The method of obtaining (6s)- or (6r)-tetrahydrofolate acid

 

(57) Abstract:

Usage: in medicine. The essence of the invention: method retrieve (6S)- or (6R)-tetrahydrofolate acid or salts joining this acid to sulfuric acid or sulfonic acids by the interaction of (6R, S)-tetrahydrofolate acid and sulfuric acid or the corresponding sulfonic acid obtained Sol join acid fractional crystallization and if necessary, the resulting salt is treated with a base. Received new salt accession (6S)- and (6R)-tetrahydrofolate acid to sulfuric acid or sulfonic acids. 2 C. and 8 C.p. f-crystals.

The invention relates to a method for producing N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-(6S)-pteridinyl)methyl] amino] benzoyl] -L-glutamic acid (hereinafter referred to as (6S)-tetrahydrofolate acid) and its salts, and N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-(6R)-pteridinyl)methyl] amino] benzoyl] -L-glutamic acid (hereinafter referred to as (6R)-tetrahydrofolate acid) and its salts.

Derivatives tetrahydrofolate acids contain 2 asymmetric center. If the result of the synthesis of these derivatives of folic acid, i.e. N-(pteroyl)-L-glutamine is automatic active atom in position 6, resulting from hydrogenation of the double bond in position 5, 6 Teroldego balance is in racemic form, i.e. in the (6R,S)-form. Thus, the synthetic derivatives of tetrahydrofolate acids consist of a mixture (1:1) of two diastereomers. In living organisms, for example in the liver, the salt tetrahydrofolate acid (TGFC) occur in only one form of the diastereomers, and 5,6,7,8-THFC there in the (6S)-form.

Salt THFC, mainly calcium salt of 5-formyl-5,6,7,8-THFC (leucovorin) or 5-methyl-5,6,7,8-THFC use as a drug for the treatment of megaloblastic anemia caused by insufficient intake of folic acid in the body, as an antidote to improve portability of folic acid antagonists, in particular of aminopterin and methotrexate in anticancer therapy ("leucovorin rescue"), to enhance therapeutic effect of 5-fluorouracil, for the treatment of such autoimmune diseases as psoriasis and rheumatoid arthritis, as well as to improve portability of certain antiparasitic tools, such as a combined preparation containing trimethoprim and sulfamethoxazole in chemotherapy.

THFC is the original substance in obtaining various Pro-and the IR-chemical, chemical.

Enzymatic methods include the restoration of folic acid to 7.8-digidrofolieva carried out usually by chemical means, with subsequent enzymatic recovery of the latter to (6S)-5,6,7,8-THFC, for example, by the method described by author L. Rees al. in Tetrahedron 42(1), 117-36 (1986), or according to European patent EP-A2-About 356 934.

The disadvantage of this method is the difficulty in suspending the synthesis stage chemical recovery to 7.8-digidrofolieva acid. In addition, the enzymatic recovery have very low output volume per unit of time. The method also requires the expensive cofactor, such as NADPH, and sophisticated methods of food processing. Finally, the famous still enzymatic methods for obtaining optically pure TGFC to obtain this compound in krupnorazmernyh scale is not suitable.

Also known attempt chromatographic separation of diastereoisomers (see J. Feeney with TCS. Biochemistry, 20, 1837/1981 g). But this method proved to be unsuitable to obtain diastereomers in krupnorazmernyh scale.

Also known physico-chemical method of asymmetric recovery folievaya recovery process concentrations of folic acid (usually 10-3M) and difficult to implement separation of asymmetric inductor named after recovery of the reaction is unsuitable for obtaining optically pure TGFC in krupnorazmernyh scale.

There is a chemical way asymmetric hydrogenation of folic acid in the presence of an optically active catalyst (see for example, P. H. Boyle with TCS. J. Chem. Soc. Chem. Commun. 1974, 10, 375-6). But this synthesis requires the use of expensive catalysts, separation from which the final product is a time consuming process.

So still there is no way suitable for receiving in krupnorazmernyh scale clean THFC.

Thus, the objective of the invention is to develop a simple, suitable for practical use and cost-effective method of obtaining optically pure THFC.

Unexpectedly, it was found that aqueous solutions of (6R,S)-THFC or its salts after adding a sulfonic acid or sulfuric acid is allocated the corresponding salt of accession, enriched optically pure THFC. This salt can be separated by filtration. Then from the filter can be distinguished diastereomers Sol connection. Both salts can is a translate in salt accession. The fact of enrichment optically pure TGFC in the crystallization of salt attaching her to the sulfonic acid or sulfuric acid so unexpected that when recrystallization other salts, for example salts of joining TGFC to hydrochloric acid, concentration of optically pure component is not observed (W. Frick with TCS. Helv. Chim. Acta, 57, 2658-61, 1974). The application of other strong acids, such as Hydrobromic, uudistoodetena, nitric, phosphoric, formic, oxalic, chloro-, dichloro - and trichloroacetic acid, also failed to achieve the enrichment of one of epimeric forms THFC.

The object of the present invention is a method for (6S)- and (6R)-THFC and its salts join sulfonic acids and sulfuric acid, wherein the (6R,S)-THFC subjected to reaction with a sulfonic acid or sulfuric acid, the obtained Sol accession fractional crystallization and, if necessary, from the obtained diastereomeric salts accession processing base release and allocate (6S) and/or (6R)-THFC.

Applied (6R,S)-THFC can be used after separation or preferably in the form of product recovery, folic acid, or before the proposed method sulfonic acids are aromatic sulfonic acid with the number of atoms of from 6 to 14, analiticheskie sulfonic acid with the number of atoms of from 7 to 9 or aliphatic sulfonic acids with the number of atoms With from 1 to 3.

As aromatic sulfonic acids can be used benzene - or toluensulfonate acid, xylene, nitrobenzene, chlorobenzene, nitrotoluene-, naphtalenesulfonic acid, substituted naphthalenesulfonate acid, naphtaline or camphorsulfonic acid.

As analiticheskoi sulfonic acid is preferably used phenylmethanesulfonyl acid, as well as aliphatic sulfonic acids predominantly methane and econsultancy acid.

Preferred salts of the merger are those of the benzene or toluensulfonate acid and sulfuric acid.

The crystallization process is carried out in a polar environment. Especially suitable for these purposes are water or mixtures of water with water-soluble lower aliphatic carboxylic acid, in particular acetic acid, and lactic acid, or liquid water-soluble amidon such as formed DMF), dimethylacetamide, 1-organic, 2-piperidine. The mixture typically contains at least 50% water. The use of such mixtures typically improves optical what about the material you can easily determine the optimal reaction conditions through systematic experiments.

Due to the sensitivity of THFC to oxidation, it is recommended to use antioxidants, such as 2-mercaptoethanol.

When the first crystallization usually falls salt accession (6S)-THFC and diastereomers (6R)-connection concentrated in the filtrate.

From the obtained salt by adding a base without difficulty we can extract enriched optically pure THFC.

Another method of chemical and optical cleaning product is the recrystallization of salts attach (6S) and (6R)-THFC and/or re-transfer in salt mounting with a sulfonic acid and/or sulfuric acid after release THFC.

The proposed method is a very simple and particularly efficient method of obtaining (6S) and (6R)-THFC and its salts with strong bases or acids.

The subject of this invention are also new salt accession (6S)-tetrahydrofolate acid to sulfuric acid or sulfonic acids, selected from the range: toluene-4-sulfonic acid, benzolsulfonat acid, methane-, ethane-, phenylmethane-camphor-10-, naphthalene-1-, naphthalene-2-, sulfonic acid and naphthalene-1,5-disulfonate acid, or salt accession (6R)-the.

The preferred salt of the accession is salt, which are bansilalpet (6S)-tetrahydrofolate acid or bansilalpet (6R)-tetrahydrofolate acid; toluene-4-sulfonate of (6S)-tetrahydrofolate acid or toluene-4-sulfonate (6R)-tetrahydrofolate acid; sulfate (6S)-tetrahydrofolate acid or sulfate (6R)-tetrahydrofolate acid; salt of accession (6S)-tetrahydrofolate acid to methane-, ethane - or phenylmethane-, or camphor-10-or naphthalene-1-, or naphthalene-2 - sulfonic acid or naphthalene-1,5-disulfonic acid;

The object of the present invention are also salts of accession (6S) and (6R)-tetrahydrofolate acid to sulfonic acids or sulfuric acid as intermediates for obtaining optically pure 5,10-methylentetrahydrofolate, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate acids and their salts with strong bases and acids.

Obtaining optically pure 5,10-methylentetrahydrofolate, 5-methyl - or 5-familientherapie acid is performed by the interaction of the above salts joining with formaldehyde.

Here are some examples, for example, 5-formyl-(6S)-tetrahydrofolic is reprieval acid, leading to the 5-formyl-(6R)-tetrahydrofolate acid. This is confirmed by the fact that both the reaction and the reaction of the racemic tetrahydrofolate acid, can be carried out in the same conditions. I.e (6R,S)-tetrahydrofolate acid reacts with the formation of 5-formyl-(6R, S)-tetrahydrofolate acid. During this reaction does not occur transformations of the two diastereoisomeric forms. It should be noted that as (6S)-tetrahydrofolate acid, and (6R)-tetrahydrofolate acid behave in the described reactions are the same and the reactions take place at the same speed. It is clear that the conformation of the C-6 atom plays no role.

The same applies to the reaction of tetrahydrofolate acid upon receipt 5,10-methylenetetrahydrofolic acid and 5-methyltetrahydrofolate acid. All of these reactions are known to the prior art and described countless times (see R. L. Blakley, Chemistry and Biochemistry of Folates, 1984, pages 93-109, in particular, page 99, section 1(5-formyltetrahydrofolate acid), page 102, section 2 (5,10-methylentetrahydrofolate acid) and page 103, section 2 (5-methylenetetrahydrofolic acid).

The absolute configuration at C-6 atom of the natural tetrahydrofolate acid should be Alieva acid and 5,10-methylentetrahydrofolate acid as R [see Kalbematten with TCS. Helv. Chim. Acta, 64(8), 2627 (1981), note. 4] for Any of the above reactions do not occur in the transformation configuration at C-6. On the basis of "natural" tetrahydrofolates acid [(6S)-tetrahydrofolate acid] also get its "natural" derivatives, such as 5-formyl-(6S)-tetrahydrofolic acid or 5,10-methylene-(6S)-tetrahydrofolic acid. Conversely, when using "unnatural" tetrahydrofolates acid [(6R, S)-tetrahydrofolate acid] get "unnatural" derivatives of tetrahydrofolate acid, such as 5-formyl-(6R)-tetrahydrofolic acid, 5-methyl-(6R)-tetrahydrofolic acid or 5,10-methylene-(6R)-tetrahydrofolic acid.

Examples illustrating the invention.

To determine the content THFC, 5-formyl-, 5-methyl - 5,10-methylene-THFC used the method WSIH with the following parameters:

Solvent A: 0,03 M Na2HPO4+ 0,03 M KH2PO4in water

Solvent: 1 part of a mixture of 0.03 M Na2HPO4+ 0,03 M KH2PO4in water, 3 parts of menthol and then bringing the pH value of the mixture to 7.8

Gradient: within 25 min from 2% to solvent up to 95% solvent

Column: ODS (hypersil)

Detection: UV 300 nm

To define or its salt accession dissolved in a mixture of acetonitrile and water (1:1) and subjected to reaction with 2,3,4,6-Tetra-o-acetyl- - -D-glucopyranosyloxy.

Solvent: 2.5 parts of acetonitrile, 1.5 parts of methanol, and 6.0 parts of citric acid (0.02 M).

Column: RP-8 (Lichrospher).

Detection: UV 270 nm.

Example 1. 14.2 g of toluene-4-sulfonic acid (150 mol.) at 60oC in an atmosphere of nitrogen dissolved in 440 ml of water, containing 0.1% 2-mercaptoethanol. Within 5 minutes the solution is injected to 25.0 g of pure (6R,S)-THFC. The obtained suspension is cooled to 40oC. After 2-5 hours, filtered off the precipitated product and washed with water and ethanol.

The result of 16.9 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 86,7% (according to VSGH).

By recrystallization of the resulting product from a mixture of 110 ml of N,N'-dimethylformamide and 220 ml of water are salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 97.5% (according to VSGH).

[]2D5= -60,6(C=0.5% in DMF)

For the release of (6S)-THFC 170 ml of water, containing 0.1% 2-mercaptoethanol, in a nitrogen atmosphere cooled to 10oC. Then injected 5.0 g of salt accession (6S)-THFC to toluene-4-sulfonic acid. To the resulting suspension to 2oC filtered phase of 97.7% (according to VSGH).

[]2D5= -44,5(C=1% in water)

Example 2. 13 g of toluene-4-sulfonic acid (135 mol.) at 20oC in an atmosphere of nitrogen dissolved in 200 ml of acetic acid and 200 ml of water containing 0.2% 2-mercaptoethanol. The solution is rapidly injected to 25.0 g of pure (6S,R)-THFC. The resulting solution tatrallyay a small amount of salt accession (6S)-THFC to toluene-4-sulfonic acid. After 5 hours, filtered off the precipitated product, and washed with a mixture of acetic acid and water and then with ethanol.

The result of 12.7 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 93,6% (according to VSGH).

10.0 g thus obtained salt accession (6S)-THFC to toluene-4-sulfonic acid at 25oC in nitrogen atmosphere weighed into 100 ml of water, and 30% sodium hydroxide solution was adjusted pH value of the suspension to > a 3.5. The pH of the resulting solution with 37% hydrochloric acid adjusted to <1. After 12 hours, filtered off the precipitated product, which is then washed with water and ethanol.

Get 8,9 salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 99,7% (according to VSGH).

[]2D5= -62 the PTA is dissolved in 220 ml of L(+)-lactic acid and 200 ml of water, containing 0.2% 2-mercaptoethanol. The solution is rapidly injected to 25.0 g of pure (6S, R)-THFC. The resulting solution tatrallyay a small amount of salt accession (6S)-THFC to toluene-4-sulfonic acid and cooled to 20oC. After 15-20 hours is filtered off the precipitated product, and washed with a mixture of lactic acid and water and then with ethanol.

The result of 15.1 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 92,5% (according to VSGH).

Example 4. 14.3 g of toluene-4-sulfonic acid (150 mol.) when the 27oC in an atmosphere of nitrogen dissolved in 110 ml of 1-methyl-2-pyrrolidone and 110 ml of water containing 0.4% 2-mercaptoethanol. The solution is rapidly injected to 25.0 g of pure (6S, R)-THFC. The resulting solution was diluted with 220 ml of water and cooled to 20oC. After 15-20 hours is filtered off the precipitated product, and washed with a mixture of 1-methyl-2-pyrrolidone and water, and then ethanol.

The result of 13.3 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in to 94.7% (according to VSGH).

Example 5. 11.5g toluene-4-sulfonic acid (150 mol.) when the 27oC in an atmosphere of nitrogen dissolved in 90 ml of N,N'-dimethylformamide and 90 ml of water containing 0.4% 2-mercaptoethanol. In rest is 5-20 hours is filtered off the precipitated product, and washed it with a mixture of N, N'-dimethylformamide and water and then with ethanol.

The result of 11.3 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 91,4% (according to VSGH).

Example 6. 11.5g toluene-4-sulfonic acid (150 mol.) when the 27oC in an atmosphere of nitrogen dissolved in 90 ml of N,N'-dimethylformamide and 80 ml of water containing 0.4% 2-mercaptoethanol. In the solution rapidly administered 20 g of pure (6R, S)-THFC. The resulting solution was diluted with 160 ml of water and cooled to 20oC. After 15-20 hours is filtered off the precipitated product, and washed it with a mixture of N, N'-dimethylformamide and water and then with ethanol.

The result of 11.0 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a share of (6S)-component in 91,5% (according to VSGH).

Example 7. 12 g of benzosulfimide acid (150 mol.) if 70oC in an atmosphere of nitrogen dissolved in 440 ml of water, containing 0.1% 2-mercaptoethanol. Within 5 minutes the solution is injected to 25.0 g of pure (6R,S)-THFC. The obtained suspension is cooled to 60oC. After 2-5 hours, filtered off the precipitated product and washed with water and ethanol.

The result of 13.8 g of salt accession (6S)-THFC to benzosulfimide acid with a share of (6S)-component in 92.4 per cent (according to VSGH).

Obtain 9.0 g of salt accession (6S)-THFC to benzosulfimide acid with a share of (6S)-component of 99.8% (according to VSGH).

[]2D5= -63,5(C=1% in DMF)

If we replace in this example, 150 mol. benzosulfimide acid 55 mol. benzosulfimide acid and 50 mol. hydrochloric acid, then under the same conditions of crystallization obtain 12.7 g of salt accession (6S)-THFC to benzosulfimide acid with a share of (6S)-component in 91.6% (according to VSGH).

For the release of (6S)-TGFC the pH of the filtrate with sodium hydroxide solution was adjusted to 3.5. After cooling to 5oC is filtered off the precipitated product and washed with water and ethanol.

10 g of the obtained residue is dissolved in 50oC in an atmosphere of nitrogen in 150 ml of water, containing 0.1% 2-mercaptoethanol, and 39 ml of 2 N. sulfuric acid. After slow cooling for 15 h at 20oC and subsequent incubation for 12 h, filtered off the precipitated product is (6S)-component in 97,7% (according to VSGH).

Example 8. 30 ml of 2 M sulfuric acid at 60oC dissolved in 130 ml of water containing 0.2% 2-mercaptoethanol and 164 ml of glacial acetic acid. Within 5 minutes the solution is injected 20 g of pure (6R,S)-THFC. The resulting solution was cooled to 50oC. After one hour, filtered off the precipitated product and washed with water and ethanol.

Gain of 11.0 g of salt accession (6S)-THFC to sulfuric acid with a share of (6S)-component in 65,5% (according to VSGH).

By double recrystallization of 10 g of salt accession (6S)-THFC to sulfuric acid from a mixture of dimethylformamide and water (1:3) gain of 3.9 g of salt accession (6S)-THFC to sulfuric acid with a share of (6S)-component in 94,3% (according to VSGH).

Example 9. (6R,S)-THFC received in city one of the methods described in the literature (see for example, R. L. Blakley with TCS. Folates and Pterins, 1, 93-104 (1984)), as such is subjected to the reaction of interaction with toluene-4-sulfonic acid.

50 g of folic acid at 25oC in nitrogen atmosphere weighed into 200 ml of water, as indicated, for example, the author C. Temple in J. Med. Chem. 22, 731 (1979 ). Using about 40 g of 30% sodium hydroxide solution to bring the pH value of the solution to 12. After adding 25 g of sodium borohydride (630 mol.) in 110 ml of heated the reaction mass to 70-756R, S)-THFC cooled to 25oC, and then added dropwise 30 g of toluene-4-sulfonic acid (150 mol.), dissolved in 200 ml of glacial acetic acid. With 96 g of 37% hydrochloric acid to bring the pH of the solution to <1. After 12 h, filtered off the precipitated product, and washed with a mixture of acetic acid and water and then with ethanol.

Get to 32.9 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with a yield of 82% and the proportion of (6S)-component in 95.4% (according to VSGH). 3,0 thus obtained salt accession (6S)-THFC to toluene-4-sulfonic acid at 25oC in nitrogen atmosphere weighed into 30 ml of water and with about 3 g of 30% sodium hydroxide solution was adjusted pH value of the suspension to 11.6. To the resulting solution was added 0.9 g of toluene-4-sulfonic acid (120 mol.), dissolved in 36 ml of glacial acetic acid. Then with the help of 22.2 g of 37% hydrochloric acid to bring the pH of the solution to <1. After 12 h, filtered off the precipitated product, and washed with a mixture of acetic acid and water and then with ethanol.

Gain of 1.81 g of salt accession (6S)-THFC to toluene-4-sulfonic acid with access to 100% and the proportion of (6S)-component in the 98.9% (according to VSGH).

Example 10. Replacing toluene-4-sulphonic CISL attach (6S)-THFC to benzosulfimide acid.

Get to 32.2 g of salt accession (6S)-THFC to benzosulfimide acid with a yield of 80% and the proportion of (6S)-component in a 94.2% (according to VSGH).

Example 11. Replacing toluene-4-sulfonic acid in example 9 equivalent amount of sulfuric acid, in a similar way you can receive sulfate (6S)-THFC acid.

Get 27,1 g sulfate (6S)-THFC access to 85% and the proportion of (6S)-component in 69.2% (according to VSGH).

Example 12. By recrystallization of the salt accession (6R,S)-THFC to methanesulfonic acid are salt accession (6S)-THFC to methanesulfonic acid with a share of (6S)-component in 68,3% (according to VSGH).

Example 13. By recrystallization of the salt accession (6R,S)-THFC to econsultancy acid are salt accession (6S)-THFC to econsultancy acid with a share of (6S)-component in 62,2% (according to VSGH).

Example 14. By recrystallization of the salt accession (6R,S)-THFC to phenylmethanesulfonyl acid are salt accession (6S)-THFC to phenylmethanesulfonyl acid with a share of (6S)-component in a 60.2% (according to VSGH).

Example 15. By recrystallization of the salt accession (6R,S)-THFC to camphor-10-sulfonic acid are salt accession (6S)-THFC to camphor-10-sulfonic acid with l is To naphthalene-1-sulfonic acid are salt accession (6S)-THFC to naphthalene-1-sulfonic acid with a share of (6S)-component in 74,1% (according to VSGH).

Example 17. By recrystallization of the salt accession (6R,S)-THFC to naphthalene-2-sulfonic acid are salt accession (6S)-THFC to naphthalene-2-sulfonic acid with a share of (6S)-component in 84,0% (according to VSGH).

Example 18. By recrystallization of the salt accession (6R,S)-THFC to naphthalene-1,5-sulfonic acid are salt accession (6S)-THFC to naphthalene-1,5-sulfonic acid with a share of (6S)-component in 65,8% (according to VSGH).

Example 19. 50 g obtained in example 8 salt accession (6S)-THFC to sulfuric acid at 20oC in an atmosphere of nitrogen dissolved in 500 ml of water with 200 ml of 2-n sodium hydroxide solution. After adding 7.5 ml of 36% formaldehyde (125 mol.) to the solution add a mixture of 275 ml of glacial acetic acid and 275 ml of 2 N. sulfuric acid. After cooling to 2oC is filtered off the precipitated product and wash it with ethanol.

Get to 39.6 g of 5,10-methylene-(6S)-THF-acid with access to 98.6% and the proportion of (6S)-component in 99,6% (according to VSGH).

Example 20. 28 g obtained in example 10 salt accession (6S)-THF-acid to benzosulfimide acid at a temperature of approximately 25oC in an atmosphere of nitrogen dissolved in 130 ml of water with 30% sodium hydroxide solution. After you add 44 ml of 36% formic acid is it 10 ml of 37% hydrochloric acid. The precipitated product is filtered and washed with water and ethanol.

Obtain 11 g of 5-methyl-(6S)-TGFC with access to 95,8% and the proportion of (6S)-component 99.5% (according to VSGH).

The other half of the solution add an excessive amount of calcium chloride, and the precipitated product is filtered off and washed with water and ethanol.

Get 14 g of the calcium salt of 5-formyl-(6S)-TGFC with access to 96.2% and the proportion of (6S)-component in 99,7% (according to VSGH).

1. The method of obtaining (6S)- or (6R)-tetrahydrofolate acid or salts joining this acid to sulfuric acid or sulfonic acids, characterized in that the (6R, S)-tetrahydrofolic acid is subjected to interaction with sulfuric acid or the corresponding sulfonic acid obtained Sol join acid fractional crystallization and if necessary, the resulting salt is treated with a base allocation of (6S)- or (6R)-tetrahydrofolate acid.

2. The method according to p. 1, characterized in that the crystallization is carried out in a polar medium, preferably in water or in mixtures of water with water-soluble lower aliphatic carboxylic acid, in particular acetic or lactic, or in a mixture of water with liquid moderator the/P> 3. The method according to p. 1 or 2, characterized in that as a sulfonic acid using an aromatic sulfonic acid with the number of carbon atoms of 6 to 14, analiticheskoy sulfonic acid with the number of carbon atoms of 7 to 9 or aliphatic sulfonic acid with the number of carbon atoms of 1 to 3.

4. The method according to one of the p. 1, 2 or 3, characterized in that the quality of the salt accession using salt accession to benzosulfimide acid, toluene-4-sulfonic acid or sulfuric acid.

5. Salt accession (6S)-tetrahydrofolate acid to sulfuric acid or sulfonic acids, selected from a number of toluene-4-sulfonic acid, benzolsulfonat acid, methane-, ethane-, phenylmethane-camphor-10-, naphthalene-1-, naphthalene-2-sulfonic acid and naphthalene-1,5-disulfonate acid, or salt accession (6R)-tetrahydrofolate acid to sulfuric acid or toluene-4-sulfonic acid, or benzosulfimide acid.

6. Salt p. 5, representing bansilalpet (6S)-tetrahydrofolate acid or bansilalpet (6R)-tetrahydrofolate acid.

7. Salt p. 5, a toluene-4-sulfonate of (6S)-tetrahydrofolate acid or toluene-4-sulfonate (6R)-tetrahydrofolate (6R)-tetrahydrofolate acid.

9. Salt p. 5, a salt accession (6S)-tetrahydrofolate acid to methane-, ethane-, or phenylmethane-, or camphor-10-or naphthalene-1-or naphthalene-2 - sulfonic acid or naphthalene-1,5-disulfonic acid.

10. Salt accessions (6S)- or (6R)-tetrahydrofolate acid to sulfonic acids or sulfuric acid as intermediates for obtaining optically pure 5,10-methylentetrahydrofolate, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate acids and their salts with strong bases and acids.

 

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2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, hydrates and/or solvates (versions) thereof, for which characteristic powder diffraction patterns with radiation CuKα1 are given, with characteristic peaks expressed in values of d (Å). Said modifications can be used to treat neurological disorder. The invention also relates to pharmaceutical compositions (versions) which may additionally contain folate, separately or together with arginine in an effective amount. The folate is folic acid or tetrahydrofolate selected from tetrahydrofolic acid, 5,10-methylene-tetrahydrofolic acid, 10-formyl-tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid or 5-methyl-tetrahydrofolic acid, or polyglutamate thereof or pharmaceutically acceptable salt thereof. The invention also relates to methods of producing (versions) said crystalline modifications. For example, the method of producing crystalline form A of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride involves dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water at ambient temperature, and (1) cooling the solution to a low temperature with solidification of the solution, and removing water at pressure ranging from 0.01 to 1 mbar, or (2) removing water from said aqueous solution by filtering and drying with evaporation of water, and extracting said crystalline form.

EFFECT: improved properties of compounds.

42 cl, 18 tbl, 15 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel dihydropteridinone derivatives of formula (I), method of obtaining thereof (versions) and their pharmaceutical application as Plk kinase derivatives. In formula

R1 and R2 each is independently selected from the group, consisting of a hydrogen atom and C1-6alkyl; R3 is selected from the group, consisting of C1-6alkyl and C5-6cycloalkyl; R4 and R5 each is independently selected from the group, consisting of a hydrogen atom, C1-6alkyl, where the alkyl is optionally substituted with one or more groups, selected from the group, consisting of C1-6alkoxyl and -NR9R10; R6 is selected from the group, consisting of C1-3alkyl, C5-6cycloalkyl, heterocyclic alkyl, selected from a 6-membered heterocyclic alkyl with 1 nitrogen atom, hexahydrocyclopenta(c)pyrrol or cyclopenta(c)piperidine, where C1-3alkyl, C5-6cycloalkyl or heterocyclic alkyl each is optionally substituted with one or more groups, selected from the group, consisting of C1-6alkyl, C1-6alkoxyl, hydroxyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, heterocyclic alkyl, N-methylmorpholine, hexahydropyrrolo[2,1-c][1,4]oxazine, -C(O)R9, -NR9R10 and C1-6alkylcarbonyloxygroup; where R9 and R10 together with a nitrogen atom which they are bound to form a 4-8-membered heterocycle, where the 4-8-membered heterocycle contains one or more N or O heteroatoms and the 4-8-membered heterocycle is optionally substituted with C1-6alkyl, optionally substituted with C3-6cycloalkyl; R7 and R8 each is independently selected from a hydrogen atom or C1-6alkyl; R9 and R10 each is independently selected from a hydrogen atom or C1-6alkyl. The invention also relates to a novel intermediate compound of formula (IA), where R1, R2 R3 R4, R5, R7, R8 R9 and R10 have the said values; R11 is selected from the group, consisting of hydroxyl or C1-6alkoxyl. The method of obtaining the formula I compound consists in the interaction of the formula

compound with R6NH2 compound, or in the interaction of the formula (IB) compound with the formula (IC) compound. Formulae (IB) and (IC) are given in the invention formula.

EFFECT: compounds can be used for obtaining the medication for treating a cell proliferation disorder, in particular, in case of a disorder, which is cancer, which is selected from the group, consisting of non-small lung cancer, squamous cell carcinoma, breast cancer, ovarian cancer, cervical cancer, papillary carcinoma or colorectal carcinoma, preferably cervical cancer or colorectal carcinoma.

11 cl, 2 tbl, 47 ex

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