Method for producing 2-acetyl-4H,9H-naphtho[2,3-B]furan-4,9-dione

Patent metadata

Field	Value
Publication number	US-10611746-B2
Application number	US-201916408861-A
Country	US
Kind code	B2
Filing date	May 10, 2019
Priority date	Jul 17, 2015
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

Abstract

The invention addresses the problem of providing a method for producing 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione that is suited to industrial production. The invention provides a method for producing 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione by reacting 3-bromo-3-buten-2-one and 2-hydroxy-1,4-naphthoquinone in the presence of a solvent, then obtaining crystals of 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione by adding an alcohol-based solvent and/or water to the reaction system, and treating the crystals by using a specific adsorbent in the presence of a solvent.

First claim

The invention claimed is:

1. A compound of 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione which is obtained by a process comprising the following steps (c) and (d):
(c) reacting 3-bromo-3-buten-2-one, 2-hydroxy-1,4-naphthoquinone, and a base in the presence of a non-alcohol, non-ketone-based solvent A, and adding an alcohol-based solvent B and/or water to obtain a crystal of 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione; and
(d) dissolving 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione obtained in the step (c) in a non-alcohol-based solvent C, followed by adding an adsorbent to purify the 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione;
wherein the purity of the compound is not less than 99.85 area % by HPLC.

2. The compound according to claim 1 , wherein in the step (c), an oxidant is added to a reaction solution after the addition of the alcohol-based solvent B and/or water.

3. The compound according to claim 2 , wherein the oxidant is at least one selected from the group consisting of oxygen, hydrogen peroxide, sodium hypochlorite, sodium chlorite, chlorine, iodine, nitric acid, and potassium nitrate.

4. The compound according to claim 3 , wherein the oxidant is oxygen.

5. The compound according to claim 1 , wherein in the step (c), a gas having an oxygen concentration of 1-25% is added to the reaction solution after the addition of the alcohol-based solvent B and/or water.

6. The compound according to claim 1 , wherein the process further comprises the following step (e) after the step (d):
(e) removing the adsorbent used in the step (d) and evaporating the non-alcohol-based solvent C.

7. The compound according to claim 6 , wherein the process further comprises the following step (f) after the step (e):
(f) crystallizing 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione obtained in the step (e) by adding at least one crystallization solvent D selected from the group consisting of a hydrocarbon-based solvent, an alcohol-based solvent, an acid-based solvent, an ester-based solvent, an ether-based solvent, and water, to obtain 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione.

8. The compound according to claim 7 , wherein the process further comprises the following step (g) after the step (f):
(g) slurrying 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione obtained in the step (f) with ethyl acetate to form a crystal of 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione.

9. The compound according to claim 1 , wherein the non-alcohol, non-ketone-based solvent A used in the step (c) is at least one selected from the group consisting of a halogen-based solvent, an amide-based solvent, a nitrile-based solvent, a sulfoxide-based solvent, an ether-based solvent, an ester-based solvent, and a hydrocarbon-based solvent.

10. The compound according to claim 9 , wherein the non-alcohol, non-ketone-based solvent A used in the step (c) is at least one selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride, monochlorobenzene, N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, propionitrile, dimethyl sulfoxide, diethyl sulfoxide, diisopropyl ether, tert-butyl methyl ether, cyclopentyl ethyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anisole, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, toluene, and xylene.

11. The compound according to claim 10 , wherein the non-alcohol, non-ketone-based solvent A used in the step (c) is at least one selected from the group consisting of chloroform, monochlorobenzene, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, anisole, ethyl acetate, toluene, and xylene.

12. The compound according to claim 11 , wherein the non-alcohol, non-ketone-based solvent A used in the step (c) is at least one selected from the group consisting of monochlorobenzene and acetonitrile.

13. The compound according to claim 1 , wherein in the step (c), 0.8 equivalent to 1.2 equivalents of 2-hydroxy-1,4-naphthoquinone is reacted in a molar ratio to 3-bromo-3-buten-2-one.

14. The compound according to claim 13 , wherein in the step (c), 0.9 equivalent to 1.1 equivalents of 2-hydroxy-1,4-naphthoquinone is reacted in a molar ratio to 3-bromo-3-buten-2-one.

15. The compound according to claim 1 , wherein the base used in the step (c) is diazabicycloundecene.

16. The compound according to claim 15 , wherein diazabicycloundecene used in the step (c) has a molar ratio of 0.9 equivalent to 5.0 equivalents to 3-bromo-3-buten-2-one.

17. The compound according to claim 16 , wherein in the step (c), 0.9 equivalent to 1.5 equivalents of diazabicycloundecene in a molar ratio to 3-bromo-3-buten-2-one is added to the reaction solution of 3-bromo-3-buten-2-one and 2-hydroxy-1,4-naphthoquinone, and after stirring for one minute to three hours, 0.01 equivalent to 1.0 equivalent of diazabicycloundecene is further added in a molar ratio to 3-bromo-3-buten-2-one.

18. The compound according to claim 1 , wherein the alcohol-based solvent B used in the step (c) is methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, or isobutyl alcohol, or mixtures thereof.

19. The compound according to claim 18 , wherein the alcohol-based solvent B used in the step (c) is methanol or ethanol, or mixtures thereof.

20. The compound according to claim 1 , wherein the non-alcohol-based solvent C used in the step (d) is at least one selected from the group consisting of an ether-based solvent, an amide-based solvent, a ketone-based solvent, a halogen-based solvent, a sulfoxide-based solvent, an ester-based solvent, a hydrocarbon-based solvent, and a nitrile-based solvent.

21. The compound according to claim 18 , wherein the non-alcohol-based solvent C used in the step (d) is at least one selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride, monochlorobenzene, N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, propionitrile, dimethyl sulfoxide, diethyl sulfoxide, diisopropyl ether, tert-butyl methyl ether, cyclopentyl ethyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anisole, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

22. The compound according to claim 20 , wherein the non-alcohol-based solvent C used in the step (d) is at least one selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, anisole, ethyl acetate, propyl acetate, and butyl acetate.

23. The compound according to claim 20 , wherein the non-alcohol-based solvent C used in the step (d) is anisole.

24. The compound according to claim 1 , wherein the adsorbent used in the step (d) is at least one selected from the group consisting of activated alumina, zeolite, activated carbon, and silica gel.

25. The compound according to claim 24 , wherein the adsorbent used in the step (d) is silica gel.

26. The compound according to claim 1 , wherein the adsorbent used in the step (d) is a 0.01 to 0.3-fold amount in a weight ratio to 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione.

27. The compound according to claim 26 , wherein the adsorbent used in the step (d) is a 0.02 to 0.2-fold amount in a weight ratio to 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione.

28. T

Assignees

• Sumitomo Dainippon Pharma Co Ltd

Inventors

• Yagi Toshikazu
• Suzuki Satoshi
• Tatamidani Hiroto
• Hashimoto Kazuki

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C49/227

  containing halogen · CPC title

• C07C45/65

  by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• C07B63/02

  by treatment giving rise to a chemical modification · CPC title