 1999-11-19 2004-01-13 Corvas International Inc Plasminogen activator inhibitor antagonists
WO2011073409A1 (en) 2009-12-18 2011-06-23 Bracco Imaging Spa Process for the preparation of thyroid hormones and salts thereof
EP2338875A1 (en) 2009-12-18 2011-06-29 Bracco Imaging S.p.A Process for the preparation of thyroid hormones and derivatives thereof
US8759572B2 (en) 2009-12-18 2014-06-24 Bracco Imaging S.P.A. Process for the preparation of thyroid hormones and salts thereof

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DE69516529D1 (en) 2000-05-31
DE69516529T2 (en) 2000-08-10
ES2144639T3 (en) 2000-06-16
DK0785921T3 (en) 2000-08-07
PT785921E (en) 2000-08-31
EP0785921B1 (en) 2000-04-26
ATE192137T1 (en) 2000-05-15
GB9420705D0 (en) 1994-11-30
EP0785921A1 (en) 1997-07-30
AU3841395A (en) 1996-05-06
US5917087A (en) 1999-06-29
GR3033346T3 (en) 2000-09-29
CA2202094A1 (en) 1996-04-25

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