2-CYANO-2-FLUOROETHENOLATE SALTS (CFES): VERSITILE ACTIVE PHARMACEUTICAL INTERMEDIATES

Abstract

The present invention relates to new enolate structures with utility as active pharmaceutical intermediates for the preparation of efficacious drugs such as those derived from 5-fluorocytosine (5-FC).

Claims

1-8. (canceled)

9. A compound of formula: ##STR00003## wherein the compound is isolated in solid form, M.sup.+ is an alkali metal cation, and R is hydrocarbyl, or substituted hydrocarbyl.

10. The compound of claim 9, wherein M is potassium (K).

11. The compound of claim 9, wherein M is sodium (Na).

12. The compound of claim 9, wherein M is lithium (Li).

13. The compound of claim 9, wherein R is hydrocarbyl.

14. The compound of claim 9, wherein R is substituted hydrocarbyl.

15. The compound of claim 9, wherein M is selected from the group consisting of Li, Na, K, Rb, and Cs.

16. A compound of formula: ##STR00004## wherein M.sup.+ is an alkali metal cation, and R is hydrogen.

17. The compound of claim 16, wherein M is potassium (K).

18. The compound of claim 16, wherein M is sodium (Na).

19. The compound of claim 16, wherein M is lithium (Li).

20. The compound of claim 16, wherein M is selected from the group consisting of Li, Na, K, Rb, and Cs.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0004] FIG. 1 shows the chemical formula for the cyanofluoroenolate salts (CFES) described in this invention. The atom connectivity, but not the double bond geometry ((E)- or (Z)-isomeric form), of the CFES is specified by this drawing.

DETAILED DESCRIPTION OF THE INVENTION

2-Cyano-2-fluoroethenolate Salts (CFES)

[0005] The present invention relates to new enolate structures with utility as active pharmaceutical intermediates for the preparation of efficacous drugs such as those derived from 5-fluorocytosine (5-FC).

[0006] According to the present invention there is provided a new class of substituted enolates of the formula:

##STR00002##

[0007] wherein M.sup.+ is a stable, non-reactive, cation, and R is hydrogen, hydrocarbyl, or substituted hydrocarbyl (FIG. 1).

[0008] CFES may be obtained through a Claisen-type condensation from fluoroacetonitrile (Example 1). A simple and low-cost 2-step synthesis of 5-FC starting from CFES (Example 2) provides an example of the utility of CFES. An overall yield up to 82% could be achieved for 5-FC using the new CFES composition and the route is devoid of any chromatographic purifications. This new route made possible by the CFES composition is lower cost and more efficient than presently available methods.

Example 1

Potassium (Z)-2-cyano-2-fluoroethenolate

[0009] In a flame-dried Schlenk flask, KO.sup.tBu (9.1 g, 81 mmol, 1.5 eq.) was dissolved in dry tetrahydrofuran (THF) (26 mL) under argon atmosphere. The solution was cooled to 15 C. using a cryostat. In a second flame-dried Schlenk flask, a solution containing fluoroacetonitrile (3.0 mL, 54 mmol, 1.0 eq.), ethyl formate (17.4 mL, 21.6 mmol, 4.0 eq.) and dry THF (30 mL) was prepared under argon atmosphere and cooled to 15 C. By using a syringe pump the KOtBu/THF solution was added dropwise to the fluoroacetonitrile/ethyl formate/THF solution at a rate of 1 mL/min while stirring vigorously. After the addition was complete, the reaction mixture was cooled for a further 20 min. The colorless suspension was stirred overnight (20 h) at room temperature. Afterwards, n-hexane (30 mL) was added and the slightly brown suspension was cooled in an ice bath. After 5 min, the precipitate was filtered off and washed with cold n-hexane. The obtained solid was dried in a vacuum desiccator to yield a slight brownish solid (6.21 g) which contains (Z)-2-cyano-2-fluoroethenolate (5.17 g 41.3 mmol, 77%, estimated by .sup.1H NMR) and potassium formate. The yield was corrected for the content of potassium formate. T.sub.m=91 C. (decomposition). .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =7.48 (d, .sup.3J.sub.H-F=30.5 Hz, 1H, H-1) ppm. .sup.13C-NMR, HSQC, HMBC (75 MHz, DMSO-d.sub.6): =157.9 (d, .sup.3J.sub.C-F=9.0 Hz, C-1), 124.2 (.sup.2J.sub.C-F=33.5 Hz, CN), 120.5 (d, .sup.1J.sub.C-F=196.5 Hz, C-2) ppm. .sup.19F-NMR (282 MHz, DMSO-d.sub.6): =207.1 (d, .sup.3J.sub.F-H=30.5 Hz) ppm. IR (ATR): v=2180, 1593, 1350, 1323, 1206 cm.sup.1. ESI-HRMS: Calcd for C.sub.3HFKNO ([M].sup.): m/z=86.0046, Found: m/z=86.0046.

Example 2

5-Fluoropyrimidine-2,4-diamine

[0010] In a flame-dried Schlenk flask, guanidine carbonate (2.22 g, 24.7 mmol, 3.0 eq.) was dissolved in dry methanol (18 mL) under argon atmosphere. A 5.4M methanolic sodium methoxide solution (4.7 mL, 26 mmol, 3.1 Eq.) was dripped quickly into the solution, before potassium (Z)-2-cyano-2-fluoroethenolate (1.03 g, 8.23 mmol, 1.0 eq.) was added portionwise over 5 min. The brownish suspension was stirred at rt for 18 h. The solvent was evaporated at 40 C. under reduced pressure and the residue was dissolved in water (20 mL). The aqueous suspension was extracted with ethyl acetate (420 mL). The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. 5-fluoropyrimidine-2,4-diamine (0.96 g, 7.5 mmol, 91%) was obtained as a colorless to slight brownish powder. T.sub.m=157.6-160.8 C. TLC (SiO.sub.2): R.sub.f=0.30 (ethyl acetate:MeOH=20:1). .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =7.65 (d, .sup.3J.sub.H-F=3.9 Hz, 1H, H-6), 6.64 (s.sub.b, 2H, NH.sub.2), 5.81 (s.sub.b, 2H, NH.sub.2) ppm. .sup.13C-NMR, HMBC, HSQC (75 MHz, DMSO-d.sub.6): =159.8 (d, .sup.4J.sub.C-F=3.0 Hz, C-2), 153.6 (.sup.2J.sub.C-F=12.3 Hz, C-4), 140.0 (d, .sup.1J.sub.C-F=239.5 Hz, C-5), 139.9 (d, .sup.2J.sub.C-F=18.4 Hz, C-6) ppm. .sup.19F-NMR (282 MHz, DMSO-d.sub.6): =171.2 (d, .sup.3J.sub.F-H=3.9 Hz) ppm. IR (ATR): v=3408, 3330, 3139, 1671, 1590, 1442, 1213 cm.sup.1. ESI-HRMS: Calcd for C.sub.4H.sub.5FN.sub.4 ([M+H].sup.+): m/z=129.0571, Found: m/z=129.0570.

5-Fluorocytosine

[0011] In a round bottom flask, 5-fluoropyrimidine-2,4-diamine (4.32 g, 33.7 mmol, 1.0 eq.) was dissolved in water (100 mL) and cooled in an ice-bath. Precooled half-concentrated sulfuric acid (18.7 mL, 84.3 mmol, 2.5 eq.) was added slowly. While keeping the reaction temperature at 1-3 C., a 2.5N sodium nitrite solution (5.82 g NaNO.sub.2 in 34 mL water, 84.3 mmol, 2.5 eq.) added within 17 min. The reaction mixture was stirred for another 20 min while cooling and 1 h at rt. The clear yellow solution was adjusted to pH=7.4 by adding conc. ammonia solution (20 mL, 25 wt %) whereby a slightly orange suspension was formed. The mixture was concentrated in vacuo at 40 C. to half of its original volume and cooled in an ice-bath. The precipitate was collected by suction filtration and washed with small portions of ice water (34 mL). After drying the solid in air and in a desiccator over molecular sieves, 5-fluorocytosine (3.61 g, 28.0 mmol, 83%) was obtained as a colorless to slightly brown powder. T.sub.m=295 C. (decomposition) (Lit.: 295-300 C., decomposition [Harsanyi et al. Org. Process Res. Dev., 2017, 21(2), pp 273-27]). TLC (SiO.sub.2): R.sub.f=0.29 (ethyl acetate:MeOH=3:1). .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =7.60 (d, .sup.3J.sub.H-F=6.2 Hz, 1H, H-6), 7.34 (s.sub.b, 1H, NH) ppm. .sup.13C-NMR, HMBC, HSQC (75 MHz, DMSO-d.sub.6): =158.2 (d, .sup.2J.sub.C-F=13.0 Hz, C-4), 155.3 (s, C-2), 136.0 (d, .sup.1J.sub.C-F=237.9 Hz, C-5), 127.0 (d, .sup.2J.sub.C-F=29.3 Hz, C-6) ppm. .sup.19F-NMR (282 MHz, DMSO-d.sub.6): =171.6 (d, .sup.3J.sub.F-H=6.2 Hz) ppm. IR (ATR): v=3337, 3126, 2724, 1678, 1542, 1460, 1227, 1123 cm.sup.1. ESI-MS: m/z=130.1 (100%, [M+H].sup.+). The spectroscopic data are consistent with literature values. [Harsanyi et al. Org. Process Res. Dev., 2017, 21(2), pp 273-27]