Folates, compositions and uses thereof

Abstract

The present invention relates to folates, compositions and uses thereof; In particular, this invention describes a crystalline or amorphous compound which is a substituted or unsubstituted folate or a reduced folate, or the natural or unnatural isomers thereof, of at least one organic base, as well as compositions and uses thereof. The compounds of the invention show a long lasting stability as well as a peculiarly high water-solubility.

Description

technical field

[0001] The present invention relates to folates, compositions and uses thereof; in particular, the present invention describes crystalline and amorphous compounds which are folates of at least one organic base or reduced folic acid, as well as compositions and uses thereof salts, or their natural or unnatural isomers. Background technique

[0002] Folic acid, which is N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, and Folate, and its anion, are the precursor forms of water-soluble vitamin B9 and dihydrofolate and tetrahydrofolate, and their respective anion forms. They are mostly found naturally in food in the form of their conjugates, especially in liver, kidney, yeast, fruit and green leafy vegetables, and can also be taken as supplements. Commercially available folic acid, and its derivatives as described above, are still produced synthetically.

[0003] Folic acid exists in the form of yellow or light orange cryst...

Examples

Embodiment 1

[0037] Preparation of D-glucosamine 5-methyl-(6R,S)-tetrahydrofolate

[0038] 4.60 g (10 mmol) of 5-methyl-(6R,S)-tetrahydrofolate were added in portions and completely dissolved in 30 ml of an aqueous solution of D-glucosamine (3.58 g, 20 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.

[0039] analyze data:

[0040] HPLC titer determination of 5-methyl-(6R, S)-tetrahydrofolate: calculated value is 56.18% (dry product); measured value is 55.22% (98.3% of theoretical value);

[0041] Specific rotation [α] 20 D =+54.2° (C=1, in water)

[0042] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

Embodiment 2

[0044] Preparation of D-glucosamine 5-methyl-(6R,S)-tetrahydrofolate

[0045] 9.19 g (20 mmol) of 5-methyl-(6R,S)-tetrahydrofolate were added in portions and completely dissolved into 60 ml of an aqueous solution of D-glucosamine (7.12 g, 40 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was spray dried to afford 16.9 g of the title product.

[0046] analyze data:

[0047] HPLC titer determination of 5-methyl-(6R, S)-tetrahydrofolate: calculated value 56.18% (dry product); measured value 55.13 (98.2% of theoretical value);

[0048] Specific rotation [α] 20 D =+54.0 (C=1, in water)

[0049] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

Embodiment 3

[0051] Preparation of D-glucosamine 5-methyl-(6S)-tetrahydrofolate

[0052] 4.60 g (10 mmol) of 5-methyl-(6S)-tetrahydrofolate obtained by splitting the corresponding (6R,S)-5-methyltetrahydrofolate was added in portions and completely dissolved in a stirred tank under nitrogen. 30ml of D-glucosamine (3.58g, 20mmol) in aqueous solution. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.

[0053] analyze data:

[0054] HPLC titer determination of 5-methyl-(6S)-tetrahydrofolate: calculated value 56.18% (dry product); measured value 55.7% (99.1% of theoretical value);

[0055] Specific rotation [α] 20 D =+42.6°(C=1, in water)

[0056] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

technical field

[0001] The present invention relates to folates, compositions and uses thereof; in particular, the present invention describes crystalline and amorphous compounds which are folates of at least one organic base or reduced folic acid, as well as compositions and uses thereof salts, or their natural or unnatural isomers. Background technique

[0002] Folic acid, which is N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, and Folate, and its anion, are the precursor forms of water-soluble vitamin B9 and dihydrofolate and tetrahydrofolate, and their respective anion forms. They are mostly found naturally in food in the form of their conjugates, especially in liver, kidney, yeast, fruit and green leafy vegetables, and can also be taken as supplements. Commercially available folic acid, and its derivatives as described above, are still produced synthetically.

[0003] Folic acid exists in the form of yellow or light orange cryst...

Examples

Embodiment 1

[0037] Preparation of D-glucosamine 5-methyl-(6R,S)-tetrahydrofolate

[0038] 4.60 g (10 mmol) of 5-methyl-(6R,S)-tetrahydrofolate were added in portions and completely dissolved in 30 ml of an aqueous solution of D-glucosamine (3.58 g, 20 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.

[0039] analyze data:

[0040] HPLC titer determination of 5-methyl-(6R, S)-tetrahydrofolate: calculated value is 56.18% (dry product); measured value is 55.22% (98.3% of theoretical value);

[0041] Specific rotation [α] 20 D =+54.2° (C=1, in water)

[0042] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

Embodiment 2

[0044] Preparation of D-glucosamine 5-methyl-(6R,S)-tetrahydrofolate

[0045] 9.19 g (20 mmol) of 5-methyl-(6R,S)-tetrahydrofolate were added in portions and completely dissolved into 60 ml of an aqueous solution of D-glucosamine (7.12 g, 40 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was spray dried to afford 16.9 g of the title product.

[0046] analyze data:

[0047] HPLC titer determination of 5-methyl-(6R, S)-tetrahydrofolate: calculated value 56.18% (dry product); measured value 55.13 (98.2% of theoretical value);

[0048] Specific rotation [α] 20 D =+54.0 (C=1, in water)

[0049] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

Embodiment 3

[0051] Preparation of D-glucosamine 5-methyl-(6S)-tetrahydrofolate

[0052] 4.60 g (10 mmol) of 5-methyl-(6S)-tetrahydrofolate obtained by splitting the corresponding (6R,S)-5-methyltetrahydrofolate was added in portions and completely dissolved in a stirred tank under nitrogen. 30ml of D-glucosamine (3.58g, 20mmol) in aqueous solution. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.

[0053] analyze data:

[0054] HPLC titer determination of 5-methyl-(6S)-tetrahydrofolate: calculated value 56.18% (dry product); measured value 55.7% (99.1% of theoretical value);

[0055] Specific rotation [α] 20 D =+42.6°(C=1, in water)

[0056] NMR (D 2 O): 7.45(d, 2H); 6.55(d, 2H); 5.20(b s, 2H); 4.05(m, H); 3.70-3.40(m, 7H); 3.38-3.00(m, 6H); 2.99 -2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).

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