DE1470441C - Process for producing pyridoxal phosphate - Google Patents

Description

HO

CH = N-R

CH ₂ OH

10

where R is an aryl group or an aralkyl group which is also lower with halogen Alkyl groups or lower alkoxy groups can be substituted with a 'phosphorylating agent,

b) the pyridoxal triphosphate Schiff's bases are heated with dilute mineral acid,

c) adjusts the pH of the reaction mixture to about 2 to 4 and

d) the resulting pyridoxal phosphate Schiff base of the general formula

CH = N-R

HO

CH ₂ -OP-OH OH

CH ₃
hydrolyzed with alkali.

30th

35

40

The present invention relates to a method for producing pyridoxal phosphate from a Pyridoxal-Schiff base as starting material.

Various processes are already known for the production of pyridoxal.

In US Pat. No. 2,703,323 (corresponding to Swiss Pat. No. 297191), a Process described in the pyridoxal after the aldehyde radical of pyridoxal with hydroxylamine or hydrazine has been sequestered into which phosphate is converted. The produced phosphate solution is treated in a weak hydrochloric acid solution containing nitrous acid or its metal salts, to selectively hydrolyze the phosphate bond protecting the aldehyde. The resulting monophosphate is deposited in a known manner as calcium or magnesium salt.

This process is cumbersome and does not have a satisfactory yield, which is already the case in the British Patent specification 880 595 on page 1, in the left column, lines 38 to 40, is clearly indicated.

In addition, there is an additional, laborious process step for isolation with the aid of ion exchange resin necessary to convert the possibly isolated Ca or Mg salt into the monophosphate.

In British Patent 880 595 is pyridoxazolidine, which by reacting the pyridoxal with / S-amino alcohol is obtained as a masking agent, subjected to hydrolysis and thereby obtained pyridoxal phosphate.

In this process, too, the atom group protecting the aldehyde group and 2 mol Orthophosphoric acid in the intermediate product is split off at the same time with the help of the dilute mineral acid, wherein the ion exchange resin treatment to separate the pyridoxal phosphate from a large one Amount of inorganic accompanying material becomes indispensable.

The process for the preparation of the pyridoxal phosphate from pyridoxamine phosphates according to the prior publications Journ. At the. Chem. Soc, 76, pp. 169-175 (1954), U.S. Patent 2,666,061, Journ. At the. Chem. Soc, 73, pp. 4693 and 4694, has a disadvantage that is apparent from the description of the aforementioned British Patent 880,595 on page 1, left column, lines 20 to 28 clearly appears.

Finally, in a method according to German Auslegeschrift 1 101 421 (corresponds to USA patent specification 2,755,284, British patent 749 800, Austrian patent 190641) an aqueous solution of Alkali metal salt of pyridoxamine phosphate and pyruvic acid with a water-soluble cupric, Treated with iron or cobalt salt.

In this process too, the solution of the pyridoxal phosphate in the water is treated with cation exchange resin necessary in the last stage in order to separate off the pyridoxal phosphate in the form of an acid.

In Hoppe-Seylers Zeitschr. f. physiolog. Chem., 316, Pp. 45 to 60 (1959), is also a treatment of pyridoxal phosphate from natural source material described by means of an absorbent.

As mentioned above, in any known method, the ion exchange resin treatment is for Purification of the pyridoxal phosphate is indispensable, which is particularly important when such a process is carried out causes great difficulties on an industrial scale. .

The aim of this invention is to provide pure pyridoxal phosphate without the disadvantages described in the Isolation or purification of the end product with the help of ion exchange resin occur in technical To make a scale.

The invention relates to a method for producing pyridoxal phosphate, which is characterized is that one

a) Pyridoxal-Schiff bases of the general CH = N-R

HO

CH ₇ OH

where R denotes an aryl group or an aralkyl group, also with halogen, lower alkyl groups or lower alkoxy groups may be substituted with a phosphorylating agent implements,

b) the pyridoxal triphosphate Schiff bases are heated with dilute mineral acid,

c) adjusts the pH of the reaction mixture to about 2 to 4 and

d) the resulting pyridoxal phosphate Schiff base of the general formula

HO

IO

hydrolyzed with alkali. .

This process can be illustrated by the following reaction formulas:

CH = N-R

HO _

CH-OH phosphorylation

20th

HO

CH ₃
CH = NR 00 O

Il Il 'Il

CH ₂ • O - POPOP - OH OH OH OH

30th

Hydrolysis H ^s ,
pH 2 to 4

CH = N-R O

. Il

HO I CH ₂ -OP-OH

OH

CH,

HO

ΟΗ ^Θ

hydrolysis

CHO O

Il

CH ₇ -OP-OH

OH

40

45

5 °

The process of the present invention is extremely economical as an industrial manufacturing process to be carried out, since the pyridoxal triphosphate-Schiff bases very easily in pure form from the hydrolysis product can be separated off by adjusting the pH of the hydrolysis product solution to about 2 to 4.

The hydrolysis of the pyridoxal phosphate Schiff's bases is carried out under alkaline conditions in the Process according to the invention carried out. There is the great advantage that the phosphoric acid ester is not decomposed and the amine obtained very quickly by extraction with an organic solvent can be removed.

In the process according to the invention, the intermediate product, the pyridoxal phosphate Schiffschen Bases preserved in a very pure state. Also the pyridoxal phosphate, which by hydrolyzing of the intermediate is also very pure. Because of this, become industrial uneconomical processes such as must be used in the known processes, such as cation exchange resin treatment and subsequent low temperature reduction of the dilute aqueous solution is not necessary here.

One method of making Schiff bases is described in the journal American Chem. Soc, 70, p. 3669 to 3671 (1948), in which pyridoxal is used in its free form.

A mixture of can be used as various phosphorylating agents for the process according to the invention Orthophosphoric acid and phosphorus pentoxide, metaphosphoric acid, a mixture of phosphorus oxychloride and water, a mixture of phosphorus pentoxide and water can be used (compare Ulimanns Encyclopedia of Technical Chemistry, Volume 13, Urban & Schwarzenberg, Munich and Berlin 1962, "p. 525, last paragraph, and W. T h e i 1-heimer, Synthetic Methods of Organic Chemistry Yearbook, Vol. 15, 1961, Basel (Switzerland) S. Karger, New York, p. 104..

When using a mixture of orthophosphoric acid and phosphorus pentoxide (weight ratio 1 to 2: 1), 1 mol of pyridoxal Schiff base is dissolved in 10 to 20MoI the mixture, and the solution is heated for 2 to 20 hours at about 30 to 8O ⁰ C.

When using phosphorus oxychloride and water, 1 mole of the pyridoxal Schiff's base is used 10 to 20 moles of phosphorus oxychloride and water (1: 1 in a molar ratio) reacted with stirring and cooling.

Will phosphorus pentoxide and water (4 to 5: 1 weight ratio) is used, 1 mole of the pyridoxal Schiff base in 10 to 20 moles of the phosphorus pentoxide-water mixture introduced and the solution heated to about 30 to 80 ° C for 2 to 20 hours.

The triphosphate obtained in this way is hydrolyzed using dilute hydrochloric acid, and the pH value the hydrolyzed solution is adjusted to 2 to 4, preferably to 3 by carefully adding Alkali with stirring and cooling.

The pyridoxal phosphate Schiff base is then dissolved in concentrated caustic alkali solution (preferably in 2 normal solution), about five times the volume of the Schiff base to be hydrolyzed. the Organic amines formed during hydrolysis are removed by means of organic solvents such as ether, Dichloroethane, chloroform, removed. The remaining aqueous phase is treated with a mineral acid neutralized, the volume of which corresponds approximately to the ethalkali used, the end product being pyridoxal phosphate crystallized in an exceptionally pure form.

The pyridoxal phosphate obtained is used as a therapeutic agent for the treatment of dermatitis, pellagra, Liver damage and other purposes with vitamin gust effect used.

example 1

a) In 40 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 im Weight ratio) 4.0 g of pyridoxylidene-p-toluidine are dissolved and heated to 45 ° C. for 6 hours. The reaction product obtained is 15 minutes on

IO

60 ^° C. with the addition of 40 ml of 0.1 N hydrochloric acid for hydrolysis. The hydrolysis solution obtained is adjusted to pH = 3 by adding 120 ml of a 50% sodium hydroxide solution with stirring and cooling. 4.09 g of pyridoxylidene-p-toluidene phosphate are obtained. The yield is 82%, and the result of the elemental analysis is shown in the following table

C ₁₅ H ₁₇ N ₂ O ₅ P (molecular weight = 336):
Calculated ... C 53.57, H 5.06, N 8.34%;
found .... C 53.53, H 5.29, N 8.19%.

b) 2.0 g of the pyridoxylidene-p-toluidine phosphate thus obtained are dissolved in 10 ml of 2N sodium hydroxide solution, after removing the released Amines by extraction with chloroform, 10 ml of 2N hydrochloric acid are added to the aqueous phase, and the solution is kept cold for 1 day. The precipitated pyridoxal phosphate is filtered off collected, washed with ethyl alcohol and dried. The amount of the final product was 1.12 g and the yield is 74.7%.

B e i s ρ i e 1 2

In. 30 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 by weight) are 3.0 g of pyridoxylidene-p-phenetidine dissolved and treated the solution according to Example 1 section a). There are 3.1 g of pyridoxylidenephenetidine phosphate receive. The yield was 77%.

Ultraviolet Absorption Values: Molar Extinction Coefficient 388 πΐμ (0.1 N NaOH solution) = 6680.

C ₁₆ H ₁₉ N ₂ O ₆ P (molecular weight = 366): Calculated ... C 52.46, H 5.19, N 7.65%;
found .... C 52.44, H 5.29, N 7.48%.

2.0 g of the pyridoxylidene-p-phenetidine phosphate thus obtained are dissolved in 10 ml of 2N sodium hydroxide and treated further according to Example 1, section b). 0.98 g of pyridoxal phosphate are obtained in a yield of 71.0%.

Example 3

45

In an analogous way, 3.0 g of pyridoxylideno-anisidine are used in 30 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.3: 1 in weight ratio) Implemented at 40 ° C for 8 hours. The reaction product is according to Section a), Example 1, Working up 3.2 g of pyridoxylidene-o-anisindine phosphate are used Obtained in a yield of 78.5%.

The result of the elemental analysis is shown in the following table:

C ₁₅ H ₁₇ N ₂ O ₆ P (molecular weight = 352): Calculated ... C 51.20, H 4.86, N 7.94%;
found .... C 50.17, H 4.94, N 7.62%.

2.0 g of the pyridoxylidene-o-anisidine phosphate are worked up according to section b) of Example 1. 1.09 g of the pyridoxal phosphate are obtained in a yield of 76.0%.

Example 4

1.0 g of pyridoxylidene-o-phenetidine was used according to section a) of Example 1 treated. 1.24 g of pyridoxylidene-o-phenetidine phosphate are obtained. the The yield was 92%.

C ₁₆ H ₁₉ N ₂ O ₆ P (molecular weight = 366):

Calculated ... C 52.46, H 5.19, N 7.65%;
found .... C 52.02, H 5.19, N 7.38%.

The further conversion takes place according to section b) of example 1.

Example 5

a) In 10 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 in weight ratio) 1.0 g of pyridoxylidene-aniline are dissolved and the solution is heated to 45 ° C. for 6 hours. The obtained reaction product was hydrolyzed by heating at 60 ° C for 15 minutes Addition of 10 ml of 0.1 N hydrochloric acid.

The hydrolyzate solution obtained is adjusted to pH = 3 by adding 30 ml of 50% sodium hydroxide solution with stirring and cooling. 0.92 g of pyridoxylidene aniline phosphate was used in one yield of 68.0% obtained.

C ₁₄ H ₁₅ N ₂ O ₅ P (molecular weight = 322):

Calculated ... C 52.17, H 4.65, N 8.70%;
found .... C 51.90, H 4.82, N 8.23%.

b) 0.9 g of the pyridoxylidene aniline phosphate were dissolved in 5 ml of 2N sodium hydroxide solution. The The amine released was separated off by means of ether extraction, and the remaining aqueous phase was kept for a day in the cold with the addition of 5 ml of 2N hydrochloric acid to the pyridoxal phosphate to fail. This is filtered off, washed with acetone and dried. The final weight is 0.52 g and the yield 70.2%.

Example 6

a) In 10 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 im Weight ratio) was 1.0 g of pyridoxylidene p-chloroaniline dissolved. The solution is heated to about 45 ° C for 8 hours. One works according to section a) of Example 1 and receives 0.7 g of pyridoxylidene-p-chloroaniline phosphate. The yield is 51.2% and the result of the elemental analysis is shown in the following table.

C ₁₄ H ₁₄ N ₂ O ₅ PCl (molecular weight = 356.5)

Calculated ... C 47.10, H 3.96, N 7.85%;
found .... C 46.91, H 4.01, N 7.65%.

b) 2.0 g of the pyridoxylidene-p-chloroaniline phosphate are dissolved in 10 ml of 2N sodium hydroxide solution and treated further according to section b) of Example 1. 0.89 g of pyridoxal phosphate are obtained. The yield is 63.0%.

Example 7

In 30 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 in weight ratio) 3.0 g of pyridoxylidene-benzylamine are added dissolved and this solution heated to 56 ° C for 18 hours. By treating this product according to section a) of Example 1, 2.5 g of pyridoxylidenebenzylamine phosphate in a yield of 60.5% receive.

C ₁₅ H ₁₇ N ₂ O ₅ P (molecular weight = 336)

Calculated ... C 53.57, C 5.06, N 8.34%;
found .... C 52.78, H 4.98, N 8.46%.

When 2.0 g of the pyridoxylidene benzylamine phosphate

are treated according to section b) of Example 1, 0.82 g of pyridoxal phosphate is obtained in one yield of 62%.

Examples

As already described, 2.0 g of pyridoxylidenephenetylamine are treated with 20 ml of a mixture of 85% orthophosphoric acid and phosphorus pentoxide (1.1: 1 in the weight ratio) and receives 1.35 g of pyridoxylidene phenethylamine phosphate. The yield is 53%.

C ₁₆ H ₁₉ N ₂ O ₅ P (molecular weight = 350):

Calculated ... C 54.85, H 5.43, N 8.00%;
found .... C 54.33, H 5.35, N 7.89%.

By treating 2.0 g of pyridoxylidene phenethylamine phosphate according to section b) of Example 1 0.90 g of pyridoxal phosphate are obtained in a yield of 59.3%.

B e i s ρ i e 1 9

• In 10 ml of a "mixture of phosphorus pentoxide and water (5: 1 by weight), 1.0 g of pyridoxylidene-p-toluidine is dissolved, and the solution is according to Section a) of Example 1 treated further. 1.05 g of pyridoxylidene-p-toluidine phosphate are obtained. The yield is 85% and the analysis result showed the following values:

C ₁₅ H ₁₇ N ₂ O ₅ P (molecular weight = 336): Calculated ... C 53.57, H 5.06, N 8.34%;
found .... C 53.58, H 5.29, N 8.49%.

15th

20th

Example 10

1.0 g of pyridoxylidene-p-phenetidine was in metaphosphoric acid dissolved by dehydration of 10 ml of 85% orthophosphoric acid by heating at 340 ° C. The reaction mixture is kept at 45 ° C. for 6 hours. By treating of the reaction product according to section a) of Example 1 are 1.0 g of pyridoxylidene-p-phenetidine phosphate obtained in a yield of 75%.

Q ₆ H ₁₉ N ₂ O ₆ P (molecular weight = 366):

Calculated ... C 52.46, H 5.19, N 7.65%;
found .... C 52.48, H 5.28, N 7.85%.

Example 11

In 45 g of phosphorus oxychloride, 5.3 g of water are slowly added while cooling with ice, and then kept at room temperature overnight.

5.0 g of pyridoxylidene-p-toluidine are then added to the above-mentioned reaction mixture. The mixture is then stirred for 3 hours and 300 ml of ether are added to the reaction product obtained. The separated, oily product is dissolved in 50 ml of water and heated by heating for ¹ J ₄ . Hydrolyzed to 60 ° C for a minute. The pH of the solution is then adjusted to 3 by adding 10% sodium hydroxide solution with cooling. 4.5 g of pyridoxylidene-p-toluidine phosphate are obtained in this way. The yield is 72%.

Elemental analysis and infrared absorption of the compound show complete identity with the samples, which are obtained according to Example 1.

209 524,521

Claims (1)

i 470441 Claim: Process for the production of pyridoxal phosphate, characterized in that one a) Pyridoxal-Schiff bases of the general formula