SE128716C1 - - Google Patents

Description

Inventors: B. A. Hems and T. C. ° Layton.

Priority requested from 31 December 1948 (United Kingdom).

The present invention relates to the preparation of thyroxine and its derivatives.

The preparation of thyroxine by iodination of 3,5-diiodothyronine using iodine in concentrated aqueous ammonia solution is known. However, this method has some risks due to the possible occurrence of nitrogen triiodide. The invention has hi. a. to foremal to overcome namnd.a responsibility.

It has been shown; that thyroxine and its derivatives can be suitably prepared by iodizing 3,5-diiodothyronine or a suitable derivative thereof in the presence of a suitable base.

The term "thyroxine and its derivatives" denotes compounds of the general formula HO - ('\> - 0 ethyl group and van in Y means vate, a formyl, acetyl or f1-carboxypropionyl group.

By "a suitable organic resin" is meant here a primary or secondary aliphatic amine which may contain a cyclohexyl or alkylcyclohexyl group or one or two hydroxyl groups, piperidine, a C-alkylpiperidine or morpholine, the base in no case having more than 8 carbon atoms. Examples of suitable bases are: methylamine, ethylamine, butylamine, ethylenediamine, dimethylamine, dibutylamine, monoethanolamine and diethanolamine.

In the process according to the invention, compounds of the general formula HO - of a suitable organic hash as defined above.

As «suitable solvent», water, dioxane or a lower aliphatic alcohol can be used, e.g. methanol or ethanol resp. a mixture thereof. The solvent is suitably selected but not Usually so that the diiodothyronine or its derivatives are soluble in the base solution in the solvent or solvent mixture: in general, water is the most suitable solvent.

It has further been found that the method according to the invention can advantageously be carried out in the presence of hydrogen peroxide, in which case the amount of iodine required is reduced to half due to the oxidation of the hydrogen iodide to iodine.

A further feature of the invention is therefore that the reaction proceeds in the presence of a water period.

The iodine can e.g. added in solid form, in solution in aqueous potassium iodide or in solution in one of the suitable solvents. Usually hello-vas two parts of iodine for the reaction, but when using hydrogen peroxide one part of iodine is sufficient.

The reaction can be carried out, for example, at C, but preferably at room temperature. / - 2- - R consists of the group - CH, CH COX, NHY which contains an asymmetric carbon atom, leads the use of an optically active starting material to an optically active product. This fact is important in the synthesis of 1-thyroxine, which compound has greater rysiological activity Sn d-thyroxine.

The invention is further illustrated by the following examples: Example 1.

Iodination of 3,5-diiodothyronine in methylamine solution.

To 2 g of 3,5-diiodothyronine in a stirred solution in 20 ml of 20% methylamine solution was added dropwise a solution of iodine in 8.2 ml of potassium iodide (1.85 n; 4 equivalents). Iodine uptake proceeds quickly. At the end of the addition, the mixture is stirred for 10 minutes and then acidified with glacial acetic acid. The precipitated thyroxine is filtered off and dissolved again in 20 inl of ethyl alcohol and 10 ml of 2 n-sodium hydroxide solution. After treatment with decolorizing charcoal and filtration, the boiling mixture is acidified with acetic acid, after which thyroxine precipitates as a white, microcrystalline powder with a melting point and a melting point of 231-232 ° C (special case). Yield 2.6 g, i.e. 90%.

If aqueous solutions of ethylamine, butylamine, ethylenediamine and dimethylamine are used according to the same method, the thyroxine yield varies between 70 and 90%.

Iodination of 3,5-diiodothyronine during use of flagon other base.

I morpholine.

To a suspension of 0.5 g of finely divided 3,5-diiodothyronine in 25 ml of a 50% morpholine aqueous solution is added dropwise, while stirring, a solution of iodine in 2 ml of 1.9 potassium iodide solution. 3The material moves slowly in solution and the brown iodine color disappears quickly. After 15 minutes, 20% hydrochloric acid was added until the solution reacted acidically on congo paper, after which the pH was adjusted to 4-5 by the addition of a saturated sodium acetate solution. The precipitated thyroxine is filtered off and recrystallized during carbon treatment by dissolving in alcoholic sodium hydroxide solution and adding 0.5 g of acetic acid. Melting point and mixed melting point of the product Sr 233 ° C (siinderfall).

I piperidine. - 0.5 g of 3,5-diiodothyronine is iodinated as above but using 25 ml of 50% piperidine solution. 0.5 g of thyroxine saison white powder sued, m.p. 233 DEG-234 DEG C. (sonderfaID) are obtained.

In monoethanolamine.

To a () afford suspension of 0.5 g of 3,5-diiodine, yronine in 25 ml of 50% ethanolamine solution is added dropwise 2 ml of 1.9 n-iodine solution. The solids slowly gave off solution and after 15 minutes the solution was acidified with glacial acetic acid to precipitate the thyroxine, which was recrystallized as above. Yield Sr 0.5 g of product with melting point 233 ° C (special case).

In diethanolamine.

This has been used in the same manner as monoethanolamine, giving 0.55 g of thyroxine, m.p. 233 DEG C. (special case).

In dibutylarnin-ethyl alcohol solution.

To a stirred suspension of 0.5 g of 3,5-diiodothyronine 11 ml of dibutylamine and 14 ml of ethyl alcohol was added 2 ml of 1.9 n-iodine solution. Iodine uptake Sr slow. After two hours, the solution is acidified with glacial acetic acid, after which water is added to precipitate the thyroxine, which is on-crystallized as usual. Yield Sr 0.4 g of product, m.p. 228-229 ° C (special case).

Example 2. (a) Iodination of 3,5-diiodothyronine In the solution of the base in an aqueous solvent To a stirred solution of 1 g of 3,5-diiodothyronine in a mixture of 10 ml of 20% methylamine and 10 ml of methyl alcohol is added dropwise a solution of iodine in 4.1 nil 1.85 n-potassium iodide (4 equivalents). After the addition is complete, an equal volume of water is mixed in and the thyroxine is precipitated by acetic acid. The product is recrystallized according to the information in Example 1 in the form of a white mass. Yield Sr 0.9 g (61%) of product, m.p., m.p. The iodination proceeds on the same salt in methylamine aqueous solution and in ethyl alcohol / n-propyl alcohol as well as in n-butyl alcohol and dioxane.

Iodization under anhydrous conditions.

To a solution of 0.1 g of 3,5-diiodothyronine in a 20% solution of n-butylamine in 10 ml of ethyl alcohol is added dropwise 0.4 ml of alcoholic 1.9 n-iodine solution. Iodine uptake proceeds slowly but completely. After the addition, the mixture was diluted with equal volume of water, after which it was acidified and treated as above. The yield is 0.07 g of thyroxine (47%) with melting point and mixed melting point 232 ° C (Onderfall).

Iodization under oxidizing conditions.

To a solution of 0.5 g of 3,5-diiodothyronine in 10 ml of 20% methylamine. 1, m1 of hydrogen peroxide (100 vol.) Was added and - - 3 the mixture is treated after 10 minutes std.- end as above. The yield is 0.5 g (70%) of thyroxine with a melting point and a melting point of 230-232 ° C (special case). (d) Iodination with alcoholic iodine solution.

This method is carried out on exactly the same salt as under (a), except that 4 equivalents of iodine are added in alcoholic solution. Thyroxine yield for 65%.

Example 3.

Thyroxine hydantoin.

To a stirred solution of 0.55 g of 5- (3 ', 5'-diiodo-4'-p-hydroxyphenoxybenzyl) -hydantoin in 20 ml of 20% methylamine solution is added dropwise 2.1 ml of 1.9 n-iodine solution. After 10 minutes, the mixture is acidified and the precipitate is crystallized from glacial acetic acid in the form of white prisms, which soften at 169-170 ° C and decompose during iodine evolution. o. m. 235 ° C. By analysis the product is identified as 5- (3 ', 5'-diiodo-4'-p-hydroxy-m, m-diiodophenoxybenzyl) -hydantoin, which contains 1 molecule of solvate acetic acid. Found: C is 25.4; t is 1.6; N is 3.4%. CJEIXO, N, 14CH400H 1u-dyer: G is 25.1; H is 1.6; N is 3%.

Example 4. (a) 3,5-Diiodo-N-acetyl-tyronine To a solution of 1 g of 3,5-diiodothyronine methyl ester in 30 ml of anisole was added a solution of 0.072 g of acetyl chloride in 2 ml of anisole. After standing for a while, the precipitate is filtered off, which is identified by melting point and mixed melting point determination as 3,5-diiodo-N-acetyl-tyronine methyl ester. The yield is 0.54 g of material with a melting point. 227 ° C (precipitation). The filtrate is evaporated to dryness in vacuo, the residue is dissolved in 5 ml of ethyl alcohol and 5 ml of n-sodium hydroxide solution. After standing for 1 hour to hydrolyze the ester group, 5 ml of hydrochloric acid and 30 ml of water are added to precipitate a white mass, which is recrystallized from glacial acetic acid. The yield is 0.35 g of white prisms, m.p. 207-208 ° C. The analysis shows C is 36.0; H for 2.65; N is 2.2; J Sr 44.8%. CIHONJ requires: C Sr 3645 H Sr 3.0; N Sr 2.5; J Sr 44.9%. (b) N-acetylthyroxine To a solution of 0.1 g of 3,5-diiodo-N-acetyltyronine 110 ml of 20% ethylamine solution is added 0.37 every 1.9 n-iodine solution. The mixture is acidified and the precipitate is recrystallized from dilute acetic acid. The product is a white mass with a salt point and a melting point of 214215 ° C (special case).

Example 5. (a) 3,5-Diiodo-N-13-carboxypropionyl-tyronine.

To a solution of 1 g of 3,5-diiodothyronine methyl ester in 20 ml of anisole was added a solution of 0.07 g / 3-carbethoxypropionyl chloride in 2 ml of anisole.

The precipitated 3,5-diiodothyronine methyl ester hydrochloride is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 5 ml of ethyl alcohol and 5 ml of n-sodium hydroxide solution. After 1 hour, 5 ml of n-hydrochloric acid are added and the filling is filtered off. The filtrate is dissolved in alcoholic alkali, treated with decolorizing charcoal and Liles Anyo with acid. The product is 3,5-diiodo-N-β-carboxypropionyltyronine in the form of white prisms, m.p. 231232 DEG C. (precipitation). Yield Sr 0.8 g. The analysis shows: C Sr 34, s; H Sr 3.1; N Sr 2.2; J Sr 41.2%.

Cil, 1-1.707NJ, collars: C Sr 36.5; H Sr 2.7; N Sr 2.2; J Sr 40.7%. (b) N-13-carboxypropionyl-thyroxine.

To a stirred solution of 0.1 g of 3,5-diiodoN-13-carboxypropionyltyronine 110 ml of 20% alcoholic ethylamine solution is atlas 0.34 ml of 1.9 n-jed solution. The mixture was diluted and acidified with acetic acid, after which the precipitate was recrystallized from dilute acetic acid. The product melts at 202--203 ° C (special case).

The analysis shows: C Sr 25.9; H Sr 1.5; N Sr 1.4; J Sr 57.5%. kriiver: C Sr 26, o; H Sr 1.7; N Sr 1.6; Sr 58.0%.

Example 6.

N-formylthyroxine.

To a single solution of 0.2 g of N-formyl-3,5-diiodothyronine in 10 ml of 33% ethylamine solution was added 0.79 g of 1.5 n-iodine solution. After 30 minutes, the mixture is acidified with 2N hydrochloric acid and precipitated N-formyltyroxine is recrystallized from aqueous acetone. Yield Sr 0.15 g of white mass with a melting point of 216 ° C.

Example 7. 1-Thyroxine To a stirred solution of 22 g of 3,5-diiodo-1-tyronine in 220 ml (40 mol) of 33% ethylamine is added dropwise 88 ml of 1.9 n-iodine solution in potassium iodide. Iodine uptake proceeds rapidly and when it is finished, the ethylamine salt of thyroxine precipitates. During introduction but without cooling, 16% hydrochloric acid was added, until the pH value Sr 4-5. After standing for 2 hours, the precipitated thyroxine is filtered off, which is washed with water and dissolved in 250 ml of ethyl alcohol and 100 ml of 2N sodium hydroxide solution. The solution is boiled and about 100 ml of hot 2N hydrochloric acid is added to adjust the pH yard to 4-5. Excessive acidification is corrected by a small amount of sodium acetate solution. After standing for 2 hours in the refrigerator, the thyroxine, which is diluted with water, and ethyl alcohol are filtered off and dried at 100 DEG C. The yield is Sr 29 g (89 product, m.p. 8 ° 4—— Example 8.

Iodination of 3,5-diiodo-di-tyronine methyl ester.

To a solution of 1 g of 3,5-diiodo-dl-tyronine methyl ester in 20 ml of methyl alcohol and 10 ml of n-butylamine was slowly added 1 g of iodine 110 ml of methyl alcohol solution. The mixture is stirred for 1 hour, after which a hydrochloric acid solution in methyl alcohol is added until the solution is acidic. The mixture was diluted with water and saturated sodium acetate solution was added to adjust the pH to 4--5. The precipitate is filtered off and dried, after which it is extracted with some methyl alcohol. A residue of pure thyroxine methyl ester with a melting point of 158-160 ° C is obtained, which is not changed by mixing with an analyzed pray. The yield is 0.7 g. The analysis shows: N is 1.7; J is 64.6%. Calculated for N is 1.7; J is 64.2%.

Example 9.

Iodination of 3,5-diiodothyronine in cyclohexylamine To a solution of 0.5 g of 3,5-diiodothyronine in ml cyclohexylamine and 14 ml of water Mites dropwise with shaking a solution of iodine in 2 ml of 1,9 n-potassium iodide. After 15 minutes, the solution is acidified with acetic acid, whereby the thyroxine precipitates. The product is recrystallized from alcoholic alkali and narrows at 230 ° C. The yield is 0.5 g.

Claims (7)

Patent claim: A process for the preparation of compounds of the only formula HO -0 -—R can be characterized in that a compound of the general formula HO- (- - / ° is matte with iodine in a suitable solvent and in the presence of a suitable organic base, wherein R represents the group - CH, • CH - COOX or - CH2 • CH --CO NHYNH NH CO X represents vate or a methyl or ethyl group and Y represents vate or a formyl, acetyl or 13-carboxypropionyl group. kannetecknat ddrav, that iodine conversion is carried out in the presence of hydrogen peroxide. 2. Set according to patent claim 1, characterized in that two parts of iodine are used for the reaction. 3. Set according to patent claim 2, characterized in that 1 molar part of iodine is added to the turnover. 4. Put according to some of the preceding patent claims, kanneteeknat & ray, that the organic base is methylamine, ethylamine, butylamine, ethylenediamine, dimethylamine, dibutylamine, monoethanolamine or diethanolamine resp. a mix 5. Set according to some of the preceding patent claims, characterized in that the turnover is carried out at 0-30 ° C. 6. It is claimed in any one of the foregoing claims that R represents the group - CH, CH - COOX NHY and that the left-handed isomer of the compound of the same formula 7. J Ho—: \ R j- was used in the reaction. Stockholm 19.19. Kungl. Boktr. P. A. Norstedt & Slitter 6-oo0s9