DK143335B - ANALOGY PROCEDURE FOR PREPARING BIS (5-MERCAPTOPYRIDOXIN) -ETHAN-1,2-DISULPHONATE - Google Patents

Description

(19) DENMARK (® £

© (12) PUBLICATION OUT 11 * 3335 B

PATENT AND TRADEMARKET DIRECTORATE

(21) Application No. 1793/76 (51) IntCI.3 C 07 D 213/66 (22) Commencement date 21 Apr. 1976 (24) Race day 21. April 1976 (41) Aim. available Nov. 10; 1976 (44) Presented Aug. 10; 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) Master Application No. -

(30) Priority May 9, 1975 # 5760 55, US

(71) Applicant MERCK & CO. INC., Rahway, US.

(72) Inventor Conrad Peter Dorn, US: Howard Jones, US: David

Penman Jacobus, US.

(74) Associate Engineer Hofman-Bang & Bout ard.

(54) Analogous process for the preparation of bis (5-mercaptopyric = dxxin) -ethane-1,2-disulfonate.

The present invention relates to an analogous process for the preparation of bis (5-mercaptopyridoxine) -ethane-1,2-disulfonate of the formula set forth in the claim which is characterized by the characterizing part of the claim. The pharmaceutically acceptable salt is a physical, chemically and pharmaceutically improved form of the known pharmacologically active 2-methyl-3-hydroxy-4- (hydroxymethyl-5-mercaptomethylpyridine- (5-mercaptopyridoxine or> 5-MP)).

The compound prepared by the process of the invention is suitable for the treatment of rheumatic arthritis.

* »I 2 143335

The compound 5-mercaptopyridoxine is reported as pharmacologically active as a radiation protection agent and as an anti-rheumatic arthritic agent, preferably used in the form of a salt with a pharmaceutically acceptable acid (DE-OS 2 428 031). Preferred salts are hydrochloride and hydrobromide.

It has been found that the known salts mentioned in the literature, especially the hydrochloride, suffer from serious physical, chemical and / or pharmaceutical disadvantages due to their chemical instability or due to other undesirable properties. It has now surprisingly been found that the ethane-1,2-disulfonate salt (edisylate) of 5-mercaptopyridoxine is substantially free of this disadvantage and therefore more suitable than the hitherto preferred salts as a component of pharmaceutical unit doses. The increased chemical stability of the salt in question is confirmed by current comparative tests.

To assess the relative stability of various salts of 5-mercaptopyridoxine, the test salts were selected (i.e., ethane-1,2-disulfonate, phosphate, sulfamate, nitrate and hydrochloride) and subjected to high temperature accelerated conditions using the salts condition. Temperatures of 80 ° C and 105 ° C are conveniently used to examine the compounds in as short a time as possible. If a large number of derivatives or salts are available, comparable data can be obtained and the test compounds can be prepared in an expected order of stability. The thermally affected salts were colorimetrically examined for unchanged thiol groups. The ethane disulfonate, hydrochloride and sulfamate were also subjected to NMR analysis to confirm the chemical analyzes. The obtained MRI data support the chemical data. The data obtained are in accumulated form shown in subsequent Table 1.

3 143335

Table 1

Comparison of thermal stability of 5-MP salts

Thermal stability% residual Salt of 5-MP 105 ° C 80 ° C

| 5 days 7 days 1 week 3 weeks

Ethanedisulfonate 97.3 99.4 101.0 100.2

Hydrochloride 57.3 - 70.5 57.3

Sulfamate 13.0 8.8 94.0 75.7

Phosphate 93.0 58.0

Nitrate - - 87.2 III '"------ 1 ..... I *' Ί i 1". " '1'

These data clearly show that the ethanedisulfonate salt is the most stable salt at the temperatures used. From these data it appears that the ethanedisulfonate salt is the preferred one.

The process of the invention can be carried out by mixing 2 molar portions of 5-mercaptopyridoxine or a soluble acid addition salt thereof, preferably the hydrochloride, and 1 molar portion of one-hand disulphonic acid or an alkali metal or alkaline earth metal salt thereof, preferably the sodium salt, in a liquid medium therein. degree can dissolve the two starting materials, at a temperature between room temperature and the boiling temperature. The product is isolated by crystallization of a liquid medium by cooling and / or, if necessary, by concentration. In a preferred embodiment, the 5-mercaptopyridoxine hydrohalide, preferably the hydrochloride, and an alkali metal or alkaline earth metal salt of an ethanedisulfonate, preferably the sodium salt, are dissolved in the above molar ratio in a minimal amount of water at room temperature and subsequently cooled.

'. . Instead, the present novel compound can be prepared by treating bis (2,2,8-trimethyl-4-Hm-dioxino [4,5-c] pyridyl-5-methyl) disulfide with a mixture of zinc or tin dust and ethanedisulfonic acid in water or a suitable organic solvent. The reaction is conveniently carried out by placing the reaction mixture on a steam bath for 1 to 10 hours, preferably an inert atmosphere. The reaction mixture is then cooled, filtered and evaporated in vacuo. The residue is extracted into boiling organic solvent and the filtrate is filtered and cooled to precipitate the desired salt.

Similarly, the present novel compound can be prepared by treating bis (2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-5-methyl) disulfide with a mixture of zinc or tin dust and ethanedisulfonic acid in water or a suitable organic solvent. The reaction is carried out as described above and the desired salt is recovered in a similar manner.

The present novel compound may also be prepared by treating 5-mercaptomethyl-2,2,8-trimethyl-4-H-m-dioxino- [4,5-c] pyridine with ethanedisulfonic acid in water or a suitable organic solvent. In this case, the reaction mixture is heated. usually in a steam bath for 2 to 10 hours, preferably an inert atmosphere. The reaction mixture is then evaporated to give the desired salt.

The process according to the invention will be illustrated in the following by way of some examples.

EXAMPLE 1

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridinyl) -ethane-1,2-di-sulfonate

A solution of 11.1 g (0.05 mol) of 5-mercaptopyridoxine hydrochloride in 40 ml of water is mixed with a solution of 5> 85 g (0.025 mol) of disodium ethanol 1,2-disulfonate in 40 ml of water. at room temperature. The mixture was cooled in an ice bath until the precipitation was complete. The precipitate (1) was collected on a filter and the filtrate was evaporated to ca. 40 ml and cooled again in an ice bath until the precipitation was complete. The precipitate (2) was collected on a filter and the filtrate was evaporated to ca. 20 ml and cooled in an ice bath until the precipitation was complete. The precipitate (3) was collected on a filter. The precipitates (1), (2) and (3) were combined and recrystallized from methanol to give 6.5 g of bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) -ethane-1,2-disulfonate mp: 178-180 ° C.

By repeating the procedure described in Example 1 with the change that instead of disodium ethanol-1,2-disulfonate an equimolar amount of di (metal) ethanedisulfonates is used, the same acid addition salt of 5-mercaptopyridoxine is obtained in accordance with Equation I .

ch2oh Equation I

2 H0V ^ yCH2SH + 0Α CS03M) 2 CH3 H®A® ch2oh

* HCyL ^ CH2SH

0¾ (0303), ¾¾ 3 H © where A O is an acid anion and M is an alkali metal or alkaline earth metal ion.

EXAMPLE 2

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridinium) ethane-1,2-disulfonat_

A mixture of 9.25 g (0.05 m) of 5-mercaptopyridoxine, 4.75 g (0.025 m) of ethane-1,2-disulfonic acid and 40 ml of water is heated until a solution is formed. This is cooled and the precipitate is filtered. Recrystallization from methanol gives bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) -ethane-1,2-disulfonate, m.p. 178 - 180 ° C.

Equation II explains the reaction in more detail.

Equation II

ch2oh 2 ΗΟγ) γαΗ28Η + C2i ^ (SO3H) 2

ch3AJ

CH 2 OH

-> HO ^ [CH-SH

XT (33ο33,2α2Η4 CH3 H © EXAMPLE 3

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-urridinium) ethane-1,2-disulfonate

A mixture of 0.1 mole of bis (2,2,8-trimethyl-4H-m-dioxino [4,5-c] pyridyl-5-methyl) disulfide, 0.2 mole of zinc dust, 0.35 mdethane-1 , 2-disulfonic acid and 200 ml of water are heated on a steam bath for approx. 5 hours under a nitrogen atom sphere. The reaction is cooled, filtered and evaporated in vacuo. The residue is extracted with 100 ml of boiling methanol and filtered and the filtrate is cooled to give the above product, which melts at 178 - 180 ° C.

EXAMPLE 4

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridinium) ethane-1,2-disulfonat_

A mixture of 0.1 mole of 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino [4,5-c] pyridine and 0.055 mole of ethane-1,2-disulfonic acid in 100 ml of water is heated in a steam bath under an atmosphere of nitrogen for approx. 3 hours. The reaction mixture is concentrated to the above product, melting at 178 - 180 ° C.

EXAMPLE 5

Bis (2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethyl-pyridinium) ethane-1,2-disulfonat_

A mixture of 0.1 mole of bis (2-methyl-3-hydroxy-4-hydroxymethyl-pyridyl-5-methyl) disulfide, 0.2 mole of zinc dust, 0.35 mole of ethane-1,2-disulfonic acid and 200 ml of water heated on a steam bath for approx. 6 hours under a nitrogen atmosphere. The reaction mixture is cooled, filtered and evaporated in vacuo. The residue is extracted with 100 ml of boiling methanol and filtered, and the filtrate is cooled to give the above compound, which melts at 178 - 180 ° C.