WO1999047531A1 - Chiral separations of pyrimidines - Google Patents

Chiral separations of pyrimidines Download PDF

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Publication number
WO1999047531A1
WO1999047531A1 PCT/US1998/005121 US9805121W WO9947531A1 WO 1999047531 A1 WO1999047531 A1 WO 1999047531A1 US 9805121 W US9805121 W US 9805121W WO 9947531 A1 WO9947531 A1 WO 9947531A1
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chiral
polar solvent
lower alkanol
mixture
groups
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Fiona O. Geiser
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Chiral Technologies Inc
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Chiral Technologies Inc
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Priority to EP98914244A priority Critical patent/EP1070076A4/en
Priority to PCT/US1998/005121 priority patent/WO1999047531A1/en
Priority to AU68647/98A priority patent/AU6864798A/en
Publication of WO1999047531A1 publication Critical patent/WO1999047531A1/en
Anticipated expiration legal-status Critical
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    • 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.

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  • 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:
Figure imgf000004_0001
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. :
Figure imgf000004_0002
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
Figure imgf000006_0001
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
Figure imgf000007_0001
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 '
Figure imgf000007_0002
*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
Figure imgf000008_0002
Figure imgf000008_0001
HO HO'
CH,OH CB,OR> X U° ^CH2OH
Figure imgf000008_0003
Figure imgf000008_0004
R\ .C-C^<] N
H. \ /
Figure imgf000008_0005
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 -
PCT/US1998/005121 1998-03-16 1998-03-16 Chiral separations of pyrimidines Ceased WO1999047531A1 (en)

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EP98914244A EP1070076A4 (en) 1998-03-16 1998-03-16 Chiral separations of pyrimidines
PCT/US1998/005121 WO1999047531A1 (en) 1998-03-16 1998-03-16 Chiral separations of pyrimidines
AU68647/98A AU6864798A (en) 1998-03-16 1998-03-16 Chiral separations of pyrimidines

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002001223A1 (en) * 2000-06-28 2002-01-03 Mip Technologies Ab Substructure approach to molecularly imprinted polymers with high selectivity for folic acid and analogues
EP1712905A4 (en) * 2004-02-03 2008-04-09 Daicel Chem METHOD FOR SEPARATING OPTICAL ISOMERS USING SUPERCRITICAL FLUID CHROMATOGRAPHY

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5196575A (en) * 1992-02-19 1993-03-23 Hoechst Celanese Corp. Supercritical separation of isomers of functional organic compounds at moderate conditions
US5202433A (en) * 1989-07-27 1993-04-13 Daicel Chemical Industries, Ltd. Polysaccharide derivatives as separating agents

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3010816B2 (en) * 1991-08-22 2000-02-21 ダイセル化学工業株式会社 Method for recovering optical isomer and solvent in optical resolution, method for recycling solvent, and method for reusing optical isomer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5202433A (en) * 1989-07-27 1993-04-13 Daicel Chemical Industries, Ltd. Polysaccharide derivatives as separating agents
US5196575A (en) * 1992-02-19 1993-03-23 Hoechst Celanese Corp. Supercritical separation of isomers of functional organic compounds at moderate conditions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1070076A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002001223A1 (en) * 2000-06-28 2002-01-03 Mip Technologies Ab Substructure approach to molecularly imprinted polymers with high selectivity for folic acid and analogues
EP1712905A4 (en) * 2004-02-03 2008-04-09 Daicel Chem METHOD FOR SEPARATING OPTICAL ISOMERS USING SUPERCRITICAL FLUID CHROMATOGRAPHY

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EP1070076A1 (en) 2001-01-24
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