NOVEL ACRIDINIUM SALT AND METHOD FOR PRODUCING SAME

Abstract

The present invention provides novel aclidinium salt of the formula (I) and a process for the production of the aclidinium salt.

##STR00001##

wherein R.sup.1 is C1-C6 alkyl or C1-C6 alkyloxy; R.sup.2 is hydrogen or C1-C6 alkyloxy; R.sup.3 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkyloxy; R.sup.4 is hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.5 is C1-C3 alkyl; and X.sup.− is an anion.

Claims

1. An aclidinium salt of the formula (I): ##STR00042## wherein R.sup.1 is C1-C6 alkyl or C1-C6 alkyloxy; R.sup.2 is hydrogen or C1-C6 alkyloxy; R.sup.3 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkyloxy; R.sup.4 is hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.5 is C1-C3 alkyl; and X.sup.− is an anion.

2. The acridinium salt according to claim 1, wherein R.sup.1 is C1-C3 alkyloxy.

3. The acridinium salt according to claim 1, wherein R.sup.2 is hydrogen or C1-C3 alkyloxy.

4. The acridinium salt according to claim 1, wherein R.sup.3 is hydrogen, halogen, C1-C3 alkyl or C1-C3 alkyloxy.

5. The acridinium salt according to claim 1, wherein R.sup.4 is C1-C3 alkyloxy, halo C1-C3 alkyloxy or dimethylamino.

6. The acridinium salt according to claim 1, wherein R.sup.5 is methyl.

7. The acridinium salt according to claim 1, wherein R.sup.1 is C1-C3 alkyloxy and R.sup.4 is C1-C3 alkyloxy.

8. The acridinium salt according to claim 1 selected from the followings: ##STR00043## ##STR00044## wherein X.sup.− is as defined in claim 1.

9. The acridinium salt according to claim 1, wherein X.sup.− is BF.sub.4.sup.− or ClO.sub.4.sup.−.

10. A process for the production of a compound of the formula (VII): ##STR00045## wherein W is O or CH.sub.2 and R.sup.6 is hydrogen or a hydroxyl protecting group, characterized by removing RA from a compound of the formula (IV): ##STR00046## wherein R.sup.6 is hydrogen or a hydroxyl protecting group; R.sup.A1 is hydrogen or RA; R.sup.A2 is hydrogen or RA; R.sup.A3 is hydrogen or RA; W is O, CH.sub.2 or CHRA; RA is a removable functional group; the carbon atom to which the RA is bonded is optically active; and provided that one of R.sup.A1, R.sup.A2 and R.sup.A3 is RA and the other two are hydrogen and W is O or CH.sub.2; or R.sup.A1, R.sup.A2 and R.sup.A3 are hydrogen and W is CHRA, in the presence of the acridinium salt according to claim 1.

11. A process for the production of a compound of the formula (VII): ##STR00047## wherein W is O or CH.sub.2 and R.sup.6 is hydrogen or a hydroxyl protecting group, characterized by removing RA from a compound of the formula (IV): ##STR00048## wherein R.sup.6 is hydrogen or a hydroxyl protecting group; R.sup.A1 is hydrogen or RA; R.sup.A2 is hydrogen or RA; R.sup.A3 is hydrogen or RA; W is O, CH.sub.2 or CHRA; RA is a removable functional group; the carbon atom to which the RA is bonded is optically active; and provided that one of R.sup.A1, R.sup.A2 and R.sup.A3 is RA and the other two are hydrogen and W is O or CH.sub.2; or R.sup.A1, R.sup.A2 and R.sup.A3 are hydrogen and W is CHRA, in the presence of an acridinium salt, imidazole and 4-isopropylbenzenethiol, under light irradiation in one or more solvents selected from the group consisting of ethanol and dichloromethane.

12. The process according to claim 11, wherein RA is removed in the presence of the aclidinium salt according to formula (I) ##STR00049## wherein R.sup.1 is C1-C6 alkyl or C1-C6 alkyloxy; R.sup.2 is hydrogen or C1-C6 alkyloxy; R.sup.3 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkyloxy; R.sup.4 is hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.5 is C1-C3 alkyl; and X.sup.− is an anion.

13. A process for the production of a compound of the formula (VIIIa) or formula (IXa) or a salt thereof: ##STR00050## comprising the process according to claim 10.

14. A process for the production of an aclidinium salt of the formula (III): ##STR00051## wherein R.sup.7 to R.sup.12 are independently hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.13 is a substituted or unsubstituted C1-C6 alkyl or aromatic carbocyclyl; R.sup.− to R.sup.18 are independently hydrogen, halogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; Y is C1-C6 alkyloxy; Z is a leaving group; and X.sup.− is an anion, characterized in that a compound of the formula (II) or a salt thereof: ##STR00052## wherein R.sup.7 to R′2 are independently hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.13 is a substituted or unsubstituted C1-C6 alkyl or aromatic carbocyclyl; Y is C1-C6 alkyloxy; and Z is a leaving group, is reacted with a monocyclic aryl metal reagent and then treated with an acid.

15. The process according to claim 14, wherein the monocyclic aryl metal reagent is a monocyclic aryl Grignard reagent.

16. A process for the production of an acridinium salt of the formula (IV): ##STR00053## wherein R.sup.7 to R′2 are independently hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.13 is a substituted or unsubstituted C1-C6 alkyl or aromatic carbocyclyl; R″ to R.sup.18 are independently hydrogen, halogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.19 is C1-C6 alkyloxy; Y is C1-C6 alkyloxy; and X.sup.− is an anion, characterized in that an acridinium salt of the formula (III): ##STR00054## wherein Z is a leaving group, and the other symbols are as defined above, is reacted with a nucleophile.

17. The process according to claim 16, wherein the nucleophile is a metal C1-C6 alkoxide or C1-C6 alkylamine.

18. The process according to claim 16, wherein the aclidinium salt of the formula (III) is that obtained by reacting a compound of the formula (II) or a salt thereof: ##STR00055## wherein R.sup.7 to R.sup.12 are independently hydrogen, C1-C6 alkyloxy, halo C1-C6 alkyloxy or C1-C6 alkylamino; R.sup.13 is a substituted or unsubstituted C1-C6 alkyl or aromatic carbocyclyl; Y is C1-C6 alkyloxy; and Z is a leaving group, with a monocyclic aryl metal reagent and then treated with an acid.

Description

EXAMPLES

[0231] The NMR analysis was carried out using Bruker NMR spectrometer. 1H (400 MHz) and 13C (101 MHz) NMR used the solvent peak as a reference. For 19F NMR (376 MHz), the values are as measured without using a reference.

Example 1

Production of Acridinium Salt 1-01

[0232] ##STR00031##

Step 1: Preparation of Acridinium salt 3

[0233] A mixture of Compound 2 (200.0 mg, 0.73 mmol), THF (6 mL) and 1M THF solution of compound 2 (1.1 mL, 1.1 mmol) was stirred at 60° C. for 5 hours under a nitrogen atmosphere. 1M THF solution of Compound 2 (0.1 mL, 0.1 mmol) was added, and the mixture was stirred further for 1.5 hours. After cooling the reaction solution to room temperature, 42% aqueous tetrafluoroboric acid solution (400 μL), water and dichloromethane were added to separate the solution. The aqueous layer was extracted with dichloromethane, and then the organic layer were combined and concentrated. The residue was dissolved in dichloromethane and washed with water. After concentrating the organic layer, the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane to dichloromethane-methanol), and a mixed solution of ethyl acetate and methyl tert-butyl ether was added to solidify. The solid was collected by filtration to obtain acridinium salt 3 (211.6 mg, yield 64%).

[0234] 1H-NMR (CDCl.sub.3) δ:1.79 (s, 6H), 3.78 (s, 3H), 5.00 (s, 3H), 6.84 (d, J=2.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.50 (t, J=8.0 Hz, 1H), 7.62-7.70 (m, 2H), 8.08 (dd, J=9.9, 2.9 Hz, 1H), 8.60 (d, J=1.2 Hz, 1H)

[0235] 19F-NMR (CDCl.sub.3) δ: −153.56.

[0236] 13C NMR (CDCl.sub.3) δ: 19.97, 39.50, 56.04, 104.18, 118.37, 121.39, 124.32, 127.65, 128.44, 129.60, 129.68, 130.44, 132.16, 133.51, 136.04, 138.76, 140.11, 144.87, 158.56, 159.10.

Step 2:Preparation of Acridinium Salt 1-01

[0237] A mixture of acridinium salt 3 (19.59 mg, 0.044 mmol), methanol (644 μL), and 28% sodium methoxide methanol solution (9 μL) was stirred at room temperature for 36 minutes. To the reaction solution was added 42% aqueous solution of tetrafluoroboric acid (10 μL), dichloromethane, and aqueous solution of sodium tetrafluoroborate to separate layers. The 25 aqueous layer was extracted with dichloromethane. The combined organic layer was washed with aqueous sodium tetrafluoroborate solution, and dried over sodium sulfate. The solvent was replaced with ethyl acetate to precipitate a solid. The solvent was replaced with methyl tert-butyl ether, and the solid was collected by filtration and washed with methyl tert-butyl ether. The obtained solid was dried under reduced pressure to obtain acridinium salt I-01 (8.41 mg, yield 43%).

[0238] 1H-NMR (CDCl.sub.3) δ:1.80 (s, 6H), 3.76 (s, 3H), 4.30 (s, 3H), 4.94 (s, 3H), 6.83 (d, J=2.8 Hz, 1H), 7.29 (dd, J=9.4, 2.1 Hz, 1H), 7.33 (d, J=7.6 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.54 (d, J=9.4 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.94 (dd, J=9.6, 2.8 Hz, 1H), 8.55 (d, J=9.8 Hz, 1H).

[0239] 19F-NMR (CDCl.sub.3) δ:−152.39.

[0240] 13C NMR (CDCl.sub.3) δ:19.97, 39.12, 55.90, 57.79, 97.25, 105.22, 120.21, 122.25, 123.68, 125.52, 128.34, 129.66, 130.15, 130.46, 132.61, 135.89, 137.10, 143.78, 156.80, 158.13, 168.12.

Example 2

Production of Acridinium Salt 1-02

[0241] ##STR00032##

Step 1: Preparation of Acridinium Salt 5

[0242] A mixture of Compound 4 (1002.1 mg, 3.5 mmol), pyridine (10 mL), and 1M THF solution of Compound 2 (13 mL, 13 mmol) was stirred at 55° C. for 6 hours under a nitrogen atmosphere. 1M THF solution of Compound 2 (5 mL, 5 mmol) was added and heated at 58° C. for 9 hours. After cooling the reaction solution to room temperature, formic acid (1120 μL, 30 mmol) and water (20 mL) were added, and the mixture was concentrated to 16.19 g. To the concentrated solution were added dichloromethane (15 mL), water (5 mL) and 42% aqueous tetrafluoroboric acid solution (2 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (2 mL). The combined organic layer was washed with a mixed solution of water (10 mL) and 42% tetrafluoroboric acid aqueous solution (1 mL), and then with a mixed solution of water (5 mL) and sodium tetrafluoroborate (191.2 mg, 1.7 mmol). The obtained organic layer was concentrated. The solvent was replaced with ethyl acetate, and the mixture was concentrated to 8.00 g. The precipitated solid was collected by filtration and washed with ethyl acetate (5 mL). The obtained solid was dried under reduced pressure to obtain acridinim salt 5 (1170 mg, yield 72%).

[0243] 1H-NMR (CDCl.sub.3) δ:1.41 (t, J=7.0 Hz, 3H), 1.79 (s, 6H), 2.24 (s, 1H), 3.95 (q, J=7.0 Hz, 2H), 4.99 (s, 3H), 6.82 (d, J=2.9 Hz, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.50 (t, J=7.6 Hz, 1H), 7.61-7.69 (m, 2H), 8.07 (dd, J=9.9, 2.9 Hz, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.76 (d, J=9.9 Hz, 1H).

[0244] 19F-NMR (CDCl.sub.3) δ:−153.49.

[0245] 13C NMR (CDCl.sub.3) δ:14.21, 19.98, 39.46, 64.69, 104.74, 118.39, 121.32, 124.28, 127.70, 128.44, 129.59, 129.64, 130.42, 132.23, 133.81, 136.05, 138.65, 140.06, 144.79, 158.42, 158.45.

Step 2: Preparation of Acridinium Salt 1-02

[0246] A mixture of aclidinium salt 5 (6.04 g, 13.0 mmol) and methanol (240 mL) was cooled to 5° C. 28% sodium methoxide methanol solution (3.00 g, 15.5 mmol) was diluted with methanol (6 mL) and added to the mixture. After stirring at 3° C. for 1 hour, the temperature was raised to 13° C., and the mixture was stirred for 1 hour. Tc the mixture was added 42% aqueous tetrafluoroboric acid solution (3.27 g, 15.6 mmol), and the mixture was concentrated to 62.4 g. To the mixture was added water (60 mL), and the mixture was concentrated to 73.06 g. Dichloromethane (60 mL) was added to separate the layers. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layer was washed with a mixed solution of water (16.77 g) and sodium tetrafluoroborate (1.72 g, 15.7 mmol). The obtained organic layer was concentrated, and the solvent was replaced with ethyl acetate. After concentrating to 16.89 g, a small amount of seed crystals were added to precipitate a solid. After adding 40 mL of ethyl acetate, the mixture was concentrated to 27.52 g. The solid was collected by filtration, and washed with ethyl acetate (24 mL). The obtained solid was dried under reduced pressure to obtain acridinium salt 1-02 (5.02 g, yield 84%).

[0247] 1H-NMR (CDCl.sub.3) δ:1.41 (t, J=7.0 Hz, 3H), 1.79 (s, 6H), 2.04 (s, 1H), 3.94 (q, J=7.0 Hz, 2H), 4.30 (s, 3H), 4.94 (s, 3H), 6.82 (d, J=2.9 Hz, 1H), 7.28 (dd, J=9.5, 2.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.92 (dd, J=9.9, 2.9 Hz, 1H), 8.53 (d, J=9.9 Hz, 1H)

[0248] 19F-NMR (CDCl.sub.3) δ: −152.45.

[0249] 13C NMR (CDCl.sub.3) δ: 14.27, 19.96, 39.08, 57.78, 64.44, 97.23, 25 105.82, 120.10, 122.21, 123.63, 125.56, 128.32, 129.63, 130.11, 130.73, 132.65, 135.89, 136.97, 143.71, 156.71, 157.46, 168.07.

Example 3:

Production of Acridinium Salt 5

[0250] ##STR00033##

[0251] Under a nitrogen atmosphere, a mixture of Compound 4 (6.10 g, 21.20 mmol), pyridine (90 mL), 1M THF solution of Compound 2 (36 mL, 36 mmol), 0.6M THF solution of lanthanum chloride/lithium dichloride complex (3.5 mL, 2.1 mmol) was heated to 43° C. for 80 minutes and then stirred at the same temperature for 230 minutes. After cooling the reaction solution to room temperature, formic acid (1.93 g, 41.9 mmol), water (49 mL) and tetrahydrofuran (50 mL) were added, and the mixture was concentrated to 63.84 g. To the concentrated mixture was added water (50 mL), and the mixture was concentrated to 59.33 g. To the concentrated mixture was added water (50 mL), and the mixture was concentrated to 93.71 g. To the concentrated mixture were added dichloromethane (70 mL), water (50 mL) and concentrated hydrochloric acid (12 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layer was washed with water (50 mL). The obtained organic layer was washed twice with a mixed solution of water (50 mL) and sodium tetrafluoroborate (2.33 g, 21.2 mmol), and washed once with a mixed solution of water (25 mL) and sodium tetrafluoroborate (1.21 g, 11.0 mmol). The obtained organic layer was dried over sodium sulfate (25.01 g), and the solid was filtered, and concentrated. The solvent was replaced with ethyl acetate, and the solution was concentrated to 40.90 g. The precipitated solid was collected by filtration and washed with ethyl acetate (42 mL). The obtained solid was dried under reduced pressure to obtain acridinium salt 5 (8.20 g, yield 83%).

Example 4

Production of Acridinium Salt 8

[0252] ##STR00034##

[0253] Under a nitrogen atmosphere, a mixture of Compound 6 (154.2 mg, 0.51 mmol), pyridine (3.85 mL), 1M THF solution of Compound 2 (1 mL, 1 mmol), 0.6M THF solution of lanthanum chloride/lithium dichloride complex (0.25 mL, 0.15 mmol) was stirred at 40° C. for 13 hours. After cooling the mixture to room temperature, formic acid (0.2 mL) and water were added. The mixture was concentrated, and the solvent was replaced with water. To the concentrated mixture were added dichloromethane and concentrated hydrochloric acid to separate the layers. The aqueous layer was extracted with dichloromethane, and the combined organic layer was washed with an aqueous solution of tetrafluoroboric acid and with an aqueous solution of sodium tetrafluoroborate. The obtained organic layer was concentrated, ethyl acetate (2 mL) and methyl tert-butyl ether (1.5 mL) were added. The precipitated solid was collected by filtration and washed with a mixture of ethyl acetate and methyl tert-butyl ether (1:1). The obtained solid was dried under reduced pressure to obtain acridinium salt 8 (162.7 mg, yield 67%).

[0254] 1H-NMR (CDCl.sub.3) δ:1.80 (s, 6H), 3.77 (s, 3H), 4.43 (s, 3H), 4.90 (s, 3H), 6.70 (s, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.50 (t, J=7.9 Hz, 1H), 7.60 (d, J=1.1 Hz, 2H), 8.01 (s, 1H), 8.43 (t, J=1.1 Hz, 1H).

[0255] 19F-NMR (CDCl.sub.3) δ: −152.26.

[0256] 13C NMR (CDCl.sub.3) δ:19.94, 39.36, 56.39, 58.89, 98.80, 103.59, 117.72, 122.58, 122.98, 128.47, 129.55, 130.38, 132.26, 135.87, 139.48, 142.33, 143.24, 151.88, 155.44, 162.44.

Example 5

Production of Acridinium Salt 1-03

[0257] ##STR00035##

[0258] A mixed solution of acridinium salt 8 (96.9 mg, 0.20 mmol), ethanol (2 mL) and 20% sodium ethoxide solution (148 μL) was stirred under ice-cooling for 3 hours. To the mixture were added 42% tetrafluoroborate aqueous solution (90 μL), dichloromethane and activated carbon, and the mixture was filtered. The solvent of the filtrate was replaced with water. The precipitated crystals were dissolved in dichloromethane, and purified by silica gel column chromatography (dichloromethane-methanol). A mixed solution of ethyl acetate and methyl tert-butyl ether was added to solidify. The solid was collected by filtration to obtain acridinium salt 1-03 (64.0 mg, yield 63%).

[0259] 1H-NMR (CDCl.sub.3) δ:1.58 (t, J=7.1 Hz,3H), 1.65(t, J=7.1 Hz,3H), 1.80 (s, 6H), 3.74 (s, 3H), 4.46 (q, J-7.1 Hz, 2H), 4.61 (q, J=7.1 Hz, 2H), 4.80 (s, 3H), 6.68 (s, 1H), 7.22 (dd, J=9.4, 2.1 Hz, 1H), 7.32 (d, J=7.6 Hz, 2H), 7.44-7.51 (m, 2H), 7.64 (d, J=2.1 Hz, 1H), 7.78 (s, 1H)

[0260] 19F-NMR (CDCl.sub.3) δ:−152.49.

[0261] 13C NMR (CDCl.sub.3) δ:14.31, 14.43, 19.90, 39.00, 56.20, 65.94, 67.18, 97.68, 98.59, 104.26, 119.91, 120.24, 121.55, 128.29, 129.64, 129.98, 132.86, 135.85, 140.66, 142.68, 150.68, 154.58, 159.79, 166.05.

[0262] The following acridinium salts were also obtained by the process described above.

##STR00036##

Aclidinium Salt 1-04

[0263] 1H-NMR (CDCl.sub.3) δ: 1.80 (s, 6H), 3.75 (s, 3H), 4.21 (s, 3H), 4.35 (s, 3H), 4.84 (s, 3H), 6.70 (s, 1H), 7.33 (d, J=7.6 Hz, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.49 (s, 1H), 7.52 (s, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.82 (s, 1H).

[0264] 19F-NMR (CDCl.sub.3) δ: −152.32.

Aclidinium Salt 1-05

[0265] 1H-NMR (acetone-d6)δ:1.49 (d, J=6.0 Hz, 6H), 1.54 (d, J=5.8 Hz, 6H), 1.85 (s, 6H), 3.76 (s, 3H), 4.87 (s, 3H), 5.24 (sept, J=6.0 Hz, 1H), 5.24 (sept, J=5.8 Hz, 1H), 6.87 (s, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.45 (dd, J=9.4, 2.2 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.97 (s, 1H).

[0266] 19F-NMR (acetone-d6)δ:−151.96.

Aclidinium Salt 1-06

[0267] 1H-NMR (CDCl.sub.3) δ:1.79 (s, 6H), 3.77 (s, 3H), 4.98 (s, 3H), 5.02 (q, J=8.0 Hz, 1H), 6.85 (d, J=3.0 Hz, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.40 (dd, J=9.5, 2.1 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.95 (dd, J=9.7, 3.0 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.50 (d, J=9.7 Hz, 1H).

[0268] 19F-NMR (CDCl.sub.3) δ:−73.42, −151.65.

Aclidinium Salt 1-07

[0269] 1H-NMR (CDCl.sub.3) δ:1.82 (s, 6H), 3.43 (s, 6H), 3.72 (s, 3H), 4.60 (s, 3H), 5.02 (q, J=8.0 Hz, 1H), 6.73 (d, J=3.0 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.19 (dd, J=9.6, 2.0 Hz, 1H), 7.29 (brd, J=7.6 Hz, 2H), 7.36 (d, J=9.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.70 (dd, J=9.8, 3.0 Hz, 1H), 8.19 (d, J=9.8 Hz, 1H).

[0270] 19F-NMR (CDCl.sub.3) δ: −152.82.

[0271] The following compounds were obtained according to the method as described in J. AM. CHEM. SOC. 2004, 126, 15999.

##STR00037## ##STR00038##

Aclidinium Salt 1-08

[0272] 1H-NMR (CDCl.sub.3) δ:1.80 (s, 6H), 3.78 (s, 3H), 5.07 (s, 3H), 6.82 (d, J=2.8 Hz, 1H), 7.37 (d, J=7.4 Hz, 2H), 7.53 (t, J=7.4 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 8.07 (dd, J=10.0, 2.8 Hz, 1H), 8.20 (dd, J=10.0, 2.2 Hz, 1H), 8.72 (dd, J=10.0, 4.8 Hz, 2 H).

[0273] 19F-NMR (CDCl.sub.3) δ: −153.32.

Aclidinium Salt 1-09

[0274] 1H-NMR (CDCl.sub.3) δ:1.81 (s, 6H), 3.78 (s, 3H), 4.43 (s, 3H), 4.94 (s, 3H), 6.68 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.98 (s, 1H), 8.08 (dd, J=9.8, 2.4 Hz, 1H), 8.43 (d, J=9.8 Hz, 1H).

[0275] 19F-NMR (CDCl.sub.3) δ: -152.31.

Aclidinium Salt I-10

[0276] 1H-NMR (CDCl.sub.3) δ:1.81 (s, 6H), 3.77 (s, 6H), 5.06 (s, 3H), 6.79 (d, J=2.8 Hz, 2H), 7.35 (d, J=7.7 Hz, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.95 (dd, J=9.9, 2.8 Hz, 2H), 8.62 (d, J=9.9 Hz, 2 H).

Aclidinium Salt I-11

[0277] Retention time of HPLC: 6.1 minutes

Measurement Conditions

[0278] Column: XSelect CSH C18 (3.5 μm, i.d. 4.6×100 mm) (Waters) [0279] Flow rate: 1.2 mL/min; UV detection wavelength: 254 nm; [0280] Column oven temperature: 37° C.; Mobile phase: [A]=0.1% aqueous formic acid and [B]=acetonitrile. [0281] Granant: linear gradient of 15% to 40% solvent [A] over 4 minutes, followed by 40% to 95% solvent [B] over 2 minutes, and then 95% solvent [B] was maintained for 1.5 minutes.

Aclidinium Salt 1-12

[0282] 1H-NMR (CDCl.sub.3) δ:1.31 (s, 18H), 1.77 (s, 6H), 5.04 (s, 3H), 7.36 (d, J=7.6 Hz, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.62 (d, J=2.2 Hz, 2H), 8.44 (dd, J=9.6, 2.2 Hz, 2H), 8.70 (d, J=9.6 Hz, 2 H).

[0283] 19F-NMR (CDCl.sub.3) δ:−153.32.

Aclidinium Salt 1-13

[0284] 1H-NMR (CDCl.sub.3) δ:1.27 (d, J=6.8 Hz, 6H), 1.78 (s, 6H), 3.09 (sept, J=6.8 Hz, 1H), 5.08 (s, 1H), 7.37 (d, J=7.6 Hz, 2H), 7.49 (d, J=2.1 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 8.26 (dd, J=9.6, 2.5 Hz, 1H), 8.32 (dd, J=9.5, 2.1 Hz, 1H), 8.72 (d, J=9.5 Hz, 1H), 8.78 (d, J=9.6 Hz, 1H).

[0285] 19F-NMR (CDCl.sub.3) δ: −153.25.

Aclidinium Salt 1-14

[0286] 1H-NMR (CDCl.sub.3) δ: 1.27 (d, J=7.0 Hz, 6H), 1.33 (t, J=7.4 Hz, 3H), 1.78 (s, 6H), 2.24-2.35 (m, 2H), 3.08 (sept, J=7.0 Hz, 1H), 5.52 (t, J=8.2 Hz, 2H), 7.37 (d, J=7.7 Hz, 2H), 7.48 (d, J=2.4 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 8.28 (dd, J=9.6, 2.4 Hz, 1H), 8.33 (dd, J=9.5, 2.3 Hz, 1H), 8.63 (d, J=9.6 Hz, 1H), 8.70 (d, J=9.5 Hz, 1H).

[0287] 19F-NMR (CDCl.sub.3) δ:−153.32.

Example 6

Elimination Reaction in the Presence of Acridinium Salt

[0288] ##STR00039##

Example 6-1

[0289] Under nitrogen atmosphere, Compound 10 (19.63 mg, 0.054 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), 9-xylyl-2,7-dimethoxy-10-methylacrydinium tetrafluoroborate (0.250 mg, 0.56 μmol) and imidazole (3.752 mg, 0.055 mmol) were dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 99% at 45 minutes of the reaction.

Example 6-2

[0290] Under nitrogen atmosphere, Compound 10 (19.63 mg, 0.054 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), acridinium salt I-01 (0.250 mg, 0.56 μmol), imidazole (3.752 mg, 0.055 mmol) was dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 99% at 45 minutes of the reaction.

Example 6-3

[0291] Under nitrogen atmosphere, Compound 10 (19.93 mg, 0.055 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), acridinium salt 1-02 (0.264 mg, 0.57 μmol), imidazole (3.685 mg, 0.054 mmol) was dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 98% at 58 minutes of the reaction. After concentrating the reaction mixture, dichloromethane (10 mL) and water (5 mL) were added to separate the layers. After concentrating the organic layer, the obtained residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain Compound 11 (16.66 mg, yield 95%).

Example 6-4

[0292] Under nitrogen atmosphere, Compound 10 (19.60 mg, 0.054 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), acridinium salt 1-03 (0.263 mg, 0.55 μmol), imidazole (3.633 mg, 0.054 mmol) was dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 98% at 35 minutes of the reaction.

Example 6-5

[0293] Under nitrogen atmosphere, Compound 10 (19.84 mg, 0.054 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), acridinium salt 1-04 (0.300 mg, 0.56 μmol), imidazole (3.711 mg, 0.054 mmol) was dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 98% at 35 minutes of the reaction.

Reference Example

[0294] Under nitrogen atmosphere, Compound 10 (19.88 mg, 0.054 mmol), 4-isopropylbenzenethiol (0.8 mg, 5 μmol), 9-mesityl-2,7-dimethyl-10-methylacrydiniumperchlorate (0.244 mg, 0.55 μmol) and imidazole (3.712 mg, 0.055 mol) were dissolved in a mixed solution of ethanol (50 μL) and dichloromethane (450 μL). The mixture was stirred at room temperature under light irradiation with a blue LED (power consumption 2.8 W). The conversion rate to Compound 11, as confirmed by HPLC, was 72% at 45 minutes of the reaction. 84% at 60 minutes of the reaction, and 97% at 90 minutes of the reaction.

Example 7

[0295] ##STR00040##

Step 1

[0296] To compound 11 (12.0 g, 24.3 mmol) were added 7,8-difluoro-6,11-dihydrodibenzothiepine-11-ol (8.0 g, 30.3 mmol), ethyl acetate (48.7 g) and cyclohexane (14.1 g), and the mixture was stirred at 25° C. To the mixture were added 50%(w/w) T3P ethyl acetate solution (20.91 g, 32.9 mmol) and then methanesulfonic acid (3.5 g, 36.4 mmol). The temperature was raised to 60° C., and the mixture was stirred for 24 hours.

[0297] After cooling to 25° C., THF (32.0 g) and water (24.0 g) were added. To the mixture was added slowly 24% aqueous sodium hydroxide solution (30.8 g), and the mixture was allowed to stand. The layers was separated into an organic layer and an aqueous layer. The organic layer was washed twice with 7% saline (60.0 g). To the obtained solution was added a mixed solution of cyclohexane (9.3 g), ethyl acetate (32.1 g) and methanesulfonic acid (2.80 g, 29.1 mmol). The mixture was stirred at 25° C. for 2 hours, and the resulting white precipitate was collected by filtration. The obtained solid was washed with ethyl acetate (43.3 g) and then dried to obtain a mesylate of compound 17 (13.65 g, yield 84.6%).

[0298] 1H-NMR (DMSO-d6)δ: 0.90 (3H, t, J=6.0 Hz), 1.29-1.36 (4H, m), 1.39-1.49 (2H, m), 1.67-1.79 (2H, m), 2.38 (3H, s), 2.94 (1H, br s), 3.30 (1H, td, J=11.6, 2.4 Hz), 3.51 (1H, t, J=10.4 Hz), 3.66 (1H, dd, J=11.2, 2.8 Hz), 3.92-4.01 (2H, m), 4.07 (1H, d, J=14.3 Hz), 4.20 (1H, s), 4.42-4.52 (1H, m), 5.43 (1H, dd, J=14.4, 2.1 Hz), 5.79-5.83 (2H, m), 6.81 (1H, td, J=7.6, 1.2 Hz), 6.96 (1H, dd, J=7.8, 1.0 Hz), 7.09 (1H, J=8.0, 1.6 Hz), 7.12-7.18 (1H, m), 7.32 (1H, d, J=7.7 Hz), 7.37-7.49 (2H, m)

Step 2

[0299] To Compound 17 (15.0 g, 22.6 mmol) was added N-methylpyrrolidone (52.4 g), and the mixture was stirred. Lithium chloride (8.6 g, 203.3 mmol) was added to the mixture, and the mixture was heated to 75° C. The mixture was stirred at 75° C. for 20 hours and then cooled to 40° C. Acetonitrile (20.0 g) was added, and water (11.6 g) was further added. After cooling to 30° C. and stirring for 30 minutes, water (142.5 g) was added slowly. After stirring at 30° C. for 1.5 hours, the resulting white precipitate was collected by filtration. The obtained solid was washed with 2-propanol (60.1 g) and dried to obtain the compound (VIIIa) (9.91 g, yield 90.7%).

Example 8

[0300] ##STR00041##

[0301] To a suspension of the compound (VIIIa) (1.00 g, 2.07 mmol) in DMA (5 ml) were added chloromethylmethylcarbonate (0.483 g, 3.10 mmol) and potassium carbonate (0.572 g, 4.14 mmol) and potassium iodide (0.343 g, 2.07 mmol), and the mixture was heated to 50° C. and stirred for 6 hours. To the 5 mixture was added further DMA (1 ml), and the mixture was stirred for 6 hours. After cooling to room temperature, DMA (6 ml) was added to the mixture, and the mixture was stirred at 50° C. for 5 minutes and filtered. To the obtained filtrate were added dropwise 1 mol/L aqueous hydrochloric acid (10 ml) and water (4 ml) under ice-cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure at 60° C. for 3 hours to obtain the compound (IXa) (1.10 g, 1.93 mmol, yield 93%).

[0302] 1H-NMR (DMSO-D6) δ: 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.44 (1H, t, J=10.4 Hz), 3.69 (1H, dd, J=11.5, 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J=10.8, 2.9 Hz), 4.06 (1H, d, J=14.3 Hz), 4.40 (1H, d, J=11.8 Hz), 4.45 (1H, dd, J 9.9, 2.9 Hz), 5.42 (1H, dd, J=14.4, 1.8 Hz), 5.67 (1H, d, J=6.5 Hz), 5.72-5.75 (3H, m), 6.83-6.87 (1H, m), 7.01 (1H, d, J=6.9 Hz), 7.09 (1H, dd, J=8.0, 1.1 Hz), 7.14-7.18 (1H, m), 7.23 (1H, d, J=7.8 Hz), 7.37-7.44 (2H, m).

INDUSTRIAL APPLICABILITY

[0303] The present invention provide a catalyst useful in a process for the production of substituted polycyclic pyridone derivatives having a cap-dependent endonuclease inhibitory activity and intermediates thereof.