Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-25
2003-09-02
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06613908
ABSTRACT:
FIELD OF THE INVENTION
The present invention includes a method for carbamoylating an alcohol with sodium cyanate in the presence of methanesulfonic acid. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety and/or a molecule including both an alcohol moiety and a sulfenyl moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine.
BACKGROUND OF THE INVENTION
The non-nucleoside reverse transcriptase inhibitor known as Capravirine can be synthesized through a route employing chlorosulfonyl isocyanate (CSI) to convert a penultimate Capravirine sulfenyl alcohol to the corresponding carbamate, Capravirine. CSI carbamoylates alcohols in high yield under desirable conditions, but has special shipping and handling requirements due to being highly reactive with water. In addition, CSI is currently available on commercial scale from only two sources, each of which is outside the U.S. These factors along with safety considerations make CSI undesirable as a reagent for the transformation of an alcohol to a carbamate.
A long-used method for carbamoylating alcohols employs sodium cyanate in the presence of trifluoroacetic acid and an inert solvent. The method achieves high yields with a variety of alcohols, but does not work for all alcohols. This synthesis proceeds through generating cyanic acid in situ by the reaction of sodium cyanate with an acid. A widely cited paper on this method by B. Loev and M. Kormendy (J. Org. Chem. 1963, 28, 3421) describes trifluoroacetic acid (TFA), as opposed to other acids, as necessary for obtaining carbamates in good yield. For example, this paper describes that substitution of methanesulfonic acid for trifluoroacetic acid reduces yields of carbamate to only trace levels.
There remains a need for a method for carbamoylating alcohol moieties in molecules also including a basic moiety and/or a sulfenyl moiety, such as Capravirine, and employing an acid other than trifluoroacetic acid.
SUMMARY OF THE INVENTION
The present invention includes a method for carbamoylating an alcohol with sodium cyanate in the presence of methanesulfonic acid. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine. This method is also suitable for carbamoylating a molecule including both an alcohol moiety and a sulfenyl moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine.
In one embodiment, the method includes contacting the alcohol with sodium cyanate in the presence of methanesulfonic acid under anhydrous conditions. In another embodiment, the method carbamoylates an alcohol moiety of a molecule also including a nitrogen heterocycle, a sulfenyl moiety, or both, the method including contacting the molecule with sodium cyanate in the presence of methanesulfonic acid. In an additional embodiment, the method carbamoylates Capravirine sulfenyl alcohol, the method including contacting Capravirine sulfenyl alcohol with sodium cyanate in the presence of methanesulfonic acid. Each of these reactions can be carried out under anhydrous conditions, preferably in an inert solvent, such as acetonitrile. The method can also include quenching the reaction and recovering or purifying a resulting carbamate.
The present invention also includes a method for carbamoylating an alcohol with sodium cyanate, potassium cyanate, cesium cyanate, or a mixture thereof in the presence of acetic acid, sulfuric acid, or a mixture thereof. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety. This method is also suitable for carbamoylating a molecule including both an alcohol moiety and a sulfenyl moiety.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term “anhydrous” refers to a reaction mixture that is very dry, typically including less than about 1 wt-% water, preferably less than about 0.7 wt-% water, preferably less than about 0.5 wt-% water, or, preferably, devoid of water. According to the present invention, anhydrous conditions suitable for carrying out the present method can be obtained by measures known to those of skill in the art. Preferably the starting alcohol is dried using known procedures for drying alcohols to a water content of less than about 0.2 wt-%. Typically, commercially available reagent grades of the solvent (e.g., acetonitrile) and acid (e.g. methanesulfonic acid) can be used without drying. Typically these commercially available solvents and acids are essentially anhydrous.
As used herein, the term “base” refers to any of a large class of compounds with one of more of properties such as bitter taste, slippery feeling in solution, ability to turn litmus paper blue and to cause other indicators to take on characteristic colors, or ability to react with (neutralize) acids to form salts. Such bases include both Lowry-Bronsted bases and Lewis bases. Lowry-Bronsted base refers to any molecular or ionic substance that can combine with a proton (hydrogen ion) to form a new compound. A Lewis base refers to any substance that provides a pair of electrons for a covalent bond with a Lewis acid. As used herein, a “basic moiety” is a fragment of a basic compound, which fragment would be a base if it were a compound itself. A compound including a basic moiety is a base. Bases and basic moieties include nitrogen heterocycles.
As used herein, “nitrogen heterocycle” refers to any carbon-containing closed-ring structure that includes a nitrogen atom. Examples of nitrogen heterocycles include pyrrole (azole), 2H-pyrrole, 3H-pyrrole, pyrazole (1,2-diazole), imidazole, 2H-imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole (azoxime), 1,2,5-oxadiazole (furazan), 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 3H-1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 5H-1,2,5-oxathiazole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine, s-triazine (1,3,5-triazine), as-triazine (1,2,4-triazine), v-triazine (1,2,3-triazine), 4H-1,2-oxazine, 2H-1,3-oxazine, 6H-1,3-oxazine, 6H-1,2-oxazine, 1,4-oxazine, 2H-1,2-oxazine, 4H-1,4-oxazine, 1,2,5-oxathiazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5,2-oxadiazine, morpholine (tetrahydro-p-isoxazine), azepine, 1,2,4-aiazepine, indole, 3H-indole (indolenine), 1H-isoindole, cyclopental[b]pyridine, pyrano[3,4-b]-pyrrole, indazole, indoxazine (benzisoxazole), benzoxazole, anthranil, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine, pyrido[4,3-b]-pyridine, 2H-1,3-benzoxazine, 2H-1,4-benzoxazine, 1H-2,3-benzoxazine, 4H-3,1-benzoxazine, 2H-1,2-benzoxazine, 4H-1,4-benzoxazine, carbazole, acridine, quinoxaline, purine, and the like.
As used herein, “sulfenyl group”, “sulfenyl moiety”, or “sulfenyl” refers to a compound including a group having the structure RS-, in which R is an organic moiety but not hydrogen. Sulfenyl groups include sulfides (thioethers). As used herein, “sulfide” or “thioether” refers to a compound including or group having the structure RSR′, in which R and R′ are each an organic moiety but not hydrogen.
As used herein, the term “Capravirine sulfenyl alcohol” refers to a compound represented by the structural formula:
As used herein, the term “Capravirine” refers to a compound represented by the structural formula:
As used herein, the term “about” modifying the quantity of an ingredient, the ratios of ingredients, or temperatures employed in the methods of the invention refers to variation in the numerical quantity that can occur, for example, through typical weighing, measuring, liqui
Hutchinson Keith D.
Richardson Peter
Seaman D. Margaret
Warner-Lambert & Company
Zielinski Bryan C.
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