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.

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• 1998
  • 1998-03-16 EP EP98914244A patent/EP1070076A4/de not_active Withdrawn
  • 1998-03-16 AU AU68647/98A patent/AU6864798A/en not_active Abandoned
  • 1998-03-16 WO PCT/US1998/005121 patent/WO1999047531A1/en not_active Ceased

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