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WO1998000425A1 - 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 Download PDF

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Publication number
WO1998000425A1
WO1998000425A1 PCT/IB1997/000704 IB9700704W WO9800425A1 WO 1998000425 A1 WO1998000425 A1 WO 1998000425A1 IB 9700704 W IB9700704 W IB 9700704W WO 9800425 A1 WO9800425 A1 WO 9800425A1
Authority
WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/IB1997/000704
Other languages
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
Original Assignee
Pfizer Corp Belgium
Pfizer Corp SRL
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 filed Critical Pfizer Corp Belgium
Priority to BR9710018A priority Critical patent/BR9710018A/pt
Priority to EP97924195A priority patent/EP0912569A1/fr
Priority to JP9536562A priority patent/JPH11512751A/ja
Priority to AU29744/97A priority patent/AU2974497A/en
Priority to PL97330962A priority patent/PL330962A1/xx
Priority to IL12703797A priority patent/IL127037A0/xx
Publication of WO1998000425A1 publication Critical patent/WO1998000425A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (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.
PCT/IB1997/000704 1996-07-01 1997-06-16 Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido[1,2-a]pyrazine Ceased WO1998000425A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR9710018A BR9710018A (pt) 1996-07-01 1997-06-16 Preparação de (7S,trans)-2-(2-pirimidinil)-7-(hidroximetil)octa-hidro-2H-pirido[1,2-A]pirazina
EP97924195A EP0912569A1 (fr) 1996-07-01 1997-06-16 Preparation de (7s,trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2h-pyrido 1,2-a]pyrazine
JP9536562A JPH11512751A (ja) 1996-07-01 1997-06-16 （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
AU29744/97A AU2974497A (en) 1996-07-01 1997-06-16 Preparation of (7S,trans)-2-(2-pyrimidinyl)-7- (hydrooxymethyl)octahydro-2H-pyrido(1,2-a)pyrazine
PL97330962A PL330962A1 (en) 1996-07-01 1997-06-16 Method of obtaining (7s, trans)-2- (2-pyrimidinyl) -7- (hydroxymethyl) octahydro -2h-pyrido [1,2-a] pyrazine _
IL12703797A IL127037A0 (en) 1996-07-01 1997-06-16 Preparation of (7s trans)-2- (2-pyrimidinyl)-7- (hydroxamethyl) octahydro-2h- pyrido [1,2-a] pyrazine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2051196P 1996-07-01 1996-07-01
US60/020,511 1996-07-01

Publications (1)

Publication Number Publication Date
WO1998000425A1 true WO1998000425A1 (fr) 1998-01-08

Family

ID=21799016

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1997/000704 Ceased WO1998000425A1 (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)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0380217A1 (fr) * 1989-01-23 1990-08-01 Pfizer Inc. Agents bis-aza-bicycliques anxiolytiques et antidépresseurs
WO1992013858A1 (fr) * 1991-01-31 1992-08-20 Pfizer Inc. Decomposition de trans-2-(2-pyrimidinyle)-7-(hydroxymethyle)octahydro-2h-pyrido[1,2-a]pyrazine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0380217A1 (fr) * 1989-01-23 1990-08-01 Pfizer Inc. Agents bis-aza-bicycliques anxiolytiques et antidépresseurs
WO1992013858A1 (fr) * 1991-01-31 1992-08-20 Pfizer Inc. Decomposition de trans-2-(2-pyrimidinyle)-7-(hydroxymethyle)octahydro-2h-pyrido[1,2-a]pyrazine

Also Published As

Publication number Publication date
JPH11512751A (ja) 1999-11-02
BR9710018A (pt) 1999-08-10
KR20000022490A (ko) 2000-04-25
CN1221418A (zh) 1999-06-30
EP0912569A1 (fr) 1999-05-06
TR199802743T2 (xx) 1999-03-22
PL330962A1 (en) 1999-06-21
YU61098A (sh) 1999-09-27
AR008251A1 (es) 1999-12-29
AU2974497A (en) 1998-01-21
CZ434998A3 (cs) 1999-11-17
ZA975806B (en) 1998-12-30
ID19779A (id) 1998-07-30
CA2259496A1 (fr) 1998-01-08
IL127037A0 (en) 1999-09-22

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