NO150515B - PROCEDURE FOR PREPARING 5`-DEOXY-5`-METHYLTHIOADENOSINE - Google Patents
PROCEDURE FOR PREPARING 5`-DEOXY-5`-METHYLTHIOADENOSINE Download PDFInfo
- Publication number
- NO150515B NO150515B NO811346A NO811346A NO150515B NO 150515 B NO150515 B NO 150515B NO 811346 A NO811346 A NO 811346A NO 811346 A NO811346 A NO 811346A NO 150515 B NO150515 B NO 150515B
- Authority
- NO
- Norway
- Prior art keywords
- deoxy
- sam
- methylthioadenosine
- preparing
- procedure
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 claims description 14
- 229960001570 ademetionine Drugs 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 2
- WUUGFSXJNOTRMR-WOIOKPISSA-N 5'-deoxy-5'-methylthioadenosine Chemical compound O[C@@H]1[C@@H](O)[C@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-WOIOKPISSA-N 0.000 claims 2
- WUUGFSXJNOTRMR-UHFFFAOYSA-N 5alpha-Hydroxy-3abeta,5beta,8-trimethyl-1-(1,5-dimethyl-hexen-(4)-yl)-4abetaH,7abetaH-dicyclopentano[a.d]cyclooctaen-(8) Natural products OC1C(O)C(CSC)OC1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-UHFFFAOYSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av 5'-deoxy-5<1->methylthioadenison (MTA) av formel The present invention relates to a method for the production of 5'-deoxy-5<1->methylthioadenison (MTA) of formula
som er en fysiologisk forbindelse som allerede er tilstede i levende organismer, og som utviser terapeutisk aktivitet. which is a physiological compound that is already present in living organisms and that exhibits therapeutic activity.
Det er funnet en fremgangsmåte for fremstilling av denne forbindelse som er særlig enkel og økonomisk ut fra et industrielt synspunkt. Den nye fremgangsmåte er kjenne-tegnet ved at en vandig løsning av S-adenosyl-methionin av formel: A method for the production of this compound has been found which is particularly simple and economical from an industrial point of view. The new method is characterized by the fact that an aqueous solution of S-adenosyl-methionine of the formula:
konsentreres ved oppvarming under vakuum ved 35 - 40°C, den konsentrerte vandige løsning hydrolyseres ved oppvarming under tilbakeløpskjøling, og det dannede 5 *-deoxy-5'-methyl-thioadenosin separeres under avkjøling til 0 - 5°C. is concentrated by heating under vacuum at 35 - 40°C, the concentrated aqueous solution is hydrolysed by heating under reflux, and the 5*-deoxy-5'-methyl-thioadenosine formed is separated while cooling to 0 - 5°C.
Som ovenfor angitt, består den nye fremgangsmåte hovedsakelig av å utføre hydrolysen av S-adenosylmethionin (SAM) under strengt regulerte kritiske betingelser, som leder til praktisk talt total hydrolyse og fullstendig krystallisering av MTA. As stated above, the new method consists mainly of performing the hydrolysis of S-adenosylmethionine (SAM) under strictly regulated critical conditions, which leads to practically total hydrolysis and complete crystallization of MTA.
Den regulerte hydrolyseprosess kan anvendes på SAM fremstilt på hvilken som helst måte. The controlled hydrolysis process can be applied to SAM prepared in any way.
Imidlertid er fremstillingsmetoden for SAM-løsningen også- en. influerende faktor når det'gjelder utfø-relse av den nye fremgangsmåte på en økonomisk hensiktsmes-sig måte. However, the manufacturing method for the SAM solution is also the same. influencing factor when it concerns the implementation of the new method in an economically appropriate manner.
Følgende operasjonstrinn gir den mest økonomiske utførelsesform av prosessen: a) Vanlig brødgjær anrikes med SAM ved behandling med methionin etter Schlenk-metoden (Schlenk F. (1965) The following operational steps provide the most economical embodiment of the process: a) Ordinary bread yeast is enriched with SAM by treatment with methionine according to the Schlenk method (Schlenk F. (1965)
Enzymologie 29, 283). Enzymologie 29, 283).
b) Gjærcellene suspendert i vann lyseres ved behandling med ethyl eller methylacetat ved omgivende temperatur b) The yeast cells suspended in water are lysed by treatment with ethyl or methyl acetate at ambient temperature
(DT-OS P23 36401.4) . (DT-OS P23 36401.4) .
Ved justering av pH til mellom 4 og 6 og filtrering, erholdes en vandig løsning inneholdende praktisk talt By adjusting the pH to between 4 and 6 and filtering, an aqueous solution containing practically
alt tilstedeværende SAM i den opprinnelige gjær. all SAM present in the native yeast.
c) Løsningen konsentreres under vakuum ved 35 - 40° C til 1/10 av dets opprinnelige volum. d) Konsentratet kokes under tilbakeløpskjøling i ca. 30 minutter og pH justeres til 7 med soda. e) Løsningen får stå ved 0 - 5° C, og det utfelte MTA oppsamles praktisk talt fullstendig og med god renhet. c) The solution is concentrated under vacuum at 35 - 40° C to 1/10 of its original volume. d) The concentrate is boiled under reflux cooling for approx. 30 minutes and the pH is adjusted to 7 with soda. e) The solution is allowed to stand at 0 - 5° C, and the precipitated MTA is collected practically completely and with good purity.
Trinnene c, d og e, hvilke som angitt er kritisk nødvendige for erholdelse av fullstendig selektiv hydrolyse av SAM til MTA uten dannelse av biprodukter, er nye. Steps c, d and e, which are indicated to be critically necessary to obtain complete selective hydrolysis of SAM to MTA without the formation of by-products, are novel.
Det etterfølgende eksempel illustrerer oppfinnelsen. The following example illustrates the invention.
Eksempel Example
Fremstilling av 5<1->deoxy-5'-methylthioadenosin (MTA) Preparation of 5<1->deoxy-5'-methylthioadenosine (MTA)
11 liter ethylacetat og 11 liter vann ved omgivende temperatur ble tilsatt til 90 kg brødgjær som var blitt anriket med SAM ved tilsetning av methionin inntil SAM-innholdet var 6,88 g/kg. 11 liters of ethyl acetate and 11 liters of water at ambient temperature were added to 90 kg of bread yeast which had been enriched with SAM by the addition of methionine until the SAM content was 6.88 g/kg.
Etter kraftig omrøring i 30 minutter ble pH justert til 4,5 med fortynnet ^SO^, blandingen ble filtrert og residuet vasket med vann under dannelse av 140 liter løsning med et SAM —innhold på 4,40 g/liter, lik 99,5 % av tilstedeværende SAM i utgangsmaterialet. After vigorous stirring for 30 minutes, the pH was adjusted to 4.5 with dilute ^SO^, the mixture was filtered and the residue washed with water to form 140 liters of solution with a SAM content of 4.40 g/liter, equal to 99.5 % of SAM present in the starting material.
Det således erholdte lysat ble konsentrert under vakuum (30 mm Hg, 35 - 40° C) til et volum på ca. 14 liter. Den konsentrerte løsning ble kokt under tilbakeløpskjøling ved normalt trykk i 30 minutter. Den ble avkjølt til 20° C, pH ble justert til 7 med 40 % soda, og fikk stå over natten The thus obtained lysate was concentrated under vacuum (30 mm Hg, 35 - 40° C) to a volume of approx. 14 litres. The concentrated solution was boiled under reflux at normal pressure for 30 minutes. It was cooled to 20° C, the pH was adjusted to 7 with 40% soda ash, and allowed to stand overnight
i en kjølesøyle (+3° C) . in a cooling column (+3° C) .
Et hvitt bunnfall ble dannet som ble filtrert, løst i 10 liter kokende destillert vann og krystallisert ved avkjøling av denne løsning. A white precipitate formed which was filtered, dissolved in 10 liters of boiling distilled water and crystallized by cooling this solution.
410 g krystallinsk MTA med høy renhet ble erholdt, lik et utbytte på 90 % med hensyn til det SAM som ble underkastet hydrolyse. Karakteristikaene for det erholdte produkt stemte overens med de for ren MTA erholdt på annen måte. 410 g of crystalline MTA of high purity was obtained, equal to a yield of 90% with respect to the SAM subjected to hydrolysis. The characteristics of the product obtained agreed with those of pure MTA obtained in other ways.
Den terapeutiske aktivitet av den fremstilte forbindelse er beskrevet i norsk ålment tilgjengelig patent-søknad 840343. The therapeutic activity of the manufactured compound is described in Norwegian generally available patent application 840343.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO840343A NO157863C (en) | 1980-04-22 | 1984-01-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21550/80A IT1193529B (en) | 1980-04-22 | 1980-04-22 | ADENOSINIC DERIVATIVES FOR ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE PRINCIPLE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO811346L NO811346L (en) | 1981-10-23 |
| NO150515B true NO150515B (en) | 1984-07-23 |
| NO150515C NO150515C (en) | 1984-10-31 |
Family
ID=11183457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO811346A NO150515C (en) | 1980-04-22 | 1981-04-21 | PROCEDURE FOR PREPARING 5`-DEOXY-5`-METHYLTHIOADENOSINE |
Country Status (17)
| Country | Link |
|---|---|
| JP (2) | JPS56166117A (en) |
| AR (1) | AR231144A1 (en) |
| BE (1) | BE888472A (en) |
| CA (1) | CA1198105A (en) |
| CH (2) | CH645544A5 (en) |
| DE (1) | DE3116067A1 (en) |
| DK (1) | DK159453C (en) |
| ES (2) | ES501539A0 (en) |
| FI (1) | FI70227C (en) |
| FR (1) | FR2491761A1 (en) |
| GB (3) | GB2074446B (en) |
| IT (1) | IT1193529B (en) |
| LU (1) | LU83307A1 (en) |
| MX (1) | MX9203630A (en) |
| NL (1) | NL192111C (en) |
| NO (1) | NO150515C (en) |
| SE (3) | SE460198B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1177373B (en) * | 1984-12-06 | 1987-08-26 | Bioresearch Spa | SALTS OF 5'-METHYLLIUM-5'-DEOXYDENOSINE WITH LONG ALCHYLIC CHAIN SULPHONIC ACIDS |
| IT1227049B (en) * | 1988-07-29 | 1991-03-14 | Bioresearch Spa | USE OF ADENOSINIC DERIVATIVES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS HAVING IMMUNOSTIMULATING ACTIVITIES. |
| JPH0497287A (en) * | 1990-08-10 | 1992-03-30 | Nec Ic Microcomput Syst Ltd | Picture display integrated circuit |
| ES2259552B1 (en) * | 2005-03-17 | 2007-06-16 | Proyecto De Biomedicina Cima, S.L. | EMPLOYMENT OF 5'-METHYLTIOENENINE (MTA) IN THE PREVENTION AND / OR TREATMENT OF AUTOIMMUNE DISEASES AND / OR REPLACEMENT OF TRANSPLANTS. |
| EP1891961B1 (en) * | 2005-03-17 | 2009-09-16 | Proyecto de Biomedicina Cima, S.L. | Use of 5'-methylthioadenosine (mta) in the prevention and/or treatment of autoimmune diseases and/or transplant rejection |
| DE102010027595A1 (en) * | 2010-07-23 | 2012-01-26 | Helmut Vorbrüggen | Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks |
| DE102011005232A1 (en) * | 2011-03-08 | 2012-09-13 | AristoCon GmbH & Co. KG | Adenosine and its derivatives for use in pain therapy |
| WO2014163152A1 (en) * | 2013-04-05 | 2014-10-09 | ライオン株式会社 | Non-rem sleep-promoting agent, deep sleep-promoting agent and natural sleep-inducing agent |
| CN105102609B (en) * | 2013-04-05 | 2018-07-20 | 狮王株式会社 | Yeast culture and internal composition |
| KR102245628B1 (en) * | 2013-04-05 | 2021-04-28 | 라이온 가부시키가이샤 | Composition for internal use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1259341B (en) * | 1962-12-22 | 1968-01-25 | Boehringer & Soehne Gmbh | Process for the preparation of new 5'-sulfoxides of nucleosides |
| DE1545645A1 (en) * | 1965-12-06 | 1969-08-21 | Boehringer Mannheim Gmbh | Process for the preparation of disubstituted adenosine derivatives |
| GB1436509A (en) * | 1973-11-27 | 1976-05-19 | Ajinomoto Kk | Method for producing s-adenosylmethionine or methylthioadenosine from yeast |
| FR2313937A1 (en) * | 1975-06-09 | 1977-01-07 | Anvar | DRUG BASED ON 5 'THIOETHERS OF ADENOSINE |
| FR2424027A1 (en) * | 1978-04-28 | 1979-11-23 | Merieux Inst | NEW MEDICINAL PRODUCT, IN PARTICULAR SEDATIVE AND SLEEP INDUCER AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT |
-
1980
- 1980-04-22 IT IT21550/80A patent/IT1193529B/en active
-
1981
- 1981-04-17 BE BE0/204529A patent/BE888472A/en not_active IP Right Cessation
- 1981-04-21 AR AR285020A patent/AR231144A1/en active
- 1981-04-21 ES ES501539A patent/ES501539A0/en active Granted
- 1981-04-21 CA CA000375784A patent/CA1198105A/en not_active Expired
- 1981-04-21 LU LU83307A patent/LU83307A1/en unknown
- 1981-04-21 NO NO811346A patent/NO150515C/en unknown
- 1981-04-21 SE SE8102489A patent/SE460198B/en not_active IP Right Cessation
- 1981-04-21 DK DK176481A patent/DK159453C/en not_active IP Right Cessation
- 1981-04-21 JP JP5930181A patent/JPS56166117A/en active Granted
- 1981-04-22 CH CH263281A patent/CH645544A5/en not_active IP Right Cessation
- 1981-04-22 NL NL8101984A patent/NL192111C/en not_active IP Right Cessation
- 1981-04-22 CH CH4716/84A patent/CH650514A5/en not_active IP Right Cessation
- 1981-04-22 GB GB8112428A patent/GB2074446B/en not_active Expired
- 1981-04-22 FI FI811249A patent/FI70227C/en not_active IP Right Cessation
- 1981-04-22 DE DE19813116067 patent/DE3116067A1/en active Granted
- 1981-04-22 FR FR8107992A patent/FR2491761A1/en active Granted
-
1982
- 1982-04-01 ES ES511039A patent/ES511039A0/en active Granted
-
1983
- 1983-08-15 GB GB08321947A patent/GB2144409B/en not_active Expired
-
1984
- 1984-05-25 GB GB08413454A patent/GB2144038B/en not_active Expired
-
1987
- 1987-03-04 SE SE8700914A patent/SE464635B/en not_active IP Right Cessation
- 1987-03-04 SE SE8700913A patent/SE466238B/en not_active IP Right Cessation
-
1989
- 1989-02-02 JP JP1022771A patent/JPH01301692A/en active Granted
-
1992
- 1992-06-26 MX MX9203630A patent/MX9203630A/en unknown
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