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GB1572138A - Process for the preparation of d,1-5-methyltetrahydrofolic acid - Google Patents

Process for the preparation of d,1-5-methyltetrahydrofolic acid Download PDF

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GB1572138A
GB1572138A GB1237478A GB1237478A GB1572138A GB 1572138 A GB1572138 A GB 1572138A GB 1237478 A GB1237478 A GB 1237478A GB 1237478 A GB1237478 A GB 1237478A GB 1572138 A GB1572138 A GB 1572138A
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acid
methyltetrahydrofolate
sodium
ratio
reducing agent
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BIORESEARCH Sas DEL DR LIVIO C
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

(54) PROCESS FOR THE PREPARATION OF D, 1-5- METHYTETRAHYDROFOLIC ACID (71) We, BIORESEARCH S.A.S. DEL DR. LIVIO CAMOZZI & CO., Via Marcona 37, Milan, Italy, a company organised and existing under the laws of Italy, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a process for preparing d,l - N -[p - (2 - amino 3,4,5,6,7*8 - hexahydro - 5 - methyl - 4 - oxo - 6 - pteridinyl)methyl] benzoyl glutamic acid and its salts of formula
where X is hydrogen, an alkali metal or an equivalent of an alkaline earth metal.
Hereinafter, the acid (I) will be referred to only as 5 - methyl - tetrahydrofolic acid (MTHF).
The new process is applicable industrially for obtaining a high purity product simply, economically and in high yields. d,l - 5 - methyltetrahydrofolic acid is usually prepared from folic acid by a process comprising the following essential stages: - .. reduction a) tolic acid
tetrahydrotolic acid b) separation and purification of the tetrahydrofolic acid methvlation c) tetrahydrofolic acid
5-methyltetrahydrofolic acid d) separation and purification of the 5-methyltetrahydrofolic acid.
Stage (a) can be carried out both by catalytic hydrogenation and by chemical reduction, in particular by using alkaline borohydrides. (Y. Hetefi et al.-Biochem.
Prep. 7, 89 (1960); K. G. Serimgeour et al.-Biochemistry 5, 1438 (1966)). In this stage, no matter which known method is used, a mixture of folic acid, tetrahydrofolic acid and dihydrofolic acid is obtained, which consists mainly of folic and tetrahydrofolic acid and is difficult to resolve.
The only useful methods for carrying out stage (b) use large chromatography columns and a series of eluants (L-Jaenicke et al-Z.physiol Chem. 326, 168 (1961); J. C. Keresztesy et al-Biochem. Biophysic Res. Commun. 5,286 (1961); H.
Riidiger et al--FE/BS/Letters 4, 316 (1969)). Any excess alkaline borohydride being destroyed by an acid, preferably hydrochloric or acetic, before the solution is subjected to chromatographic separation.
The methylation of the tetrahydrofolic acid (stage c) can be carried out using a variety of methods, the most common and convenient of which being a reaction with formaldehyde followed by reduction of the product with, preferably, an alkaline borohydride (W. Sakami et al; Biochem. Prep. 10, 103 (1963)).
The separation and purification step (stage d) has, up to the present time, always been carried out by chromatographic processes of varying degrees of complexity depending on the nature of the mixture to be purified.
In one modification of the above method (J. A. Blair et al, Analytical Biochemistry 34,376-381 (1976) stage (b) is dispensed with altogether. The reaction mixture after stage (a) in which all the excess alkaline borohydride has been destroyed, is treated directly with formaldehyde and another alkaline borohydride. This modification does not however substantially improve the process because as stage (a) leads to a mixture as heretofore specified, dispensing with stage (b) results in a final mixture which is even more complex than normal. This in turn increases the difficulties which arise during purification stage (d) with a loss in this stage of about 60% of the product. Furthermore a high purity product, as would be required in the pharmaceutical field, is not obtained.
The above process, which is the best known at the present time, has therefore never gone beyond the stage of laboratory use and the production of small quantities for experimental use.
It has now been found that it is possible to convert folic acid (a compound easily obtained commercially at economically acceptable prices) into d, 1 - 5 methyltetrahydrofolic acid of pharmaceutical purity with very high yields and without the necessity of using costly and complicated chromatographic purification steps if the folic acid is reduced under critical reaction conditions which make the reaction nearly 100% selective in producing tetrahydrofolic acid.
Accordingly the invention provides a method of preparing d,l - 5 - methyl tetrahydrofolic acid and its salts of the formula:
wherein X is H, an alkali metal or an equivalent of an alkaline earth metal comprising: a) Reducing folic acid to tetrahydrofolic acid with Nabs4, said reduction being carried out in an aqueous alkaline medium and an inert atmosphere; the reaction temperature being 60--800C, the reaction time being 30 minutes to 2 hours and the ratio of NaBH4: folic acid being 1.5:1 to 3:1.
b) Methylating said tetrahydrofolic acid to form the sodium salt of 5-methyltetra hydrofolic acid, said methylation comprising: 1) initially reacting tetrahydrofolic acid with an aqueous solution of formalde hyde and sodium borohydride in an inert gas atmosphere, using a ratio of NaBH4: tetrahydrofolic acid of 1:1 to 1:2, a temperature range of 25-300C and a pH range of 6-8.
2) when said initial reaction with formaldehyde is finished, adding a further quantity of formaldehyde in aqueous solution and a reducing agent; said methylation using a ratio of total formaldehyde: tetrahydrofolic acid of 0.8:1 to 2.5:1.
c) separating and purifying sodium 5-methyltetrahydrofolate so formed from the The addition of a second quantity of formaldehyde after the methylation reaction has finished has the effect of destroying any excess NaBH4 in the reaction mixture. The reducing agent added in the second stage of part (b) is to prevent self oxidation of the 5-methyltetrahydrofolate to the corresponding dihydrofolic and folic acids.
The sodium 5-methyltetrahydrofolate is converted to a different salt of 5methyltetrahydrofolic acid by addition of an inorganic salt of the required metal.
The salt formed can then be converted to 5-methyltetrahydrofolic acid by addition of a mineral acid.
Preferably the reduction is carried out under the following conditions: ratio of Nabs,: folic acid is 2:1 reaction time 1 hour -pH 7-8 -temperature 70"C The methlation stage is preferably carried out under the following conditions: -pH 6.5 -temperature 30"C ratio of formaldehyde: tetrahydrofolic acid is 1.4:1 ratio of Nabs4: tetrahydrofolic acid between 1:1 and 1:2 reducing agent present in the reaction mixture is cysteine The reducing agent may also be glutathione pantotheine.
The separation/purification of the sodium 5-methyltetrahydrofolate (step c) may be carried out by treating the reaction mixture with active carbon, the quantity of active carbon being 5 to 20 times the weight of the initially treated folic acid; desorbing the sodium 5-methyltetrahydrofolate from the carbon by means of an eluant mixture comprising an alcohol having 1 to 4 carbon atoms or 2-methoxyethanol, water, ammonia and a reducing agent; the alcohol or 2-methoxyethanol and water being in the ratio to 50/50 to 95/5 v/v.
Preferably the conditions are patio of active carbon: folic acid 7:1 --eluant mixture consisting of ethanol, methanol or 2-methoxyethanol and water in a ratio of 80/20, v/v reducing agent in the reaction mixture: cysteine to the extent of 1% of the total eluant mixture -34% aqueous ammonia solution to the extent of 2% of the total eluant mixture (0.7% in toto of ammonia).
Preferably the formaldehyde is in the form of a 37% aqueous solution.
The product obtained by the new method has a purity usually exceeding 90% and the method has yields normally exceeding 80% with respect to the initial folic acid.
The stages described above can be carried out in succession in the same reactor without the necessity of separating the intermediate products.
The ratios indicated are by weight unless otherwise stated.
Comparing the process according to the invention with that process summarised at the beginning of the specification, which is the best known to the art, it can be seen that the new process enables both the intermediate and the final stages of chromatographic separation and purification to be dispensed with. This leads to a considerable simplification in producing MTHF. The new process is also more economic as the best known process requires large chromatography columns and long processing times both of which are costly. These chromatographic processes also result in large losses of useful product. Further losses also arise due to the product being in very dilute solutions.
Preferably the final separation/purification stage in the process according to the invention is an adsorption/desorption on to active carbon which produces high yields. This stage is completely new for the production of 5-methyltetrahydrofolic acid and its salts.
From the above it can be seen that the method of preparing MTHF is carried out in the presence of an inert gas, this is to prevent self-oxidation of either of the tetrahydrofolic acid or of the 5-methyltetrahydrofolic acid to the corresponding dihydrofolic and folic acids.
Stable pharmaceutical compositions of MTHF possess hemopoietic action, protective activity on the liver and antineoplastic activity and are the subject of our co-pending application no. 7290/77 (Serial No. 1,572,137). Some practical examples of the process are given hereinafter.
EXAMPLE 1.
80 1 of deionised water are fed into a reactor and 2.4 kg of d,l-folic acid are suspended therein.. Solid Na2CO3 is added, with stirring, until the folic acid is completely dissolved (final solution pH 7.8), then 4.8 kg of NaBH4 dissolved in 40 1 of H2O are added and the reaction mixture heated to 700 C. The reaction mixture is kept under a stream of nitrogen for I hour with stirring. When the reaction is finished the reactor is cooled to 300C and 3.5 kg of 37% aqueus formaldehyde and 2.4 kg of sodium borohydride dissolved in 20 1 of water are added under agitation.
The reaction is continued for I hour, with stirring, under a stream of nitrogen. Then a further 0.15 kg of 37% formaldehyde and 1 kg of cysteine are added.
17 kg of active carbon are suspended in 100 1 of deaerated water and this carbon suspension is added, with stirring, to the reaction mixture, the pH being brought to 6.5. After a few minutes the reaction mixture is filtered under nitrogen and the carbon cake on the filter washed with water containing 1% cysteine until all the inorganic salts have been completely removed. The carbon cake is then suspended in 100 1 of an eluant mixture of the following volumetric composition: 2 - methoxy - ethanol 80, water (containing 5% of cysteine) 20, ammonia (34%) 2.
The suspension is stirred for some minutes, then filtered and the filtrate concentrated to a volume of 20 litres. The concentrated filtrate is poured into a solution containing 700 g of CaCl2 in 100 litres of ethanol.
Calcium 5 - methyltetrahydrofolate precipitates and is filtered off, under nitrogen, washed with ethanol and then dried under vacuum. 2.3 kg of product are obtained, equal to a yield of 86% of the initial folic acid.
On U.V. analysis the product shows the following characteristics (pH 7; E = 32.103): maximum absorption at 290 nm minimum absorption at 245 nm ratio E,E,,, = 3.8.
Analysis over a "Sephadex" (registered Trade Mark) DEAE A-25 chromatographic column using the method of Nixon and Bertino (P. F. Nixon, J.
R. Bertino, Methods in Enzym. 18, 661 (1971)) shows only the 5-methyltetrahydrofolic acid peak. HPLC analysis ("Partisil"--1OSAX 4.6 x 250 mm column ("Partisil" is a registered Trade Mark); eluant 5% ammonium citrate; pH = 6) shows only the 5-methyltetrahydrofolic acid peak. NMR spectrum: singlet characteristic of the N5-CH3 group at T = 7.5. 1 kg of the calcium 5-methyltetrahydrofolate prepared in this manner is dissolved in 40 1 of water containing 1 kg of cysteine under heat and nitrogen.
The pH is brought to 6 with dilute hydrochloric acid and the mixture allowed to stand in a refrigerator.
5-methyltetrahydrofolic acid precipitates and is filtered off, washed with a little cold water and dried. The product shows an E29JE245 value of 3.8.
The same process was repeated but replacing the 2-methoxy-ethanol in the eluent mixture with ethanol, methanol, 4 l-propanol or 2-propanol, n-butanol, tbutanol, sec-butanol and isobutanol respectively. In each case a product was obtained of the same characteristics and the same yield as when the eluant was 2methoxyethanol.
EXAMPLE 2.
Sodium 5-methyltetrahydrofolate is prepared as described in Example 1. The carbon is eluted with a mixture having the following volumetric composition: methanol 80, water (containing 5% glutathione) 20, ammonia (34%) 2.
After filtering the active carbon, 700 g of CaCl2 dissolved in a small amount of water are added to the eluate.
Calcium 5-methyltetrahydrofolate precipitates and is filtered off under a stream of nitrogen, washed with ethanol and dried under vacuum.
2.1 kg of product are obtained, equal to a yield of 80% of the folic acid.
The product has the same characteristics as that obtained in Example 1.
EXAMPLE 3.
The preaparation is repeated as described in Example 1 except that the carbon cake is treated with an eluant mixture consisting of 2-propanol and water containing small percentages of ammonium hydrate and cysteine. The filtered eluate is then concentrated to a volume of 20 litres.
This solution is subjected to lyophylisation to give 2.1 kg of sodium 5-methyl tetrahydrofolate with a yield of 80%. The product shows a E29JE24s value of 3.8.
EXAMPLE 4.
The method of Example 1 is repeated up to the concentration of the eluate. In this case the eluate is treated with 1.3 kg of BaCI7 dissolved in 100 litres of ethanol.
Barium 5-methyltetrahydrofolate precipitates with a yield of 83%. E29E245 = EXAMPLE 5.
The method of Example 1 is repeated up to the concentration of the eluate.
In this case the eluate is treated with 0.6 kg of MgCI2 dissolved in 100 litres of ethanol.
Magnesium 5-methyltetrahydrofolate precipitates with a yield of 82%.
E290/E24s = 3.8.
EXAMPLE 6.
100 grams of calcium 5-methyltetrahydrofolate prepared as in Example 1 are dissolved in 4 litres of H2O.
The stoichiometric quantity of Na2SO4 is added to this solution. CaSO4 is precipitated and separated by filtration.
The clear solution is subjected to lyophilisation, to give sodium 5-methyltetrahydrofolate.
WHAT WE CLAIM IS: 1. A method of preparing d,l - 5 - methyltetrahydrofolic acid and its salts of the formula:
wherein X is hydrogen, an alkali metal or an equivalent of an alkaline earth metal comprising: a) Reducing folic acid to tetrahydrofolic acid with Nabs4, said reduction being carried out in an aqueous alkaline medium and an inert atmosphere; the reaction temperature being 60--80"C, the reaction time being 30 minutes to 2 hours and the ratio of NaBH4: folic acid bering 1.5:1 to 3:1.
b) Methylating said tetrahydrofolic acid to form the sodium salt of 5-methyltetra hydrofolic acid, said methylation comprising: 1) initially reacting tetrahydrofolic acid with an aqueous solution of formalde hyde and sodium borohydride in an inert gas atmosphere, using a ratio of NaBH4: tetrahydrofolic acid of 1:1 to 1:2, a temperature range of 25-300C and a pH range of 6-8.
2) when said initial reaction with formaldehyde is finished, adding a further quantity of formaldehyde in aqueous solution and a reducing agent; said methylation using a ratio of total formaldehyde: tetrahydrofolic acid of 0.8:1 to 2.5:1.
c) separating and purifying sodium 5-methyltetrahydrofolate so formed from the reaction mixture in the presence of a reducing agent; and, if desired d) converting the separated and purified sodium 5-methyltetrahydrofolate to 5 methyltetrahydrofolic acid or a salt thereof.
2. A method according to claim I wherein said separated and purified sodium 5-methyltetrahydrofolate is converted to a different salt of 5-methyltetrahydrofolic acid by addition of an inorganic salt of the required metal.
3. A method according to claim 2 further comprising converting said salt formed to 5-methyltetrahydrofolic acid by addition of a mineral acid.
4. A method according to claim 1 or 2 wherein said purification and separation of said sodium 5-methyltetrahydrofolate comprises treating said reaction mixture
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (13)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    This solution is subjected to lyophylisation to give 2.1 kg of sodium 5-methyl tetrahydrofolate with a yield of 80%. The product shows a E29JE24s value of 3.8.
    EXAMPLE 4.
    The method of Example 1 is repeated up to the concentration of the eluate. In this case the eluate is treated with 1.3 kg of BaCI7 dissolved in 100 litres of ethanol.
    Barium 5-methyltetrahydrofolate precipitates with a yield of 83%. E29E245 = EXAMPLE 5.
    The method of Example 1 is repeated up to the concentration of the eluate.
    In this case the eluate is treated with 0.6 kg of MgCI2 dissolved in 100 litres of ethanol.
    Magnesium 5-methyltetrahydrofolate precipitates with a yield of 82%.
    E290/E24s = 3.8.
    EXAMPLE 6.
    100 grams of calcium 5-methyltetrahydrofolate prepared as in Example 1 are dissolved in 4 litres of H2O.
    The stoichiometric quantity of Na2SO4 is added to this solution. CaSO4 is precipitated and separated by filtration.
    The clear solution is subjected to lyophilisation, to give sodium 5-methyltetrahydrofolate.
    WHAT WE CLAIM IS: 1. A method of preparing d,l - 5 - methyltetrahydrofolic acid and its salts of the formula:
    wherein X is hydrogen, an alkali metal or an equivalent of an alkaline earth metal comprising: a) Reducing folic acid to tetrahydrofolic acid with Nabs4, said reduction being carried out in an aqueous alkaline medium and an inert atmosphere; the reaction temperature being 60--80"C, the reaction time being 30 minutes to 2 hours and the ratio of NaBH4: folic acid bering 1.5:1 to 3:1.
    b) Methylating said tetrahydrofolic acid to form the sodium salt of 5-methyltetra hydrofolic acid, said methylation comprising: 1) initially reacting tetrahydrofolic acid with an aqueous solution of formalde hyde and sodium borohydride in an inert gas atmosphere, using a ratio of NaBH4: tetrahydrofolic acid of 1:1 to 1:2, a temperature range of 25-300C and a pH range of 6-8.
    2) when said initial reaction with formaldehyde is finished, adding a further quantity of formaldehyde in aqueous solution and a reducing agent; said methylation using a ratio of total formaldehyde: tetrahydrofolic acid of 0.8:1 to 2.5:1.
    c) separating and purifying sodium 5-methyltetrahydrofolate so formed from the reaction mixture in the presence of a reducing agent; and, if desired d) converting the separated and purified sodium 5-methyltetrahydrofolate to 5 methyltetrahydrofolic acid or a salt thereof.
  2. 2. A method according to claim I wherein said separated and purified sodium 5-methyltetrahydrofolate is converted to a different salt of 5-methyltetrahydrofolic acid by addition of an inorganic salt of the required metal.
  3. 3. A method according to claim 2 further comprising converting said salt formed to 5-methyltetrahydrofolic acid by addition of a mineral acid.
  4. 4. A method according to claim 1 or 2 wherein said purification and separation of said sodium 5-methyltetrahydrofolate comprises treating said reaction mixture
    with active carbon, said quantity of active carbon being 5 to 20 times the weight of said initially treated folic acid; desorbing said sodium 5-methyltetrahydrofolate from said carbon by means of a eluant mixture comprising an alcohol having 1 to 4 carbon atoms or 2-methoxyethanol, water, ammonia and a reducing agent said alcohol or 2-methoxyethanol and water being in the ratio of 50/50 to 95/5 v/v.
  5. 5 A method according to any one of claims 1 to 4 wherein the reaction conditions for stage (a) are: Nabs,: folic acid ratio of 2:1; temperature of 70"C; pH range of 7-8, and a reaction time of 1 hour.
  6. 6. A method according to any one of the preceding claims wherein stage (b) is carried out with a total formaldehyde: tetrahydrofolic acid ratio of 1.4:1, a Nabs,: tetrahydrofolic acid ratio of 1:1, a temperature of 30"C and a pH of 6.5, and said reducing agent being cysteine.
  7. 7. A method according to claim 4, wherein said eluant mixture has a ratio of alcohol or 2-methoxyethanol to water of 80/20 v/v; said quantity of reducing agent is equal to 1% by volume; and said quantity of ammonia is 0.7%.
  8. 8. A method according to claims 4 or 7 wherein said quantity of active carbon is 7 times the weight of said initially treated folic acid.
  9. 9. A method according to claims 4, 7 or 8 wherein said alcohol is methanol, ethanol, I-propanol, 2-propanol, n-butanol, t-butanol, sec-butanol or isobutanol,
  10. 10. A method according to claim 10 wherein said reducing agent is cysteine, glutathione or pantothiene.
  11. 11. A method according to claim 10 wherein said reducing agent is cysteine.
  12. 12. A method according to claim 1 wherein said sodium 5-methyltetrahydro folate is separated by concentrating the eluate and lyophilising the concentrate.
  13. 13. A method according to claim 1 substantially as described in Examples l.
GB1237478A 1977-02-22 1977-02-22 Process for the preparation of d,1-5-methyltetrahydrofolic acid Expired GB1572138A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409125A1 (en) * 1989-07-21 1991-01-23 Cerbios-Pharma S.A. Salts of N5, N10-methylene-5,6,7,8-tetrahydrofolic acid
EP0537842A3 (en) * 1991-10-10 1993-05-05 Apr Applied Pharma Research S.A. A process for the preparation of substituted tetrahydrofolic derivatives in the 6(r,s)(-) forms and of their active 6(s)(-) n5 diastereoisomers in form of alkali and earth alkali metal salts
US5223500A (en) * 1977-02-22 1993-06-29 Bioresearch S.P.A. Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223500A (en) * 1977-02-22 1993-06-29 Bioresearch S.P.A. Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate
EP0409125A1 (en) * 1989-07-21 1991-01-23 Cerbios-Pharma S.A. Salts of N5, N10-methylene-5,6,7,8-tetrahydrofolic acid
EP0537842A3 (en) * 1991-10-10 1993-05-05 Apr Applied Pharma Research S.A. A process for the preparation of substituted tetrahydrofolic derivatives in the 6(r,s)(-) forms and of their active 6(s)(-) n5 diastereoisomers in form of alkali and earth alkali metal salts
US5350850A (en) * 1991-10-10 1994-09-27 Apr Applied Pharma Research S.A. Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N5 diastereoisomers in form of alkali and alkaline earth metal salts

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