Naphthofuran derivatives, preparation, and methods of use thereof

Abstract

Provided herein are methods of preparation of I by reacting i with acid where R.sub.1 and R.sub.2 are each independently a leaving group. Intermediates to make i are also claimed. ##STR00001##

Claims

1. A method of making a compound having formula (I): ##STR00086## or a prodrug, a pharmaceutically acceptable salt, or a solvate thereof; comprising reacting a compound having formula (i): ##STR00087## or a salt or solvate thereof, with an acid; wherein R.sub.1 and R.sub.2 each independently is a leaving group.

2. The method of claim 1, wherein R.sub.1 is chosen from halides, OR.sub.a, and NR.sub.bR.sub.c; where R.sub.a is chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, alkenyl groups, substituted alkenyl groups, cycloalkenyl groups, substituted cycloalkenyl groups, alkynyl groups, substituted alkynyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and R.sub.b and R.sub.c each is independently chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups, or R.sub.b and R.sub.c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group.

3. The method of claim 1, wherein R.sub.1 is NR.sub.bH, where R.sub.b is phenyl or substituted phenyl.

4. The method of claim 1, wherein R.sub.2 is chosen from halides, carboxylates, alkoxycarboxylates, and aryloxycarboxylates.

5. The method of claim 1, wherein R.sub.2 is chosen from Cl, Br, —COOH, —COO—, methoxycarboxylate, ethoxycarboxylate, isopropoxycarboxylate, and tert-butoxycarboxylate.

6. The method of claim 1, wherein R.sub.2 is tert-butoxycarboxylate.

7. The method of claim 1, wherein the compound having formula (i) has formula (i-a): ##STR00088## or a salt or solvate thereof.

8. The method of claim 1, further comprising reacting a compound having formula (ii): ##STR00089## or a salt or solvate thereof; wherein X is O or N—R.sub.4, and R.sub.3 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; R.sub.4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)R.sub.g, S(═O).sub.2R.sub.e, P(═O).sub.2R.sub.e, C(═O)OR.sub.e, C(═O)NR.sub.bR.sub.c, S(═O).sub.2NR.sub.bR.sub.c, and P(═O).sub.2NR.sub.bR.sub.c; wherein R.sub.b and R.sub.c each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups, or R.sub.b and R.sub.c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group; R.sub.c is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and R.sub.g is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; with a compound having formula (iii): ##STR00090## wherein R.sub.2 and R.sub.5 each independently is a leaving group.

9. The method of claim 8, wherein the compound having formula (ii) has the formula (ii-b) ##STR00091## wherein R.sub.4 is chosen from methyl, ethyl, isopropyl, tert- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, and pyrrolyl.

10. The method of claim 8, wherein R.sub.4 is phenyl.

11. The method of claim 8, wherein the compound having formula (ii) has formula (ii-c): ##STR00092## or a salt or solvate thereof.

12. The method of claim 11, wherein the compound having formula (iii) has the formula (iii-a): ##STR00093##

13. The method of claim 8, further comprising converting a 2-hydroxynaphthalene-1,4-dione having formula (iv): ##STR00094## or a salt or solvate thereof, to the compound having formula (ii).

14. The method of claim 1, wherein the acid comprises an acid chosen from sulfuric acid (H.sub.2SO.sub.4), phosphoric acid (H.sub.3PO.sub.4), nitric acid (HNO.sub.3), perchloric acid (HClO.sub.4), hydrofluoric acid (HF), hydrochloric acid (HCl), hydrobromic acid (HBr), and hydroiodic acid (HI).

15. The method of claim 1, wherein the acid is sulfuric acid (H.sub.2SO.sub.4), phosphoric acid (H.sub.3PO.sub.4), or hydrochloric acid (HCl).

16. The method of claim 1, wherein the acid is chosen from formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, chloroacetic acid, and chloroacetic anhydride.

17. The method of claim 1, wherein the acid comprises an acid chosen from sulfuric acid (H.sub.2SO.sub.4), acetic acid, and acetic anhydride.

18. The method of claim 1, comprising reacting a solution of the compound having formula (i) with the acid.

19. The method of claim 18, wherein the solution comprises a solvent chosen from isopropyl acetate, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dimethylimidazolidinone (DMI).

20. The method of claim 8, comprising reacting the compound having formula (ii) in the presence of a base chosen from NaHCO.sub.3, KHCO.sub.3, Na.sub.3PO.sub.4, Na.sub.2HPO.sub.4, K.sub.3PO.sub.4, K.sub.2HPO.sub.4, LiOCH.sub.2CH.sub.3, NaOCH.sub.2CH.sub.3, KOCH.sub.2CH.sub.3, LiOC(CH.sub.3).sub.3, NaOC(CH.sub.3).sub.3, KOC(CH.sub.3).sub.3, triethylamine (TEA), diisopropylethylamine (DIPEA), and triethanolamine.

21. The method of claim 13, comprising reacting the 2-hydroxynaphthalene-1,4-dione having formula (iv) with a compound of formula (v): ##STR00095## wherein R.sub.4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)R.sub.g, S(═O).sub.2R.sub.e, P(═O).sub.2R.sub.e, C(═O)OR.sub.e, C(═O)NR.sub.bR.sub.c, S(═O).sub.2NR.sub.bR.sub.c, and P(═O).sub.2NR.sub.bR.sub.c; wherein R.sub.b and R.sub.c each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups, or R.sub.b and R.sub.c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group; R.sub.e is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and R.sub.f and R.sub.g each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups.

22. The method of claim 21, wherein R.sub.f is chosen from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

Description

EXAMPLES

(1) ##STR00085##

Example 1

(2) Aniline (300 g, 3.22 mol) was added to a 1 L reactor containing triethyl orthoformate (790 mL, 1.5 eq) and HCl (0.01 eq, 10.68 mL 11% solution in methanol) at 23-31° C. over 0.5 h. The reaction mixture was heated from 30° C. to 120° C. with stripping off ethanol over 3 hours. Ethanol stripping was stopped and the mixture was cooled to 35° C. Precipitation occurred. The mixture was heated back to 120° C. The pressure was slowly reduced and ethanol/triethyl orthoformate mixture was collected from 700 mbar. The product was collected from 36 mbar and approximately 100 ml residue remained in the reactor after distillation. The residue solidified at 50° C. The solid was dissolved in methanol. The main crop (295.9 g, NMR assay 102%) and additional crop (63 g, NMR assay 97%) of ethyl N-phenylformimidate (v-a) were obtained.

Example 2

(3) Compound (iv) (2-hydroxy-1,4-naphthoquinone, “HNQ”) (83 g, 477 mmol) was heated in 620 mL of anisole to 110° C. Ethyl N-phenylformimidate (v-a, 100 g, 1.4 equivalents) was added in one portion. The flask was rinsed with 30 mL of anisole and the rinse was added to reaction mixture. Internal temperature dropped to 106° C. Slight boiling and almost instantaneous formation of an orange precipitate was observed after mixture was heated back to 110° C. An exotherm was observed and the mixture was heated to 121° C. The reaction mixture was maintained at 120° C. for 10 minutes and UPLC sample showed full conversion of HNQ at this point. The mixture was cooled to 22° C., and the resulting solid was filtered, rinsed with 250 mL of anisole and dried at 50° C./15 mbar for 16 h. A bright yellow, shiny, flaky solid (ii-c, 99.6 g, 75% yield, with UPLC purity 100%) was obtained.

(4) B. Synthesis of Schiff base in anisole. HNQ at 90° C.—(10.0 g, 56.3 mmol) was heated in 70 mL of anisole to 90° C. under nitrogen atmosphere. Ethyl N-phenylformimidate (v-a, 2.7 g, 0.3 equivalents) was added dropwise over 15 minutes. Ethyl N-phenylformimidate (6.1 g, 0.7 eq) addition was continued over an hour. Crystallization started when about 0.5 eq. of ethyl-N-phenylformimidate was added. Full conversion of HNQ was observed 1 hour after completion of addition. Mixture was left to cool to room temperature over 2 hours. Schiff base (ii-c, 14.33 g, 90% yield, yellow solid, 100% purity by UPLC) was obtained by filtering the mixture and the solids rinsed with 70 mL of anisole and dried at 50° C./15 mbar for 16 h.

(5) C. Synthesis of Schiff base in anisole at 70° C. Ethyl N-phenylformimidate (v-a, 9.42 g, 1.1 equivalents, assay 98.8%) was added in one portion to HNQ (10.0 g, 56.3 mmol) and was heated in 70 mL of anisole to 70° C. under nitrogen atmosphere. Crystallization started at 50° C. after 15 minutes. Full conversion of HNQ was observed 3 hours after completion of addition. Mixture was left to cool to room temperature over 2 hours. Schiff base was filtered, rinsed with 40 mL of anisole. Dried for 16 h at 50° C. at 15 mbar of pressure. Compound ii-c (15.19 g, 95% yield, and 99.6% purity by UPLC) was obtained as a golden-yellow solid.

(6) D. Synthesis of Schiff base in 1,2-dichlorobenzene. Compound (iv) (65 g, 373 mmol) was dissolved in 750 mL of 1,2-dichlorobenzene at 110° C. Ethyl N-phenyl formimidate (va) (85.4 g, 1.5 equivalents) was added over 10 minutes. A full conversion of compound (iv) was observed after 20 minutes at 110-140° C. and 40 minutes at 140° C. The mixture was cooled to 55° C. Methylcyclohexane (100 mL) was added and the mixture was cooled to room temperature. The resulting solid was filtered off, washed with 300 mL of methylcyclohexane three times, and dried in a vacuum dryer at 15 mbar and 45° C. for 16 h. The Schiff base (iia, 96.8 g) was obtained as a fluffy yellow solid with UPLC purity 100% and NMR assay 99.1%. The yield corrected according to the NMR assay was determined to be 93%.

(7) Synthesis of Schiff base in DMF. HNQ (iv, 5 g, 28.7 mmol) was heated in 50 mL of DMF to 110° C. Ethyl N-phenylformimidate (v-a, 6.42 g, 1.5 eq) was added dropwise. No boiling was observed at this point. The mixture was heated to 118° C. and formation of a dark solid was observed. The mixture was stirred for 5 minutes and a sample was obtained for UPLC analysis, which showed full conversion of HNQ. After cooling to 18° C., the mixture was filtered and the solid was rinsed with 120 mL of DMF, 60 mL of iPrOH and then dried in a vacuum chamber at 50° C./15 mbar for 17 h. The Schiff base (ii-c, 6.38 g, UPLC purity 100% by area) was obtained as a fluffy yellow solid. Reaction yield calculated by weight was determined to be 80%.

Example 3

(8) DMF (40 mL) was added to Schiff base (ii-c, 10 g, 36.1 mmol) and micronized NaHCO.sub.3 (12.12 g, 4 eq.). The mixture was heated to 44° C. and crude BrAA (iii-a, 12.83 g, 1.4 eq.) was added in one portion. The mixture was maintained at 45-50° C. 0.2% of unreacted Schiff base (ii-c) was detected in reaction mixture after 3 h. The mixture was filtered and the collected solids were washed with 15 mL of DMF. The crude compound (i-a, 71.41 g, yield 83%) solution was obtained.

Example 4

(9) The crude compound (i-a) crude solution (337.3 g) in DMF was concentrated to 166.3 g (Ti=50° C./19 mbar, reduced by 50%). A minor amount of white mineral salt precipitation was observed. The concentrated mixture (including precipitated mineral salt) was added to 340 mL of sulfuric acid/acetic acid (1:1) mixture over 1 h at 18-22° C. Gas emission was observed. Formation of a yellow precipitate was observed after ˜¾ of the mixture was added. The resulting solid was filtered off, the slurry was washed on filter with 500 mL of water and then with 250 mL of iPrOH, and then solid was dried at 50° C./15 mbar for 18 h. A mustard-yellow powder (24.3 g, 99.6% by area, 97% isolated yield corrected to NMR assay) was obtained.

Example 5a

(10) 2-Hydroxynaphthalene-1,4-dione (iv, 5 g, 28.7 mmol) was dissolved in 50 mL of DMI at 80-90° C. The solution was heated to 140° C. Ethyl N-phenylformimidate (va, 6.62 g, 1.5 eq) was added slowly to the heated solution. A full conversion of 2-hydroxynaphthalene-1,4-dione (iv) and formation of fine precipitate was observed after 15 minutes.

(11) The mixture was cooled to 45° C. A thick slurry was formed (black solution and yellow precipitate). This slurry was used in the next step without any purification.

Example 5b

(12) DMI (20 mL), NaHCO.sub.3 (14.11 g, 6 eq), and tert-butyl-2-bromo-acetoacetate (iii-a) (12.46 g, 1.5 eq) were added to the crude Schiff base (ii-c) mixture in DMI at 45° C. A full conversion of Schiff base (ii-c) was observed after 6 h at 45-50° C.

(13) The inorganic salt was filtered off and rinsed with 20 mL of DMI. The yield over two steps corrected according to the NMR assay was 57%. The filtrate containing the dihydronaphthofuran derivative (i-a) was used in the next step without any further purification.

Example 5c

(14) Acetic acid (100 mL) and sulfuric acid (100 mL) were mixed and cooled to 20° C. in a water bath. The filtrate from the previous step (Example 5b, 100 g, 6.86% solution in DMI) was added dropwise to the mixture over 1.5 h at 18-24° C. A black, clear, and thick solution was observed.

(15) The resulting mixture was poured into ice/water mixture (300 mL) at 0-15° C. and slowly stirred for 45 minutes. A very fine precipitate was filtered off, rinsed with water, and dried in vacuum chamber at 50° C./15 mbar for 15 h. A brown precipitate (compound (I), 3.95 g) was obtained. Assay by NMR 68.1%. Step 3 yield corrected to NMR assay was 71%.

(16) The isolated yield from 2-hydroxynaphthalene-1,4-dione (iv) corrected to NMR assay was 39%. With the isolated Schiff base (ii-c) and alkylation in DMF, the isolated yield of crude compound (I) over three steps was 71%.

Example 6

(17) Compound (I) (200 g, 1×, crude-1) and silica gel (1.3×, 100-200 mesh) were charged into a reactor and then anisole (15 V) was added. The reaction mixture was heated to 100-110° C. and stirred for 1-2 h. The reaction mixture was then cooled to 80° C., and filtered through 0.5˜1.0× of diatomite. The solids were combined with anisole (3 V) at 80-90° C. and then filtered. The combined filtrate was heated to 80-90° C. and then slowly cooled to 0-5° C. The solids were filtered and dried at 50-60° C. under vacuum to give compound (I) (crude-2). The crude-2 was triturated in hot EtOAc (25 V) to give compound (I) (75% yield form crude-1).

(18) Compound (I) (3 g, crude, assay 91.5%) was combined with anisole (90 mL, 30 vol) at 100-110° C. Activated carbon (100 mesh, 40% w/w) was added and the mixture was stirred for 1 h. The carbon was filtered hot through a carton-board lined glass filter and washed with 20 mL of hot anisole. The resulting filtrate was concentrated to ˜13 vol at 70° C./30 mbar. The resulting mixture was reheated to 110° C. and was then cooled to 0° C. over 2 h. After cooling, the mixture was filtered and the collected solids were rinsed with 20 mL of cold anisole and dried in vacuum chamber at 50° C./15 mbar for 18 h. 2.4 g of Fine, orange-yellow needles (compound (I), 2.4 g) were obtained. UPLC purity was determined to be 100% by area. The purity was determined by the NMR assay to be 99.1% and the yield was determined to be 87%.

(19) Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the following claims.