WO1995033749A1 - A process for the preparation and separation of diastereomeric salts of folinic acid - Google Patents
A process for the preparation and separation of diastereomeric salts of folinic acid Download PDFInfo
- Publication number
- WO1995033749A1 WO1995033749A1 PCT/EP1995/002073 EP9502073W WO9533749A1 WO 1995033749 A1 WO1995033749 A1 WO 1995033749A1 EP 9502073 W EP9502073 W EP 9502073W WO 9533749 A1 WO9533749 A1 WO 9533749A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diamino
- folinate
- process according
- water
- solvent
- Prior art date
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- 0 C*C(CC(*)(*[C@](*)CN)C1)(C*1(*)N(*)*)*(C)CN Chemical compound C*C(CC(*)(*[C@](*)CN)C1)(C*1(*)N(*)*)*(C)CN 0.000 description 2
Classifications
-
- 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
Definitions
- This invention refers to a process for the preparation, separation and purification of stereoisomer ⁇ of the salts of folinic acid which, in its calcium salt form, is used, in antitumoral therapy, as an antidote for the folic acid antagonists, such as antagonists of aminopterine or methotrexate.
- these substances block the metabolism of folic acid in the organism, preventing the transformation of dihydrofolic acid into tetrahydrofolic acid.
- calcium folinate increases the activity of folic acid.
- the folinic acid calcium salt is also used in all anaemic forms deriving from the lack of folates.
- the process of the invention allows the preparation of the two diastereomeric forms of said salts in a convenient way, in good yields and with an high optical purity.
- Folinic acid N-(5-formyl-(6RS)-5,6,7,8- tetrahydropteroyl)-L-glutamic acid, when synthetically obtained, consists of the equimolar mixture of two diastereomeric forms, (6R) and (6S) respectively.
- This invention refers to a process which allows, starting from a known key intermediate, namely (6RS)- 5,10-methenyl-5,6,7,8-tetrahydrofolic acid chloride hydrochloride [for instance obtained according to C. Temple; US 4,148,999; US 4,206,307; J. Med.Chem. 21, 731 (1979)], the preparation, separation and isolation of the diastereomeric salts of folinic acid with an at least dibasic organic amine, obtaining chemical and optical purity levels so high that the following transformation into the desired corresponding calcium salts is possible without performing further complex purification steps, providing therefore definite advantages from the industrial point of view.
- (6RS)- 5,10-methenyl-5,6,7,8-tetrahydrofolic acid chloride hydrochloride for instance obtained according to C. Temple; US 4,148,999; US 4,206,307; J. Med.Chem. 21, 731 (1979)
- the folinic acid calcium salt is usually prepared starting from folic acid, which contains a (S) chiral centre in the part of the molecule corresponding to (S)-glutamic acid.
- folic acid which contains a (S) chiral centre in the part of the molecule corresponding to (S)-glutamic acid.
- 6RS a new chiral centre is formed in position 6 with a (6RS) configuration.
- (6RS)-5,10- methenyl-5,6,7,8-tetrahydrofolic acid formate By acidification with hydrochloric acid the crystallization of the corresponding chloride hydrochloride is obtained.
- This intermediate is hydrolyzed, preferably with strong inorganic bases (for instance NaOH), or with strongly basic organic monoamines such as triethylamine, and under strictly controlled pH conditions.
- strong inorganic bases for instance NaOH
- strongly basic organic monoamines such as triethylamine
- the mixture of diastereomeric salts of folinic acid is transformed into the mixture of the corresponding calcium salts (with CaC ⁇ ). Said mixture is precipitated from ethanol to give (6RS) crude calcium folinate which is purified through various purification steps. By treating with acids an aqueous solution of purified (6RS) calcium folinate, (6RS) folinic acid precipitates which is ready for the diastereomeric separation.
- said hydrolysis reaction can be performed in the presence of a suitable amount of a relatively weak base, consisting of an at least dibasic organic amine, which allows a high conversion and selectivity of the reaction.
- a relatively weak base consisting of an at least dibasic organic amine, which allows a high conversion and selectivity of the reaction.
- said dia ine in addition to its hydrolyzing function, acts at the same time as salifying agent for the folinic acid which has been formed.
- the final crude solution which contains the mixture of the diastereomeric diamine salts of (6RS)-folinic acid with diamine, can be directly used in order to selectively crystallize one of the two diastereomeric forms with an optical purity usually higher than 95%.
- the type of diamine used highly affects the selectivity of the crystallization: for instance the (6S) diamine salt can be isolated first and then the corresponding (6R) form can be recovered from the crystallization mother liquors. For instance this occurs when piperazine is used as dibasic amine.
- the opposed effect can equally be achieved.
- ethylenediamine is used as a base, then the first isomer which crystallizes is the (6R) salt and the corresponding (6S) form can subsequently be recovered from mother liquors by a further crystallization.
- the preferential crystallization of the less water-soluble diastereomeric salt from the crude solution of the hydrolysis reaction can be carried out according to known methods (WO 9317022, BRACCO).
- said solution is suitably diluted with solvents such as a dipolar aprotic solvent or an organic protic solvent or a mixture thereof, in order to promote the crystallization of the less water- soluble form.
- the optical and chemical purities of the diamino folinate diastereomer directly crystallized from the crude product deriving from hydrolysis are so high that they allow an easy conversion of said salt into the corresponding calcium salt without further purifications.
- (6RS)-5,10-methenyl-5,6,7,8-tetrahydrofolic acid chloride hydrochloride to diamine salt of folinic acid depends on the basicity of the amino groups of the used diamine.
- ethylenediamine and l,3-diamino-2- propanol are used in a 2:1 molar ratio to the starting product (i.e. in a stoichiometric ratio to the quantity of acid to be neutralized).
- a 3:1 molar ratio is preferred for piperazine and N,N- dimethyl piperazine, less basic than the previous ones.
- the obtained diastereomeric salt consists of folinic acid and diamine in a 1:1 molar ratio, since each of the remaining two diamine moles neutralizes one equivalent of hydrochloric acid (for instance giving piperazine monohydrochloride) .
- Suitable at least dibasic organic amines may be selected from the group of aliphatic, linear, cyclic or heterocyclic, substituted or unsubstituted, racemic or optically active amines, containing at least two amino groups which are linked by at least a hydrocarbon chain, substituted or not, comprising at least 2 carbon atoms.
- Particularly preferred amines are the diamines of the general formulae (I) to (III):
- R l— >R 8 which are the same or different, are H or a linear or branched alkyl group, substituted or not by 1-4 OH groups;
- R 9 —>R 1Q which are the same or different, have the same meanings as R- ⁇ -R ⁇ or represent hydroxy groups; n is an integer from 0 to 6, m is an integer from 2 to 8.
- Examples of particularly preferred amines are selected from: ethylenediamine, 1,2-diamino-propane, 1,3-diamino-propane, 1,3-diamino-2-hydroxy-propane, (cis)-l,2-diamino-cyclohexane, (trans)-l,2-diamino- cyclohexane, piperazine, 1,4-dimethyl-piperazine, 2- methyl-piperazine, 2,5-dimethylpiperazine.
- Suitable solvents for the crystallization of diastereomeric mixtures of folinic acid salts with said amines are preferably binary or ternary mixtures of water/organic dipolar aprotic solvent or water/organic aprotic dipolar solvent/protic organic solvent.
- Preferred aprotic dipolar solvents are, for example, di ethylformamide (DMF), dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), N-methyl-pyrrolidone (NMP), hexamethylphosphoramide (HMPA).
- Preferred organic protic solvents are ethanol, ethanol, n-propanol, isopropanol, n-butanol, sec- butanol, ethylene glycol, 1,2-propylene glycol, 1,3- propylene glycol, forma ide, N-methyl-formamide.
- the reaction is preferably performed under the following conditions: acid/diamine molar ratio: from 1:2 to 1:4, preferably from 1:2 to 1:3.2 solvent: water or a water/aprotic dipolar solvent mixture (for instance DMAC) in a weight ratio from
- 1:0.5 to 1:20 acid/solvent mixture dilution ratio from 1:2 to 1:80 w/w, preferably from 1:4 to 1:45 w/w temperature: from 60 to 100"C reaction time: from 3 to 12 h, preferably from 5 to 8 h.
- the reaction is preferably performed under inert gas atmosphere. Preferential crystallization of the less water-soluble diastereomer of diamine folinate from the crude solution after hydrolysis.
- the crude solution obtained once the hydrolysis reaction is over is cooled and then treated according to one of the following methods: possible further dilution with aprotic dipolar solvent (for instance DMAC) to increase the water/aprotic dipolar solvent ratio, preferably up to a maximum of 1:60 w/w. • if necessary, further addition of an organic protic solvent (for instance EtOH), preferably in order to reach a maximum weight 12 times higher than the solution weight.
- aprotic dipolar solvent for instance DMAC
- EtOH organic protic solvent
- the crystallization is generally carried out at temperatures ranging from 0 to 25 ⁇ C and for 10 to 120 h, preferably from 24 to 72 h.
- the exchange takes place in an aqueous solution in the presence of an excess of calcium salt (preferably CaCl,) at a nearly neutral pH, preferably under the following conditions: dilution ratio diamine salt/water: from 1:4 to 1:40 w/w preferably from 1:8 to 1 * dia r" ⁇ a ⁇ / -- ⁇ -io: from 1:1 to 1:6 w/w preferably from 1:3 to 1:5 w/w temperature: from 5 to 25 ⁇ C crystallization time: from 10 to 60 h • pH: between 6.5 and 7.5, if necessary with the addition of IN NaOH.
- calcium salt preferably CaCl
- the preferred conditions are basically similar to those disclosed in WO 9317022 (BRACCO), and involve the crystallization of the diamine salt of the remaining diastereomer by dilution of mother liquors with a suitable solvent or solvent mixtures, its recrystallization and the subsequent transformation into the corresponding calcium salt.
- the calcium salt can be obtained directly from the diamine salt in the starting mother liquors; recovery and purification can be carried out according to known methods (WO 9317022, BRACCO).
- (6S)-calcium folinate starting from the mother liquors of example 6.
- 80 g of calcium chloride dihydrate are added to the mother liquors of example 6.
- the solution is kept under stirring for 30 min, the precipitate is filtered, and washed with 40 g of ethanol.
- the product is dried, then redissolved in water and reprecipitated at pH 7 by addition of ethanol.
- 16 g of (6S)-calcium folinate, 75% optically pure, are obtained.
- the product is recrystallized three times from water, at pH 7 and in the presence of ⁇ 4 parts by weight of calcium chloride dihydrate.
- ethylenediamine(6R)-folinate obtained according to example 9, are dissolved in 20 g of water.
- a solution of 12 g of calcium chloride dihydrate in 15 g of water is added. pH is adjusted to 7 with IN NaOH, and 50 g of ethanol are added to precipitate (6R)- calcium folinate.
- Example 11 Hydrolysis with l,3-diamino-2-propanol and preferential crystallization of l,3-diamino-2-propanol (6R)-folinate.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU26726/95A AU2672695A (en) | 1994-06-08 | 1995-05-31 | A process for the preparation and separation of diastereomeric salts of folinic acid |
DE0755397T DE755397T1 (en) | 1994-06-08 | 1995-05-31 | METHOD FOR PRODUCING AND SEPARATING DIASTEREOMERIC SALTS FROM FOLEIC ACID |
EP95921797A EP0755397B1 (en) | 1994-06-08 | 1995-05-31 | A process for the preparation and separation of diastereomeric salts of folinic acid |
JP50033096A JP4241925B2 (en) | 1994-06-08 | 1995-05-31 | Preparation and separation of diastereomeric salts of folinic acid |
DE69504189T DE69504189T2 (en) | 1994-06-08 | 1995-05-31 | METHOD FOR PRODUCING AND SEPARATING DIASTEREOMERIC SALTS FROM FOLIC ACID |
KR1019960706965A KR100262684B1 (en) | 1994-06-08 | 1995-05-31 | A Process for the Prearation and Separation of Diastereomeric Salts of Folinic Acid |
GR970300023T GR970300023T1 (en) | 1994-06-08 | 1997-08-29 | A process for the preparation and separation of diastereomeric salts of folinic acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI941193A IT1270185B (en) | 1994-06-08 | 1994-06-08 | PROCESS FOR OBTAINING AND SEPARATING DIASTEREOISOMER SALTS OF FOLINIC ACID |
ITMI94A001193 | 1994-06-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995033749A1 true WO1995033749A1 (en) | 1995-12-14 |
Family
ID=11369074
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1995/002073 WO1995033749A1 (en) | 1994-06-08 | 1995-05-31 | A process for the preparation and separation of diastereomeric salts of folinic acid |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0755397B1 (en) |
JP (1) | JP4241925B2 (en) |
KR (1) | KR100262684B1 (en) |
AT (1) | ATE169918T1 (en) |
AU (1) | AU2672695A (en) |
DE (2) | DE755397T1 (en) |
ES (1) | ES2101665T1 (en) |
GR (1) | GR970300023T1 (en) |
IL (1) | IL114050A0 (en) |
IT (1) | IT1270185B (en) |
WO (1) | WO1995033749A1 (en) |
ZA (1) | ZA954692B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013025203A1 (en) * | 2011-08-16 | 2013-02-21 | Watson Laboratories, Inc. | Resolution of tetrahydrofolic acid derivatives |
CN103102350A (en) * | 2011-11-11 | 2013-05-15 | 重庆华邦胜凯制药有限公司 | Preparation method of levofolinate |
CN113666931A (en) * | 2021-09-07 | 2021-11-19 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0455013A1 (en) * | 1990-04-12 | 1991-11-06 | Cerbios-Pharma S.A. | Ammoniumsalts of N(5)-methyl-5,6,7,8-tetrahydrofolic acid |
DE4136921A1 (en) * | 1991-11-11 | 1993-05-13 | Knoll Ag | METHOD FOR SEPARATING 5-METHYL-TETRAHYDROFOLIC ACID |
WO1993017022A1 (en) * | 1992-02-20 | 1993-09-02 | Bracco S.P.A. | Process for separating stereoisomers of folinic acid |
-
1994
- 1994-06-08 IT ITMI941193A patent/IT1270185B/en active IP Right Grant
-
1995
- 1995-05-31 JP JP50033096A patent/JP4241925B2/en not_active Expired - Lifetime
- 1995-05-31 AU AU26726/95A patent/AU2672695A/en not_active Abandoned
- 1995-05-31 WO PCT/EP1995/002073 patent/WO1995033749A1/en active IP Right Grant
- 1995-05-31 EP EP95921797A patent/EP0755397B1/en not_active Expired - Lifetime
- 1995-05-31 DE DE0755397T patent/DE755397T1/en active Pending
- 1995-05-31 AT AT95921797T patent/ATE169918T1/en not_active IP Right Cessation
- 1995-05-31 DE DE69504189T patent/DE69504189T2/en not_active Expired - Lifetime
- 1995-05-31 KR KR1019960706965A patent/KR100262684B1/en active IP Right Grant
- 1995-05-31 ES ES95921797T patent/ES2101665T1/en active Pending
- 1995-06-07 IL IL11405095A patent/IL114050A0/en not_active IP Right Cessation
- 1995-06-07 ZA ZA954692A patent/ZA954692B/en unknown
-
1997
- 1997-08-29 GR GR970300023T patent/GR970300023T1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0455013A1 (en) * | 1990-04-12 | 1991-11-06 | Cerbios-Pharma S.A. | Ammoniumsalts of N(5)-methyl-5,6,7,8-tetrahydrofolic acid |
DE4136921A1 (en) * | 1991-11-11 | 1993-05-13 | Knoll Ag | METHOD FOR SEPARATING 5-METHYL-TETRAHYDROFOLIC ACID |
WO1993017022A1 (en) * | 1992-02-20 | 1993-09-02 | Bracco S.P.A. | Process for separating stereoisomers of folinic acid |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013025203A1 (en) * | 2011-08-16 | 2013-02-21 | Watson Laboratories, Inc. | Resolution of tetrahydrofolic acid derivatives |
CN103102350A (en) * | 2011-11-11 | 2013-05-15 | 重庆华邦胜凯制药有限公司 | Preparation method of levofolinate |
CN113666931A (en) * | 2021-09-07 | 2021-11-19 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
CN113666931B (en) * | 2021-09-07 | 2023-11-03 | 浙江大为药业有限公司 | Preparation method of high-purity calcium levofolinate |
Also Published As
Publication number | Publication date |
---|---|
GR970300023T1 (en) | 1997-08-29 |
KR100262684B1 (en) | 2000-08-01 |
DE69504189T2 (en) | 1998-12-24 |
ITMI941193A1 (en) | 1995-12-08 |
AU2672695A (en) | 1996-01-04 |
IT1270185B (en) | 1997-04-29 |
ES2101665T1 (en) | 1997-07-16 |
EP0755397B1 (en) | 1998-08-19 |
DE755397T1 (en) | 1997-09-25 |
KR970703343A (en) | 1997-07-03 |
ITMI941193A0 (en) | 1994-06-08 |
EP0755397A1 (en) | 1997-01-29 |
IL114050A0 (en) | 1995-10-31 |
DE69504189D1 (en) | 1998-09-24 |
JP4241925B2 (en) | 2009-03-18 |
ZA954692B (en) | 1996-01-29 |
ATE169918T1 (en) | 1998-09-15 |
JPH10500972A (en) | 1998-01-27 |
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