BACKGROUND OF THE INVENTION

The present invention relates to a novel process for the preparation of an important intermediate used in the preparation of ribonucleotide reductase inhibitors. A process for the preparation of several of these intermediates was disclosed by Wemple et al. [Synthesis 1977, 791] which employs a fairly exotic and expensive reagent with extended reaction times under harsh conditions. More specifically, chloromethyl phenyl sulfide is treated with 18-crown-6 and potassium fluoride in acetonitrile at reflux for 100 hours to provide an 83% yield of fluoromethyl phenyl sulfide.

The novel process of the present invention utilizes starting material of structure (A)

wherein Y is chlorine, bromine or iodine, X is a hydrogen or a suitable electron withdrawing group and R-^ and R ₂ are each independently hydrogen, halogen, ^C _ή alkyl or C _χ -C ₄ alkoxy. The desired intermediate wherein Y is fluorine in structure (A) can now be obtained in much shorter reaction times, with comparable yields and it employs considerably less exotic and expensive reagents.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing a compound of formula

wherein X is a hydrogen or a suitable electron withdrawing group and R _L and R ₂ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl or ^-^ alkoxy comprising reacting a compound of the formula

wherein Y is a halogen with a fluoride ion source in a solvent comprising from about 20% to about

95% poly(ethylene glycol) in acetcnitrile.

DETAILED DESCRIPTION OF TEE INVENTION

As used herein the term "C ₁ -C ₄ alkyl" refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. The term "Ar" or "aryl" refers to an aromatic radical of from about 6 to 12 carbon atoms, such as phenyl, napnthyl or phenyl(C^C^alkyl groups, wherein said groups are optionally substituted with one, two or three substituents selected from the group consisting of C _χ -C ₄ alkyl, halo-substituted C _: -C ₄ alkyl, halogen or C^C, alkoxy. The term "phenyl(C^C _j )alkyl" refers to a phenyl group substituted with a C _χ -C ₄ alkyl including phenylmethyl, phenethyl and the like. Specifically included within the scope of the term "Ar" or "aryl" are phenyl, p-toluyl, naphthyl, p-chlorophenyl and the like. The term " C ₁ -C alkoxy" refers to an alkyloxy radical made up of an oxygen radical bearing a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and specifically includes methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tertiary butyloxy and the like. The term "halogen" or "halo" refers to a chlorine, bromine, or iodine atom.

The general synthetic process of the present invention is set forth in Scheme A. All the substituents, unless otherwise indicated, are previously defined. The reagents and starting materials for use in this process are readily available to one of ordinary skill in the art.

Scheme A

b)Oxidation

B

X= hydrogen or an electron withdrawing group Y=C1, Br or I

In Scheme A, step a, the appropriately ^" substituted halomethyl phenyl sulfide (A) wherein X is hydrogen or a suitable electron withdrawing group is dissolved in a solvent mixture of a suitable concentration of an appropriate poly(ethylene glycol) and acetonitrile. An electron withdrawing group as described by March ["Advanced Organic Chemistry: Reactions, Mechanisms and Structure", McGraw-Hill Book Company, 2nd Ed., 1977, 21] is one that will draw electrons to itself more than a hydrogen atom would if it was in the same position. Examples of suitable electron withdrawing groups are C0 ₂ R, CON(R) ₂ , ?0(OR) ₂ , CN, N0 ₂ and the like, wherein R is a C^ - ^ alkyl or a substituted phenyl group. Preferred suitable electron withdrawing groups are C0 ₂ Me, C0 ₂ Ξt, C0 ₂ 3u ^t , CONMe ₂ , CONEt ₂ ,

PO(OMe) ₂ , PO(OEt) ₂ , PO(OC ₆ H ₅ ) ₂ and the like. The most preferred suitable electron withdrawing group is PO(OEt) ₂ . An appropriate poly(ethylene glycol) should have a molecular weight between about 100 and 400 g/mol. The preferred molecular weight for an appropriate poly(ethylene glycol) is about 200 g/mol. A suitable concentration of poly(ethylene glycol) in acetonitrile should fall between about 20% and 95%. The preferred concentration of pol (ethylene glycol) in acetonitrile is about 33%. The solution is then reacted with a fluoride ion source at about 20°C to 100°C for about 0.5 hours to 24 hours to provide the fluoromethyl phenyl sulfide of Formula I. A fluoride ion source is one that when placed in poly(ethylene glycol/acetonitrile mixture will sufficiently dissolve so as to produce dissociated negatively charged fluoride ions. Fluoride ion sources are cesium fluoride, potassium fluoride, sodium fluoride, tetrabutylammonium fluoride and the like. The preferred fluoride ion source is cesium fluoride.

More specifically, the appropriately substituted halomethyl phenyl sulfide (A) is dissolved in a solvent mixture of 33% poly(ethylene glycol)-200 in acetonitrile. The solution is treated with excess cesium fluoride and heated to approximately 80°C for about 1.75 hours. After cooling, the fluoromethyl phenyl sulfide of Formula I is isolated by techniques well known to one skilled in the art. For example, water is added to the cooled solution which is then extracted with a suitable organic solvent such as chloroform. The organic extracts are dried over a suitable drying agent such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the fluoromethyl phenyl sulfide of Formula I.

In Scheme A, step b, the fluoromethyl phenyl sulfide of Formula I is then oxidized to fluoromethyl phenyl sulfone (B) by techniques well known to one skilled in the art.

For example, the appropriately substituted fluoromethyl phenyl sulfide of Formula I is dissolved in a suitable organic solvent, such as methanol, cooled to approximately 0°C and an excess of potassium peroxymonosulfate dissolved in water is slowly added to the reaction. After stirring for approximately 4 hours the fluoromethyl phenyl sulfone (B) is isolated and purified by techniques well known to one skilled in the art. For example, the solvent is removed under vacuum and the resulting slurry suction filtered through diatomaceous earth, rinsing with chloroform. The organic phase is separated from the aqueous phase. The aqueous phase is then extracted with additional chloroform and the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue can be purified by distillation to provide the fluoromethyl phenyl sulfone (B).

The following examples present typical syntheses as described by Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated: "g" refers to grams, "mmol" refers to millimoles, " L" refers to milliliters, " ^C C" refers to degrees Celsius,

"TLC" refers to thin layer chromatography, "mg" refers to milligrams, "μL" refers to icroliters and "δ" refers to parts per million downfield from tetramethlysiiane.

ExamDle 1

Fluoromethyl phenyl sulfide

Scheme A, step a; Flush a 3 neck 100 mL round bottom flask with nitrogen and charge with chloromethyl phenyl sulfide (9.9 g, 62.4 mmol), cesium fluoride (19.1 g, 126 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (38 L of in a 1:2 ratio). Heat the reaction to 80°C with stirring for 1.75 hours. Then cool the reaction and dilute with water (125 mL). Extract the reaction with chloroform (2 X 125 mL), combine the organic extracts, wash with water (50 mL) and dry over anhydrous magnesium sulfate. Filter and concentrate under vacuum to yield the title compound as a yellow oil. The sulfide should be stored at low temperature or immediately oxidized to the sulfone as it will rapidly polymerize at room temperature.

Example 2

Fluoromethyl phenyl sulfone

Scheme A, step b; Dissolve the fluoromethyl phenyl sulfide prepared above in methanol (85 mL) and cool to 0°C. Add a solution of potassium peroxymonosulfate (38.9 g, 63.3 mmol in 85 mL water) slowly with stirring at 0°C. The temperature will increase to approximately 55°C. Cool the reaction to room temperature and allow to stir for an additional 4 hours. Then concentrate the reaction under vacuum and suction filter the remaining slurry through diatomaceous earth (10 g) rinsing with chloroform (150 L) . Separate the aqueous layer of the filtrate and extract with additional chloroform (2 X 100 mL). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by Kugelrohr distillation (115-132°C/ >lmmΞg) . The distillate will crystallize upon cooling. Rinse the crystals with hexane and dry under vacuum to provide the title compound (7.6 g, 70% overall yield for steps a and b), mp 47-48.5°C.

Example 3

Fluoromethyl phenyl sulfide Scheme A, step a; Heat a mixture of chloromethyl phenyl sulfide (1.6 g, 10 mmol), potassium fluoride (1.6 g, 27 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 6 mL in a 1:2 ratio) to a gentle reflux for 24 hours. Cool the reaction and dilute with diethyl ether (50 mL). Rinse the organic with water (2 X 50 mL) and saturated sodium bicarbonate (50 mL) . Back extract the combined aqueous washes with diethyl ether (50 L) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound (1.9 g). The sulfone can be prepared by following essentially the same procedure as described in example 2.

Example 4

Diethyl 1-fluoro-l-(phenylsulfide)methanephosphonate

Scheme A, step a; Heat a mixture of diethyl 1-chloro-l- (phenyisulfide)methanephosphonate (200 g, 0.68 mmol), cesium fluoride (310 mg, 2 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (4 mL in a 1:2 ratio) to 80°C for 0.5 hours. Cool the reaction and dilute

with water and methylene chloride. Separate the layers and dry the organic phase over anhydrous magnesium sulfate, filter and concentrate the provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.

Example 5

Diethyl 1-fluoro-l-(phenylsulfide)methanephosphonate

Scheme A, step a; Heat a mixture of diethyl 1-chloro-l- (phenylsulfide)methanephosphonate (200 g, 0.68 mmol), potassium fluoride (230 mg, 4 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 4 mL in a 1:2 ratio) to 80°C for 6 hours. Cool the reaction and dilute with diethyl ether (50 mL) . Rinse the organic with water (2 X 50 mL) and saturated sodium bicarbonate (50 mL) . Back extract the combined aqueous washes with diethyl ether (50 mL) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.

Example 6

Fluoromethyl p-chlorophenyl sulfide

Scheme A, step a; Heat a mixture of chloromethyl p- chlorophenyl sulfide (1 g, 5.2 mmol), cesium fluoride (1.55 g, 10.4 mmol) and a mixture of poly(ethyleneglycol)-200 and acetonitrile ( 5 mL in a 1:2 ratio) to 80°C for 1 hour. Cool the reaction and dilute with water and methylene chloride. Separate the layers and dry the organic phase over anhydrous magnesium sulfate. Filter and concentrate to provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.

Example 7

Diethyl 1-fluoro-l-(p-chlorophenylsulfide) methanephosphonate

Scheme A, step a; Heat a mixture of diethyl l-chloro-l-(p- chlorophenylsulfide) ethanephosphonate (0.68 mmol) which can be prepared according to Kim et al. [Tetrahedron Lett. 1985, 26, 3479], cesium fluoride (310 mg, 2 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (4 mL in a 1:2 ratio) to 80°C for approximately 1 hour. Cool the reaction and dilute with water and methylene chloride. Separate the layers and dry the organic phase over anhydrous magnesium sulfate, filter and concentrate the provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.