FI67082B - Foerfarande foer framstaellning av d 1-5-metyltetrahydrofolsyra och salter daerav - Google Patents
Foerfarande foer framstaellning av d 1-5-metyltetrahydrofolsyra och salter daerav Download PDFInfo
- Publication number
- FI67082B FI67082B FI780565A FI780565A FI67082B FI 67082 B FI67082 B FI 67082B FI 780565 A FI780565 A FI 780565A FI 780565 A FI780565 A FI 780565A FI 67082 B FI67082 B FI 67082B
- Authority
- FI
- Finland
- Prior art keywords
- acid
- weight ratio
- aqueous solution
- formaldehyde
- process according
- Prior art date
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Claims (9)
1. Förfarande för framställning av d,l-5-metyltetra-hydrofolsyra och dess salter med den allmänna formeln (I) COOX n Pu NH—/ \ CO—NH—CH ? f03 l \_/ I A CH0 HN" CH ( z (I) lii CH h-N—L L ch2 I ! H väri X är väte, en alkalimetall eller en ekvivalent av en alkalisk jordartsmetall, kännetecknat därav, att a) folsyra reduceras tili tetrahydrofolsyra med NaBH4 i en alkalisk vattenlösning i en inert gasatmosfär under användning av ett viktförh&llande NaBH^ : folsyra av 0,5 : 1 - 3 : 1, en reaktionstemperatur av 60-80°C, ett pH-värde av 7-8 och en reaktionstid av 0,5 - 2 timmar, b) tetrahydrofolsyran metyleras tili 5-metyltetrahydrofolsyra med en vattenlösning av formaldehyd och natrium-borhydrid i en inert gasatmosfär under användning av ett viktförhällande totalmängd formaldehyd : tetrahydrofolsyra av 0,25 : 1-1,5 : 1, en temperatur av 25 - 30°C, ett pH-värde av 6-8, varvid formaldehyden tillsätts i form av successiva fraktioner, varav fraktionen med ett viktförhäl-lande formaldehyd : tetrahydrofolsyra av 0,15 : 1 tillsätts efter det att reaktionen avslutats, och i slutet av steget tillsätts ett antioxidationsmedel, vilket utgörs av cystein, reducerad glutation eller pantetein, c) natrium-5-metyltetrahydrofolatet isoleras ur vatten-lösningen innehällande detsamma i närvaro av ett antioxidationsmedel, vilket utgörs av cystein, reducerad glutation eller pantetein, 15 67082 och att stegen utförs successivt i en och samma reaktor utan att isolera mellanprodukten.
2. Förfarande enligt patentkravet 1, känneteck-n a t därav, att separationssteget c) utförs genom att be-handla reaktionsblandningen med en tillsatsmängd av aktivkol med en vikt av 5-20 ganger vikten av den ursprungligen be-handlade folsyran, och att natrium-5-metyltetrahydrofolatet desorberas frän kolet med en eluent innehällande Cj^-alko- hol eller 2-metoxietanol och vatten i ett viktförhällande av 50 : 50 - 95 : 5.
3. Förfarande enligt patentkravet 1, känneteck-n a t därav, att separationssteget c) utförs genom behandling av vattenlösningen med ett Ca-salt och kylning av lösningen tili 0-5°C, varvid viktförhällandet folsyra : kalciumsalt är 2:1-3:1.
4. Förfarande enligt patentkravet 1, känneteck-n a t därav, att i steg a) är viktförhällandet NaBH^ : folsyra 0,7 : 1-2 : 1, temperaturen 70°C, pH 7-8 och reaktions-tiden 1 timme och att i steg b) är viktförhällandet totalmängd 37-%:ig formaldehyd : tetrahydrofolsyra 1,4 : 1, viktförhällandet NaBH^ : tetrahydrofolsyra 0,5 : 1 - 1 : 1, temperaturen 30°C och pH 6,5.
5. Förfarande enligt patentkravet 2, känneteck-n a t därav, att i steg c) är mängden av aktivkol 7 gänger vikten av den ursprungligen behandlade folsyran och att sä- som eluent används en blandning innehällande metanol, etanol, 2-metoxietanol, 1- eller 2-propanol, n-butanol, tert.-butanol, sek.-butanol eller isobutanol och vatten i ett förhällande av 80 : 20 v/v och innehällande 1 vol-% av ett antioxidations-medel och 0,7 % ammoniak i en vattenlösning.
6. Förfarande enligt patentkravet 1, känneteck-n a t därav, att 5-metylt.etrahydrofolsyra utfälls ur en vattenlösning i form av ett sait av en alkalimetall eller en aikaiisk jordartsmetall genom att surgöra vattenlösningen.
7. Förfarande enligt patentkravet 2, känneteck-n a t därav, att 5-metyltetrahydrofolsyran erhälls i form av natriumsalt genom att koncentrera eluatet och lyofilisera koncentratet.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB729077 | 1977-02-22 | ||
| GB7290/77A GB1572137A (en) | 1977-02-22 | 1977-02-22 | Stable compositions for therapeutic use based on d,1-5-methyltetrahydrofolic acid and its salts |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI780565A FI780565A (fi) | 1978-08-23 |
| FI67082B true FI67082B (fi) | 1984-09-28 |
| FI67082C FI67082C (fi) | 1985-01-10 |
Family
ID=9830275
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI780565A FI67082C (fi) | 1977-02-22 | 1978-02-21 | Foerfarande foer framstaellning av d,1-5-metyltetrahydrofolsyra och salter daerav |
Country Status (32)
| Country | Link |
|---|---|
| JP (1) | JPS5831353B2 (sv) |
| AR (1) | AR215162A1 (sv) |
| AT (1) | AT380020B (sv) |
| AU (1) | AU520715B2 (sv) |
| BE (1) | BE863808A (sv) |
| CA (1) | CA1093554A (sv) |
| CH (1) | CH635344A5 (sv) |
| CZ (1) | CZ279815B6 (sv) |
| DD (1) | DD134099A5 (sv) |
| DE (1) | DE2807393A1 (sv) |
| DK (1) | DK144944C (sv) |
| EG (1) | EG13399A (sv) |
| ES (1) | ES467153A1 (sv) |
| FI (1) | FI67082C (sv) |
| FR (2) | FR2381047A1 (sv) |
| GB (1) | GB1572137A (sv) |
| GR (1) | GR71704B (sv) |
| HU (1) | HU179422B (sv) |
| IE (1) | IE46402B1 (sv) |
| IL (1) | IL54052A (sv) |
| IN (1) | IN149574B (sv) |
| LU (1) | LU79067A1 (sv) |
| MX (1) | MX5288E (sv) |
| NL (1) | NL190285C (sv) |
| NO (1) | NO147793C (sv) |
| NZ (1) | NZ186465A (sv) |
| PL (1) | PL118654B1 (sv) |
| PT (1) | PT67656B (sv) |
| SE (1) | SE437028B (sv) |
| SU (1) | SU747427A3 (sv) |
| YU (1) | YU40505B (sv) |
| ZA (1) | ZA78837B (sv) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5838285A (ja) * | 1981-08-25 | 1983-03-05 | Kanegafuchi Chem Ind Co Ltd | ５−メチル−（６ｒｓ）−５，６，７，８−テトラヒドロ−ｌ−葉酸のマグネシウム塩またはその遊離酸の製法 |
| GB8621268D0 (en) * | 1986-09-03 | 1986-10-08 | Univ Strathclyde | Separation of substances |
| IT1229517B (it) * | 1989-01-31 | 1991-09-03 | Bioresearch Spa | Impiego di acido 5-metiltetraidrofolico, di acido 5 formiltetraidrofolico, e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato adatte ad essere impiegate nella terapia dei disordini depressivi e composizioni farmaceutiche relative. |
| IT1229203B (it) * | 1989-03-22 | 1991-07-25 | Bioresearch Spa | Impiego di acido 5 metiltetraidrofolico, di acido 5 formiltetraidrofolico e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato attive nella terapia dei disturbi mentali organici e composizioni farmaceutiche relative. |
| NL8901432A (nl) * | 1989-06-06 | 1991-01-02 | Pharmachemie Bv | Bij koelkasttemperatuur stabiele waterige folinaatoplossing, alsmede werkwijze ter bereiding daarvan. |
| CH680731A5 (sv) * | 1990-04-12 | 1992-10-30 | Sapec Fine Chemicals | |
| US5217974A (en) * | 1991-03-29 | 1993-06-08 | Eli Lilly And Company | Method for treating gar-transformylase tumors in mammals and reducing mammalian toxicity |
| CH683261A5 (it) * | 1991-10-10 | 1994-02-15 | Applied Pharma Res | Procedimento per la preparazione dell'acido metiltetraidrofolico nella forma (6(R,S)(-))N-5 e separazione del diastereoisomero attivo (6(S)(-))N-5) sotto forma di sali. |
| CH682665A5 (de) * | 1991-10-29 | 1993-10-29 | Sapec Fine Chemicals | Verfahren zur Reinigung von rohen Erdalkalimetallsalzen von N(5)-Methyl-5,6,7,8-tetrahydrofolsäure. |
| US6162914A (en) * | 1998-04-24 | 2000-12-19 | Cerbios-Pharma S.A. | Process for the reduction of pterins |
| CH693905A5 (de) * | 1999-04-15 | 2004-04-15 | Eprova Ag | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
| CH698729B1 (de) * | 2007-05-30 | 2009-10-15 | Cerbios Pharma Sa | Stabile, kristalline (6S)-N(5)-Methyl-5, 6,7,8-tetrahydrofolsäure. |
| CN103214487A (zh) * | 2013-04-12 | 2013-07-24 | 张家港威胜生物医药有限公司 | 一种重要医药化工原料(6s)-5-甲基四氢叶酸盐的合成 |
| WO2015193778A1 (en) | 2014-06-16 | 2015-12-23 | Mylan Laboratories Ltd. | Crystalline form of levomefolate calcium |
| MX2021002446A (es) | 2018-08-28 | 2021-04-28 | Pmc Organometallix Inc | Ester libre o con bajo contenido de 2-mercaptoetanol y usos del mismo. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL80276C (sv) * | ||||
| GB1293541A (en) * | 1969-03-18 | 1972-10-18 | John Alexander Blair | Folic acid derivatives |
| US3856959A (en) * | 1972-07-24 | 1974-12-24 | Department Of Health Education | Inhibition of leukemia utilizing 5-methyltetrahydrohomofolate |
| US4148999A (en) * | 1977-08-22 | 1979-04-10 | The Government Of The United States Of America | Preparation and purification of citrovorum factor |
| CH649550A5 (en) * | 1984-02-09 | 1985-05-31 | Eprova Ag | Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid |
-
1977
- 1977-02-22 GB GB7290/77A patent/GB1572137A/en not_active Expired
-
1978
- 1978-02-09 AT AT0090378A patent/AT380020B/de not_active IP Right Cessation
- 1978-02-09 BE BE185038A patent/BE863808A/xx not_active IP Right Cessation
- 1978-02-09 IE IE285/78A patent/IE46402B1/en not_active IP Right Cessation
- 1978-02-09 CA CA296,754A patent/CA1093554A/en not_active Expired
- 1978-02-13 NZ NZ186465A patent/NZ186465A/xx unknown
- 1978-02-13 ZA ZA00780837A patent/ZA78837B/xx unknown
- 1978-02-15 IL IL54052A patent/IL54052A/xx unknown
- 1978-02-15 IN IN174/CAL/78A patent/IN149574B/en unknown
- 1978-02-15 PT PT67656A patent/PT67656B/pt unknown
- 1978-02-15 LU LU79067A patent/LU79067A1/xx unknown
- 1978-02-16 NL NLAANVRAGE7801775,A patent/NL190285C/xx not_active IP Right Cessation
- 1978-02-18 PL PL1978204747A patent/PL118654B1/pl unknown
- 1978-02-20 AU AU33430/78A patent/AU520715B2/en not_active Expired
- 1978-02-20 DD DD78203761A patent/DD134099A5/xx unknown
- 1978-02-20 GR GR55500A patent/GR71704B/el unknown
- 1978-02-20 YU YU379/78A patent/YU40505B/xx unknown
- 1978-02-21 NO NO780594A patent/NO147793C/no unknown
- 1978-02-21 SE SE7801973A patent/SE437028B/sv not_active IP Right Cessation
- 1978-02-21 ES ES467153A patent/ES467153A1/es not_active Expired
- 1978-02-21 FR FR7804847A patent/FR2381047A1/fr active Granted
- 1978-02-21 EG EG103/78A patent/EG13399A/xx active
- 1978-02-21 DE DE19782807393 patent/DE2807393A1/de active Granted
- 1978-02-21 SU SU782588551A patent/SU747427A3/ru active
- 1978-02-21 DK DK76578A patent/DK144944C/da not_active IP Right Cessation
- 1978-02-21 MX MX786871U patent/MX5288E/es unknown
- 1978-02-21 FI FI780565A patent/FI67082C/fi not_active IP Right Cessation
- 1978-02-22 HU HU78BI562A patent/HU179422B/hu unknown
- 1978-02-22 AR AR271183A patent/AR215162A1/es active
- 1978-02-22 JP JP53018637A patent/JPS5831353B2/ja not_active Expired
- 1978-02-22 CZ CS781129A patent/CZ279815B6/cs unknown
- 1978-02-22 CH CH193678A patent/CH635344A5/de not_active IP Right Cessation
- 1978-07-13 FR FR7820936A patent/FR2385397A1/fr active Granted
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MA | Patent expired | ||
| MA | Patent expired |
Owner name: BIORESEARCH S.P.A. |