US3288781A - Process for deacylating anhydro-lyxofuranosyl with nitrogen base - Google Patents

Process for deacylating anhydro-lyxofuranosyl with nitrogen base Download PDF

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Publication number
US3288781A
US3288781A US419552A US41955264A US3288781A US 3288781 A US3288781 A US 3288781A US 419552 A US419552 A US 419552A US 41955264 A US41955264 A US 41955264A US 3288781 A US3288781 A US 3288781A
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US
United States
Prior art keywords
anhydro
lyxofuranosyl
benzoyl
nitrogen base
uracil
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.)
Expired - Lifetime
Application number
US419552A
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English (en)
Inventor
James H Hunter
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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 Upjohn Co filed Critical Upjohn Co
Priority to US419552A priority Critical patent/US3288781A/en
Priority to GB49968/65A priority patent/GB1114870A/en
Priority to IL24689A priority patent/IL24689A/xx
Priority to NL6516393A priority patent/NL6516393A/xx
Priority to CH1738565A priority patent/CH460788A/de
Priority to DE19651620617 priority patent/DE1620617A1/de
Priority to FR42783A priority patent/FR1460359A/fr
Application granted granted Critical
Publication of US3288781A publication Critical patent/US3288781A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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

Definitions

  • the invention provides a process for selectively removing a 5-benzoyl group from a 1-(2,3- anhydro-5'-O-benzoyl-lyxofuranosyl) 2 ketopyrimidine nucleoside by reaction with a nitrogen base without cleaving the 2',3 '-anhydro group.
  • a 1-(2',3'-anhydro-5-O- benzoyl-B-D-lyxofuranosyl)-2-ketopyrimidine nucleoside is converted to the corresponding 1-(2',3'-anhydro-,B-D- lyxofuranosyl)-2-ketopyrimidine nucleoside by reaction with ammonia at about 0 C.
  • Equation 1 A representative embodiment of the process of this invention is as shown in the following Equation 1:
  • the pyrimidine base, uracil, depicted above can be replaced by any pyrimidine base having a keto group in the 2-position, e.g., other 2-ketopyrimid ine bases such as cytosine, azauracil, thymine, S-fluorouracil, other substituted uracil-s, and the like.
  • Y Letting the symbol Y signify this variable, the general representation of the process of the invention is as shown in the following Equation 2:
  • the process of the invention contemplates aminolysis (including ammonolysis) of, for example, l-(2',3-anhydro-5'-O-benzoyl fi-D lyxofuranosyl)uracil, 1-(2',3'-anhydro-5'-O-benzoyl-fi-D-lyxofuranosyl)thy: mine, 1-(2',3'-anhydro-5-O-benzoyl-B-D-lyxofuranosyl)- S-fluorouracil, 1-(2',3'-anhydro-5'-O-benzoyl-B-D-lyxofuranosyl)cytosine, and the like.
  • the process is novel because it was not heretofore known in the art. It is useful because it provides 1-(2',3'-anhydro-lyxofuranosyl)-2-ketopyrimidine nucleosides that can be converted into therapeutic agents.
  • the process of the invention is unobvious, because it was not known that aminolysis of a 1-(2,3-anhydro 5'-O benzoyl-lyxofuranosyl) -2-ketopyrimidine nucleoside could be carried out under temperature conditions which would yield the corresponding 1- 2,3 -anhydro-lyxofuranosyl) -2-ketopyrimidine nucleoside.
  • the art well knows the removal of acyl groups from nucleosides with alcoholic ammonia and amines; and the art well knows the reaction of 2',3-anhydronucleosides with alcoholic ammonia and amines to form amino deoxy-nuwithout cleaving the 2',3-anhydro (i.e., 2',3-epoxide) linkage and forming an amino deoxy-lyxofur-anoside.
  • the novel process of this invention is effected by reacting a 1-(2,3-anhydro-5-O-benzoyl-1yxofuranosyl)-2- ketop-yrimidine nucleoside with .a nitrogen base at a temperature in the range of about -20 C. to about 25 C.
  • a convenient and preferred temperature for the reaction is about 0 C.
  • Nitrogen bases suitable for the reaction include primary and secondary amines, ammonia, and hydrazine, said nitrogen bases being characterized ⁇ by having dissociation constants in water (K in the range about 1.0 10 to about 1.0 10- Nitrogen bases having dissociation constants in water (K in the range about 1.0x 11) to about 1.0 l0- are preferred.
  • suitable primary and secondary amine are methylamine, dimethylamine, ethylamine, di-
  • pentylamin'e isopentylamine, benzylamine, cyclohexylamine, ethylenediamine, p-phenylenediamine, piperazine, piperidine', and the like.
  • the 1-(2',3+anhydro-5'-'O- benzoyl-lyxo-furanosyl)-2-ketopyrimidine and a nitrogen base are reacted in the presence of an inert solvent, illustratively an alkanol, e.'g., methanol, ethanol, propyl alcohol, and the like.
  • the debenzoylated 1-(2 ,3'-anhydro-lyxofuranosyl)-2-ketopyrimidine is re covered from the reaction mixture by removing the solvent (e.g., evaporation) and purifying the product by conventional methods such as solvent extraction, solvent evaporation, and crystallization.
  • solvent e.g., evaporation
  • the 1-'(2',3'-anhydro-5'-O benzoyl-B-D-1yxofuranosyl) uracil of Formula In is a known compound. It can be prepared according to the method described by Codington et al., J. Org. Chem. 27, 163 (1962). According to a preferred method, 2',3',5'-trimesyloxyuridine [1-(2', 3',S'tri-O-mesyl-B-D-ribofuranosyl)uracil] is heated, for a short time at to C., with sodium benzoate according to the method described by Codington et al., J.A.C.S.
  • EXAMPLE 1 Ammonolysis of 1 (2',3-5'-O-benzoyl-B-D-lyxofumnosyl) uracil to produce 1-(2',3-anhydro-fi-D-lyxofuranosyl)uracil Two mixtures, one consisting of 41.3 g. (0.125 mole) of 1-v2',3'-anhydro-SObenzoyl-B-D-lyxofuranosyl)uracil and 1.9 l. of methanol (previously saturated with anhydrous ammonia at C.) in a stoppered 3-1. pressure flask, the other consisting of 14.8 g.
  • the evacuated syrup was then thoroughly dispersed in a mixture of 150 ml. of chloroform and 75 ml. of water.
  • the chloroform was permitted to separate and was removed.
  • the aqueous layer was extracted times with fresh 100-ml. portions of chloroform.
  • the aqueous layer thus obtained was a yellowish partially emulsified mixture. It was treated was activated charcoal and the mixture was filtered through a diatornaceous earth filter aid (Celite modified by two washings with 6 N hydrochloric acid, separate washings with water, warm:methanol, and ether, and drying).
  • the filter cake was washed with water and the washings were combined with the original filtrate and refrigerated at 0 C. overnight.
  • GEL-1 Green oil mull

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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)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US419552A 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base Expired - Lifetime US3288781A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US419552A US3288781A (en) 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base
GB49968/65A GB1114870A (en) 1964-12-18 1965-11-24 Process for the preparation of pyrimidine nucleosides
IL24689A IL24689A (en) 1964-12-18 1965-11-26 Process for preparing 1-(2',3'-anhydrolyxofuranosyl)-2-ketopyrimidine nucleosides
NL6516393A NL6516393A (fr) 1964-12-18 1965-12-16
CH1738565A CH460788A (de) 1964-12-18 1965-12-16 Verfahren zur Herstellung von 1-(2',3'-Anhydro-lyxofuran-osyl)-2-ketopyrimidin-nucleosiden
DE19651620617 DE1620617A1 (de) 1964-12-18 1965-12-16 Verfahren zur Herstellung von 1-(2',3'-Anhydrolyxofuranoxyl)-2-ketopyrimidin-nucleosiden
FR42783A FR1460359A (fr) 1964-12-18 1965-12-17 Procédé de fabrication de 1-(2', 3'-anhydro-lyxofuranosyl)-2-cétopyrimidine nucléosides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US419552A US3288781A (en) 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base

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US3288781A true US3288781A (en) 1966-11-29

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US419552A Expired - Lifetime US3288781A (en) 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base

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US (1) US3288781A (fr)
CH (1) CH460788A (fr)
DE (1) DE1620617A1 (fr)
FR (1) FR1460359A (fr)
GB (1) GB1114870A (fr)
IL (1) IL24689A (fr)
NL (1) NL6516393A (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4941921A (en) * 1988-01-11 1990-07-17 Cerestar Holding Dv Method of adding boric acid of a borate to a mixing CER-1 or reaction zone
US20050080065A1 (en) * 2002-02-04 2005-04-14 Coote Steven John Process for the production of 6.alpha.,9.alpha-difluoro-17.alpha.-(1-oxo-propoxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4-diene-17.beta.-carbothioic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4941921A (en) * 1988-01-11 1990-07-17 Cerestar Holding Dv Method of adding boric acid of a borate to a mixing CER-1 or reaction zone
US20050080065A1 (en) * 2002-02-04 2005-04-14 Coote Steven John Process for the production of 6.alpha.,9.alpha-difluoro-17.alpha.-(1-oxo-propoxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4-diene-17.beta.-carbothioic acid

Also Published As

Publication number Publication date
GB1114870A (en) 1968-05-22
CH460788A (de) 1968-08-15
FR1460359A (fr) 1966-11-25
NL6516393A (fr) 1966-06-20
IL24689A (en) 1969-05-28
DE1620617A1 (de) 1970-05-14

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