[go: up one dir, main page]

WO2008031284A1 - Procédé de résolution d'acide 5-méthyltétrahydrofolique et sa salinisation - Google Patents

Procédé de résolution d'acide 5-méthyltétrahydrofolique et sa salinisation Download PDF

Info

Publication number
WO2008031284A1
WO2008031284A1 PCT/CN2006/002615 CN2006002615W WO2008031284A1 WO 2008031284 A1 WO2008031284 A1 WO 2008031284A1 CN 2006002615 W CN2006002615 W CN 2006002615W WO 2008031284 A1 WO2008031284 A1 WO 2008031284A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyltetrahydrofolate
mthf
salt
phenethylamine
resolution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2006/002615
Other languages
English (en)
Chinese (zh)
Inventor
Xin Chen
Guangxu Zhu
Wei Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NAN JING RHINE PHARM TECH Inc
Original Assignee
NAN JING RHINE PHARM TECH Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NAN JING RHINE PHARM TECH Inc filed Critical NAN JING RHINE PHARM TECH Inc
Publication of WO2008031284A1 publication Critical patent/WO2008031284A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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

  • the present invention relates to the field of organic chemistry, and in particular to a method for the resolution and salt formation of an organic drug (6S)-5-methyltetrahydrofolate from (6R,S)-5-methyltetrahydrofolate.
  • (6S)-5-methyltetrahydrofolate N-(5-methyl)-6(S)-5,6,7,8,-tetrahydropteroyl-L-glutamic acid, abbreviated (6S)-5-MTHF, the structural formula is as follows:
  • (6S)-5-methyltetrahydrofolate is the predominant form of tissue and blood folic acid. Participate in many important biochemical reactions in the body (such as biosynthesis of sputum and thymine).
  • the naturally occurring 5-MTHF is only S-type, while the synthetic R-form is biochemically inactive and excreted through the kidneys.
  • (6S)-5-MTHF does not require a cumbersome enzymatic metabolic step in the human body and can be directly utilized. (Zhang Yue et al, Fine and Chemical, 13, (22), 13, 2005).
  • (6S)-5-MTHF has two important roles as a drug: in oncology treatment, combined with methotrexate (Methotrexate) and 5-fluorouracil (5-Fluorouracil) for treatment of tumor; treatment by folic acid Caused by anemia.
  • Methotrexate methotrexate
  • 5-fluorouracil 5-fluorouracil
  • 6S-5-MTHF is the only drug in folic acid that can pass through the blood-brain barrier and has the effect of preventing Alzheimer's disease (Alzheimer's disease).
  • Synthetic (6S)-5-MTHF is the main active ingredient of pharmaceuticals and food additives, preventing fetal neural tube defects, arteriosclerosis, treating megaloblastic anemia And so on.
  • (6S)-5-MTHF is difficult and expensive.
  • the synthesis method is a hydrogenation and methylation reaction of folic acid to prepare a (6R,S) racemate (Federico.G et al, GB 1572 138, 1977; U.S. 5,124,452, 1978). It has been suggested that chemical resolution of the corresponding enantiomer 6R-acid or 6S-acid is not possible. (Clinical Science and Molecular Medicine 45, 625-631, 1973).
  • the present invention proposes an organic base ⁇ -phenethylamine and its pair which are readily available in the market.
  • a method for the preparation of (6S)-5-methyltetrahydrofolate by resolution of a racemate (6R,S)-5-methyltetrahydrofolate, characterized by a resolving agent, followed by alkaline earth metal hydroxide A (6S)-5-methyltetrahydrofolate calcium salt or a magnesium or zinc salt is prepared from an object or an oxide such as calcium hydroxide or magnesium hydroxide or zinc oxide.
  • the present invention is further precipitated and crystallized with 95% ethanol or anhydrous ethanol, preferably 95% ethanol.
  • the present invention relates to a process for the preparation of (6S)-5-methyltetrahydrofolate, which is obtained by resolution from a racemate by the use of an organic base, wherein the organic base is alpha-phenethylamine or (+) or (- Enantiomer of ⁇ ; phenethylamine is dissolved in water, heated to 20-80 ° C, stirred a small amount of (6R, S)-5-MTHF aqueous suspension, stirred and gradually dissolved completely Salt formation, the salt is cooled to 20 ° C, and the salt formed by the 6S-acid is filtered and separated; the salt formed by the 6S-acid is suspended in water, and the sodium hydroxide solution is added to dissolve the sodium salt; 20-60 ⁇ , then add calcium hydroxide, a small amount of stirring to complete the addition until dissolved; then add 95% ethanol to produce a precipitate, that is, the (6S)-5-methyltetrahydrofolate calcium salt is prepared.
  • the organic base is al
  • ⁇ -phenethylamine may be a racemate or a single optical isomer, and (-)- ⁇ -phenethylamine is preferred.
  • the racemate (6R, S 5-MTHF is prepared by Calcium Falinate from Suzhou Surui Pharmaceutical Co., Ltd., Jiangsuzhou, and is prepared by neutralization reduction; ⁇ -phenylethylamine and enantiomer are Provided by Jiangsu Changzhou Kerunda Chemical Co., Ltd.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de (6S)-5-méthyltétrahydrofolate de calcium. Ce procédé comprend les étapes consistant à : résoudre de l'acide (6R,S)-5-méthyltétrahydrofolique racémique à l'aide d'α-phénéthylamine pour obtenir de l'acide (6S)-5-méthyltétrahydrofolique, et saliniser cet acide (6S)-5-méthyltétrahydrofolique à l'aide d'un hydroxyde de métal alcalino-terreux, en particulier un hydroxyde de calcium, pour obtenir du (6S)-5-méthyltétrahydrofolate de calcium.
PCT/CN2006/002615 2006-09-13 2006-10-08 Procédé de résolution d'acide 5-méthyltétrahydrofolique et sa salinisation Ceased WO2008031284A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610041541.4 2006-09-13
CN2006100415414A CN101143863B (zh) 2006-09-13 2006-09-13 5-甲基四氢叶酸的拆分及其成盐方法

Publications (1)

Publication Number Publication Date
WO2008031284A1 true WO2008031284A1 (fr) 2008-03-20

Family

ID=39183367

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/002615 Ceased WO2008031284A1 (fr) 2006-09-13 2006-10-08 Procédé de résolution d'acide 5-méthyltétrahydrofolique et sa salinisation

Country Status (2)

Country Link
CN (1) CN101143863B (fr)
WO (1) WO2008031284A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103333A1 (fr) * 2008-02-20 2009-08-27 Gnosis S.P.A. Procédé de résolution diastéréoisomérique d'acide 5-méthyltétrahydrofolique
WO2015193778A1 (fr) * 2014-06-16 2015-12-23 Mylan Laboratories Ltd. Forme cristalline de lévoméfolate de calcium

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516247A (zh) * 2010-12-15 2012-06-27 连云港金康医药科技有限公司 A型l-5-甲基四氢叶酸钙盐多晶型及其制备方法
CN102584826B (zh) * 2012-01-20 2015-04-29 连云港金康医药科技有限公司 (6s)-5-甲基四氢叶酸盐晶型及其制备方法
CN102702200B (zh) * 2012-04-25 2014-11-12 连云港金康和信药业有限公司 (6rs)-5-甲基四氢叶酸钙盐晶型及其制备方法
CN104557937B (zh) * 2012-01-20 2017-03-08 连云港金康和信药业有限公司 (6s)‑5‑甲基四氢叶酸盐晶型及其制备方法
KR101673979B1 (ko) * 2012-04-13 2016-11-08 리안윤강 진강 해신 파머수티컬 코. 엘티디. 화합물 jk12a 및 그 제조
CN103664945B (zh) * 2012-09-07 2016-01-20 南京莱因医药科技有限公司 L-5-甲基四氢叶酸氨基酸盐的制备方法
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
CN109164182B (zh) * 2018-09-19 2021-06-11 无锡紫杉药业有限公司 一种对l-四氢叶酸对甲苯磺酸盐（6s）光学纯度的分析检测方法
CN111620777A (zh) * 2020-06-10 2020-09-04 成都蓝蜻蜓生物技术有限公司 一种(s)-1，2，3，4-四氢-1-萘甲酸的拆分方法
CN111635405A (zh) * 2020-07-02 2020-09-08 无锡紫杉药业有限公司 一种四氢叶酸钙制剂生产工艺

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457202A (en) * 1991-11-11 1995-10-10 Knoll Aktiengesellschaft Resolution of 5-methyltetrahydrofolic acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457202A (en) * 1991-11-11 1995-10-10 Knoll Aktiengesellschaft Resolution of 5-methyltetrahydrofolic acid

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009103333A1 (fr) * 2008-02-20 2009-08-27 Gnosis S.P.A. Procédé de résolution diastéréoisomérique d'acide 5-méthyltétrahydrofolique
WO2015193778A1 (fr) * 2014-06-16 2015-12-23 Mylan Laboratories Ltd. Forme cristalline de lévoméfolate de calcium

Also Published As

Publication number Publication date
CN101143863B (zh) 2010-08-11
CN101143863A (zh) 2008-03-19

Similar Documents

Publication Publication Date Title
WO2008031284A1 (fr) Procédé de résolution d'acide 5-méthyltétrahydrofolique et sa salinisation
KR20150036210A (ko) 야누스 키나제 억제제（Ｒ）―３―（４―（７Ｈ―피롤로［２，３－ｄ］피리미딘―4―일）―1Ｈ―피라졸―1―일）―３―사이클로펜틸프로판니트릴의 염
US9284320B2 (en) Ticagrelor adducts with divalent metal salts
WO2012122165A2 (fr) N-aryl-pyridinones substituées
MX2015002310A (es) Nuevas amidas de fenil-piridina/pirazina para el tratamiento de cancer.
CN104169270A (zh) 达比加群酯甲磺酸盐的固体形式以及它们的制备方法
US9150982B2 (en) Crystal form of (6S)-5-methyltetrahydrofolate salt and method for preparing same
WO2024099478A1 (fr) Thiazide cyclique aromatique inhalable et analogue, composition pharmaceutique contenant la thiazine cyclique aromatique inhalable, et utilisation de la thiazine cyclique aromatique inhalable comme anti-inflammatoire et anti-tumoral
CN103864760A (zh) 一种盐酸法舒地尔化合物
TWI326684B (fr)
JP2004526706A (ja) オクスカルバゼピンの新しい結晶形態及びそれらの調製方法
JP2025061823A (ja) 葉酸塩
RU2439063C1 (ru) Способ получения лекарственного средства
JPH03503162A (ja) 化学療法における毒性特性の改良
CN102775408B (zh) 稳定的5-甲基四氢叶酸晶型及其制备方法
CN102746227B (zh) 一种磷酸二甲啡烷晶型ⅱ及制备方法和药物组合物
JPH0912573A (ja) １−（５−イソキノリンスルホニル）ホモピペラジン塩酸塩３水和物
JP5960460B2 (ja) 結晶性レボホリン酸及びその調製方法
CN110684066B (zh) 胞二磷胆碱药物制剂及其脑梗塞急性期意识障碍的新用途
US20220047563A1 (en) Combination therapy for the treatment of estrogen-receptor positive breast cancer
CN112409195A (zh) 一种(s)-氯胺酮盐酸盐的制备方法及其中间体、其晶型
CN101209994A (zh) 选择性m4受体拮抗剂及其医药用途
US20250019379A1 (en) New crystal form of compound, and preparation method therefor and use thereof
US6864241B2 (en) Amine salt of lignan compounds
BR122024020702A2 (pt) Sais de folato, seu método de preparação, composição farmacêutica que os compreende e uso dos mesmos

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06791198

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06791198

Country of ref document: EP

Kind code of ref document: A1