[go: up one dir, main page]

EP0912569A1 - Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine - Google Patents

Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine

Info

Publication number
EP0912569A1
EP0912569A1 EP97924195A EP97924195A EP0912569A1 EP 0912569 A1 EP0912569 A1 EP 0912569A1 EP 97924195 A EP97924195 A EP 97924195A EP 97924195 A EP97924195 A EP 97924195A EP 0912569 A1 EP0912569 A1 EP 0912569A1
Authority
EP
European Patent Office
Prior art keywords
salt
solution
enantiomer
formula
tartaric acid
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.)
Withdrawn
Application number
EP97924195A
Other languages
German (de)
English (en)
Inventor
Sally Gut Ruggeri
Philip Dietrich Hammen
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.)
Pfizer Corp Belgium
Pfizer Corp SRL
Pfizer Inc
Original Assignee
Pfizer Corp Belgium
Pfizer Corp SRL
Pfizer 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 Pfizer Corp Belgium, Pfizer Corp SRL, Pfizer Inc filed Critical Pfizer Corp Belgium
Publication of EP0912569A1 publication Critical patent/EP0912569A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to a process for the preparation of (7S,trans)-2-(2- pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1,2-a]pyrazine which is used to prepare pyrazine compounds, both of which are disclosed in European Patent
  • the present invention also relates to the tartrate salts that are formed as intermediates in the foregoing process.
  • the present invention relates to a process for separating trans-2-(2-pyrimidinyl)- 7-(hydroxymethyl) octahydro-2H-pyrido[1 ,2-a]pyrazine which is a racemic mixture of an enantiomer of the formula
  • diastereomeric salt formation such that the optical purity of the separated diastereomer is at least about 98.5%, comprising:
  • trans-2-(2-pyrimidinyl)-7- (hydroxymethyl)octahydro-2H-pyrido[1 ,2-a]pyrazine is resolved using either L-(+) or D-(-)-tartaric acid.
  • the pyrazine is reacted with the tartaric acid in an inert polar solvent.
  • Suitable solvents include methanol, isopropanol, ethyl acetate and tetrahydrofuran. Methanol is the preferred solvent.
  • Methanol is the preferred solvent.
  • One of the diastereomeric tartrate salts precipitates.
  • the 7S enantiomer remains in solution and the salt of the 7R enantiomer precipitates.
  • the D-(-) tartaric salt is formed, the 7R enantiomer remains in solution and the salt of the 7S enantiomer precipitates. If the salt of the desired enantiomer remains in solution, it is recovered by evaporating the liquid.
  • trans-2-(2- pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1 ,2-a]pyrazine is resolved using either L-(+) or D-(-)-tartaric acid, producing a salt with an optical purity of at least 98.5%, in order to result in an enantiomer with an optical purity of at least 99.7% and to commercially produce the final product.
  • the optical purity can be evaluated using methods known in the art, such as the method disclosed in Enantiomers. Racemates and Resolutions J Jacques, et al., John Wiley & Sons, New York 1981.
  • the pyrazine is combined with methanol and the temperature is adjusted to a temperature of from about 50 to about 70 °C, preferably from about 50 to about 60 °C, most preferably fron about 50 to about 55 °C.
  • From about 0.5 to about 1.0 equivalents, preferably abc 0.75 equivalents, of D-(-) or L-(+)tartaric acid is added to the pyrazine and metha r solution, while maintaining the temperature, to form the tartrate salts of each of the enantiomers.
  • one of the diastereomeric tartrate salts precipitates, as described in the previous paragraph.
  • the desired diastereomeric salt remains in solution, it is recovered by evaporating the liquid.
  • the salt is dissolved in water and the pH is raised to between about 10 to about 14 preferably pH 12, using an inorganic base, and the base is extracted from the aqueous layer using an inert non-polar solvent, such as isopropyl ether, diethyl ether, 1 ,1 ,1-trichloroethane, or methylene chloride, preferably the latter, or is collected by filtration.
  • an inert non-polar solvent such as isopropyl ether, diethyl ether, 1 ,1 ,1-trichloroethane, or methylene chloride, preferably the latter, or is collected by filtration.
  • the pyrazine compounds disclosed in European Patent Application Publication Number 0380217 (A1) are administered in an antianxiety amount of about 2 to about 200 mg/day, in single or divided daily doses. In particular cases, dosages outside that range are prescribed at the discretion of the attending physician.
  • the preferred route of administration is generally oral, but parenteral administration (e.g., intramuscular, intravenous, intradermal) will be preferred in special cases, e.g. where oral absorption is impaired as by disease, or the patient is unable to swallow.
  • These compounds are generally administered in the form of pharmaceutical compositions including a pharmaceutically acceptable vehicle or diluent.
  • Such are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; and, for parenteral administration, in the form of injectable solutions or suspensions, and the like.
  • the tartrate salt (3.0 g, 7.54 mmol) is dissolved in 150 ml of water taken to pH 12 with 2M NaOH and extracted twice with 100 ml of methylene chloride. The combined organic phases are then dried over sodium sulfate, filtered, and evaporated to provide the free base as a light brown solid, clean by NMR. To provide an optically pure free base, the free base is then slurried in a mixture of 20 ml of methylene chloride and 20 ml of hexanes of 15 minutes, filtered, washed with hexanes and dried under vacuum to provide the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de séparation des énantiomères d'un mélange racémique de trans-2-(2-pyrimidinyl)-7-(hydroxyméthyl)octahydro-2H-pyridol[1,2-a]pyrazine, qui consiste à effectuer la réaction du mélange racémique avec de l'acide tartarique D-(-) ou L-(+) et à séparer les sels diastéréomères de tartrate obtenus.
EP97924195A 1996-07-01 1997-06-16 Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine Withdrawn EP0912569A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US2051196P 1996-07-01 1996-07-01
US20511P 1996-07-01
PCT/IB1997/000704 WO1998000425A1 (fr) 1996-07-01 1997-06-16 Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido[1,2-a]pyrazine

Publications (1)

Publication Number Publication Date
EP0912569A1 true EP0912569A1 (fr) 1999-05-06

Family

ID=21799016

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97924195A Withdrawn EP0912569A1 (fr) 1996-07-01 1997-06-16 Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine

Country Status (16)

Country Link
EP (1) EP0912569A1 (fr)
JP (1) JPH11512751A (fr)
KR (1) KR20000022490A (fr)
CN (1) CN1221418A (fr)
AR (1) AR008251A1 (fr)
AU (1) AU2974497A (fr)
BR (1) BR9710018A (fr)
CA (1) CA2259496A1 (fr)
CZ (1) CZ434998A3 (fr)
ID (1) ID19779A (fr)
IL (1) IL127037A0 (fr)
PL (1) PL330962A1 (fr)
TR (1) TR199802743T2 (fr)
WO (1) WO1998000425A1 (fr)
YU (1) YU61098A (fr)
ZA (1) ZA975806B (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008148A1 (fr) * 1989-01-23 1990-07-26 Pfizer Inc. Agents anxiolytiques bis-aza-bicycliques
JP2609410B2 (ja) * 1991-01-31 1997-05-14 ファイザー・インコーポレーテッド （７Ｓ，トランス）−２−（２−ピリミジニル）−７−（ヒドロキシメチル）オクタヒドロ−２Ｈ−ピリド［１，２−ａ］ピラジンの製造

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9800425A1 *

Also Published As

Publication number Publication date
AR008251A1 (es) 1999-12-29
YU61098A (sh) 1999-09-27
BR9710018A (pt) 1999-08-10
CN1221418A (zh) 1999-06-30
CA2259496A1 (fr) 1998-01-08
KR20000022490A (ko) 2000-04-25
TR199802743T2 (xx) 1999-03-22
WO1998000425A1 (fr) 1998-01-08
ID19779A (id) 1998-07-30
ZA975806B (en) 1998-12-30
PL330962A1 (en) 1999-06-21
CZ434998A3 (cs) 1999-11-17
JPH11512751A (ja) 1999-11-02
IL127037A0 (en) 1999-09-22
AU2974497A (en) 1998-01-21

Similar Documents

Publication Publication Date Title
WO2004011463A1 (fr) Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere
EP3424908A1 (fr) Procédé de préparation de levosimendan
EP0569387B1 (fr) Decomposition de trans-2-(2-pyrimidinyle)-7-(hydroxymethyle)octahydro-2h-pyrido 1,2-a]pyrazine
CN1612880A (zh) 制备苯基丝氨酸及其类似物的方法
WO2000062782A1 (fr) Nouvelle synthese et cristallisation de composes contenant de la piperazine
US6670476B2 (en) Resolution of trans-7-(hydroxy-methyl)octa-hydro-2H-pyrido[1,2-a]pyrazine
JP2002544184A (ja) （１ｒ，２ｓ，４ｒ）−（−）−２−［（２’−｛ｎ，ｎ−ジメチルアミノ｝−エトキシ）］−２−［フェニル］−１，７，７−トリ−［メチル］−ビシクロ［２．２．１］ヘプタン及びその薬学上許容される酸付加塩の製法
EP0912569A1 (fr) Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine
US6576764B2 (en) Synthesis and crystallization of piperazine ring-containing compounds
US20050054669A1 (en) Process for the synthesis of zolpidem
KR102350458B1 (ko) (r)-2-((4-아미노페네틸)아미노)-1-페닐에탄올의 신규한 제조방법
EP1337533B1 (fr) Resolution de trans-7-(hydroxy-methyl)octa-hydro-2h-pyrido-1,2a)pyrazine
HK1019608A (en) Preparation of (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido[1,2-a]pyrazine
JP2003500333A (ja) ４−［（２’，５’−ジアミノ−６’−ハロゲンピリミジン−４’−イル）アミノ］シクロペント−２−エンイルメタノールの製造方法
CA1281322C (fr) Pyrimidoindoles substitues
US20040176591A1 (en) Novel synthesis and crystallization of peperazine ring-containing compounds
WO2006013546A2 (fr) Procede de preparation de galantamine pure
JPH04279586A (ja) キサンチン誘導体
WO2006018703A2 (fr) Procedes de preparation de la narwedine et son utilisation dans la synthese de galantamine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19981204

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 20000201

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20000614

RTI1 Title (correction)

Free format text: PREPARATION OF (7S,TRANS)-2-(2-PYRIMIDINYL)-7-(HYDROXYMETHYL)OCTAHYDRO-2H-PYRIDO 1,2-A PYRAZINE