Method for preparing treprostinil and intermediate therefor

Abstract

The present invention relates to a cost-effective and efficient method for preparing treprostinil with high purity, and an intermediate therefor.

Claims

1. A compound of the following formula (9): ##STR00021## wherein, represents a single or double bond between carbon atoms, R.sub.1 represents hydrogen or a halogen, Y represents -OR.sub.5:-H or -H:-OR.sub.5, R.sub.5 represents hydrogen, and Z represents a C.sub.1-C.sub.6 alkyl group.

2. The compound of formula (9) according to claim 1, wherein represents a single bond between carbon atoms, R.sub.1 represents chlorine, Y represents -OR.sub.5:-H, R.sub.5 represents hydrogen, and Z represents n-butyl.

3. A method for preparing a compound of the following formula (9), which comprises a step of subjecting a compound of the following formula (8) to intramolecular Friedel-Crafts allylic alkylation: ##STR00022## wherein, represents a single or double bond between carbon atoms, R.sub.1 represents hydrogen or a halogen, Y represents -OR.sub.5:-H or -H:-OR.sub.5, R.sub.5 represents hydrogen, and Z represents a C.sub.1-C.sub.6 alkyl group.

4. A method for preparing a compound of the following formula (10), which comprises a step of subjecting a compound of the following formula (9) to hydrogenation: ##STR00023## wherein, represents a single or double bond between carbon atoms, R.sub.1 represents hydrogen or a halogen, Y represents -OR.sub.5:-H or -H:-OR.sub.5, R.sub.5 represents hydrogen, and Z represents a C.sub.1-C.sub.6 alkyl group.

5. The method according to claim 3, wherein the intramolecular Friedel-Crafts allylic alkylation is carried out using a palladium catalyst and a ligand.

6. The method according to claim 5, wherein the palladium catalyst is bis(dibenzylideneacetone)palladium(0), and the ligand is triphenylphosphine.

7. The method according to claim 4, wherein the hydrogenation is carried out using Pd/C under a basic condition.

8. A method for preparing a compound of the following formula (1), which comprises the steps of: (vii) subjecting a compound of the following formula (9) to hydrogenation to obtain a compound of the following formula (10); (viii) subjecting the compound of the following formula (10) to alkylation with a compound of the following formula (11) to obtain a compound of the following formula (12); and (ix) hydrolyzing an ester group of the compound of the following formula (12) to give the compound of formula (1): ##STR00024## wherein, represents a single or double bond between carbon atoms, R.sub.1 represents hydrogen or a halogen, R.sub.3 represents a C.sub.1-C.sub.6 alkyl group, Y represents -OR.sub.5:-H or -H:-OR.sub.5, R.sub.5 represents hydrogen, Z represents a C.sub.1-C.sub.6 alkyl group, and X represents a halogen.

Description

BEST MODE

(1) The present invention will be described in more detail by following examples. It will be obvious to those skilled in the art that these examples are merely described for illustration of the present invention and the scope of the present invention is not limited thereto.

Example 1: Synthesis of Compound of Formula (4a)

(2) ##STR00012##

(3) The compound of formula (3a) (15.29 g) was dissolved in diethylether (230 mL), cooled to 68 C., and then stirred for 30 minutes, t-Butyl lithium (45.65 mL) was slowly added dropwise for 20 minutes with maintaining the internal temperature of 60 C., and the resulting solution was stirred for 30 minutes with maintaining the temperature below 65 C. Copper cyanide (1.66 g) was added at the temperature of 60 C. or lower and the resulting solution was warmed to 15 C. to observe complete dissolution, followed by cooling below 65 C. To the resulting solution was slowly added dropwise the compound of formula (2a) (8.21 g) dissolved in diethylether (120 mL) with maintaining the temperature of 60 C. or lower. The resulting solution was stirred for 10 minutes and then warmed to 10 C. A solution (400 mL) mixing saturated ammonium chloride aqueous solution with ammonia water at a ratio of 6:1 was added dropwise thereto, followed by stirring for 30 minutes. When the color of the aqueous layer turned into dark blue, the organic layer was separated, and dried over sodium sulfate, followed by filtration, and concentration of the filtrate under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:10) to give the compound of formula (4a) (9.52 g, 70.4%).

(4) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.65-7.69 (m, 4H), 7.34-7.44 (m, 6H), 7.06 (dd, J=6.9 Hz, 1H), 6.65-6.66 (m, 1H), 6.59-6.62 (m, 2H), 5.02-5.05 (m, 1H), 4.43 (d, J=5.4 Hz, 1H), 3.39 (bs, 2H), 1.39 (s, 3H), 1.33 (s, 3H), 1.09 (s, 9H).

Example 2: Synthesis of Compound of Formula (5a)

(5) ##STR00013##

(6) 20% Nysted reagent (26.36 mL) was added to THF (120 mL) at room temperature, followed by cooling to 20 C. To the resulting mixture was slowly added dropwise the compound of formula (4a) (8.53 g) dissolved in methylene chloride (60 mL). The resulting solution was cooled to 60 C. or lower, and 1.0M titanium tetrachloride (12 mL) was slowly added dropwise thereto with maintaining the temperature below 60 C. The resulting solution was warmed to room temperature and stirred for 2 hours. Saturated sodium hydrogen carbonate aqueous solution (400 mL) was added thereto. After the resulting solution turned from black into white, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (100 mL). The combined organic layer was dried over sodium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:10) to give the compound of formula (5a) (7.94 g, 93.3%).

(7) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.67-7.69 (m, 4H), 7.32-7.45 (m, 6H), 7.01 (d, J=8.7 Hz, 1H), 6.70 (d, J=3.0 Hz, 1H), 6.52 (dd, J=8.7 Hz, 1H), 5.14 (s, 1H), 4.82 (s, 1H), 4.72 (d, J=6.0 Hz, 1H), 4.26 (d, J=6.0 Hz, 1H), 3.51 (q, J=4.5 Hz, 1H), 2.79-2.92 (m, 2H), 2.46 (t, J=7.8 Hz, 1H), 1.73 (t, J=7.2 Hz, 1H), 1.55 (s, 3H), 1.20-1.30 (m, 15H), 1.10 (s, 9H), 0.86 (m, 12H)

Example 3: Synthesis of Compound of Formula (6a)

(8) ##STR00014##

(9) The compound of formula (5a) (7.9 g) was dissolved in THF (24 mL) and then cooled to 0 C. 90% trifluoroacetic acid (63.52 mL) was slowly added dropwise thereto. After warming the resulting solution to room temperature, 6N sodium hydroxide aqueous solution was added to adjust pH to 8-9. Ethyl acetate (200 mL) and water (100 mL) were added thereto, followed by stirring. Then, the organic layer was separated and dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=2:1) to give the compound of formula (6a) (5.52 g, 86.7%).

(10) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.68-7.71 (m, 4H), 7.35-7.46 (m, 6H), 7.05 (d, J=8.7 Hz, 1H), 6.58-6.61 (m, 2H), 5.12 (s, 1H), 4.74 (s, 1H), 4.21 (t, J=4.8 Hz, 1H), 3.64 (bs, 1H), 3.41 (bs, 1H), 2.84-2.91 (m, 1H), 2.55-2.62 (m, 1H), 2.46 (bs, 1H),2.27-2.36 (m, 2H), 1.53-1.59 (m, 1H), 1.47 (bs, 1H), 1.23-1.32 (m, 9H), 1.09 (s, 9H), 0.88 (t, J=6.3 Hz, 3H).

Example 4: Synthesis of Compound of Formula (7a)

(11) ##STR00015##

(12) The compound of formula (6a) (242 mg) was dissolved in THF (3 mL), and CDI (127 mg) and DMAP (95 mg) were added thereto, followed by stirring at room temperature for an hour and 30 minutes. After the completion of the reaction was confirmed, saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (30 mL) were added and stirred. The organic layer was separated and dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:2.5) to give the compound of formula (7a) (162 mg, 64.3%).

(13) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.67-7.71 (m, 4H), 7.34-7.45 (m, 6H), 7.04 (d, J=8.4 Hz, 1H), 6.55-6.61 (m, 2H), 5.32 (s, 1H), 5.14 (d, J=5.1 Hz, 1H) 4.98 (s, 1H), 4.66 (dd, J=7.2 Hz, 1H), 3.42 (bs, 1H), 2.63-2.80 (m, 2H), 2.43-2.49 (m, 1H), 2.03 (s, 1H), 1.94-1.96 (m, 1H), 1.54 (s, 1H), 1.22-1.35 (m, 10H), 1.10 (s, 9H), 0.88 (t, J=6.6 Hz, 3H).

Example 5: Synthesis of Compound of Formula (5a)

(14) ##STR00016##

(15) The compound of formula (7a) (95 mg) was dissolved in THF (3 mL), and cooled to 0 C. TBAF (47 mL) was added thereto, followed by additional stirring for 30 minutes. After the completion of the reaction was confirmed, saturated ammonium chloride aqueous solution (20 mL) and ethyl acetate (40 mL) were added, followed by additional stirring for 30 minutes. The organic layer was separated and dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:1) to give the compound of formula (8a) (60 mg, 97.9%).

(16) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.85 (s, 1H), 7.15 (d, J=8.4 Hz, 1H) 6.61-6.68 (m, 2H), 5.41 (s, 1H), 5.23 (d, J=7.2 Hz, 1H), 5.10 (s, 1H), 4.79 (d, J=6.9 Hz, 1H), 3.51 (bs, 1H), 2.79 (bs, 4H), 2.13 (bs, 1H), 2.05 (s, 1H), 1.23-1.37 (m, 10H), 0.87 (t, J=6.3 Hz, 3H).

Example 6: Synthesis of Compound of Formula (9a)

(17) ##STR00017##

(18) The compound of formula (8a) (60 mg) was dissolved in toluene (3.5 mL), and Pd(dba).sub.2 (4.48 mg) and PPh.sub.3 (4.59 mg) were added thereto, followed by stirring at room temperature for an hour. After the completion of the reaction was confirmed, saturated ammonium chloride aqueous solution (10 mL) and ethyl acetate (30 mL) were added, followed by additional stirring. The organic layer was separated and dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:1) to give the compound of formula (9a) (34.7 mg, 64.7%).

(19) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 6.93 (d, J=8.7 Hz, 1H), 6.52 (d, J=8.7 Hz, 1H), 5.45 (s, 1H), 4.40 (s, 1H), 3.51 (m, 1H), 3.49 (s, 1H), 3.33-3.42 (m, 2H), 3.23-3.28 (m, 1H), 2.19-2.24 (m, 2H), 1.64-1.74 (m, 2H), 1.49-1.61 (m, 3H), 1.20-1.40 (m, 8H), 0.84 (t, J=6.6 Hz, 3H).

Example 7: Synthesis of Compound of Formula (10a)

(20) ##STR00018##

(21) The compound of formula (9a) (34.7 mg) was dissolved in methanol (3 mL), and 10% Pd/C (9 mg) and triethylamine (10.7 mg) were added thereto, followed by stirring under hydrogen condition for 15 hours. After the completion of the reaction was confirmed, the resulting solution was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:1) to give the compound of formula (10a) (20.5 mg, 65%).

(22) .sup.1H NMR (300 MHz. CDCl.sub.3, ppm): 6.92 (t, J=7.5 Hz, 1H), 6.64 (d, J=7.8 Hz, 2H), 3.53-3.68 (m, 2H), 2.45-2.74 (m, 4H), 2.27-2.34 (m, 1H), 2.06-2.12 (m, 1H), 1.88-1.98 (m, 1H), 1.05-1.24 (m, 14H), 0.94 (t, J=6.6 Hz, 3H).

Example 8: Synthesis of Compound of Formula (12a)

(23) ##STR00019##

(24) To the compound of formula (10a) (440 mg) dissolved in acetone (4.0 mL) were added potassium carbonate (549 mg) and the compound of formula (11a) (405 mg). The resulting solution was stirred at 50-60 C. for 10-16 hours, and the completion of the reaction was confirmed by HPLC. The resulting solution was cooled to 15-25 C., filtered, and concentrated. Ethyl acetate (4.5 mL) and water (5.0 mL) were added and stirred. The organic layer was separated and dried over sodium sulfate (1.0 g), followed by filtration and concentration. The resulting residue was subjected to chromatography (ethyl acetate:n-hexane=1:1) to give the compound of formula (12a) (400 mg, 74.8%).

(25) .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 7.07 (t, J=7.8, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.63 (d, J=7.8 Hz, 1H), 4.63 (s, 2H), 3.79 (s, 3H), 3.54-3.76 (m, 2H), 2.88 (dd, J=14.7, 5.7 Hz, 1H), 2.76 (dd, J=14.1, 6.0 Hz, 1H), 2.42-2.59 (m, 2H), 2.14-2.30 (m, 2H), 1.85-1.94 (m, 1H), 1.12-1.75 (m, 14H), 0.90 (t, J=7.0 Hz, 3H).

(26) .sup.13C NMR (75 MHz, CDCl.sub.3, ppm): 169.72, 154.89, 141.06, 127.81, 126.14, 121.63, 109.69, 76.60, 72.58, 66.00, 52.31, 52.16, 41.44, 41.28, 37.45, 35.00, 33.74, 32.79, 31.91, 28.66, 25.98, 25.38, 22.65, 14.06.

Example 9: Synthesis of Compound of Formula (1a)

(27) ##STR00020##

(28) To the compound of formula (12a) (0.38 g) dissolved in ethanol (2.0 mL) was added sodium hydroxide (75 mg) dissolved in water (2.0 mL), followed by stirring for 3-5 hours. The completion of the reaction was confirmed by HPLC. After the reaction solvent was evaporated, water (2.0 mL) was added, followed by stirring. Hydrochloric acid (0.21 g) dissolved in water (1.82 mL) was added for acidification to pH 3-4. Ethyl acetate (4.5 mL) was added and stirred for 20-30 minutes, and the organic layer was separated. Water (5.0 mL) was added to the separated organic layer and stirred for 20-30 minutes, and then the organic layer was separated. Saline water (5.0 mL) was added to the separated organic layer, followed by stirring for 20-30 minutes. The organic layer was separated, and dried over sodium sulfate, followed by filtration and concentration to give the compound of formula (1a) (367 mg, 100%).

(29) .sup.1H NMR (300 MHz, MeOD, ppm): 7.05 (t, J=8.0 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 3.52-3.67 (m, 2H), 2.61-2.80 (m, 3H), 2.50 (dd, J=14.4, 6.0 Hz, 1H), 2.21-2.34 (m, 1H), 1.86-2.12 (m, 2H), 1.05-1.76 (m, 14H), 0.92 (t, J=7.0 Hz, 3H).

(30) .sup.13C NMR (75 MHz, MeOD, ppm): 172.93, 156.52, 142.16, 128.69, 127.15, 122.42, 110.79, 77.61, 72.89, 66.56, 52.71, 498.83, 49.55, 49.26, 42.30, 42.01, 38.28, 36.04, 34.56, 34.06, 33.14, 29.60, 26.61, 26.48, 23.73, 14.41.