EP1070076A4 - Chiral separations of pyrimidines - Google Patents

Chiral separations of pyrimidines

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Publication number
EP1070076A4
EP1070076A4 EP98914244A EP98914244A EP1070076A4 EP 1070076 A4 EP1070076 A4 EP 1070076A4 EP 98914244 A EP98914244 A EP 98914244A EP 98914244 A EP98914244 A EP 98914244A EP 1070076 A4 EP1070076 A4 EP 1070076A4
Authority
EP
European Patent Office
Prior art keywords
chiral
polar solvent
lower alkanol
mixture
groups
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Withdrawn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
EP98914244A
Other languages
German (de)
French (fr)
Other versions
EP1070076A1 (en
Inventor
Fiona O Geiser
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.)
Chiral Technologies Inc
Original Assignee
Chiral Technologies 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 Chiral Technologies Inc filed Critical Chiral Technologies Inc
Publication of EP1070076A1 publication Critical patent/EP1070076A1/en
Publication of EP1070076A4 publication Critical patent/EP1070076A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the separation of chiral materials utilizing high performance liquid chromatography (HPLC) techniques.
  • the present invention pertains to a method of separating an enantiomeric mixture of chiral pyrimidines, or a salt thereof, into their respective enantiomers.
  • This method comprises subjecting the chiral mixture to chromatography on chiral polysaccharide stationary phase, eluting with a polar mobile phase, preferably a liquid lower alkanol.
  • Pyrimidines constitute an important class of biologically active compounds, encompassing monocyclic nucleic acid bases such as uracil, cytosine, thymine, and 5- methylcytosine, bicyclopyrimidines such as the purine bases adenine, guanine, xanthine, and hypoxanthine, folates and folic acid antagonists, etc. Numerous compounds of this type have been synthesized as antiviral and anticancer drugs. Typical pyrimidine structures include for example:
  • Al 0 so include ⁇ d arex the hy>droge Q nated fo O rms of th 0 e forego 0 ing struc 0 tures.
  • enantiomers Often the final compounds containing such ring systems will be substituted with a chiral group, thereby giving rise to the existence of enantiomers, and in such cases it generally is desirable to separate the enantiomers into chirally pure form.
  • iodoxuridine, vidarabine, azidothymidine, sparsomycin, cytosine arabinoside, 5-fluorouridine, methotrexate, DDATHF, and aminopterin are biologically active pyrimidine compounds containing a center of chirality.
  • enantiomeric separations encompassed by the present invention utilize chiral polysaccharides as stationary phases.
  • chiral polysaccharides as stationary phases.
  • aromatic carbamate or ester derivatives of cellulose or amylose which can be generically represented by the formula:
  • glucosidic linkage is either (amylose) or ⁇ (cellulose).
  • R groups can be for example a phenylcarbamate or ⁇ -phenethylcarba- mate. which itself is chiral, or a benzoate group.
  • Typical R groups thus include 3,5- dimethylphenyl carbamate, ⁇ -phenethylcarbamate, and 4- methylbenzoate, e.g. :
  • Such chiral polysaccharide stationary supports are commercially available from Chiral Technologies, Inc., Exton, PA, under the trademarks CHIRALPAK ® amylosic stationary phase and CHIRALCEL cellulosic stationary phase.
  • Suitable materials include CHIRALPAK AD , an amylose derivative in which each glucose monomer carries three 3,5-dimethylphenyl carbamate groups, CHIRALPAK" AS , an amylose derivative in which each glucose monomer carries three (S)- -phenethylcarbamate groups, CHIRALCEL OD , a cellulose derivative in which each glucose monomer carries three 3.5-dimethylphenyl carbamate groups, and CHIRALCEL OJ , a cellulose derivative in which each glucose monomer carries three 4-methylbenzoyl groups.
  • CHIRALPAK AD an amylose derivative in which each glucose monomer carries three 3,5-dimethylphenyl carbamate groups
  • CHIRALPAK an amylose derivative
  • the stationary phase conveniently can be packed in columns adapted for use with commercially available HPLC systems, as for example those available from 3
  • the particle diameter will be from about 1 to about 100 ⁇ m, typically from about 5 to about 75 ⁇ m. Multiple or single columns can be employed.
  • a simulated moving bed apparatus also can be employed, as described for example in U.S. Patent Nos. 5,434,298, 5,434,299, 5,456,825, and 5,498,752, the disclosures of which are incorporated herein by reference.
  • the eluent or mobile phase comprises a liquid polar solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, acetonitrile, supercritical carbon dioxide and the like, preferably acetonitrile or a liquid lower alkanol such as ethanol or methanol. Also of value is supercritical carbon dioxide, alone or in combination with at one or more of acetonitrile and a liquid lower alkanol.
  • a liquid polar solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, acetonitrile, supercritical carbon dioxide and the like, preferably acetonitrile or a liquid lower alkanol such as ethanol or methanol.
  • supercritical carbon dioxide alone or in combination with at one or more of acetonitrile and a liquid lower alkanol.
  • the separation will be conducted at ambient temperatures; e.g., 25-40°C. pH will vary depending upon the nature of the material being chromatographed but generally will be from about 2 to about 7. Typical flow rates are from about 0.2 mL/min. to about 25 mL/min., depending on the apparatus, column dimensions, and stationary phase.
  • Separation can be monitored by measuring UV absorption, optical rotation, refractive index, evaporative light scattering, or a similar physical parameter. Detection can be conducted for example by measuring UN absorption at an appropriate wavelength of the eluted material, utilizing a UN spectrophotometer, or the optical activity of the eluted material, using for example a device such as the IBZ Chiralyser ® instrument (available from JM Science, Inc., Grand Island, ⁇ Y) which monitors the rotation of plane polarized light. The parameter selected for detection will depend on the specific pyrimidine compound being eluted. The following examples will serve to further typify the nature of the invention but should not be construed as limitation on the scope thereof which is defined solely by the appended claims.
  • Example 2 was separated into its two enantiomers using the procedure of Example 1. Good separation into two distinct peaks was observed. The first enantiomer eluted was dextrorotatory.
  • Example 2 was separated into its two enantiomers using the procedure of Example 1. Good separation into two distinct peaks was observed. The first enantiomer eluted was the dextrorotatory form.
  • R is for example t-butyldiphenylsilyloxy
  • each of R , R . and R is hydrogen, methyl, chloro, fluoro, trifluoromethyl, or trichloromethyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

An enantiomeric mixture of a chiral compound containing a pyrimidine ring is separated into its respective enantiomers through chromatography on a chiral polysaccharide stationary phase eluting with a mobile phase comprising a polar solvent, preferably a lower alkanol or acetonitrile.

Description

Chiral Separations of Pyrimidines
The present invention relates to the separation of chiral materials utilizing high performance liquid chromatography (HPLC) techniques.
Detailed Description
The present invention pertains to a method of separating an enantiomeric mixture of chiral pyrimidines, or a salt thereof, into their respective enantiomers. This method comprises subjecting the chiral mixture to chromatography on chiral polysaccharide stationary phase, eluting with a polar mobile phase, preferably a liquid lower alkanol.
Pyrimidines constitute an important class of biologically active compounds, encompassing monocyclic nucleic acid bases such as uracil, cytosine, thymine, and 5- methylcytosine, bicyclopyrimidines such as the purine bases adenine, guanine, xanthine, and hypoxanthine, folates and folic acid antagonists, etc. Numerous compounds of this type have been synthesized as antiviral and anticancer drugs. Typical pyrimidine structures include for example:
Al 0so include ζd arex the hy>droge Qnated foOrms of th 0e forego0ing struc 0tures.
Often the final compounds containing such ring systems will be substituted with a chiral group, thereby giving rise to the existence of enantiomers, and in such cases it generally is desirable to separate the enantiomers into chirally pure form. For example iodoxuridine, vidarabine, azidothymidine, sparsomycin, cytosine arabinoside, 5-fluorouridine, methotrexate, DDATHF, and aminopterin, to mention but a few, are biologically active pyrimidine compounds containing a center of chirality.
The enantiomeric separations encompassed by the present invention utilize chiral polysaccharides as stationary phases. Typically these are aromatic carbamate or ester derivatives of cellulose or amylose which can be generically represented by the formula:
in which the depicted glucosidic linkage is either (amylose) or β (cellulose).
The depicted R groups can be for example a phenylcarbamate or α-phenethylcarba- mate. which itself is chiral, or a benzoate group. Typical R groups thus include 3,5- dimethylphenyl carbamate, α-phenethylcarbamate, and 4- methylbenzoate, e.g. :
O H CH
N - ^g)
O
-I -CH,
Such chiral polysaccharide stationary supports are commercially available from Chiral Technologies, Inc., Exton, PA, under the trademarks CHIRALPAK® amylosic stationary phase and CHIRALCEL cellulosic stationary phase. Suitable materials include CHIRALPAK AD , an amylose derivative in which each glucose monomer carries three 3,5-dimethylphenyl carbamate groups, CHIRALPAK" AS , an amylose derivative in which each glucose monomer carries three (S)- -phenethylcarbamate groups, CHIRALCEL OD , a cellulose derivative in which each glucose monomer carries three 3.5-dimethylphenyl carbamate groups, and CHIRALCEL OJ , a cellulose derivative in which each glucose monomer carries three 4-methylbenzoyl groups. Reference may be made to U.S. Patent Nos. 4,912,205 and 5,434,299 for further details, the disclosures of which are incorporated herein by reference. The amylose derivatives are preferred.
The stationary phase conveniently can be packed in columns adapted for use with commercially available HPLC systems, as for example those available from 3
Shimadzu, Columbia, MD, and Jasco, Easton, MD. Generally the particle diameter will be from about 1 to about 100 μm, typically from about 5 to about 75 μm. Multiple or single columns can be employed. A simulated moving bed apparatus also can be employed, as described for example in U.S. Patent Nos. 5,434,298, 5,434,299, 5,456,825, and 5,498,752, the disclosures of which are incorporated herein by reference.
The eluent or mobile phase comprises a liquid polar solvents such as methanol, ethanol, n-propanol, isopropanol, butanol, acetonitrile, supercritical carbon dioxide and the like, preferably acetonitrile or a liquid lower alkanol such as ethanol or methanol. Also of value is supercritical carbon dioxide, alone or in combination with at one or more of acetonitrile and a liquid lower alkanol.
The separation will be conducted at ambient temperatures; e.g., 25-40°C. pH will vary depending upon the nature of the material being chromatographed but generally will be from about 2 to about 7. Typical flow rates are from about 0.2 mL/min. to about 25 mL/min., depending on the apparatus, column dimensions, and stationary phase.
Separation can be monitored by measuring UV absorption, optical rotation, refractive index, evaporative light scattering, or a similar physical parameter. Detection can be conducted for example by measuring UN absorption at an appropriate wavelength of the eluted material, utilizing a UN spectrophotometer, or the optical activity of the eluted material, using for example a device such as the IBZ Chiralyser® instrument (available from JM Science, Inc., Grand Island, ΝY) which monitors the rotation of plane polarized light. The parameter selected for detection will depend on the specific pyrimidine compound being eluted. The following examples will serve to further typify the nature of the invention but should not be construed as limitation on the scope thereof which is defined solely by the appended claims.
Example 1
A chiral mixture of 2-amino-6-hydroxy-9-(2-hydroxymethylcyclopropylidene- methyl)purine: OH
CH— CH2— OH
CH=< CIH2
was chromatographed on a 4.6 mm id x 250 mm column in which the stationary phase was CHIRALCEL AD , an amylose derivative in which each glucose monomer carries three 3,5-dimethylphenyl carbamate groups. The run was conducted at room temperature at a flow rate of 1.0 mL/min., utilizing 100% methanol as the mobile phase. Separation was measured by absorption at 254 n . Good separation into two distinct peaks was observed with the dextrorotatory enantiomer being eluted first.
Example 2
A chiral mixture of 2-amino-6-chloro-9-(2-hydroxymethylcyclopropylidenemeth- yl)purine:
Cl
H7N- r N '
^Nx- *N> CH-CH,— OH
CH=< CIH2
was separated into its two enantiomers using the procedure of Example 1. Good separation into two distinct peaks was observed. The first enantiomer eluted was dextrorotatory.
Example 3
A chiral mixture of 2,6-diamino-9-(2-hydroxymethylcyclopropylidenemeth- yl)purine: NHo
CH7— OH
was separated into its two enantiomers using the procedure of Example 1. Good separation into two distinct peaks was observed. The first enantiomer eluted was the dextrorotatory form.
Example 4
A chiral mixture t 2-(2-methylpropionamido)-6-hydroxy-9-(2-hydroxymethyl- cyclopropylidenemet )p -rine:
OH
.N
3
(CH3), C-NH X-^^NX^^N > CH-CH,— OH
CH-C
CH2
was separated into _ two enantiomers using the procedure of Example 1. Good separation into tv,o istinct peaks was observed. Dextrorotatory 2-(2- methylpropionamic >)-6 droxy-9-(2-hydroxymethylcyclopropylidenemethyl)purine was eluted first.
Example 5 A chiral mixture ι-( -methyl-5-benzoyloxymethylfur-2-yl))thymiine:
OH L ^CH3
N
HO X^ ^N ' *CH3 was separated into its two enantiomers using the procedure of Example 1 but eluting with acetonitrile. Good separation into two distinct peaks was observed.
Example 6
Other chiral pyrimidines which can be similarly separated include the following:
Cl OH
N N
N
HO HO'
CH,OH CB,OR> X U° ^CH2OH
R\ .C-C^<] N
H. \ /
R3
• HC1
HO O^^ ^NN' ^R4 I O' H
N.
HOCHy Η
4 • in which R is for example t-butyldiphenylsilyloxy, and each of R , R . and R , is hydrogen, methyl, chloro, fluoro, trifluoromethyl, or trichloromethyl.

Claims

What is claimed is: 1. The method of separating an enantiomeric mixture of a chiral pyrimidine compound, or a salt thereof, into its respective enantiomers which comprises subjecting said mixture to chromatography on a chiral polysaccharide stationary phase eluting with a mobile phase of at least one polar solvent. 2. The method of claim 1 wherein said polar solvent is a liquid lower alkanol.. 3. The method of claim 2 wherein said lower alkanol is methanol. 4. The method of claim 2 wherein said lower alkanol is ethanol. 5. The method of claim 1 wherein said polar solvent is acetonitrile. 6. The method of claim 1 wherein said polar solvent comprises supercritical carbon dioxide. 7. The method of claim 6 wherein said polar solvent comprises supercritical carbon dioxide in combination with at one of acetonitrile and a liquid lower alkanol. 8. The method of claim 1 wherein said chiral polysaccharide stationary phase is an amyl- ose derivative in which each glucose monomer carries three 3,5-dimethylphenyl carbamate groups or α-phenethylcarbamate groups. 9. The method of separating an enantiomeric mixture of a chiral nucleotide which com- prises subjecting said mixture to chromatography on chiral polyamylose stationary phase, in which each glucose monomer of the polyamylose carries three 3,5- dimethylphenyl carbamate groups or α-phenethylcarbamate groups, with a mobile phase comprising 100% methanol.
-1 -
EP98914244A 1998-03-16 1998-03-16 Chiral separations of pyrimidines Withdrawn EP1070076A4 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/005121 WO1999047531A1 (en) 1998-03-16 1998-03-16 Chiral separations of pyrimidines

Publications (2)

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EP1070076A1 EP1070076A1 (en) 2001-01-24
EP1070076A4 true EP1070076A4 (en) 2002-05-29

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AU (1) AU6864798A (en)
WO (1) WO1999047531A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0002463D0 (en) * 2000-06-28 2000-06-28 Boerje Sellergren Substructure approach to molecular imprinted polymers with high selectivity for folic acid and analogues
CN1914505A (en) * 2004-02-03 2007-02-14 大赛璐化学工业株式会社 Method of optical isomer separation with use of supercritical fluid chromatography

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5434299A (en) * 1991-08-22 1995-07-18 Daicel Chemical Industries, Ltd. Process for recovering optical isomers and solvent, process for using solvent by circulation and process for reusing optical isomers in optical resolution

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US4861872A (en) * 1986-03-20 1989-08-29 Daicel Chemical Industries, Ltd. Alkyl-phenylcarbamate derivative of polysaccharide
US4912205A (en) * 1986-03-20 1990-03-27 Daicel Chemical Industries, Ltd. Alkyl-substituted phenylcarbamate derivative of polysaccharide
JP2648516B2 (en) * 1989-07-27 1997-09-03 ダイセル化学工業株式会社 Separation of stereoisomers
US5196575A (en) * 1992-02-19 1993-03-23 Hoechst Celanese Corp. Supercritical separation of isomers of functional organic compounds at moderate conditions

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US5434299A (en) * 1991-08-22 1995-07-18 Daicel Chemical Industries, Ltd. Process for recovering optical isomers and solvent, process for using solvent by circulation and process for reusing optical isomers in optical resolution

Non-Patent Citations (6)

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Title
COUSINS R P C ET AL: "Enzymic Resolution of Oxathiolane Intermediates - An Alternative Approach to the Anti-viral Agent Lamivudine (3TC)", TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 6, no. 2, 1 February 1995 (1995-02-01), pages 393 - 396, XP004048446, ISSN: 0957-4166 *
CSUK R ET AL: "Enantiomerically Pure Cyclopropanoid Nucleoside Analogues: Synthesis and Analysis", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 52, no. 18, 29 April 1996 (1996-04-29), pages 6383 - 6396, XP004104129, ISSN: 0040-4020 *
DI MARCO M P ET AL: "High-performance liquid chromatographic determination of the isomeric purity of a series of dioxolane nucleoside analogs", JOURNAL OF CHROMATOGRAPHY A, ELSEVIER SCIENCE, NL, vol. 645, 1993, pages 107 - 114, XP002100671, ISSN: 0021-9673 *
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SCHUSTER A ET AL: "Chiral separation of 3-phenyl-3-(2-pyridyl)propylamines, and analogous guanidines and guanidine-N-carboxylic acid esters with high-performance liquid chromatography and capillary zone electrophoresis", JOURNAL OF CHROMATOGRAPHY A, ELSEVIER SCIENCE, NL, vol. 793, no. 1, 9 January 1998 (1998-01-09), pages 77 - 90, XP004107172, ISSN: 0021-9673 *
See also references of WO9947531A1 *

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Publication number Publication date
AU6864798A (en) 1999-10-11
WO1999047531A1 (en) 1999-09-23
EP1070076A1 (en) 2001-01-24

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