JP2929943B2 - Calcitriol intermediate and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is to produce an important intermediate corresponding to the A-ring of calcitriol represented by the following formula 9 when producing a therapeutic drug calcitriol and related vitamin derivatives for osteoporosis and other diseases. And a process for producing the same.

[0002]

2. Description of the Related Art Calcitriol and its related vitamin derivatives have been used as therapeutic agents for osteoporosis and other diseases. The development of a more efficient method for this method, particularly for the synthesis of the A-ring portion of calcitriol, has been required. I have been asked.

[0003] The A of calcitriol represented by the following formula 9
A method for producing a compound corresponding to the ring portion is known (EGBagg
iolini et al., J. Am. Chem. Soc., 104, 2945 (1982)). Also,
In the present invention, a method for producing a chain compound represented by the formula 7c, which is an intermediate of a compound corresponding to the ring A, is also known (B.
M. Trost et al., J. Am. Chem. Soc., 114, 9836 (1992)).

[0004]

The above-mentioned known methods have many industrial problems and there has been a demand for the development of a better method. That is, in the former method, d-carboxyl is used as a raw material, sterically-specifically epoxidized, and then reacted with a carbanion of diethyl (carboxyethyl) phosphate by a Horner-Emmons reaction. : The Z-isomer / E-isomer mixture is separated by a silica gel column, the Z-isomer is removed, the epoxy group is opened, the diacetate is formed, the isopropenyl group is oxidized to an acetyl group, then to acetate, and the triacetate is removed. After hydrolysis to form a triol, the compounds represented by the formulas 9a and 9b have been synthesized by a method in which only the secondary hydroxyl group is protected with a t-butyldimethylsilyl group and dehydrated to convert it into an exomethylene group. This is a process that requires a great deal of care so that the steps are long and the reaction in the middle does not cause a side reaction.

In the latter method, the intermediate 3-hydroxy-
5-t-butyldiphenylsiloxyoct-7-yn-
The syn-form and anti-form of 1-ene must be separated,
In order to increase the economic efficiency, it is necessary to invert the 3-position hydroxyl group of the syn-form by the Mitsunobu method to obtain the anti-form, and furthermore, the (+)-form of the racemic mixture of the syn-form is subjected to dynamic resolution. Asymmetric epoxidation and removal by the principle of the method,
It is necessary to recover the unreacted (-) form, and it is not easy to obtain a large amount of a product with good optical purity, and there is a disadvantage that the operation is complicated as an industrial production method.

[0006]

In view of the above, the present inventor has considered,
The present invention is directed to a method for efficiently obtaining a key intermediate in the A-ring of calcitriol and its related vitamin derivatives, that is, the compounds represented by formulas 8a and 8b and 9a and 9b, by a simple reaction route with little by-products. As a result of the examination, the compound S-5-hydroxy-octa-2, represented by the formula 1,
According to the following reaction route (I) using 7-diyn-1-ol and its silyl derivative as starting materials, a new method for obtaining the above-mentioned compound of interest has been found. In the following reaction pathway, TM
S represents a trimethylsilyl group, THP represents a tetrahydropyranyl group, and TBS represents a t-butyldimethylsilyl group.

Reaction pathway (I)

Embedded image

The present invention provides a compound S- represented by the following formula 1.
5-hydroxy-octa-2,7-diyn-1-ol, its silyl derivative and its preparation.

[0009]

Embedded image (However, R ¹ represents hydrogen or a trimethylsilyl group; R ²
Represents hydrogen or a t-butyldimethylsilyl group, and R ³ represents a tetrahydropyranyl group or hydrogen. )

Hereinafter, the present invention will be described with reference to Reaction Scheme I. The compound S-5-hydroxy-octa-2,7-diyn-1-ol of the present invention represented by the formula 1 and its silyl derivative can be produced as follows. That is, when lithium acetylide obtained from propargyl tetrahydropyranyl ether is reacted with a compound represented by the formula 2 in the presence of trifluoroboron etherate, R ¹ is a trimethylsilyl group, R ² is hydrogen and R ³ is a tetrahydropyranyl group. The compound of formula 1a is obtained. Also R-
The compound 1a can also be obtained by reacting 5,6-oxiranylhex-2-ynyltetrahydropyranyl ether (3) with lithium trimethylsilyl acetylide.

The reaction of lithium acetylide obtained from propargyl tetrahydropyranyl ether with the compound of the formula 2 can be carried out as follows. Propargyl tetrahydropyranyl ether, for example, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol, or a hydrocarbon such as hexane as a solvent,
Lithium acetylide produced by reacting with an equivalent or more of a strong base such as methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium and the like is converted into a compound S-5-trimethylsilyl-1,2-oxira of formula 2 Reaction of nilpenta-4-yne (2) with a Lewis acid such as trifluoroboron etherate gives the compound of formula 1a. This reaction is desirably performed at a low temperature of -30 ° C to -100 ° C. Although this reaction proceeds without a catalyst, the addition of a Lewis acid as described above accelerates the reaction.

R-5,6-oxiranylhexa-2
The reaction between -inyltetrahydropyranyl ether (3) and lithium trimethylsilyl acetylide can be carried out as follows. That is, trimethylsilyl acetylene is used as a solvent with ethers such as tetrahydrofuran, diethyl ether and ethylene glycol, or hydrocarbons such as hexane as solvents, and strong bases such as methyl lithium, n-butyl lithium, sec-butyl lithium and t-butyl lithium. Is reacted with a compound of the formula 3 to give a compound of the formula 1a. This reaction is desirably performed at a low temperature of -30 ° C to -100 ° C.

The starting material S-5-trimethylsilyl-1,2
-Oxiranyl penta-4-yne (2) was obtained from R-epichlorohydrin of high optical purity by Tetrahedron Asymmetry, 3,
853 (1992). Another raw material, R-5,6-oxiranylhex-2-ynyltetrahydropyranyl ether (3), was obtained from Angew. Chem. Int. Ed, En.
gl., 28, 1272 (1989), from S-epichlorohydrin.

The conversion of the compound of the formula 1a into the compounds of the formulas 1b, 1c and 1d is carried out as follows. Reaction of the compound of formula 1a with t-butyldimethylsilyl chloride in dimethylformamide in the presence of imidazole gives S-8-
Trimethylsilyl-5-t-butyldimethylsiloxy-
Octa-2,7-diynyltetrahydropyranyl ether (1b) is obtained. Hydrolysis of the compound of formula 1b in methanol in the presence of a catalytic amount of pyridinium p-toluenesulfonate gives the primary alcohol (1c). Heating the compound of formula 1c with potassium carbonate in methanol removes the trimethylsilyl group to give a compound of formula 1d.

Important intermediates corresponding to the A ring portion when producing calcitriol and its related vitamin derivatives from the compound represented by the formula 1 of the present invention, ie, represented by the formulas 8a and 8b and the formulas 9a and 9b. The production of the compound according to the reaction scheme (I)
And can be performed as follows.

The compound represented by the formula 1c is converted to an ether, t-
In a solvent such as butyl methyl ether, 1,2 dimethoxyethane, tetrahydrofuran, dioxane, etc.
Reduction with sodium bis (methoxyethoxy) aluminum hydride, the acetylene at the 2-position is partially reduced to give SE-8-trimethylsilyl-5-t-butyldimethylsiloxy-oct-2-en-7-yne. -1
-Ol (4a) and SE-5-tert-butyldimethylsiloxy-oct-2-en-7-yn-1-ol (4
b) is obtained in 65% and 32% yield, respectively. These can be easily separated, but can also be used as a mixture. Similarly, when the compound of the formula 1d is similarly partially reduced, only the compound of the formula 4b can be obtained although the yield is as low as 27%. Similarly, the compound of formula 4a is almost quantitatively converted to the compound of formula 4b by heating the compound of formula 4a with a base such as sodium carbonate or potassium carbonate in a solvent such as C ₁ -C ₄ alcohol to remove the trimethylsilyl group. can do.

Oxidation of the compound of formula 4a with m-chloroperbenzoic acid in a solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. together with a small amount of α-epoxide provides the desired configuration of formula 6a. Β with
An epoxide compound is obtained with a yield of 73%. The compound of formula 6a is subjected to the conditions of Katsuki-Sharpless asymmetric epoxidation, ie, L-
Epoxidation of the compound of formula 4a in the presence of diisopropyl tartrate can be obtained almost quantitatively. The compound of formula 4b is similarly oxidized with m-chloroperbenzoic acid to give a β-epoxide compound 6c having the same configuration as that of formula 6a in a yield of 74%.

Next, the compounds of formulas 6a and 6c are reacted with iodine in the presence of triphenylphosphine and imidazole to obtain the iodine compounds of formulas 6b and 6d, respectively. Reaction of iodide of formula 6b with C ₁ -C ₄ zinc dust activated with a solvent such as an alcohol containing acetic acid Formula 7
Compound 5R, 3R-8-trimethylsilyl-5-t of a
-Butyldimethylsilyl-3-hydroxy-oct-7
-In-1-ene is obtained in a yield of 85%. When the compound of the formula 7a is heated with a base such as sodium carbonate or potassium carbonate in a solvent such as a C ₁ -C ₄ alcohol, the compound of the formula 7b from which the silyl group at the 8-position is eliminated can be obtained almost quantitatively. The compound of formula 7b can also be obtained by reacting the compound of formula 6d with activated zinc in methanol containing acetic acid. This was silylated with t-butyldimethylsilyl chloride in dimethylformamide in the presence of imidazole and dimethylaminopyridine to give a compound of formula 7c,
Methyl lithium, n- butyl lithium, sec- butyl lithium, t-after with lithium acetylide with an alkyl lithium C ₁ -C ₄ such as butyl lithium, calcitriol which is reacted with methyl chlorocarbonate or methyl chlorocarbonate intended And one of the related key intermediates, the chain compounds of formulas 8a and 8b. Equations 8a and 8
When the compound b is subjected to a cyclization reaction using a tris (dibenzylideneacetone) dipalladium-chloroform complex as a catalyst, another important intermediate of the desired calcitriol and its related compounds, a dimer represented by the formulas 9a and 9b, An alkylidenecyclohexane derivative is obtained.

[0019]

【Example】

Example 1 <Synthesis of Compound of Formula 1a> To a solution of trimethylsilylacetylene (6.8 g, 69.4 mM) in tetrahydrofuran (110 ml) was slowly added a 1.56 M n-butyllithium n-hexane solution (37 ml, 57.8 mM) at −78 ° C. And stirred at the same temperature for 1.5 hours. Further, a trifluoroboron ether complex (7.2 ml, 57.8 mM) was gradually added dropwise, and the mixture was stirred at the same temperature for 0.5 hour. A solution of the compound of formula 3 (7.6 g, 38.6 mM) in tetrahydrofuran (10 ml) was gradually added dropwise to the reaction solution at -78 ° C, and the mixture was stirred at the same temperature for 2.5 hours and then gradually heated to room temperature. Water (20 ml) was added to the reaction solution, and ether (300 ml) was added.
And extracted twice. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 8.8 g of a colorless compound of the formula 1a from a fraction of ether / n-hexane (1: 3). The yield is 78%, but considering the recovery of raw materials, the yield is
82%.

The compound of the formula 1a could also be synthesized by the following method. That is, to a solution of propargyl tetrahydropyranyl ether (2.0 g, 13.64 mM) in tetrahydrofuran (20 ml) was slowly added dropwise a solution of 1.4 M n-butyllithium in n-hexane (7.8 ml, 10.91 mM) at −78 ° C. For 0.5 hour, trifluoroboron ether complex (1.3 ml, 10.91 mM) was gradually added dropwise, and the mixture was stirred at the same temperature for 0.5 hour. The compound of formula 2 (1.4 g, 9.09 mM) was added to the reaction mixture.
Of tetrahydrofuran (5 ml) was slowly added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 2.5 hours, and then gradually heated to room temperature. Water (20 ml) was added to the reaction solution, and ether 250
Extracted twice with ml. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.79 g of a colorless compound of the formula 1 from a fraction of ether / n-hexane (1: 3). The yield was 67%. The spectral data of the compound of formula 1a obtained by this method was consistent with the compound obtained by the previous method. The spectrum data and elemental analysis result of the compound of the formula 1a are as follows.

IRνmax (neat) cm ^-1 ; 3438, 2954, 2
872, 2174, 1249, 1025, 841. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.77 (t, 1 H, J = 2.9 H
z), 4.28 (dt, 1H, J = 15.4, 2.2Hz), 4.19 (dt, 1
H, J = 1.8, 15.8Hz), 3.94-3.76 (m, 2H), 3.57-3.
45 (m, 1H), 2.50 (d, 1H, J = 6.2Hz), 2.62 to 2.38
(M, 4H), 2.87 to 2.44 (m, 6H), 0.13 (s, 9H). MS; 293 (M ^{< + >-} H ^{< + >} ), 85 (100%). Anal. Calcd. For C ₁₆ H ₂₆ O ₃ Si, C; 65.27, H; 8.91. Found: C; 65.01, H; 8.85.

Example 2 <Synthesis of Compound of Formula 1b> Compound of Formula 1a (2.1 g, 7.11)
Immidazole (1.8 ml, 27.0 mM) and t-butyldimethylsilyl chloride (1.7 mg, 11.4 mM) were added to a dimethylformamide (18 mM) solution at room temperature and stirred for 6 hours. Water (10 ml) was added to the reaction solution, and the mixture was extracted twice with 200 ml of ether. The combined organic layers are dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ether / n-hexane (1: 1:
From the fraction of 20), 2.9 g of the compound of the formula 1b was obtained as a colorless oil.
The yield was almost quantitative. The spectrum data and elemental analysis result of the compound of the formula 1b are as follows.

IRνmax (neat) cm ^-1 ; 2954, 2856, 21
76, 1250, 1107, 1025, 840. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.79 (t, 1 H, J = 2.9 H
z), 4.28 (dt, 1H, J = 15.4, 2.2Hz), 4.18 (dt, 1
H, J = 2.2, 15.8Hz), 4.00-3.78 (m, 2H), 3.58-3.
47 (m, 1H), 2.53 (dd, 1H, J = 5.5, 16.9Hz), 2.39
(Dd, 1H, J = 6.2, 16.8Hz), 2.59 ~ 2.34 (m, 2H),
1.89 to 1.46 (m, 6H), 0.89 (s, 9H), 0.14 (s, 9
H), 0.11 (s, 3H), 0.10 (s, 3H). MS; 351 (M ⁺ -t-Bu), 107 (100%), 85 (100
%). Anal. Calcd. For C ₁₈ H ₃₁ O ₃ Si ₂ , C; 64.67, H; 9.8
7. Found: C; 64.41, H; 9.96.

Example 3 <Synthesis of Compound of Formula 1c> Compound of formula 1b (44.2 mg, 0.2
Pyridinium p-toluenesulfonate (10 mg, 0.04 mM) was added to a solution of 11 mM) in methanol (1 ml), and the solution was added at room temperature.
Stir for 17 hours. The solvent of this reaction solution was distilled off under reduced pressure,
Saturated saline (5 ml) was added, and the mixture was extracted twice with 30 ml of ether. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ether / n-hexane (1:10).
28.4 mg of the compound of the formula 1c was obtained as a colorless oil from the fraction. The yield was 81%, however, considering the recovery of the raw materials, the yield was 88%. The spectrum data and elemental analysis result of the compound of the formula 1c are as follows.

[Α] _D ³⁰ ; + 9.0 ° (C = 1.01, methanol). IRνmax (neat) cm ^-1 ; 3362, 2956, 2930, 2856,
2176, 1250, 1103, 840 ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.31 to 4.21 (m, 2
H), 3.93 (quint, 1H, J = 5.9Hz), 2.53 (dd, 1H, J =
16.5, 5.5Hz), 2.40 (dd, 1H, J = 6.2, 16.8Hz), 2.6
0 ~ 2.34 (m, 2H), 1.50 (dd, 1H, J = 6.2, 5.9Hz),
0.90 (s, 9H), 0.15 (s, 9H), 0.13 (s, 6H). MS; 324 (M ⁺ ), 267 (M ⁺ -57), 73 (100%). _{.. Anal Calcd for C 17 H} 32 O 1 Si 2, C; 62.90, H; 9.9
Four . Found: C; 62.51, H; 10.03.

Example 4 <Synthesis of Compound of Formula 1d> Compound of formula 1c (1.38 g, 4.
26mM) in methanol (50ml) and potassium carbonate (1.47)
g, 10.65 mM) at room temperature, and the mixture was heated to 40 ° C. and stirred for 0.5 hour. The solvent of this reaction solution was distilled off under reduced pressure, saturated saline (5 ml) was added, and the mixture was extracted twice with 30 ml of ether. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.04 g of a compound of the formula 1d as a colorless oil from a fraction of ether / n-hexane (1: 2). 97% yield
Met. The spectrum data and elemental analysis result of the compound of the formula 1d are as follows.

[Α] _D ²⁶ ; -1.6 ° (C = 0.86, methanol). IRνmax (neat) cm ^-1 ; 3310, 2930, 2856, 2228,
2120, 1256, 1110. ¹ H-NMR (300 MHz, CDCl ₃ ; δ 4.25 (dt, 2H, J = 5.9,
1.8Hz), 3.94 (quint, 1H, J = 5.9Hz), 2.58-2.35 (
m, 4H), 2.00 (t, 1H, J = 2.6Hz), 1.58 (t, 1H, J = 5.
9Hz), 0.90 (s, 9H), 0.11 (s, 6H). MS; 251 (M ⁺ -H ⁺ ), 235 (M ⁺ -OH), 213 (M
⁺ -HC = CCH) 75 (100%). Anal.Calcd. For C ₁₄ H ₂₄ O ₂ Si, C; 66.61, H; 9.5
8. Found: C; 66.53, H; 9.66.

Example 5 <Synthesis of compound of formula 4a> Compound of formula 1c (2.35 g, 7.
25mM) in ether (50ml) solution with 35% sodium bis (2-methoxyethoxy) aluminum hydride /
A toluene solution (21 ml, 34.8 mM) was added at 0 ° C., and the temperature was gradually raised to room temperature, followed by stirring for 1 hour. Add 10% NaOH to the reaction
Add an aqueous solution (7 ml), stir for 20 minutes, and add dichloromethane
Extracted twice with 300 ml. The combined organic layer was washed with saturated saline 30
After washing with ml, the solution was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from a fraction of ether / n-hexane (1: 2), 1.51 g (64%) of a colorless oily compound of the formula 4a and 573 mg (31%) of a colorless oily compound of the formula 4b ) Got. Raw material recovery was 44 mg (2%). The spectrum data and elemental analysis result of the compound of the formula 4a are as follows.

[Α] _D ²⁸ ; + 3.9 ° (C = 0.92, methanol). IRνmax (neat) cm ^-1 ; 3344, 2956, 2930, 2898,
2858, 2176, 1250, 1101, 840, 773. ¹ H-NMR (500 MHz, CDCl ₃ ); δ 5.72 to 5.64 (m, 2H)
4.13 to 4.04 (m, 2H) 3.83 (ddd, 1H, J = 5.5, 6.1, 1
1.6Hz), 2.32 (d, 2H, J = 6.1Hz), 2.36 to 2.21 (m, 2
H), 1.24 (dd, 1H, J = 5.5, 6.1Hz), 0.87 (s, 9H),
0.12 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H). MS; 325 (M ⁺ -H ⁺ ), 269 (M ⁺ -57), 73 (100
%). Anal.Calcd. For C ₁₄ H ₂₄ O ₂ Si, C; 62.51, H; 10.4
9. Found: C; 62.44, H; 10.42.

Example 6 <Synthesis of Compound of Formula 4b> Compound of formula 1d (692 mg, 2.
75mM) in ether (12.5ml) in 35% sodium bis (2-methoxyethoxy) aluminum hydride /
Toluene solution (7.6ml, 13.2mM) was added at 0 ° C and 1 hour
After stirring for 20 minutes, the mixture was heated to room temperature and stirred for 6 hours. A 10% aqueous NaOH solution (4 ml) was added to the reaction solution, and the mixture was stirred for 20 minutes.
Extracted twice with 150 ml of dichloromethane. The combined organic layer was washed with 15 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 188 mg of the compound of the formula 4b was obtained as a colorless oil from a fraction of ether / n-hexane (1: 2).
I got The yield was 27%. The spectrum data and elemental analysis result of the compound of the formula 4b are as follows.

[Α] _D ²⁵ ; −6.0 ° (C = 0.86, chloroform) IRνmax (neat) cm ⁻¹ ; 3312, 2952, 2932, 2856,
2120, 1100, 835. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.73 to 5.70 (m, 2H)
4.13 to 4.10 (m, 2H) 3.86 (quint, 1H, J = 5.9Hz), 2.
32 (dd, 2H, J = 2.6, 6.2Hz), 2.44 to 2.25 (m, 2H),
1.99 (t, 1H, J = 2.6Hz), 1.26 (t, 1H, J = 5.9Hz), 0.
89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). MS; 237 (M ⁺ -OH), 215 (M ⁺ -CH ₂ C≡CH), 143
(M ⁺ -111), 75 (100%). Anal.Calcd. For C14H26O2Si, C; 66.09, H; 10.3
0. Found: C; 66.04, H; 10.10.

Example 7 <Synthesis of Compound of Formula 6a> A compound of Formula 4a (240 mg, 0.2 g
Sodium bicarbonate (185 mg, 2.21 mM) and m-chloroperbenzoic acid (270
mg, 1.10 mM) at 0 ° C. and stirred at the same temperature for 2 hours.
To this reaction solution was added a saturated aqueous solution of sodium hydrogen sulfite (20 ml) at 0 ° C., and the mixture was stirred for 20 minutes, heated to room temperature, and extracted twice with 120 ml of dichloromethane. The combined organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (20 ml) and then with a saturated saline solution (20 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ether / n-hexane (1: 3)
From the fractions, 183.5 mg (yield 73%) and 18.4 mg (7.3% yield) of a colorless oily β-epoxide represented by the formula 6a and its isomer α-epoxide were obtained, respectively. The spectrum data and elemental analysis result of the compound of the formula 6a are as follows.

[Α] _D ³² ; -43.3 ° (C = 1.28, chloroform) IRνmax (neat) cm ⁻¹ ; 3446, 2954, 2856, 2176, 1
744, 1731, 663. ¹ H-NMR (500 MHz, CDCl ₃ ); δ 4.01 to 3.97 (m, 1H)
3.91 (ddd, 1H, J = 3.1, 5.5, 12.8Hz), 3.61 (ddd, 1
H, J = 4.3, 7.3, 12.2 Hz), 3.09 to 3.05 (m, 1H), 2.4
1 to 2.36 (m, 2H), 1.83 to 1.73 (m, 2H), 1.70 (dd,
1H, J = 5.5, 7.3Hz), 0.87 (s, 9H), 0.11 (s, 9
H), 0.09 (s, 6H). MS; 285 (M ⁺ -57), 267 (M ⁺ -75), 145 (M ⁺
−197), 73 (100%). Anal.Calcd. For C ₁₇ H ₃₄ O ₃ Si ₂ , C; 59.61, H; 1
0.01. Found: C; 59.42, H; 9.99.

Example 8 <Synthesis of Compound of Formula 6c> Compound of formula 4b (1.23 g, 4.
86 mM) in dichloromethane (80 ml) solution and sodium hydrogencarbonate (1.22 g, 14.57 mM) and m-chloroperbenzoic acid (1.2
6 g, 7.29 mM) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
To this reaction solution was added a saturated aqueous solution of sodium hydrogen sulfite (60 ml) at 0 ° C., and the mixture was stirred for 20 minutes. The combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (60 ml) and then with a saturated saline solution (60 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ether / n-hexane (1: 1).
From the above fraction, 969.2 mg (yield 74%) and 80.8 mg (6.2% yield) of a colorless oily β-epoxide represented by the formula 6c and its isomer α-epoxide were obtained. The spectrum data and elemental analysis result of the compound of the formula 6c are as follows.

[Α] _D ²⁷ ; −51.4 ° (C = 1.04, chloroform) IRνmax (neat) cm ⁻¹ ; 3422, 3310, 2934, 2856,
2120, 1256, 1102. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.07 to 3.99 (m, 1H)
3.93 (ddd, 1H, J = 2.6, 5.5, 12.5Hz), 3.64 (ddd,
1H, J = 4.0, 7.3, 11.7Hz), 3.11 (ddd, 1H, J = 2.2, 4.
8, 7.0Hz), 3.00 to 2.94 (m, 1H), 2.40 to 2.36 (m,
2H), 2.00 (t, 1H, J = 2.6Hz), 1.91 to 1.74 (m, 2
H), 1.66 (dd, 1H, J = 5.5, 7.0Hz), 0.90 (s, 9H),
0.11 (s, 3H), 0.10 (s, 3H). MS; 231 (M ⁺ -39), 213 (M ⁺ -57), 145 (M ⁺
−125), 75 (100%). _{HRMS Calcd. For C11H23O3Si (-CH 2} C = CH), 231.
1416. Found: 231.1429.

Example 9 <Synthesis of Compound of Formula 6b> A compound of Formula 6a (430 mg, 1.
26mM) was dissolved in a mixed solvent of 4: 1-tetrahydrofuran / acetonitrile (24 ml; 6 ml), and triphenylphosphine (990 mg, 3.77 mM) and imidazole (642 mg, 9.43) were dissolved.
mM) and iodine (960 mg, 7.54 mM) in that order.
Stirred for minutes. To this reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate (10 ml), and the mixture was extracted twice with 120 ml of ether.
The combined organic layers were washed sequentially with 10% aqueous sodium sulfite solution (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated saline solution (10 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a β-epoxy iodide represented by the formula 6b was obtained as a colorless oil from a fraction of ether / n-hexane (1:20).
486.3 mg (85% yield) were obtained. The spectrum data and elemental analysis result of the compound of the formula 6b are as follows.

[Α] _D ³¹ ; −26.3 ° (C = 1.19, chloroform) IRνmax (neat) cm ⁻¹ ; 2956, 2898, 2856, 2176,
1252, 1099, 840. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.06 to 3.94 (m, 1
H) 3.21 (dd, 1H, J = 5.9, 9.9Hz), 3.13 (dd, 1
H, J = 5.9, 10.3Hz), 3.05 (dt, 1H, J = 1.8, 6.2Hz),
2.98 (dt, 1H, J = 1.8, 6.6Hz), 2.43 (d, 2H, J = 6.2H
z), 1.85 (ddd, 1H, J = 5.1, 7.3, 13.9Hz), 1.73 (d
dd, 1H, J = 4.0, 7.0, 13.9Hz), 0.90 (s, 9H), 0.14
(S, 9H), 0.11 (s, 3H), 0.10 (s, 3H). MS; 395 (M ⁺ -57), 341 (M ⁺ -111), 283 (M
⁺ -169), 73 (100%). Anal.Calcd. For C ₁₇ H ₃₃ O ₂ Si ₂ I, C; 45.12, H; 7.
35, I; 28.04. Found: C; 45.03, H; 7.22, I; 27.90.

Example 10 <Synthesis of Compound of Formula 6d> Compound of formula 6c (1.05 g, 3.
89 mM) in a solution of 4: 1-tetrahydrofuran / acetonitrile (70 ml: 18 ml) was added to triphenylphosphine (3.06 g,
11.67 mM), imidazole (1.99 g, 29.17 mM) and iodine (2.96 g, 23.33 mM) were sequentially added, followed by stirring at room temperature for 30 minutes. Ornament calculation: A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added to the reaction solution, and the mixture was extracted twice with 200 ml of ether. The combined organic layer is 40m 10% sodium sulfite aqueous solution
l 、 Saturated sodium bicarbonate aqueous solution 40ml 、 saturated saline 40m
After successive washing with l, the resultant was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.25 g (84% yield) of a colorless oily β-epoxy iodide represented by the formula 6d from a fraction of ether / n-hexane (1:15). The spectrum data and elemental analysis result of the compound of the formula 6d are as follows.

[Α] _D ²⁹ ; −26.9 ° (C = 1.17, chloroform) IRνmax (neat) cm ⁻¹ ; 3306, 2954, 2930, 2888,
2856, 2120, 1255, 1099. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 4.04 to 3.96 (m, 1H)
3.22 (dd, 1H, J = 5.9,9.5Hz), 3.12 (dd, 1H, J = 5.9,
9.9Hz), 3.06 (dt, 1H, J = 1.8, 5.9Hz), 2.99 (ddd,
1H, J = 1.8, 4.8, 7.0Hz), 2.40 (dd, 2H, J = 2.6, 6.2H
z), 2.00 (t, 1H, J = 2.6Hz) 1.90 (ddd, 1H, J = 4.8,
7.7, 14.3Hz), 1.72 (ddd, 1H, J = 3.7, 7.0, 13.9H
z), 0.90 (s, 9H), 0.11 (s, 6H). MS; 341 (M ⁺ -39), 255 (M ⁺ -125), 185 (M
⁺ -195), 127 (M ⁺ -253), 73 (100%). Anal.Calcd. For C ₁₄ H ₂₅ O ₂ SiI, C; 44.21, H; 6.6
3, I; 33.37. Found: C; 44.42, H; 6.73, I; 33.59.

Example 11 <Synthesis of Compound of Formula 7a> Compound of formula 6b (456 mg, 1.
Activated zinc (198 mg, 3.03 mM) and acetic acid (0.5 ml) were sequentially added to a solution of (01 mM) in methanol (14 ml) at room temperature, heated to 40 ° C., and subjected to ultrasonic waves for 1 hour. The reaction mixture was diluted with 70 ml of ether and filtered through celite, and the filtrate was washed successively with 10 ml of a 5% aqueous hydrochloric acid solution, 10 ml of a saturated aqueous sodium hydrogen carbonate solution (10 ml) and 10 ml of a saturated saline solution, dried over magnesium sulfate, and dried under reduced pressure. The solvent was distilled off. The residue was subjected to silica gel column chromatography to give ether / n-
From the fraction of hexane (1:30), 287.2 mg (87% yield) of a compound represented by the formula 7a was obtained as a colorless oil. The spectrum data and elemental analysis result of the compound of the formula 7a are as follows.

[Α] _D ²⁸ ; −26.0 ° (C = 1.055, chloroform) IRνmax (neat) cm ⁻¹ ; 3444, 2954, 2858, 2176,
1250, 1098. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.86 (ddd, 1 H, J = 4.
9, 10.4, 17.1Hz), 5.25 (bd, 1H, J = 17.1Hz), 5.08
(Bd, 1H, J = 10.4Hz), 4.43 to 4.40 (m, 1H), 4.15 to
4.10 (m, 1H), 2.88 (d, 1H, J = 3.1Hz), 2.47 (d, 2
H, J = 6.1Hz), 1.82 (ddd, 1H, J = 3.1, 6.1, 14.6H
z), 1.74 (ddd, 1H, J = 3.7, 9.8, 13.4Hz), 0.88 (
s, 9H), 0.12 (s, 9H), 0.10 (s, 6H). MS; 269 (M ⁺ -C ₄ H ₉ ), 215 (M ⁺ -111), 159
(M ⁺ -167), 73 (100%). Anal. Calcd. For C ₁₇ H ₃₄ O ₂ Si ₂ , C; 62.54, H; 1
0.50. Found: C; 62.63, H; 10.52.

Example 12 <Synthesis of Compound of Formula 7b> Compound of formula 7a (259.9 mg,
To a solution of 0.80 mM) in methanol (4.5 ml) was added potassium carbonate (275 mg, 1.99 mM) at room temperature, and the mixture was heated to 40 ° C. and stirred for 1 hour. The solvent of this reaction solution was distilled off under reduced pressure, 10 ml of saturated saline was added, and the mixture was extracted twice with 70 ml of ether. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction of ether / n-hexane (1: 2), 196.5 mg (97% yield) of a compound represented by the formula 7b as a colorless oil was obtained.
I got

The compound of the formula 7b was synthesized by the following method as another method. Compound of formula 6b (1.24 g, 3.26 m
Activated zinc (640m) in methanol (40ml) solution of M)
g, 9.79 mM) and acetic acid (1 ml) were sequentially added at room temperature, heated to 40 ° C., and subjected to ultrasonic wave for 1 hour. This reaction solution is
After dilution with 200 ml, the mixture was filtered through celite, and the filtrate was washed successively with 30 ml of a 5% aqueous hydrochloric acid solution, 30 ml of a saturated aqueous sodium hydrogen carbonate solution and 30 ml of a saturated saline solution, dried over magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to give ether / n-hexane (1:
Compound 720 represented by the formula 7b as a colorless oil from the fraction of 2)
mg (87% yield). The spectrum data and elemental analysis result of the compound of the formula 7b are as follows.

[Α] _D ²⁷ ; −32.3 ° (C = 1.15, chloroform) IRνmax (neat) cm ⁻¹ ; 3446, 3312, 2954, 2932,
2858, 1256, 1098, 837, 774. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.89 (ddd, 1 H, J = 5.
5, 10.3, 16.9Hz), 5.27 (dt, 1H, J = 17.2, 1.1Hz),
5.10 (dt, 1H, J = 10.3, 1.5Hz), 4.47 to 4.37 (m, 1
H), 4.21-4.10 (m, 1H), 2.72 (d, 1H, J = 3.3Hz),
2.45 (dd, 2H, J = 2.9, 6.6Hz), 2.01 (t, 1H, J = 2.8H
z), 1.90-1.72 (m, 2H), 0.90 (s, 9H), 0.12 (
s, 6H). MS; 255 (M ⁺ + H ⁺ ), 197 (M ⁺ -C ₄ H ₉ ), 75 (1
00%). Anal.Calcd. For C ₁₄ H ₂₆ O ₂ Si, C; 66.09, H; 10.3
0. Found: C; 65.83, H; 10.43.

Example 13 <Synthesis of Compound of Formula 7c> A compound of formula 7b (164.6 mg,
Imidazole (168 mg, 2.46 mM), a catalytic amount of 4-dimethylaminopyridine, and t-butyldimethylsilyl chloride (156 mg, 1.04 mM) were sequentially added to a solution of 0.65 mM) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 12 hours. did. 5 ml of water was added to the reaction solution, and extracted twice with 40 ml of ether. The combined organic layer was washed with 5 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction of ether / n-hexane (1:30) was converted to a colorless oil of the formula 7c
224.9 mg (yield 94%) of the compound represented by were obtained. Equation 7c
The spectrum data and elemental analysis result of the compound are as follows.

[Α] _D ³⁰ ; -10.3 ° (C = 1.50, chloroform) IRνmax (neat) cm ⁻¹ ; 3316, 2956, 2932, 2890,
2858, 1254, 1091, 835, 772. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.82 (ddd, 1 H, J = 7.
3, 10.3, 17.3Hz), 5.14 (bd, 1H, J = 16.9Hz), 5.04
(Bd, 1H, J = 10.3Hz), 4.22 (dt, 1H, J = 5.5, 7.0H
z), 3.98-3.88 (m, 1H), 2.40-2.32 (m, 2H),
1.98 (t, 1H, J = 2.4Hz), 1.88 (ddd, 1H, J = 5.1, 7.
3, 13.2Hz), 1.65 (ddd, 1H, J = 5.1, 6.2, 13.6Hz),
0.89 (s, 18H), 0.09 (s, 6H), 0.06 (s, 3H),
0.04 (s, 3H). _{^{MS; 311 (M + -C 4}} H 9), 171 (100%), 73 (100
%). Anal. Calcd. For C ₂₀ H ₄₀ O ₂ Si ₂ , C; 65.17, H; 1
0.95. Found: C; 64.99, H; 10.93.

Example 14 <Synthesis of Compound of Formula 8a> A compound of Formula 7c (202 mg, 0.2 g
55 mM) in tetrahydrofuran (4 ml) at -78 ° C.
4M n-butyllithium / n-hexane solution (0.47 ml,
0.66 mM) was gradually added dropwise, and the mixture was stirred at the same temperature for 40 minutes. −
At 78 ° C, add methyl chlorocarbonate (0.08ml, 0.77m
M) was slowly added dropwise and stirred for 2 hours. This reaction solution is
The temperature was raised to 0 ° C., 1 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was stirred for 20 minutes and heated to room temperature. Water 10
After adding twice with 70 ml of ether, the organic layers were combined, washed with 10 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and ether / n-hexane (1:
80) The compound of the formula 8a which is a colorless oil from the fraction of 18)
1.2 mg (78% yield) were obtained. The spectrum data and elemental analysis result of the compound of the formula 8a are as follows.

[Α] _D ²⁸ ; −4.7 ° (C = 1.145, chloroform) IRνmax (neat) cm ⁻¹ ; 2954, 2932, 2890, 2858,
2240, 1721, 1255, 1077, 837, 773. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.80 (ddd, 1 H, J = 7.
3, 10.3, 17.2Hz), 5.14 (bd, 1H, J = 17.2Hz), 5.05
(Bd, 1H, J = 10.3Hz), 4.21 (dt, 1H, J = 5.5, 7.0H
z), 4.07-3.92 (m, 1H), 3.75 (m, 3H), 2.56 (
dd, 1H, J = 5.5, 16.8Hz), 2.46 (dd, 1H, J = 5.5, 17.
2Hz), 1.82 (ddd, 1H, J = 5.9, 7.3, 13.2Hz), 1.70
(Dt, 1H, J = 13.9, 5.5Hz), 0.89 (s, 18H), 0.10
(S, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04
(S, 3H). MS; 411 (M ⁺ -15), 369 (M ⁺ -57), 171 (100
%), 147 (M ⁺ -279), 73 (100%). Anal.Calcd. For C ₂₂ H ₄₂ O ₄ Si ₂ , C; 61.93, H; 9.
93. Found: C; 61.79, H; 10.03.

Example 15 <Synthesis of Compound of Formula 8b> A compound of Formula 7c (500 mg, 1.
36 mM) in tetrahydrofuran (10 ml) at -78 ° C.
4M n-butyllithium / n-hexane solution (1.2ml,
1.63 mM) was gradually added dropwise, followed by stirring at the same temperature for 40 minutes. −
Ethyl chlorocarbonate (0.2ml, 1.90m
M) was slowly added dropwise, followed by stirring for 2.5 hours. The temperature of the reaction solution was raised to 0 ° C., 2 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was stirred for 20 minutes and heated to room temperature. Add water to the reaction
After adding 20 ml and extracting twice with 150 ml of ether, the organic layers were combined, washed with 20 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 482.1 mg (yield: 81%) of a compound represented by the formula 8b as a colorless oil from a fraction of ether / n-hexane (1:30). The spectrum data and elemental analysis result of the compound of the formula 8b are as follows.

[Α] _D ²⁵ ; −3.5 ° (C = 1.23, chloroform) IRνmax (neat) cm ⁻¹ ; 2956, 2932, 2856, 2236,
1715, 1252, 1073, 836, 773. ¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.80 (ddd, 1 H, J = 7.
3, 10.3, 17.2Hz), 5.14 (bd, 1H, J = 17.2Hz), 5.05
(Bd, 1H, J = 10.3Hz), 4.24 to 4.17 (m, 3H), 3.98 (
dt, 1H, J = 5.9, 11.7Hz), 2.56 (dd, 1H, J = 5.5, 16.
9Hz), 2.46 (dd, 1H, J = 5.9, 17.2Hz), 1.82 (ddd,
1H, J = 5.9, 7.3, 13.2Hz), 1.70 (dt, 1H, J = 13.9,
5.5Hz), 1.30 (t, 3H, J = 7.1Hz), 0.89 (s, 18H),
0.10 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.0
4 (s, 3H). MS; 425 (M ⁺ -15), 383 (M ⁺ -57), 171 (100
%), 147 (M-279), 73 (100%). Anal. Calcd. For C ₂₃ H ₄₄ O ₄ Si ₂ , C; 62.67, H; 1
0.06. Found: C; 62.70, H; 10.06.

Example 16 <Synthesis of Compound of Formula 9a> Compound of formula 8a (35 mg, 82.2
μ) in benzene (2 ml) solution, trimethyl phosphite (8.3 μl, 70.4 μ), Pd ₂ (dba) ₃ · CHCl ₃ (17 mg,
16.4 μM, dba is an abbreviation for dibenzylideneacetone. The same applies to the following examples. ), Acetic acid (1μl, 1.7μM
) Were sequentially added at room temperature, and the mixture was stirred at the same temperature for 12 hours under a nitrogen atmosphere. After evaporation of the solvent, the residue was subjected to silica gel column chromatography to obtain 22.3 mg (yield: 64%) of a compound represented by the formula 9a as a colorless oil from a fraction of ether / n-hexane (1:20). . The spectrum data and elemental analysis result of the compound of the formula 9a are as follows.

IRνmax (neat) cm ^-1 ; 2930, 2856, 1
721, 1642, 1471. ¹ H-NMR (500 MHz, CDCl ₃ ); δ 5.89 (s, 1 H), 5.07
(Bs, 1H), 5.05 (bs, 1H), 4.58 to 4.53 (m, 1H),
4.27 to 4.19 (m, 1H), 3.68 (s, 3H), 3.33 (dd, 1
H, J = 5.2, 14.7Hz), 2.67 (bd, 1H, J = 14.7Hz), 1.98
Up to 1.89 (m, 1H), 1.80 to 1.70 (m, 1H) 0.88 (s, 9
H), 0.84 (s, 9H), 0.04 (s, 12H). ¹³ C-NMR (125 MHz, CDCl ₃ ); δ 167.02, 157.48,
152.08, 116.06, 109.96, 70.22, 67.14, 51.07
, 43.73, 37.58, 25.87, 25.76, 18.31, 18.12,
−4.93, −5.00. MS; 411 (M ⁺ -15), 395 (M ⁺ -31), 369 (M ⁺
-57), 73 (100%).

Example 17 <Synthesis of Compound of Formula 9b> Compound of formula 8b (30 mg, 68.2)
μM) in benzene (2 ml) solution and ethylenebis (diphenylphosphine (2.7 mg, 6.8 μM), Pd ₂ (dba) ₃
・ CHCl ₃ (14mg, 13.5μM), pivalic acid (4μl, 34.
1 μM) at room temperature, and the mixture was heated to 50 ° C. and stirred under a nitrogen atmosphere for 15 hours. After evaporating the solvent, the residue was subjected to silica gel column chromatography to obtain 21.1 mg (yield: 69%) of a compound represented by the formula 9b as a colorless oil from a fraction of ether / n-hexane (1:20). The spectral data of the compound of formula 9b is as follows.

¹ H-NMR (300 MHz, CDCl ₃ ); δ 5.89 (b
rs, 1H), 5.07 (t, 1H, J = 1.8Hz), 5.06 (t, 1H, J =
1.8Hz), 4.57 to 4.54 (m, 1H), 4.26 to 4.22 (m, 1
H), 4.18 to 4.10 (m, 2H), 3.36 (dd, 1H, J = 5.5, 1
4.7Hz), 2.64 (dt, 1H, J = 2.4, 14.7Hz), 1.97-1.9
2 (m, 1H), 1.75 (ddd, 1H, J = 1.8, 9.2, 11.6Hz),
1.26 (t, 3H, J = 7.3Hz), 0.85 (s, 9H), 0.04 (s, 1
2H).

[0055]

INDUSTRIAL APPLICABILITY According to the present invention, an important intermediate corresponding to the A ring portion in the production of calcitriol and its related vitamin derivatives for the treatment of osteoporosis and other diseases can be obtained efficiently and in a simple reaction route. It is important as a raw material compound that can be used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07F 7/18 C07F 7/18 FSW // C07D 303/20 C07D 303/20 (58) Investigated field (Int.Cl. ⁶ , DB name) C07C 33/04 C07C 29/56 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound S-5-hydroxy-octa-2,7-diyn-1-ol represented by the formula 1 and a silyl derivative thereof. Embedded image (However, R ¹ represents hydrogen or a trimethylsilyl group; R ²
Represents hydrogen or a t-butyldimethylsilyl group, and R ³ represents a tetrahydropyranyl group or hydrogen. ) 2. R ^{1 of the} formula ¹ is a trimethylsilyl group, R ²
Is a hydrogen and R ³ is a tetrahydropyranyl group. 3. The method according to claim 2, wherein the compound of formula 2 is reacted with propargyl tetrahydropyranyl ether and n-butyllithium. 2. A method for producing the compound according to 2. Embedded image (However, TMS represents a trimethylsilyl group) 4. The compound according to claim 2, wherein the compound R-5,6-oxiranylhex-2-ynyltetrahydropyranyl ether of the formula 3 is reacted with trimethylsilylacetylene and n-butyllithium. Preparation of the compound of Embedded image (However, THP represents a tetrahydropyranyl group)