JP3391248B2 - Method for producing calcitriol intermediate - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an important intermediate corresponding to the A ring part in the production of calcitriol and its related vitamin derivatives for the treatment of osteoporosis and other diseases, and a novel intermediate obtained in this process. The body and its manufacturing method.

[0002]

BACKGROUND OF THE INVENTION Calcitriol and its related vitamin derivatives are used as therapeutic agents for osteoporosis and other diseases.
There has been a demand for the development of a more efficient method for this production method, particularly for the synthesis method of the A ring portion of calcitriol. As a method for synthesizing the A ring part,
b)

[Chemical 13] (In the formula, R means methyl (9a compound) or ethyl (9b compound), and TBS means t-butyldimethylsilyl) (E. G. Bag)
Giolini et al., J. Am. Chem. Soc., 1
04, 2945 (1982)) and the following formula (10).

[Chemical 14] (In the formula, TBS is the same as the above.) (B. M. Trost et al., J. Am. Chem. S.)
oc., 114, 9836 (1992)).

However, these methods have many industrial problems, and development of more excellent methods has been required. That is, in the former method, d-carvone is used as a raw material,
After stereospecific epoxidation, it was reacted with the carbanion of diethyl (carboxyethyl) phosphate in the Horner-Simons reaction, and the resulting α, β-unsaturated ester mixture of Z and E forms (9: 1) was formed. After separation with a silica gel column, removal of the Z-form, ring opening of the epoxy group, conversion to diacetate, oxidation of the isopropenyl group to acetyl and then acetate to triacetate, hydrolysis to triol Although only the secondary hydroxyl group is protected with t-butyldimethylsilyl group and dehydrated to be converted into an exomethylene group, it is synthesized, but the process is long and it is very careful not to cause side reactions during the reaction. Is a process that requires In the latter method, the intermediate 3-hydroxy-5-
t-Butyldiphenylsiloxyoct-7-in-1-
The syn-form and anti-form of ene must be separated, and in order to improve economic efficiency, the hydroxyl group at the 3-position of the syn-form needs to be stereo-inverted by the Mitsunobu method to form the anti-form. Unreacted by removing the (+) form of the racemic mixture by selective asymmetric epoxidation by the principle of dynamic resolution.
It was necessary to collect the (-) form, and it was not easy to obtain a large amount of products with high optical purity, and the operation was complicated as an industrial production method.

[0004]

In view of the above, the present inventor has made
As a result of earnest studies on a method for efficiently obtaining an intermediate of the A ring portion of calcitriol and its related vitamin derivative, that is, a compound represented by the following formula (5), by a simple reaction route with little by-products, 4 represented by the following formula (1)
Using hydroxy-δ-valerolactone as a raw material, a new process for producing a target compound was found according to the following reaction route. The present invention relates to a method for producing an intermediate corresponding to the A ring portion of calcitriol and related vitamin derivatives, a precursor thereof, and a method of producing the same. The production process of compound (5) according to the present invention is shown below.

[Chemical 15] (In the formula, Bn is a benzyl group or an analog group thereof, R ¹ is a silyl protecting group, R ² is a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group or a phenyl group, and R ³ is an ether type protecting group. Group, R ⁴ means a silyl protecting group.)

The hydroxy group of 4-hydroxy-δ-valerolactone represented by the formula (1) is protected with a silyl group and then reduced to obtain a diol body represented by the formula (2). After selectively converting the primary hydroxyl group of the diol represented by the formula (2) into a phenylthio group, the secondary hydroxyl group is subjected to sulfonylation, deprotection and epoxidation to obtain the epoxy compound represented by the formula (3). . Formula (3)
After the hydroxyl group of the epoxy compound represented by the formula (4) is protected with an ether-based protecting group, it is reacted with a lithium acetylene ethylenediamine complex to obtain the acetylene compound represented by the formula (4). Then, after deprotecting the acetylene compound represented by the formula (4), it is protected with a silyl group to oxidize a sulfide to a sulfoxide, followed by thermal elimination and silylation again to obtain the objective (5)
To synthesize. More specifically, 4-hydroxy-δ-valerolactone represented by the formula (1), preferably 6-benzyloxymethyl-4-hydroxy-δ-valerolactone, is used as a non-carboxylic acid such as N, N-dimethylformamide or dimethyl sulfoxide. Protic polar solvent, tetrahydrofuran,
Ether solvent such as 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol monomethyl ether, dichloroethane, 1,2
-Hydrogen solvent such as dichloroethane, and in a solvent such as a mixed solvent thereof, triethylamine, pyridine, after silylation in the presence of an organic base such as imidazole, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, It is reduced with a metal hydride such as lithium borohydride, sodium borohydride or diisobutylaluminum hydride in an ether solvent such as diglyme, triglyme or diethylene glycol monomethyl ether to be converted into the diol body represented by the formula (2). Examples of the silylating agent include trimethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride and the like, but t-butyldimethylsilyl chloride is preferred.

A disulfide reagent and a trialkylphosphine, or triphenylphosphine, preferably tributylphosphine, is allowed to act on the diol represented by the formula (2) to convert only the primary hydroxyl group into a sulfide group. Examples of the disulfide reagent include dimethyl disulfide, diethyl disulfide, diallyl disulfide, diphenyl disulfide, dibenzyl disulfide and the like.
Diphenyl disulfide is preferred. Subsequently, the secondary hydroxyl group is used with a sulfonyl halide such as methanesulfonyl halide, benzenesulfonyl halide, or p-toluenesulfonyl halide, or a sulfonic anhydride such as methanesulfonic anhydride or p-toluenesulfonic anhydride. Converted to sulfonyloxy group and debenzylated
(De-Bn conversion) and de-silylation are performed at the same time, followed by base treatment,
Preferably, it is converted to the epoxy compound represented by the formula (3) using sodium hydroxide or potassium hydroxide. The preferred reagent for debenzylation and desilylation is borane tribromide. After protecting the hydroxyl group of the epoxy compound represented by the formula (3), the lithium acetylide ethylenediamine complex is reacted in dimethyl sulfoxide to open the epoxy to deprotect the acetylene compound represented by the formula (4). ,
Aprotic polar solvent such as N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,
Ether solvent such as 4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol monomethyl ether, dichloroethane, 1,2-
In a halogen-based solvent such as dichloroethane or a mixed solvent thereof, in the presence of an organic base such as triethylamine, pyridine or imidazole, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, etc. After silylating the two hydroxyl groups with the silylating agent, it is oxidized with m-chloroperbenzoic acid, hydrogen peroxide, etc. to a sulfoxide, which is heated under reflux in dimethyl sulfoxide to convert it to a vinyl group, and then N, N-dimethylformamide. Aprotic polar solvent such as dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, ether solvent such as diethylene glycol monomethyl ether, dichloroethane,
In a halogen-based solvent such as 1,2-dichloroethane or a mixed solvent thereof, in the presence of an organic base such as triethylamine, pyridine or imidazole, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyl The target formula (5) is obtained by silylating with a silylating agent such as diphenylsilyl chloride.
A compound represented by

The preferred intermediates (1)-(4) used in the above reaction process and the preferred target compound (5) obtained are as follows. As the compound of formula (1), the compound of formula (1a):

[Chemical 16] (In the formula, Bzl means a benzyl group.) As the compound of formula (2), the compound of formula (2a):

[Chemical 17] (In the formula, R ¹¹ is trimethylsilyl, triethylsilyl,
t-Butyldimethylsilyl, or t-butyldiphenylsilyl, and Bzl means benzyl group. ) As the compound of formula (3), the compound of formula (3): as the compound of formula (4), the compound of formula (4a):

[Chemical 18] (In the formula, R ²¹ represents a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a phenyl group, and R ³¹ represents a methoxymethyl group or a tetrahydropyranyl group.) As the compound of the formula (5), Compound of formula (5a):

[Chemical 19] (In the formula, R ⁴¹ is trimethylsilyl, triethylsilyl,
It means t-butyldimethylsilyl or t-butyldiphenylsilyl. ) According to the method of the present invention, 4-hydroxy-δ-valerolactone represented by the formula (1) is optically active (4S, 6R).
If the body is used, significant racemization does not occur and (3R, 5
R) -form compound (2), (2S, 4R) -form compound (3), and (4R, 6R) -form compound (4) to (4R, 6R)
A calcitriol intermediate represented by body formula (5) is obtained. 4-Hydroxy-δ-valerolactone represented by the formula (1) used as a starting material is synthesized from epichlorohydrin via benzyl glycidyl ether and then to Synthesis,
It can be produced by the method described on page 539 (1989) or a method analogous thereto. Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto. The abbreviations Bzl and TB used in the examples
S, Ph, Ms, MOM, DMF, DMSO, THF,
DMAP means benzyl, t-butyldimethylsilyl, phenyl, methanesulfonyl, methoxymethyl, N, N-dimethylformamide, dimethylsulfoxidetetrahydrofuran and 4-dimethylaminopyridine, respectively.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Example 1 (4S, 6R) -6-benzyloxymethyl-4-t-
Synthesis of butyldimethylsilyloxy-tetrahydro-2-pyrone (11)

[Chemical 20] (4S, 6R) -6-Benzyloxymethyl-4-hydroxy-tetrahydro-2-pyrone (1.704g, 7.2
1 mmol) in DMF (30 ml) under ice-cooling t-butyldimethylsilyl chloride (2.714 g, 14.42 m)
mol) and imidazole (1.963 g, 28.84 m)
(mol) was sequentially added and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with diethyl ether, washed with water and saturated saline,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the residue by flash chromatography (4S, 6R)-
6-benzyloxymethyl-4-t-butyldimethylsilyloxy-tetrahydro-2-pyrone (2.395 g,
Yield 94.8%) was obtained.

[Α] _D ²⁹ -4.0 (c 1.23, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.40-7.26 (m, 5H), 4.89
-4.80 (m, 1H), 4.59 (dd, J = 15.9, 12.1 Hz), 4.38-
4.32 (m, 1H), 3.71 (dd, 1H, J = 10.7, 3.8 Hz), 3.61
(dd, 1H, J = 10. 7, 4.1 Hz), 2.62-2.55 (m, 2H), 2.00
-1.80 (m, 2H), 0.87 (s, 9H), 0.06 (s, 3H), 0.0 4
(s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 169.9 (s), 137.86 (s),
128.4 (d), 127.7 (d), 127.6 (d), 75.0 (d), 73.4
(t), 71.7 (t), 63.4 (d), 39.1 (t), 32.6 (t), 25.5
(q), 17.7 (s), -5.2 (q); IR (neat): n = 1737, 1252, 1235 cm ^-1 .MS: m / z = 293 (M ⁺ -57), 91 (100%) HRMS: Calculated for C ₁₅ H ₂₁ O ₄ Si: 293.1210 (M ⁺ -57). Found: 293.1226.

Synthesis of (3R, 5R) -3-t-butyldimethylsilyloxy-6-benzyloxy-1,5-hexanediol (12)

[Chemical 21] (4S, 6R) -6-Benzyloxymethyl-4-t-butyldimethylsilyloxy-tetrahydro-2-pyrone
Lithium borohydride (54 mg, 2.49 m) in a THF (13 ml) solution of (874 mg, 2.49 mmol) under ice cooling.
mol) was gradually added, and the mixture was stirred at the same temperature for 4 hours and then at room temperature for 4 hours.
Stir for hours. The reaction mixture was diluted with diethyl ether, water under ice cooling was added, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain (3R, 5R) -3-t-butyldimethylsilyloxy-6-benzyloxy-1,5-hexanediol (731 mg, yield 82.8%).

[Α] _D ²⁵ +15.6 (c 0.91, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.40-7.28 (m, 5H), 4.56
(s, 2H), 4.23-4.12 (m, 1H), 3. 98-3.88 (m, 1H),
3.86-3.65 (m, 2H), 3.47 (dd, 1H, J = 9.3, 3.6 Hz),
3.35 (dd, 1H, J = 9.5, 7.6 Hz), 2.69 (br s, 1H, D ₂ O
Compatibility), 2.29 (brs, 1H, D ₂ O compatibility), 1.96-1.84
(m, 1H), 1.80-1.60 (m, 3H), 0.89 (s, 9H), 0.11 (s,
3H), 0.09 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ138.1 (s), 128.6 (d), 1
28.0 (d), 127.9 (d), 74.7 (t), 73.7 (t), 69.7 (d),
68.1 (d), 39.8 (t), 38.1 (t), 25.8 (q), 17.8 (s),
-4.7 (q); IR (neat): n = 3394 cm ^-1 .MS: m / z = 297 (M ⁺ -57), 91 (100%). HRMS: Calculated as C ₁₅ H ₂₅ O ₄ Si. : 297.1522 (M ⁺ -57). Measurement: 297.1507.

Synthesis of (2R, 4R) -4-t-butyldimethylsilyloxy-1-benzyloxy-6-phenylthio-2-hexanol (13)

[Chemical formula 22] (3R, 5R) -3-t-butyldimethylsilyloxy-
6-benzyloxy-1,5-hexanediol (75
Diphenyl disulfide (69 mg, 318 μmol) and tributylphosphine (79 μl, 318 μmol) were sequentially added to a pyridine solution (mg, 212 μmol) under ice cooling, and the mixture was stirred at room temperature for 8 hours, and the solvent was concentrated under reduced pressure. By purifying the residue by flash chromatography (2R, 4R)
-4-t-Butyldimethylsilyloxy-1-benzyloxy-6-phenylthio-2-hexanol (85 m
g, yield 89.8%).

[Α] _D ²⁵ +3.86 (c 1.05, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.40-7.24 (m, 9H), 7.20
-7.13 (m, 1H), 4.55 (s, 2H), 4.10-4.00 (m, 1H), 3.
96-3.86 (m, 1), 3.44 (dd, 1H, J = 9.6, 3.8 Hz), 3.34
(dd, 1H, J = 9.3, 7.1 Hz), 2.95 (t, 2H, J = 7.7 Hz),
2.76 (d, 1H, J = 2.8 Hz, D ₂ O compatible), 1. 94-1.77
(m, 2H), 1.72-1.54 (m, 2H), 0.88 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 138.0 (s), 136.6 (s),
129.0 (d), 128.9 (d), 128.4 (d), 127.8 (d), 125.8
(d), 74.5 (t), 73.2 (t), 69.4 (d), 68.1 (d), 39.8
(t), 36.2 (t), 29.0 (t), 25.7 (q), 17.8 (s), -4.6
(q), -4.8 (q); IR (neat): n = 3444 cm ^-1 .MS: m / z = 389 (M ⁺ -57), 91 (100%). HRMS: C ₂₁ H ₂₉ O ₃ Calculated as SSi: 389.1607 (M ⁺ -57).
Measured: 389.1597.

Synthesis of (2R, 4R) -4-t-butyldimethylsilyloxy-1-benzyloxy-2-methanesulfonyloxy-6-phenylthiohexane (14)

[Chemical formula 23] (2R, 4R) -4-t-butyldimethylsilyloxy-
A solution of 1-benzyloxy-6-phenylthio-2-hexanol (149 mg, 334 μmol) in methylene chloride was cooled with methanesulfonyl chloride (39 μl, 501) under ice cooling.
μmol) and triethylamine (94 μl, 668 μm
ol) and DMAP (7 mg) were sequentially added, and the mixture was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure, the obtained residue was diluted with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to give (2R, 4R) -4-t-butyldimethylsilyloxy-1-benzyloxy-2-methanesulfonyloxy-6-phenylthiohexane (16R).
9 mg, yield 96.4%) was obtained.

[Α] _D ²⁸ +5.46 (c 1.23, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.39-7.24 (m, 9H), 7.20
-7.13 (m, 1H), 4.93-4.82 (m, 1H), 4.53 (dd, 2H, J =
19.4, 12.0 Hz), 3.99-3.90 (m, 1H), 3.67-3.54 (m, 2
H), 3.02-2.9 0 (m, 5H), 1.99-1.70 (m, 4H), 0.87
(s, 9H), 0.03 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 137.5 (s), 136.4 (s),
129.0 (d), 128.9 (d), 128.6 (d), 128.1 (d), 127.9
(d), 125.9 (d), 79.5 (d), 73.3 (t), 71.6 (t), 67.5
(d), 38.9 (t), 38.5 (q), 35.9 (t), 29.0 (t), 25.
7 (q), 17.8 (s), -4.7 (q), -4.8 (q); IR (neat): n = 1358, 1173 cm ^-1 .MS: m / z = 467 (M ⁺ -57), 91 (100%). HRMS: Calculated as C ₂₂ H ₃₁ O ₅ S ₂ Si: 467.1382 (M ⁺ -57).
Measurements: 467.1425

(2R, 4R) -1,4-dihydroxy-
Synthesis of 2-methanesulfonyloxy-6-phenylthiohexane (15)

[Chemical formula 24] (2R, 4R) -4-t-butyldimethylsilyloxy-
1-benzyloxy-2-methanesulfonyloxy-6
-Phenylthiohexane (233 mg, 444 μmol)
A methylene chloride (5 ml) solution of 1 was added dropwise with 1M boron tribromide (1.33 ml, 1.33 mmol) at −30 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with chloroform, washed with saturated sodium hydrogen carbonate, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by flash chromatography (2R,
4R) -1,4-dihydroxy-2-methanesulfonyloxy-6-phenylthiohexane (101 mg, 71.0
%).

[Α] _D ²⁷ +8.30 (c 0.80, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.41-7.24 (m, 4H), 7.23
-7.16 (m, 1H), 5.02-4.83 (m, 1H), 4.10-3.93 (m, 1
H), 3.87 (dd, 1H, J = 12.5, 2.9 Hz), 3.76 (dd, 1H, J =
12.8, 5.6 Hz), 3.16-2.78 (m, 7H), 1.90 (t, 2H, J =
6.0 Hz), 1.81 (dd, 2H, J = 13.5, 6.9 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.0 (s), 129.2 (d),
129.1 (d), 126.2 (d), 81.6 (d), 67.0 (d), 63.8 (t),
38.9 (t), 38.4 (q), 36.5 (d), 29.7 (t); IR (neat): n = 3394, 1336, 1170 cm ^-1 .MS: m / z = 320 (M ⁺ ), 123 ( _{100%) HRMS:. C 13} H 20 O 5 S 2 calculated: 320.0752 (M ⁺⁾ found:. 320.0727

(2S, 4R) -1,2-epoxy-6-
Synthesis of phenylthio-4-hexanol (16)

[Chemical 25] (2R, 4R) -1-Benzyloxy-4-hydroxy-
2-Methanesulfonyloxy-6-phenylthiohexane (81 mg, 253 μmol) in THF (5 ml) was added sodium hydroxide (51 mg, 1.27 mmol) under ice cooling.
Was added and stirred at room temperature for 30 minutes. The reaction solution was diluted with diethyl ether, added with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by flash chromatography, (2S, 4R) -1,2
-Epoxy-6-phenylthio-4-hexanol (5
5 mg, yield 96.9%) was obtained.

[Α] _D ²⁷ +12.00 (c 1.08, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.39-7.24 (m, 4H), 7.22
-7.14 (m, 1H), 4.06-3.93 (m, 1H), 3.17-2.97 (m, 3
H), 2.82 (t, 1H, J = 4.4 Hz), 2.61 (dd, 1H, J = 4.7,
2.7 Hz), 2.35 (d, 1H, J = 4.1 Hz, D ₂ O compatible), 1.96-
1.73 (m, 3H), 1.65-1.55 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.3 (s), 129.04 (d),
128.96 (d), 126.0 (d), 67.8 (d), 50.0 (d), 46.8
(t), 36.4 (t), 36.0 (t), 29.7 (t); IR (neat): n = 3432 cm ^-1 .MS: m / z = 224 (M ⁺ ), 123 (100%). HRMS Calculated as: C ₁₂ H ₁₆ O ₂ S: 224.0871 (M ⁺ ). Measured: 224.0882

(2S, 4R) -1,2-epoxy-4-
Methoxymethyloxy-6-phenylthiohexane (1
Synthesis of 7)

[Chemical formula 26] (2S, 4R) -1,2-epoxy-6-phenylthio-
TH of 4-hexanol (160 mg, 713 μmol)
F (10 ml) solution was cooled with ice to methoxymethyl chloride (1
72 μl, 2.27 mmol) and diishipropylethylamine (792 μl, 4.55 mmol) were sequentially added, and the mixture was stirred at room temperature for 48 hours. The reaction solution was diluted with diethyl ether, added with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to give (2S, 4R) -1,2-epoxy-4-methoxymethyloxy-6-phenylthiohexane (175 mg, yield 91.5%).

[Α] _D ³⁰ +4.75 (c 1.28, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.37-7.24 (m, 4H), 7.22
-7.15 (m, 1H), 4.69 (dd, 2H, J = 9.6, 6.9 Hz), 3.98
-3.89 (m, 1H), 3.39 (s, 3H), 3.10-2.92 (m, 3H), 2.
79 (t, 1H, J = 4.5 Hz), 2.49 (dd, 1H, J = 5.1, 2.6 H
z), 2.01-1.78 (m, 3H), 1.66-1.54 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.4 (s), 129.2 (d),
129.0 (d), 126.0 (d), 96.0 (t), 74.3 (d), 55.6 (q),
49.2 (d), 47.2 (t), 37.8 (t), 34.4 (t), 29.2 (t); IR (neat): n = 1146, 1096, 1035 cm ^-1 .MS: m / z = 268 (M ^{+), 45 (100%)} HRMS:. C 14 H 20 O 3 S calculated: 268.1137 (M ⁺⁾ found:. 268.1140

(4R, 6R) -4-hydroxy-6-methoxymethyloxy-8-phenylthio-1-octyne
Synthesis of (18)

[Chemical 27] (2S, 4R) -1,2-epoxy-4-methoxymethyloxy-6-phenylthiohexane (108 mg, 40
2 μmol) was dissolved in dimethylsulfoxide (4 ml) and cooled under ice with lithium acetylide ethylenediamine complex.
(111 mg, 1.21 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was sequentially diluted with diethyl ether and water, acidified by adding a 5% aqueous hydrochloric acid solution, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by flash chromatography (4R,
6R) -4-hydroxy-6-methoxymethyloxy-
8-Phenylthio-1-octyne (112 mg, yield 9
2.9%).

[Α] _D ³¹ -26.61 (c 1.05, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.38-7.24 (m, 4H), 7.22
-7.15 (m, 1H), 4.67 (s, 2H), 4.07-3.95 (m, 2H),
3.40 (s, 3H), 3.04-2.94 (m, 3H), 2.39 (dd, 2H, J =
6.0, 2.7 Hz), 2.04 (t, 1H, J = 2.6 Hz), 2.01-1.68
(m, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.2 (s), 129.3 (d),
129.0 (d), 126.1 (d), 96.6 (t), 80.8 (d), 74.6 (d),
70.6 (d), 66.3 (d), 55.9 (q), 40.4 (t), 34.3 (t),
29.4 (t), 27.2 (t); IR (neat): n = 3450, 3290, 2116 cm ^-1 .MS: m / z = 294 (M ⁺ ), 45 (100%). HRMS: C ₁₆ H ₂₂ Calculated as O ₃ S: 294.1290 (M ⁺ ). Found: 294.1277.

(4R, 6R) -4,6-dihydroxy-
Synthesis of 8-phenylthio-1-octyne (19)

[Chemical 28] (4R, 6R) -4-hydroxy-6-methoxymethyloxy-8-phenylthio-1-octyne (105 mg,
357 μmol) in methanol (3 ml) was added concentrated hydrochloric acid (1
(Droplet) was added and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (4R, 6
R) -4,6-Dihydroxy-8-phenylthio-1-octyne (83 mg, yield 92.9%) was obtained.

[Α] _D ³⁰ +10.76 (c 1.66, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.45-7.24 (m, 4H), 7.23
-7.14 (m, 1H), 4.17-4.00 (m, 2H), 3.15-2.87 (m, 4
H), 2.40 (dd, 2H, J = 6.0, 2.7 Hz), 2.06 (t, 1H, J =
2.7 Hz), 1.92- 1.57 (m, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.2 (s), 129.2 (d),
129.1 (d), 126.1 (d), 80.7 (d), 71.0 (d), 67.8 (d),
67.2 (d), 41.6 (t), 36.3 (t), 30.0 (t), 27.3 (t); IR (neat): n = 3432 cm ^-1 .MS: m / z = 250 (M ⁺ ), 123 (100%). HRMS: Calculated as C ₁₄ H ₁₈ O ₂ S: 250.1028 (M ⁺ ). Measured: 294.1019.

Synthesis of 10 (4R, 6R) -4,6-bis (t-butyldimethylsilyloxy) -8-phenylthio-1-octyne (20)

[Chemical 29] DMF of (4R, 6R) -4,6-dihydroxy-8-phenylthio-1-octyne (83 mg, 332 μmol)
(3 ml) The solution was cooled in ice with t-butyldimethylsilyl chloride (298 mg, 1.98 mmol) and imidazole (2
70 mg, 3.96 mmol) were sequentially added, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to give (4R, 6R) -4,6-bis (t-butyldimethylsilyloxy) -8-phenylthio-1-octyne (156m
g, yield 98.1%).

[Α] _D ²⁷ -3.39 (c 1.09, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.35-7.20 (m, 4H), 7.20
-7.15 (m, 1H), 3.96-3.80 (m, 2H), 3.20-2.87 (m, 2
H), 2.32 (dd, 1H, J = 5.8, 2.5 Hz), 1.98 (t, 1H, J =
2.6 Hz), 0.88 (br s, 18H), 0.08 (s, 3H), 0.07 (s,
3H), 0.06 (s, 3H), 0.05 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 136.8 (s), 129.2 (d),
129.0 (d), 125.9 (d), 81.2 (d), 70.5 (d), 69.0 (d),
68.7 (d), 44.9 (t), 37.2 (t), 29.2 (t), 28.0 (t),
25.9 (q), 25.8 (q), 18.0 (s), -4.2 (q), -4.5 (q); IR (neat): n = 3312, 2120 cm ^-1 .MS: m / z = 478 (M ^{+), 123 (100%)} HRMS:. C 26 H 46 O 2 SSi 2 calculated: 478.2757 (M ⁺⁾ found:. 478.2743

11 (4R, 6R) -1- (phenylsulfinyl) -3- (t-butyldimethylsilyloxy) -5-
Synthesis of hydroxy-7-octyne (21)

[Chemical 30] (4R, 6R) -4,6-bis (t-butyldimethylsilyloxy) -8-phenylthio-1-octyne (150 m
g, 313 μmol) in methylene chloride (5 ml)-
With stirring at 78 ° C, m-chloroperbenzoic acid (60 mg, 34
5 μmol) was added and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to give (4R, 6R) -1- (phenylsulfinyl) -3- (t-butyldimethylsilyloxy) -5-hydroxy-7-octyne (140 mg,
The yield was 90.1%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.64-7.48
(m, 5H), 3.97-3.78 (m, 2H), 2.99-2.74 (m, 2H), 2.3
3-2.26 (m, 2H), 1.98-1.48 (m, 5H), 0.88-0.85 (m, 1
8H), 0.09--0.13 (m, 12H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 143.93, 143.86, 131.0,
129.3, 124.2, 80.9, 70.5, 68.6, 68.5, 68.4, 52.
3, 52.2, 44.6, 29.5, 29.3, 27.93, 27.88, 25.7, 17.
91, 17.86 -4.2, -4.4, -4.5, -4.6; IR (neat): n = 3312, 1047 cm ^-1 .MS: m / z = 437 (100%, M ⁺ -57), 437 (100% HRMS: Calculated for C ₂₂ H ₃₇ O ₃ SSi ₂ : 437.2003 (M ⁺ ). Found: 437.2004.

Synthesis of 12 (3S, 5R) -3,5-bis (t-butyldimethylsilyloxy) -1-octen-7-yne (22)

[Chemical 31] (4R, 6R) -1- (phenylsulfinyl) -3- (t
-Butyldimethylsilyloxy) -5-hydroxy-7
-Octyne (68 mg, 138 μmol) in DMSO (2
The solution was heated to reflux for 1 hour. The reaction solution was diluted with diethyl ether, added with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in DMF (1 ml) without purification, and t-under ice cooling.
Butyldimethylsilyl chloride (83mg, 552μm
ol) and imidazole (75 mg, 1.10 mmol) were sequentially added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by flash chromatography, (3S, 5R) -3,5-bis
(t-Butyldimethylsilyloxy) -1-octene-7
-In (38 mg, yield 74.7%) was obtained.

[Α] _D ³⁰ -9.1 (c 0.51, CHCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ): δ 5.82 (ddd,
1H, J = 17.2, 10.2, 7.1H
z), 5.14 (br d, 1H, J = 17.
3, Hz), 5.04 (br d, 1H, J
= 10.3 Hz), 4.27-2.18 (m,
1H), 3.98-3.89 (m, 1H),
2.38-2.33 (m, 2H), 1.97
(T, 1H, J = 2.6 Hz), 1.88
(Ddd, 1H, J = 13.9, 7.6, 5.
2 Hz), 1.65 (ddd, 1H, J =
13.7, 6.6, 5.2 Hz), 0.89
(S, 3H), 0.09 (s, 3H), 0.
08 (s, 3H), 0.06 (s, 3H
H), 0.04 (s, 3H);

─────────────────────────────────────────────────── --- Continuation of the front page (56) References JP-A-2-286647 (JP, A) JP-A-8-225480 (JP, A) JP-A-7-25883 (JP, A) JP-A-7- 112968 (JP, A) JP-A-7-145093 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07F 7/00 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. The following formula (4): (In the formula, R ² represents a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a phenyl group, and R ³ represents an ether-based protecting group.)
Protecting with a silyl group, oxidizing a sulfide to a sulfoxide, followed by thermal elimination and re-silylation, represented by the following formula (5): (R ⁴ represents a silyl protecting group.) A method for producing a calcitriol intermediate. 2. The following formula (1): (In formula, Bn means a benzyl group or its related group.)
The hydroxy group of 4-hydroxy-δ-valerolactone represented by the following is protected with a silyl group and then reduced to give the following formula (2): (R ¹ is a silyl protecting group and Bn is the same as the above.), A primary hydroxyl group of this diol (2) is selectively converted to a sulfide group, and then a sulfonyl group of the secondary hydroxyl group is obtained. By the following formula (3): (In the formula, R ² means a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a phenyl group.) A compound represented by the formula (3) is protected with a hydroxyl group, and then lithium acetylene is obtained. Reaction with ethylenediamine complex
(4) [Chemical 6] (In the formula, R ³ means an ether-based protecting group and R ² is the same as the above.), And the acetylene body is deprotected and then protected with a silyl group to oxidize the sulfide. To form a sulfoxide, followed by thermal desorption and re-silylation, the following formula (5): (R ⁴ represents a silyl protecting group.) A method for producing a calcitriol intermediate. 3. A compound represented by the formula (1) is (4S, 6R)
3. The method according to claim 2, wherein the compound represented by the formula (5) is a (4R, 6R) body using a body. 4. The following formula (4a): (In the formula, R ²¹ represents a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a phenyl group, and R ³¹ represents a methoxymethyl group, or a tetrahydropyranyl group.). 5. The conformation is (4R, 6R).
Compound of.