METHOD FOR PRODUCING MAXACALCITOL, AND INTERMEDIATE THEREFOR

Abstract

A new and improved method for preparing maxacalcitol and an intermediate therefor is provided. The method is an efficient and cost-effective process for preparing maxacalcitol and an intermediate therefor.

Claims

1. A process for preparing a compound of the following formula (5), which comprises the steps of: (i) subjecting a compound of the following formula (2) to ozonolysis and reduction to obtain a compound of the following formula (3); (ii) subjecting the compound of the following formula (3) to Baeyer-Villiger oxidation to obtain a compound of the following formula (4); and (iii) subjecting the compound of the following formula (4) to Homer-Wadsworth-Emmons reaction with a compound of the following formula (6): ##STR00013## ##STR00014## wherein TBS is t-butyldimethylsilyl, and Ph is phenyl.

2. The process according to claim 1, wherein the ozonolysis of step (i) is carried out using ozone in the presence of a base.

3. The process according to claim 1, wherein the Baeyer-Villiger oxidation of step (ii) is carried out using performic acid.

4. The process according to claim 1, wherein the Horner-Wadsworth-Emmons reaction of step (iii) is carried out in the presence of a base.

5. A compound of the following formula (5): ##STR00015## wherein TBS is t-butyldimethylsilyl.

6. A process for preparing maxacalcitol of the following formula (1), which comprises the steps of: (iv) subjecting a formate group of a compound of the following formula (5) to hydrolysis to obtain a compound of the following formula (7); (v) subjecting the compound of the following formula (7) to nucleophilic substitution with a compound of the following formula (8) to obtain a compound of the following formula (9); (vi) subjecting an epoxide group of the compound of the following formula (9) to ring-opening reduction to obtain a compound of the following formula (10); and (vii) deprotecting a t-butyldimethylsilyl protecting group of the compound of the following formula (10): ##STR00016## ##STR00017## wherein, TBS is t-butyldimethylsilyl.

7. The process according to claim 6, wherein the hydrolysis of step (iv) is carried out in the presence of a base.

8. The process according to claim 6, wherein the nucleophilic substitution of step (v) is carried out in the presence of a base.

9. The process according to claim 6, wherein the ring-opening reduction of step (vi) is carried out using L-selectride.

10. The process according to claim 6, wherein the deprotection of step (vii) is carried out in the presence of a fluoride compound.

Description

BEST MODE

[0071] 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: Preparation of Compound of Formula (3)

[0072] The compound of formula (2) (50.000 g, 126.05 mmol) and sodium bicarbonate (0.741 g, 8.82 mmol) were dissolved in dichloromethane (1.500 L, 30 v/w) and methanol (0.500 L, 10 v/w), followed by stirring in an acetone-dry ice bath. When the temperature of the resulting solution reached −70° C., an ozone generator was operated. When the resulting solution turned completely blue after stirring for 6 hours, the ozone generator was stopped. Argon was injected for 3 hours while stirring until the resulting solution became transparent to remove the supersaturated ozone in the resulting solution. When the temperature of the resulting solution reached −30° C. after removing the acetone-dry ice bath, dimethylsulfide (0.046 L, 630.26 mmol) was added thereto. After stirring at 20° C. for 16 hours, the resulting solution was concentrated to remove dichloromethane and methanol. Dichloromethane (0.500 L, 10 v/w) and water (0.750 L, 15 v/w) were added to the concentrated residue. A work-up process was performed by adding sodium sulfite (79.44 g, 630.26 mmol) to the solution having separated layers, followed by stirring for 2 hours. The separated organic layer was dried over sodium sulfate, followed by filtration and concentration. The concentrated residue weighed 33.60 g, and the compound of formula (3) containing impurities was used to prepare the compound of formula (4) without further purification.

[0073] .sup.1H NMR (300 MHz, CDCl.sub.3) δ9.61 (d, 1H, J=2.9 Hz), 2.49 (dd, 1H, J=7.6 Hz, 11.6 Hz), 2.43-2.35 (m, 1H), 2.34-2.25 (m, 2H), 2.11-1.74 (m, 7H), 1.51-1.35 (m, 1H), 1.17 (d, 3H, J=6.9 Hz), 0.95 (dd, 1H, J=6.8 Hz, 10.7 Hz), 0.69 (s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) δ 211.2, 204.2, 61.0, 51.4, 50.0, 49.1, 40.9, 38.6, 26.4, 23.9, 19.5, 13.4, 12.8.

Example 2: Preparation of Compound of Formula (4)

[0074] The concentrated residue (33.6 g) containing the compound of formula (3) obtained from Example 1 was dissolved in dichloromethane (151.2 mL, 4.5 v/w), followed by stirring in an ice bath. When the temperature of the resulting solution reached 0 to 4° C., formic acid (126.0 mL, 3.75 v/w) was added thereto. And then, 30% of hydrogen peroxide solution (69.3 mL, 2.06 v/w) was slowly added dropwise thereto for 30 minutes. After removing the ice bath and stirring at 20° C. for 16 hours, dichloromethane (120 mL) was added to dilute the reaction solution, and the organic layer separated from the aqueous layer was obtained. The separated organic layer was washed once with 30% of sodium thiosulfate aqueous solution (300 mL) and once with 7% of sodium bicarbonate aqueous solution (300 mL). The organic layer was separated and dried over sodium sulfate, followed by filtration and concentration. The concentrated residue was purified by column chromatography (hexane:ethyl acetate=10:1) to give the compound of formula (4) (13.52 g, 47.8% from the compound of formula (2)).

[0075] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.02 (s, 1H), 5.13-5.04 (m, 1H), 2.49 (dd, 1H, J=7.5 Hz, 11.4 Hz), 2.35-2.17 (m, 2H), 2.09-1.71 (m, 7H), 1.66-1.49 (m, 2H), 1.31 (d, 3H, J=6.3 Hz), 0.66 (s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) δ 210.9, 160.6, 71.8, 61.5, 55.6, 48.8, 40.8, 37.8, 24.5, 23.6, 20.6, 19.0, 13.1.

Example 3: Preparation of Compound of Formula (5)

[0076] The compound of formula (6) (42.88 g, 73.6 mmol) in which the solvent was completely dried was dissolved in tetrahydrofuran (225.0 mL, 15 v/w), followed by stirring. While the temperature of the resulting solution was maintained at −45 to −40° C. under argon gas, 2.5 M of n-butyllithium hexane solution (38.4 mL, 15.4 mmol) was slowly added dropwise thereto for 1 hour, followed by stirring at −45 to −40° C. for 1 hour. While the temperature of the resulting solution was maintained at −75 to −70° C., a solution of the compound of formula (4) (15.00 g, 66.9 mmol) dissolved in tetrahydrofuran (30.0 mL, 2 v/w) was slowly added dropwise thereto for 1 hour, followed by stirring at the same temperature for 30 minutes. After warming to 0 to 5° C. slowly for 30 minutes, water (150.0 mL, 10 v/w) was added dropwise thereto for 10 minutes maintaining the same temperature. The resulting solution was warmed to 20° C. slowly for 30 minutes, followed by stirring at the same temperature for 30 minutes. After ethyl acetate (500.0 mL) was added to dilute the reactants, the organic layer was washed with water (500.0 mL), and combined organic layer was dried over sodium sulfate, followed by filtration and concentration. The concentrated residue was purified by column chromatography (hexane:ethyl acetate=30:1) to give the compound of formula (5) (16.54 g, 42%), which can be used to prepare the compound of formula (7) without purification.

[0077] .sup.1H NMR (300 MHz, CDCl.sub.3) δ8.26 (s, 1H), 6.23 (d, 1H, J=11.2 Hz), 6.03 (d, 1H, J=11.3 Hz), 5.18 (d, 1H, J=1.4 Hz), 5.11-5.04 (m, 1H), 4.85 (d, 1H, J=2.4 Hz), 4.37 (dd, 1H, J=3.8 Hz, 6.5 Hz), 4.23-4.15 (m, 1H), 2.85 (dd, 1H, J=3.8 Hz, 14.4 Hz), 2.45 (dd, 1H, J=3.7 Hz, 13.1 Hz), 2.21 (dd, 1H, J=7.4 Hz, 13.0 Hz), 1.90-1.65 (m, 8H), 1.55-1.50 (m, 4H), 1.36-1.19 (m, 5H), 0.87 (s, 18H), 0.55 (s, 3H), 0.06 (s, 12H); .sup.13C NMR (75 MHz, CDCl.sub.3) δ 160.8, 148.3, 139.7, 135.6, 122.9, 118.5, 111.3, 73.3, 72.1, 67.5, 56.1, 55.6, 46.1, 44.8, 39.6, 28.7, 25.9, 25.8, 25.1, 23.1, 22.0, 20.8, 18.2, 18.1, 12.5, −4.7, −4.8, −5.1.

Example 4: Preparation of Compound of Formula (7)

[0078] The compound of formula (5) (30.00 g, 50.9 mmol) obtained from Example 3 was dissolved in methanol (180.0 mL, 6 v/w) and tetrahydrofuran (30.0 mL, 1 v/w), and potassium carbonate (1.41 g, 10.2 mmol) was added thereto. The resulting solution was stirred at 20 to 25° C. for 4 hours, followed by distilling under reduced pressure to remove 150 to 200 mL of the solvent. Water (300.0 mL) and ethyl acetate (300.0 mL) were added to the concentrated reactants, followed by enough mixing to obtain the organic layer. The organic layer was dried over sodium sulfate, followed by filtration and concentration. The concentrated residue was purified by column chromatography (hexane:ethyl acetate=20:1) to give the compound of formula (7) (27.88 g, 98%).

[0079] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.22 (d, 1H, J=11.2 Hz), 6.03 (d, 1H, J=11.3 Hz), 5.18 (dd, 1H, J=1.0 Hz, 2.4 Hz), 4.86 (d, 1H, J=2.3 Hz), 4.37 (dd, 1H, J=3.8 Hz, 6.6 Hz), 4.22-4.15 (m, 1H), 3.73-3.69 (m, 1H), 2.83 (dd, 2H, J=3.8 Hz, 11.3 Hz), 2.44 (dd, 1H, J=3.8 Hz, 13.1 Hz), 2.21 (dd, 1H, J=7.3 Hz, 13.1 Hz), 2.04-1.1.75 (m, 5H), 1.75-1.43 (m, 7H), 1.33-1.22 (m, 5H), 0.87 (m, 18H), 0.53 (s, 3H), 0.06 (m, 12H); .sup.13C NMR (75 MHz, CDCl.sub.3) δ 148.3, 140.2, 135.4, 123.0, 118.3, 111.2, 72.0, 70.3, 67.5, 58.7, 56.1, 46.0, 44.8, 39.6, 28.7, 25.9, 25.8, 24.9, 23.6, 23.1, 22.1, 18.25, 18.16, 12.6, −4.65, −4.68, −4.8, −5.1.

Example 5: Preparation of Compound of Formula (9)

[0080] The compound of formula (7) (31.87 g, 56.87 mmol) in which the solvent was completely dried was dissolved in tetrahydrofuran (49.1 mL, 1.54 v/w), and 60% w/w of sodium hydride (5.69 g, 142.17 mmol) was added thereto, followed by stirring at 20 to 25° C. for 30 minutes. The compound of formula (8) (18.20 g, 113.74 mmol) was added to the resulting solution, followed by heating to 65 to 70° C. and stirring for 1 hour. 10% of ammonium chloride aqueous solution (100 mL, 3.14 v/w) was slowly added dropwise thereto at 0 to 5° C. for 30 minutes, followed by extracting twice using ethyl acetate (100 mL, 3.14 v/w). The obtained organic layer was dried over sodium sulfate, followed by filtration and concentration. The residue was purified by column chromatography (hexane:ethyl acetate=49:1) to give the compound of formula (9) (31.76 g, 87%).

[0081] 1H NMR (300 MHz, CDCl.sub.3) δ 6.23 (d, 1H, J=11.2 Hz), 6.03 (d, 1H, J=11.2 Hz), 5.19 (d, 1H, J=1.5 Hz), 4.86 (d, 1H, J=2.4 Hz), 4.38 (dd, 1H, J=3.9 Hz, 6.6 Hz), 4.21-4.18 (m, 1H), 3.66 (ddd, 1H, J=2.3 Hz, 5.5 Hz, 10.8 Hz), 3.45-3.23 (m, 2H), 2.92 (dt, 1H, J=1.9 Hz, 5.4 Hz), 2.83 (dd, 1H, J=3.3 Hz, 11.9 Hz), 2.44 (dd, 1H, J=3.7 Hz, 13.1 Hz), 2.21 (dd, 1H, J=7.2 Hz, 13.1 Hz), 2.08-1.94 (m, 2H), 1.94-1.77 (m, 3H), 1.77-1.60 (m, 3H), 1.58-1.41 (m, 4H), 1.38-1.25 (m, 8H), 1.23-1.11 (m, 3H), 0.88-0.87 (m, 18H), 0.53-0.52 (m, 3H), 0.07-0.06 (m, 12H).

Example 6: Preparation of Compound of Formula (10)

[0082] The compound of formula (9) (31.66 g, 49.07 mmol) in which the solvent was completely dried was dissolved in tetrahydrofuran (126.6 mL, 4 v/w) under argon gas, and 1M of L-selectride tetrahydrofuran solution (88.3 mL, 88.33 mmol) was added dropwise thereto at 20 to 25° C. for 30 minutes. The resulting solution was heated to 65 to 70° C. while stirring for 2 hours, and 10% of sodium hydroxide aqueous solution (70 mL, 2.21 v/w) was added dropwise thereto for 30 minutes while maintaining 0 to 5° C. And then, 30% of hydrogen peroxide solution (31.7 mL, 1 v/w) was added dropwise thereto for 30 minutes. After the resulting solution was stirred at 20 to 25° C. for 1 hour, 30% of sodium thiosulfate aqueous solution (100 mL, 3.16 v/w) was added thereto at the same temperature, followed by stirring at 20 to 25° C. for 1 hour. Ethyl acetate (100 mL, 3.16 v/w) was added to the resulting solution for extraction, and then ethyl acetate (200 mL, 6.32 v/w) was added to the aqueous layer to extract once. Afterwards, the combined organic layer was dried over sodium sulfate, followed by filtration and concentration. The residue was purified by column chromatography (hexane:ethyl acetate=19:1) to give the compound of formula (10) (29.85 g, 94%).

[0083] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.22 (d, 1H, J=11.2 Hz), 6.02 (d, 1H, J=11.2 Hz), 5.19 (d, 1H, J=1.4 Hz), 4.86 (d, 1H, J=2.3 Hz), 4.38 (dd, 1H, J=4.2 Hz, 6.5 Hz), 4.22-4.13 (m, 1H), 3.87-3.81 (m, 1H), 3.77 (s, 1H), 3.52-3.45 (m, 1H), 3.29-3.20 (m, 1H), 2.52 (dd, 1H, J=3.0 Hz, 11.5 Hz), 2.44 (dd, 1H, J=3.7 Hz, 13.2 Hz), 2.21 (dd, 1H, J=7.1 Hz, 13.2 Hz), 2.02-1.78 (m, 5H), 1.78-1.61 (m, 5H), 1.60-1.41 (m, 5H), 1.31 (dd, 1H, J=4.2 Hz, 12.6 Hz), 1.24 (d, 6H, J=2.5 Hz), 1.19 (d, 1H, J=6.0 Hz), 0.88-0.87 (m, 18H), 0.52 (s, 1H), 0.07-0.06 (m, 12H).

Example 7: Preparation of Compound of Formula (1)

[0084] The compound of formula (10) (23.94 g, 36.99 mmol) in which the solvent was completely dried was dissolved in tetrahydrofuran (23.9 mL, 1 v/w) under argon gas, and 1M of tetrabutylammonium fluoride tetrahydrofuran solution (185.0 mL, 185.00 mmol) was added thereto at 20 to 25° C., followed by stirring at the same temperature for 72 hours. 10% of ammonium chloride aqueous solution (300 mL, 12.53 v/w) and ethyl acetate (100 mL, 4.18 v/w) were added to the resulting solution to separate layers, and the organic layer was obtained. Ethyl acetate (300 mL, 12.53 v/w) was added to the aqueous layer to extract twice. The combined organic layer was dried over sodium sulfate, followed by filtration and concentration. The residue was purified by column chromatography (dichloromethane:acetonitrile=2:1) to give the compound of formula (1) (15.42 g, 94%). The obtained compound of formula (1) was recrystallized (hexane:ethyl acetate=40:9) to give the compound of formula (1) (11.34 g, 74%) which is a purified crystalline solid.

[0085] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.35 (d, 1H, J=11.2 Hz), 6.03 (d, 1H, J=11.3 Hz), 5.32 (m, 1H), 4.98 (m, 1H), 4.42 (m, 1H), 4.21 (m, 1H), 3.87-3.81 (m, 2H), 3.51-3.44 (m, 1H), 3.30-3.22 (m, 1H), 2.83 (dd, 1H, J=3.3 Hz, 11.8 Hz), 2.58 (dd, 1H, J=3.4 Hz, 13.4 Hz), 2.30 (dd, 1H, J=6.6 Hz, 13.4 Hz), 2.18-2.16 (m, 1H), 2.04 (m, 1H), 2.04-1.85 (m, 5H), 1.73 (d, 1H, J=5.6 Hz), 1.69-1.44 (m, 7H), 1.31 (dd, 1H, J=3.9 Hz, 12.7 Hz), 1.23 (s, 6H), 1.19 (d, 3H, J=6.0 Hz), 0.53 (s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) M47.7, 142.1, 133.5, 124.6, 117.5, 111.9, 78.7, 70.7, 70.6, 66.7, 65.5, 57.1, 56.1, 45.2, 44.8, 42.8, 41.5, 39.5, 29.2, 29.1, 28.9, 25.6, 23.2, 22.2, 18.9, 12.6.