JPH0873390A - Calcitriol intermediate and its production - Google Patents

Abstract

PURPOSE: To obtain a new S-5-hydroxy-octa-2,7-diyn-1-ol compound useful as a raw material compound capable of efficiently and simply providing an important intermediate corresponding to a part of ring A for producing a therapeutic agent calcitriol for osteoporosis, etc. CONSTITUTION: This compound is expressed by formula I (R<1> is H or trimethylsilyl; R<2> is H or t-butydimethylsilyl; R<3> is H or tetrahydropyranyl), e.g. a compound of formula II (TMS is trimethylsilyl; THP is tetrahydropyranyl). The exemplified compound of formula II is obtained by reacting S-5- trimethylsilyl-1,2-oxiranylpent-4-yne of formula III with propargyl tetrahydropyranyl ether and n-butyl-lithium.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention produces an important intermediate corresponding to the A ring portion of calcitriol represented by the following formula 9 when producing calcitriol and its related vitamin derivative for the treatment of osteoporosis and other diseases. The present invention relates to a novel compound and a method for producing the same.

[0002]

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

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 A ring part 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 more excellent methods. That is, in the former method, d-carvone is used as a raw material, and after stereospecifically epoxidizing it, it is reacted with a carbanion of diethyl (carboxyethyl) phosphate by a Horner-Emmons reaction to produce 9 of α, β-unsaturated ester. The Z-form / E-form mixture of 1 is separated by a silica gel column, the Z-form is removed, the epoxy group is opened, the diacetate is converted, and the isopropenyl group is oxidized to an acetyl group and then to an acetate to give triacetate. Then, the compound represented by the formula 9a or 9b is synthesized by a method in which only the secondary hydroxyl group is protected with a t-butyldimethylsilyl group after being hydrolyzed to a triol, and dehydration is performed to convert it into an exomethylene group. However, the process is long, and very careful not to cause side reactions during the reaction.

In the latter method, the intermediate 3-hydroxy-
5-t-butyldiphenylsiloxyoct-7-yne-
The syn-form and anti-form of 1-ene must be separated,
In order to improve the economic efficiency, it is necessary to sterically invert the hydroxyl group at the 3-position of the syn-form to the anti-form by the Mitsunobu method. Further, the (+)-form of the racemic mixture of the syn-form is dynamically resolved. Asymmetric epoxidation is selectively removed by the principle of the method,
It is necessary to collect the unreacted (-) form, and it is not easy to obtain a large amount of products with good optical purity, and there is a drawback that the operation is complicated as an industrial production method.

[0006]

In view of the above, the present inventor has made
A method for obtaining a key intermediate of the A ring part of calcitriol and its related vitamin derivatives, that is, a compound represented by the formulas 8a, 8b and 9a, 9b, efficiently and with a simple reaction route in which there are few byproducts As a result of examination, the compound S-5-hydroxy-octa-2 represented by the formula 1
A new method for obtaining the above-mentioned compound of interest was found according to the following reaction route (I) using 7-diyn-1-ol and its silyl derivative as raw materials. TM in the following reaction path
S represents a trimethylsilyl group, THP represents a tetrahydropyranyl group, and TBS represents a t-butyldimethylsilyl group.

Reaction pathway (I)

[Chemical 4]

The present invention is a compound S-represented by the following formula 1.
5-Hydroxy-octa-2,7-diyn-1-ol and silyl derivatives thereof and a method for producing the same.

[0009]

[Chemical 5] (However, R ¹ is hydrogen or trimethylsilyl group, R ²
Represents hydrogen or a t-butyldimethylsilyl group, and R ³ represents a tetrahydropyranyl group or hydrogen. )

The present invention will be described below with reference to Reaction Route I. The compound S-5-hydroxy-octa-2,7-diyn-1-ol of the present invention represented by 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. A compound of formula 1a is obtained. Also R-
The compound of 1a above can also be obtained by reacting 5,6-oxiranylhex-2-ynyltetrahydropyranyl ether (3) with lithium trimethylsilylacetylide.

The reaction of lithium acetylide obtained from propargyl tetrahydropyranyl ether with the compound of formula 2 can be carried out as follows. Propargyl tetrahydropyranyl ether as a solvent, for example, tetrahydrofuran, diethyl ether, ethers such as ethylene glycol, or hydrocarbons such as hexane,
Lithium acetylide formed by reacting with methyl lithium, n-butyllithium, sec-butyllithium, t-butyllithium or the like with an equal amount or more of a strong base is used to form a compound of formula 2, S-5-trimethylsilyl-1,2-oxila Reaction of nylpent-4-yne (2) with a Lewis acid, such as trifluoroboron etherate, provides a compound of formula 1a. It is desirable to carry out this reaction at a low temperature of -30 ° C to -100 ° C. This reaction proceeds even without a catalyst, but the addition of the Lewis acid as described above accelerates the reaction.

R-5,6-oxiranylhexa-2
The reaction of -inyl tetrahydropyranyl ether (3) with lithium trimethylsilyl acetylide can be carried out as follows. That is, trimethylsilylacetylene is used as a solvent, for example, ethers such as tetrahydrofuran, diethyl ether, and ethylene glycol, or hydrocarbons such as hexane, and a strong base such as methyllithium, n-butyllithium, sec-butyllithium, and t-butyllithium. The compound of formula 1a is obtained by reacting the lithium acetylide formed by reacting with the compound of formula 3 in an amount equal to or greater than It is desirable to carry out this reaction at a low temperature of -30 ° C to -100 ° C.

Starting material S-5-trimethylsilyl-1,2
-Oxiranyl penta-4-yne (2) was prepared from high optical purity R-epichlorohydrin by Tetrahedron Asymmetry, 3,
It can be produced by the method described in 853 (1992). Another raw material R-5,6-oxiranyl hexa-2-ynyl tetrahydropyranyl ether (3) is Angew.Chem.Int.Ed, En.
It can be prepared from S-epichlorohydrin by the method described in gl., 28, 1272 (1989).

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

In the production of calcitriol and its related vitamin derivatives from the compound of formula 1 of the present invention, an important intermediate corresponding to the A ring part, that is, formula 8a, 8b and formula 9a, 9b Reaction route (I)
Then, it can be performed as follows.

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

Oxidation of a 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 the formula 6a is subjected to the condition of Kazuki-Sharpless asymmetric epoxidation, namely, L-
Epoxidation of the compound of formula 4a in the presence of diisopropyl tartrate gives almost quantitative results. Similarly, from the compound of formula 4b, β-epoxide compound 6c having the same configuration as that of formula 6a can be obtained by oxidation with m-chloroperbenzoic acid 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 iodine compounds of formulas 6b and 6d, respectively. Reaction of the iodide of formula 6b with zinc dust activated in a solvent such as a C ₁ -C ₄ alcohol containing acetic acid yields formula 7
a compound 5R, 3R-8-trimethylsilyl-5-t
-Butyldimethylsilyl-3-hydroxy-octa-7
-In-1-ene is obtained with a yield of 85%. When the compound of 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, a compound of formula 7b in which the silyl group at the 8-position is eliminated is 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,
The target calcitriol is obtained by reacting with methyl chlorocarbonate or methyl chlorocarbonate after forming lithium acetylide with C _{1 to} C ₄ alkyllithium such as methyllithium, n-butyllithium, sec-butyllithium, and t-butyllithium. And a chain compound of the formula 8a, 8b, which is one of the important intermediates related thereto. Formula 8a, 8
When the compound of b is subjected to a cyclization reaction using a tris (dibenzylideneacetone) dipalladium-chloroform complex as a catalyst, another important intermediate of calcitriol and its related compounds, which is represented by the formulas 9a and 9b, is used. An alkylidenecyclohexane derivative is obtained.

[0019]

【Example】

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

The compound of formula 1a can also be synthesized by the following method. That is, 1.4M n-butyllithium n-hexane solution (7.8 ml, 10.91 mM) was gradually added dropwise to a tetrahydrofuran (20 ml) solution of propargyl tetrahydropyranyl ether (2.0 g, 13.64 mM) at the same temperature. The mixture was stirred for 0.5 hour, and a trifluoroboron-ether complex (1.3 ml, 10.91 mM) was gradually added dropwise, followed by stirring at the same temperature for 0.5 hour. Compound of Formula 2 (1.4g, 9.09mM) in this reaction mixture
Tetrahydrofuran (5 ml) solution of was slowly added at -78 ° C, and the mixture was stirred at the same temperature for 2.5 hours, and then gradually warmed to room temperature. Water (20 ml) was added to the reaction solution, and ether 250 was added.
Extracted twice with ml. The combined organic layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.79 g of a colorless compound of the formula 1 was obtained 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 in agreement with the compound obtained by the previous method. The spectral data and elemental analysis results of the compound of formula 1a are as follows.

IRν max (neat) cm ^-1 ; 3438, 2954, 2
872, 2174, 1249, 1025, 841. ¹ H-NMR (300MHz, CDCl ₃ ); δ 4.77 (t, 1H, J = 2.9H
z), 4.28 (dt, 1H, J = 15.4, 2.2Hz), 4.19 (dt, 1
H, J = 1.8, 15.8Hz), 3.94 to 3.76 (m, 2H), 3.57 to 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
To a dimethylformamide (18 ml) solution of mM) at room temperature, imidazole (1.8 ml, 27.0 mM) and t-butyldimethylsilyl chloride (1.7 mg, 11.4 mM) were added 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:
From the fraction (20) there was obtained 2.9 g of the compound of formula 1b as a colorless oil.
The yield was almost quantitative. The spectral data and elemental analysis results of the compound of formula 1b are as follows.

IR ν max (neat) cm ^-1 ; 2954, 2856, 21
76, 1250, 1107, 1025, 840. ¹ H-NMR (300 MHz, CDCl ₃ ); δ4.79 (t, 1H, J = 2.9H
z), 4.28 (dt, 1H, J = 15.4, 2.2Hz), 4.18 (dt, 1
H, J = 2.2, 15.8Hz), 4.00 to 3.78 (m, 2H), 3.58 to 3.
47 (m, 1H), 2.53 (dd, 1H, J = 5.5, 16.9Hz), 2.39
(Dd, 1H, J = 6.2, 16.8Hz), 2.59 to 2.34 (m, 2H),
1.89 ~ 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.
Pyridinium p-toluenesulfonate (10 mg, 0.04 mM) was added to a solution of 11 mM) in methanol (1 ml) at room temperature.
It was stirred 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 layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, ether / n-hexane (1:10)
28.4 mg of the compound of formula 1c was obtained as a colorless oil from the fraction of The yield was 81%, but the yield was 88% considering the recovery of raw materials. The spectral data and elemental analysis results of the compound of formula 1c are as follows.

[Α] _D ³⁰ ; + 9.0 ° (C = 1.01, methanol). IR ν max (neat) cm ^-1 ; 3362, 2956, 2930, 2856,
2176, 1250, 1103, 840 ¹ H-NMR (300MHz, CDCl ₃ ); δ4.31 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.
To a solution of 26 mM) in methanol (50 ml), potassium carbonate (1.47
g, 10.65 mM) was added at room temperature, the temperature was raised to 40 ° C, and the mixture was stirred for 0.5 hour. The solvent of this reaction solution was evaporated under reduced pressure, saturated brine (5 ml) was added, and the mixture was extracted twice with 30 ml of ether. The combined organic layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.04 g of a compound of formula 1d was obtained as a colorless oily substance from a fraction of ether / n-hexane (1: 2). Yield 97%
Met. The spectral data and elemental analysis results of the compound of Formula 1d are as follows.

[Α] _D ²⁶ ; −1.6 ° (C = 0.86, methanol). IR ν max (neat) cm ^-1 ; 3310, 2930, 2856, 2228,
2120, 1256, 1110. ¹ H-NMR (300MHz, CDCl ₃ ; δ4.25 (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.
25 mM) in ether (50 ml) solution with 35% sodium bis (2-methoxyethoxy) aluminum hydride /
A toluene solution (21 ml, 34.8 mM) was added at 0 ° C, the temperature was gradually raised to room temperature, and the mixture was stirred for 1 hour. Add 10% NaOH to this reaction mixture.
Add an aqueous solution (7 ml) and stir for 20 minutes, then add dichloromethane.
Extracted twice with 300 ml. Combine the organic layers with saturated saline solution 30
After washing with ml, it 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), a colorless oily compound of the formula 4a (1.51 g, 64%) and a colorless oily compound of the formula 4b (573 mg, 31%) ) Got. The raw material recovery was 44 mg (2%). The spectral data and elemental analysis results of the compound of formula 4a are as follows.

[Α] _D ²⁸ ; + 3.9 ° (C = 0.92, methanol). IR ν max (neat) cm ^-1 ; 3344, 2956, 2930, 2898,
2858, 2176, 1250, 1101, 840, 773. ¹ H-NMR (500 MHz, CDCl ₃ ); δ5.72 to 5.64 (m, 2H)
4.13 ~ 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 ~ 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.
75 mM) in ether (12.5 ml) solution with 35% sodium bis (2-methoxyethoxy) aluminum hydride /
Toluene solution (7.6ml, 13.2mM) was added at 0 ℃ for 1 hour.
After stirring for 20 minutes, the temperature was raised to room temperature and stirring was continued for 6 hours. To this reaction solution was added 10% NaOH aqueous solution (4 ml) and stirred for 20 minutes,
It was extracted twice with 150 ml of dichloromethane. The combined organic layers were washed with saturated saline (15 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 188 mg of a 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 spectral data and elemental analysis results of the compound of 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 ); δ5.73 to 5.70 (m, 2H)
4.13 ~ 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> Compound of Formula 4a (240 mg, 0.
74 mM) in dichloromethane (24 ml) was added to sodium hydrogen carbonate (185 mg, 2.21 mM) and m-chloroperbenzoic acid (270
(mg, 1.10 mM) was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
A saturated aqueous sodium hydrogen sulfite solution (20 ml) was added to the reaction solution at 0 ° C., the mixture was stirred for 20 minutes, warmed to room temperature, and extracted twice with 120 ml of dichloromethane. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 ml) and then saturated brine (20 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, ether / n-hexane (1: 3).
183.5 mg (yield 73%) and 18.4 mg (yield 7.3%) of the colorless oily β-epoxide represented by the formula 6a and its isomer α-epoxide were obtained from the distillate. The spectral data and elemental analysis results of the compound of 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 ); δ4.01 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 ~ 2.36 (m, 2H), 1.83 ~ 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.
86mM) in dichloromethane (80ml) in sodium hydrogen carbonate (1.22g, 14.57mM) and m-chloroperbenzoic acid (1.2m).
6 g, 7.29 mM) was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
A saturated aqueous sodium hydrogen sulfite solution (60 ml) was added to this reaction solution at 0 ° C., the mixture was stirred for 20 minutes, warmed to room temperature, and extracted with 400 ml of dichloromethane on the second floor. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution (60 ml) and then with saturated saline (60 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, ether / n-hexane (1: 1).
From the fraction (1), 969.2 mg (yield 74%) and 80.8 mg (yield 6.2%) of β-epoxide represented by the formula 6c and its isomer α-epoxide, respectively, were obtained. The spectral data and elemental analysis results of the compound of 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 ); δ4.07 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 ~ 2.94 (m, 1H), 2.40 ~ 2.36 (m,
2H), 2.00 (t, 1H, J = 2.6Hz), 1.91 ~ 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> Compound of Formula 6a (430 mg, 1.
26 mM) was dissolved in a 4: 1-tetrahydrofuran / acetonitrile (24 ml; 6 ml) mixed solvent to prepare triphenylphosphine (990 mg, 3.77 mM) and imidazole (642 mg, 9.43).
mM) and iodine (960 mg, 7.54 mM) were added sequentially, and the mixture was stirred at room temperature for 30
Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution (10 ml) was added to the reaction solution, and the mixture was extracted twice with 120 ml of ether.
The combined organic layers were washed successively with 10% aqueous sodium sulfite solution (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain a colorless oil of β-epoxy iodide represented by the formula 6b from a fraction of ether / n-hexane (1:20).
486.3 mg (yield 85%) was obtained. The spectral data and elemental analysis results of the compound of 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 4: 1-tetrahydrofuran / acetonitrile (70 ml: 18 ml) solution with 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, and the mixture was stirred at room temperature for 30 minutes. Decorative alphabet calculation-Saturated aqueous sodium hydrogen carbonate solution (40 ml) was added to this reaction solution, and the mixture was extracted twice with 200 ml of ether. Combined organic layers 40m with 10% sodium sulfite aqueous solution
l, saturated aqueous sodium hydrogen carbonate solution 40ml, saturated saline solution 40m
After sequentially washing with l, it 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 (yield 84%) of colorless oily β-epoxy iodide represented by the formula 6d from a fraction of ether / n-hexane (1:15). The spectral data and elemental analysis results of the compound of 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 ); δ4.04 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, the temperature was raised to 40 ° C, and the mixture was subjected to ultrasonic waves for 1 hour. The reaction solution was diluted with 70 ml of ether and then filtered through Celite, and the filtrate was washed with 10 ml of 5% hydrochloric acid aqueous solution, 10 ml of saturated sodium hydrogen carbonate aqueous solution and 10 ml of saturated saline solution successively, dried over magnesium sulfate and dried under reduced pressure. The solvent was distilled off. The residue was subjected to silica gel column chromatography, ether / n-
287.2 mg (yield 87%) of a compound represented by the formula 7a was obtained as a colorless oil from a hexane (1:30) fraction. The spectral data and elemental analysis results of the compound of 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 ); δ5.86 (ddd, 1H, J = 4.
9, 10.4, 17.1Hz), 5.25 (bd, 1H, J = 17.1Hz), 5.08
(Bd, 1H, J = 10.4Hz), 4.43 ~ 4.40 (m, 1H), 4.15 ~
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,
0.80 mM) in methanol (4.5 ml) was added with potassium carbonate (275 mg, 1.99 mM) at room temperature, the temperature was raised to 40 ° C, and the mixture was stirred for 1 hour. The solvent of this reaction solution was evaporated under reduced pressure, 10 ml of saturated saline was added, and the mixture was extracted twice with 70 ml of ether. The combined organic layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 196.5 mg (yield 97%) of a colorless oily compound represented by the formula 7b from a fraction of ether / n-hexane (1: 2).
I got

As another method for synthesizing the compound of formula 7b, it was synthesized by the following method. Compound of formula 6b (1.24g, 3.26m
M) in methanol (40ml) solution activated zinc (640m
g, 9.79 mM) and acetic acid (1 ml) were sequentially added at room temperature, the temperature was raised to 40 ° C., and ultrasonication was performed for 1 hour. This reaction solution is ether
The mixture was diluted with 200 ml and filtered through Celite, and the filtrate was washed successively with 30 ml of 5% hydrochloric acid aqueous solution, 30 ml of saturated sodium hydrogen carbonate aqueous solution and 30 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel with ether / n-hexane (1:
A compound of the formula 7b which is a colorless oil from the fraction of 2) 720
mg (yield 87%) was obtained. The spectral data and elemental analysis results of the compound of 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 ); δ5.89 (ddd, 1H, 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 ~ 4.37 (m, 1
H), 4.21 to 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 to 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> Compound of Formula 7b (164.6 mg,
0.65mM) in dimethylformamide (2ml) was added with imidazole (168mg, 2.46mM), catalytic amount of 4-dimethylaminopyridine and t-butyldimethylsilyl chloride (156mg, 1.04mM), and stirred for 12 hours at room temperature. did. 5 ml of water was added to this reaction solution, and the mixture was extracted twice with 40 ml of ether. The combined organic layers were washed with 5 ml of saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain a colorless oily compound of formula 7c from a fraction of ether / n-hexane (1:30).
224.9 mg (yield 94%) of the compound represented by was obtained. Formula 7c
The spectral data and elemental analysis results 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 ); δ5.82 (ddd, 1H, 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> Compound of Formula 7c (202 mg, 0.
55 mM) in tetrahydrofuran (4 ml) at -78 ° C 1.
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. −
Methyl chlorocarbonate (0.08ml, 0.77m)
M) was gradually added dropwise, and the mixture was stirred for 2 hours. This reaction solution is
The temperature was raised to 0 ° C., 1 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was stirred for 20 minutes and warmed to room temperature. Water 10
ml was added, the mixture was extracted 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:
A colorless oily compound of the formula 8a
1.2 mg (yield 78%) was obtained. The spectral data and elemental analysis results of the compound of 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 ); δ5.80 (ddd, 1H, 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 to 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> Compound of Formula 7c (500 mg, 1.
36 mM) in tetrahydrofuran (10 ml) at -78 ° C 1.
4M n-butyllithium / n-hexane solution (1.2 ml,
1.63 mM) was gradually added dropwise, and the mixture was stirred at the same temperature for 40 minutes. −
Ethyl chlorocarbonate (0.2 ml, 1.90 m
M) was gradually added dropwise, and the mixture was stirred for 2.5 hours. The temperature of this 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 warmed to room temperature. Water in this reaction solution
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 spectral data and elemental analysis results of the compound of 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 ); δ5.80 (ddd, 1H, J = 7.
3, 10.3, 17.2Hz), 5.14 (bd, 1H, J = 17.2Hz), 5.05
(Bd, 1H, J = 10.3Hz), 4.24 ~ 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), 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 (1 μl, 1.7 μM
) Was sequentially added at room temperature, and the mixture was stirred at the same temperature for 12 hours under a nitrogen atmosphere. After distilling off 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 colorless oil from a fraction of ether / n-hexane (1:20). . The spectral data and elemental analysis results of the compound of formula 9a are as follows.

IR ν max (neat) cm ^-1 ; 2930, 2856, 1
721, 1642, 1471. ¹ H-NMR (500 MHz, CDCl ₃ ); δ5.89 (s, 1H), 5.07
(Bs, 1H), 5.05 (bs, 1H), 4.58 ~ 4.53 (m, 1H),
4.27 ~ 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
~ 1.89 (m, 1H), 1.80 ~ 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
solution of ethylene bis (diphenylphosphine (2.7mg, 6.8μM), Pd ₂ (dba) ₃ in benzene (2ml)
・ CHCl ₃ (14 mg, 13.5 μM), pivalic acid (4 μl, 34.
1 μM) was sequentially added at room temperature, the temperature was raised to 50 ° C., and the mixture was stirred for 15 hours under a nitrogen atmosphere. After distilling off the solvent, the residue was subjected to silica gel column chromatography to obtain 21.1 mg (yield 69%) of a colorless oily compound of the formula 9b 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 ~ 4.54 (m, 1H), 4.26 ~ 4.22 (m, 1
H), 4.18 ~ 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 to 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 The present invention efficiently and easily obtains an important intermediate corresponding to the A ring portion in the production of calcitriol and its related vitamin derivative for the treatment of osteoporosis and other diseases by a simple reaction route. It is important as a raw material compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07F 7/18 SW // C07D 303/20

Claims (4)

[Claims] 1. A compound of formula 1, S-5-hydroxy-octa-2,7-diyn-1-ol and silyl derivatives thereof. Embedded image (However, R ¹ is hydrogen or 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
The compound according to claim 1, wherein is hydrogen and R ³ is a tetrahydropyranyl group. 3. The compound of formula 2, S-5-trimethylsilyl-1,2-oxiranylpent-4-yne, 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 R-5,6-oxiranylhex-2-ynyltetrahydropyranyl ether represented by the formula 3 is reacted with trimethylsilylacetylene and n-butyllithium. Of the compound of. [Chemical 3] (However, THP represents a tetrahydropyranyl group)