5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and processes for their preparation

Abstract

Provided herein are 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)3,4-dihydropyrimidin-2(1H)-one and processes for their preparation which may include the use of an alkali alkoxide and an alkylating agent ##STR00001##

Claims

1. A method of making compounds of Formula III, including the steps of: contacting a compound of Formula II with an alkali alkoxide and an alkylating agent, ##STR00018## and forming a compound of Formula III: ##STR00019## wherein R.sub.1 is selected from the group consisting of: ##STR00020## and R.sub.2 is selected from the group consisting of: ##STR00021##

2. The method of claim 1, wherein the contacting step is carried out between 22° C. and 60° C.

3. The method of claim 1, wherein the contacting step further includes a solvent selected from the group consisting of: DMF, DMSO, DMA, NMP, and CH.sub.3CN.

4. The method of claim 1, wherein the alkali alkoxide is selected from the group consisting of: KO.sup.tBu, CH.sub.3ONa, CH.sub.3CH.sub.2ONa, CH.sub.3CH.sub.2OLi, CH.sub.3OLi, CH.sub.3CH.sub.2OK, and CH.sub.3CH.sub.2ONa.

5. The method of claim 1, wherein the alkylating agent is selected from the group consisting of: alkyl halides and benzyl halides.

6. The method of claim 5, wherein the alkylating agent is an alkyl halide.

7. The method of any one of claims 3, 4, 5, or 6, wherein the alkali alkoxide is KO.sup.tBu, and the solvent is DMF.

8. The method of claim 7, wherein the molar ratio of the compound of Formula II to the alkali alkoxide is from about 3:1 to about 1:1 and the molar ratio of the compound of Formula II to the alkylating agent is from about 1:1 to about 3:1.

9. The method of claim 8, wherein a molar ratio of the compound of Formula II to alkali alkoxide is about 2:1 and a molar ratio of the compound of Formula II to alkylating agent is about 1:3.

10. The method of claim 9, further including the step of diluting a completed reaction mixture with CH.sub.3CN and 2.5% aqueous Na.sub.2S.sub.2O.sub.3.

11. The method of claim 10, wherein the ratio of DMF to CH.sub.3CN is from about 1:1 to about 3:1 and the ratio of DMF to 2.5% aqueous Na.sub.2S.sub.2O.sub.3 is from about 1:2 to about 2:1.

12. The method of claim 11, wherein the ratio of DMF to CH.sub.3CN is about 2:1 and the ratio of DMF to 2.5% aqueous Na.sub.2S.sub.2O.sub.3 is about 1:1.

13. The method of claim 2, wherein the contacting step is carried out between 22° C. and 45° C.

14. The method of claim 3, wherein the solvent selected from the group consisting of: DMF, DMA, and NMP.

15. The method of claim 6, wherein the alkyl halide is methyl iodide.

16. The method of claim 6, wherein the alkyl halide is ethyl iodide.

17. The method of claim 5, wherein the alkylating agent is a benzyl halide.

18. The method of claim 17, wherein the benzyl halide is benzyl bromide.

19. The method of claim 1, wherein R is ##STR00022## and R.sub.2 is ##STR00023##

20. The method of claim 3, wherein the solvent is DMF.

Description

DETAILED DESCRIPTION

5-Fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydro-pyrimidin-2(1H)-one as shown in Examples 1-2.

Example 1

Preparation of 4-amino-5-fluoro-1-(phenylsulfonyl)pyrimidin-2(1H)-one (1):

(1) ##STR00014##

(2) To a dry 500 milliliter (mL) round bottom flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel, thermometer, and reflux condenser were added 5-fluorocytocine (20.0 grams (g), 155 millimole (mmol)) and CH.sub.3CN (100 mL). To the resulting mixture was added BSA (34.7 g, 170 mmol) in one portion and the reaction was warmed to 70° C. and stirred for 30 minutes (min). The resulting homogeneous solution was cooled to 5° C. with an ice bath and treated dropwise with benzenesulfonyl chloride. The reaction was stirred at 0° C.-5° C. for 1 h and then overnight at room temperature. The resulting pale yellow suspension was poured into cold H.sub.2O (1.5 liters (L)) and stirred vigorously for 1 h. The resulting solid was collected by vacuum filtration, washed with H.sub.2O, and dried under vacuum overnight at 40° C. to give 4-amino-5-fluoro-1-(phenylsulfonyl)pyrimidin-2(1H)-one (29.9 g, 72%) as a powdery white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.56 (s, 1H), 8.35-8.26 (m, 2H), 8.07-7.98 (m. 2H), 7.84-7.74 (m, 1H), 7.72-7.61 (m, 2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −163.46; ESIMS m/z 270 ([M+H].sup.+).

(3) The following compounds 1-3 in Table 1a were made in accordance with the reaction depicted in Scheme 1 and the procedures described in Example 1. Characterization data for compounds 1-3 are shown in Table 1b.

(4) ##STR00015##

(5) TABLE-US-00001 TABLE 1a Compound Yield Number R.sub.1 Appearance (%) 1 H Powdery White Solid 72 2 CH.sub.3 Powdery White Solid 61 3 OCH.sub.3 Powdery White Solid 57

(6) TABLE-US-00002 TABLE 1b .sup.13C NMR or Compound Mass .sup.19F NMR Number Spec. .sup.1H NMR (δ).sup.a (δ).sup.b,c 1 ESIMS .sup.1H NMR (DMSO- .sup.19F NMR m/z 270 d.sub.6) δ 8.56 (s, 1H), (DMSO-d.sub.6) δ −163.46 ([M + H].sup.+) 8.35-8.26 (m, 2H), 8.07-7.98 (m, 2H), 7.84-7.74 (m, 1H), 7.72-7.61 (m, 2H) 2 ESIMS .sup.1H NMR (DMSO- .sup.19F NMR m/z 284 d.sub.6) δ 8.54 (s, 1H), (DMSO-d.sub.6) δ −163.62 ([M + H].sup.+) 8.40-8.16 (m, 2H), 8.05-7.76 (m, 2H), 7.66-7.36 (m, 2H), 2.41 (s, 3H) 3 ESIMS .sup.1H NMR (CDCl.sub.3) .sup.19F NMR m/z 300 δ 8.10-7.91 (m, (CDCl.sub.3) δ −158.58 ([M + H].sup.+) 2H), 7.73 (d, J = 5.4 Hz, 2H), 7.11-6.94 (m, 2H), 3.90 (s, 3H), 3.32 (d, J = 0.6 Hz, 3H) .sup.aAll .sup.1H NMR data measured at 400 MHz unless otherwise noted. .sup.bAll .sup.13C NMR data measured at 101 MHz unless otherwise noted. .sup.cAll .sup.19F NMR data measured at 376 MHz unless otherwise noted.

Example 2

Preparation of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one (5):

(7) ##STR00016##

(8) To a mixture of 4-amino-5-fluoro-1-tosylpyrimidin-2(1H)-one (20 mmol, 5.66 g) and Li.sub.2CO.sub.3 (0.880 g, 12.0 mmol) in DMF (20 mL) was added CH.sub.3I (8.52 g, 60 mmol), and the resulting mixture was warmed to 40° C. and stirred for 5 h. The reaction mixture was cooled to room temperature, diluted with CH.sub.3CN (10 mL), and treated with 2.5% aqueous Na.sub.2S.sub.2O.sub.3 (20 mL). The resulting mixture was stirred at room temperature for 10 min and the solids were collected by filtration. The filter cake was washed with aqueous CH.sub.3CN (10% CH.sub.3CN in H.sub.2O) and air dried for 2 h. The cake was dissolved in CH.sub.3CN (15 mL) at 40° C. and the solution was treated with H.sub.2O (30 mL). The resulting suspension was cooled to room temperature, stirred for 2.5 h, and filtered. The filter cake was again washed with 10% aqueous CH.sub.3CN and then dried under vacuum at 50° C. to give the title compound (2.70 g, 45%) as a white solid: mp 156-158° C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (d, J=2.3 Hz, 1H), 7.99 (dd, J=6.0, 0.6 Hz, 1H), 7.95-7.89 (m, 2H), 7.53-7.45 (m, 2H), 3.12 (d, J=0.7 Hz, 3H), 2.42 (s, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) −157.86 (s); ESIMS m/z 298 ([M+H].sup.+).

(9) The following compounds 4-6 in Table 2a were made in accordance with the reaction depicted in Scheme 2 and the procedures described in Example 2. Characterization data for compounds 4-6 are shown in Table 2b.

(10) ##STR00017##

(11) TABLE-US-00003 TABLE 2a Compound Yield Number R.sub.1 R.sub.2 Appearance (%) 4 H CH.sub.3 White Solid 64 5 CH.sub.3 CH.sub.3 White Solid 45 6 OCH.sub.3 CH.sub.3 White Solid 62

(12) TABLE-US-00004 TABLE 2b .sup.13C NMR or Compound Mass .sup.19F NMR Number Spec. .sup.1H NMR (δ).sup.a (δ).sup.b,c 4 ESIMS .sup.1H NMR (CDCl.sub.3) δ .sup.19F NMR m/z 284 8.14-8.02 (m, 2H), (CDCl.sub.3) δ −158.05 ([M + H].sup.+) 7.88-7.67 (m, 3H), 7.67-7.50 (m, 2H), 3.31 (d, J = 0.7 Hz, 3H) 5 ESIMS .sup.1H NMR (CDCl.sub.3) δ .sup.19F NMR m/z 298 8.54 (d, J = 2.3 Hz, (CDCl.sub.3) ([M + H].sup.+) 1H), 7.99 (dd, J = 6.0, δ 157.86 (s) 0.6 Hz, 1H), 7.95-7.89 (m, 2H), 7.53-7.45 (m, 2H), 3.12 (d, J = 0.7 Hz, 3H), 2.42 (s, 3H) 6 ESIMS .sup.1H NMR (CDCl.sub.3) δ .sup.19F NMR m/z 314 8.10-7.91 (m, 2H), (CDCl.sub.3) δ −158.58 ([M + H].sup.+) 7.73 (d, J = 5.4 Hz, 2H), 7.11-6.94 (m, 2H), 3.90 (s, 3H), 3.32 (d, J = 0.6 Hz, 3H) .sup.aAll .sup.1H NMR data measured at 400 MHz unless otherwise noted. .sup.bAll .sup.13C NMR data measured at 101 MHz unless otherwise noted. .sup.cAll .sup.19F NMR data measured at 376 MHz unless otherwise noted.