JPH08301811A - Hydroindan-4-ol derivative and its production - Google Patents

Abstract

PURPOSE: To obtain a hydroindan-4-ol derivative which is useful as a synthetic intermediate for vitamin D derivatives as a medicine in high stereoselectivity. CONSTITUTION: This objective compound is represented by formula I [R<1> and R<2> are each H, OH-protecting group; R<3> is H, a (substituted) alkyl, an alkenyl, an alkynyl, an aryl, an aralky], for example, octahydro-7a-methyl-1-(1-hydroxy-2- propyl)-1H-indene-4-ol. This compound is prepared by allowing a base such as lithium amide to react with an acetic ester derivative of formula II (R<4> is identical to R<3> ) in a solvent such as diethyl ether and allowing the product of enolate to act on 3-(4-hydroxyhydroindan)butanal derivative of formula III (R<5> is identical to R<1> ), when necessary, followed by OH protection or deprotection.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a hydroindan-4-ol derivative and a method for producing the same. The hydroindan-4-ol derivative provided by the present invention is said to be effective for the treatment of defective calcium metabolism such as chronic renal failure, hypoparathyroidism, osteomalacia, and osteoporosis 1.
α, 23S-dihydroxyvitamin D ₃ , 1α, 23
23S- such as S, 25-trihydroxyvitamin D ₃
It is useful as a synthetic intermediate such as a hydroxyvitamin D derivative.

[0002]

2. Description of the Related Art In recent years, with the progress of research on vitamin D, many vitamin D derivatives including the above 23S-hydroxyvitamin D derivative have been developed as pharmaceuticals. Further, in developing a vitamin D derivative as a drug, it is important to synthesize a metabolite, a degradation product or a labeled compound thereof. Furthermore, recently, vitamin D derivatives having various side chains have also been studied, and as their biological activities have been tested, it has become clear that the activity is greatly affected by modifying the side chain portion. ing.

As a useful method for the synthesis of vitamin D derivatives, the A-ring component of vitamin D derivatives (A-rings
ynthons) and a CD ring synthons are combined with each other in a convergent manner. 23S
When the -hydroxyvitamin D derivative is synthesized by the astringent-type synthesis method, the hydroindan-4-ol derivative of the present invention may be mentioned as a compound corresponding to the CD ring constituent part.

Conventionally, a method for stereoselectively constructing a functional group in a side chain portion of a compound corresponding to a CD ring constituting portion, particularly 2
As a stereoselective hydroxyl group construction method for the 3-position, for example,
Method by ring-opening reaction of epoxide of 23,24-epoxy-25,26,27-norhydroindane derivative [Journal of the Organic Chemistry (Jo
urnal of the Organic Chemistry), Vol. 48, page 4433 (1983)], hydroindane-Δ ^22,23 -26-
Intramolecular iodine lactonization reaction for carboxylic acid derivatives [Journal of the Chemical Society, Chemical Communication (Journal of t
he Chemical Society, Chemical Communications), No.
See page 1229 (1992)].

[0005]

In the method by the ring-opening reaction of the epoxide described above, the asymmetric carbon at the 23-position of the compound (23-hydroxy form) obtained by the configuration of the asymmetric carbon atom at the 23-position of the epoxide is obtained. The configuration of atoms is determined. In the iodine lactonization reaction, the geometric isomer (cis or trans form) of Δ ^22,23 and 2
The configuration of the asymmetric carbon atom at the 23-position of the resulting compound (23-hydroxy form) is determined by the configuration of the asymmetric carbon atom at the 5-position. In any case, it was necessary to obtain in advance a key intermediate having a steric configuration suitable for the target compound, which required a complicated separation step.

Accordingly, one object of the present invention is to provide a hydroindan-4-ol derivative which is an intermediate of a vitamin D derivative having a hydroxyl group at the 23-position without the need for a complicated separation step as described above. It is an object of the present invention to provide a method capable of producing highly stereoselectively. Another object of the present invention is to provide the hydroindan-4-ol derivative.

[0007]

According to the present invention, the above-mentioned object is achieved by the following general formula (I):

[0008]

Embedded image

(In the formula, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group, and R ³ represents a hydrogen atom or an alkyl group which may have a substituent, an alkenyl group,
Represents an alkynyl group or an aryl group. ) Hydroindan-4-ol derivative (hereinafter abbreviated as hydroindan-4-ol derivative (I)) and the following general formula (II)

[0010]

[Chemical 6]

(In the formula, R ⁴ represents a hydrogen atom or an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group, which may have a substituent). Is abbreviated as acetic acid ester derivative (II)), and the resulting enolate is converted to the following general formula (III)

[0012]

[Chemical 7]

(In the formula, R ⁵ represents a hydrogen atom or a hydroxyl-protecting group.) 3- (4-hydroxyhydroindane) butanal derivative (hereinafter, abbreviated as hydroindanbutanal derivative (III)) A hydroindan-4-ol derivative (I), which protects or deprotects a hydroxyl group as necessary.
It is achieved by providing a manufacturing method of.

The hydroxyl-protecting group represented by R ¹ , R ² and R ⁵ is not particularly limited as long as it functions as a hydroxyl-protecting group. For example, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-
Trisubstituted silyl groups such as butyldimethylsilyl group and tert-butyldiphenylsilyl group; 1- (alkoxy) alkyl groups such as methoxymethyl group, methoxyethoxymethyl group, 1-ethoxyethyl group, 1-methoxyisopropyl group; tetrahydrofuranyl Group, 2-oxacycloalkyl group such as tetrahydropyranyl group; alkyl group such as tert-butyl group; aralkyl group such as benzyl group and paramethoxybenzyl group; alkenyl group such as allyl group and propenyl group; paramethoxyphenyl group And aryl groups such as

The alkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group which may have a substituent represented by R ³ and R ⁴ is not particularly limited as long as it is a group constituting an ester group. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group,
A butyl group, an isobutyl group, an amyl group, etc .; an alkenyl group, for example, an allyl group, a butenyl group, etc .; an alkenyl group, for example, a propargyl group, etc .; an aryl group, for example, a phenyl group, a naphthyl group, a binaphthyl group, etc .; an aralkyl group Examples of the group include a benzyl group. Such a group may have a protected hydroxy group; an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and an amyl group; an aryl group such as a phenyl group, a naphthyl group and a binaphthyl group; a benzyl group. It may have a substituent such as an aralkyl group such as a group. Furthermore, in order to stereoselectively introduce a hydroxyl group at the 23-position, these groups are preferably optically active substituents.

The manufacturing method of the present invention will be described in detail below.
The base used in the reaction for obtaining the enolate from the acetic acid ester derivative (II) is not particularly limited as long as it acts as a base, and examples thereof include lithium amide compounds such as lithium amide, lithium diisopropylamide and lithium bistrimethylsilylamide; Sodium amide compounds such as sodium amide and sodium bistrimethylsilylamide; potassium amide compounds such as potassium bistrimethylsilylamide; metal hydrides such as lithium hydride, sodium hydride and potassium hydride; metal alkoxides such as tert-butoxypotassium;
Examples thereof include carbonates such as potassium carbonate. The amount used is 0.5 to 1 mol of the acetic ester derivative (II).
A range of 100 molar equivalents is preferable, and a range of 1 to 10 molar equivalents is more preferable.

Such a reaction can be carried out in the presence or absence of a solvent, and is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; carbonization such as n-hexane, n-pentane, benzene and toluene. Hydrogen-based solvent; or a mixed solvent thereof. The amount used is preferably in the range of 5 to 200 times the weight of the acetic acid ester derivative (II).

The resulting acetic acid ester derivative (II) enolate or its solution is added to the hydroindane butanal derivative (III) or its solution and stirred, or hydroindan is added to the acetic acid ester derivative (II) enolate or its solution. Hydroindan-4 was obtained by adding butanal derivative (III) or its solution and stirring.
It is possible to obtain the -ol derivative (I). Examples of the solvent used here include the same solvents as described above.
The amount of enolate of the acetic acid ester derivative (II) used is 1 mol of the hydroindanebutanal derivative (III),
The range of 0.5 to 100 molar equivalents is preferable, and the range of 1 to 10 molar equivalents is more preferable.

The reaction may be carried out by adding a metal salt to the above reaction mixture. As the metal salt, any salt may be added as long as it does not adversely affect the reaction. For example, magnesium salts such as magnesium chloride and magnesium bromide;
Examples thereof include calcium salts such as calcium chloride and calcium bromide. The amount of the acetic ester derivative (I
I) It is preferably 0.1 mol to a large excess with respect to 1 mol.

The hydroindane thus obtained
The 4-ol derivative (I) is used for isolation of usual organic compounds.
It can be isolated and purified by the method used for purification. For example, the reaction mixture is poured into cold dilute hydrochloric acid, diethyl ether,
Extract with an organic solvent such as ethyl acetate or methylene chloride, and wash the extract with sodium bicarbonate water, water, or saline as necessary to remove acidic substances, basic substances, and water-soluble substances, and use anhydrous magnesium sulfate. After drying with a drying agent such as anhydrous sodium sulfate, the mixture is concentrated, and the resulting crude product can be purified by chromatography, recrystallization, etc., if necessary.

When the hydroindan-4-ol derivative (I) has a hydroxyl group or a protected hydroxyl group, the hydroxyl group can be protected or deprotected as necessary.

Hydroindan-4-ol derivative (I)
Can be converted into a vitamin D derivative, for example, according to the following reaction steps.

[0023]

Embedded image

(In the formula, R ¹ , R ² and R ³ are as defined above.) That is, the CD ring constituent part is formed by the alkylation reaction to the ester group, elimination of the protecting group of R ¹ and oxidation. After construction, A
Coupling reaction with A-ring synthons [eg, Journal of the Organic Chemistry, No. 51]
Vol. 30, page 3098 (1986)], the above-mentioned vitamin D derivatives having pharmacological activity can be obtained.

[0025]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.

Reference Example 1 Octahydro-7a-methyl-1- (1-hydroxy-
Synthesis of 2-propyl) -1H-inden-4-ol 5.0 g (12.6 mmol) of vitamin D ₂ was dissolved in 440 ml of methanol and 4.4 ml of pyridine,
Oxygen gas was aerated for 20 minutes at 78 ° C. Further, ozone gas was aerated at this temperature for 4 hours. After completion of the reaction, the reaction solution was aerated with oxygen gas for 20 minutes, and then 1.25 g (32.8 mmol) of sodium borotetrahydride was added. After heating to room temperature for 15 hours, sodium borotetrahydride (1.25 g, 32.8 m) was further added.
mol) was added and the mixture was stirred for 30 minutes and then concentrated under reduced pressure.
The residue was extracted with diethyl ether, the diethyl ether solution was washed successively with 5% dilute hydrochloric acid and water, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and silica gel column chromatography (developing solution:
It was purified with a 30% ethyl acetate / hexane solution) to obtain 2.1 g of octahydro-7a-methyl-1- (1-hydroxy-2-propyl) -1H-inden-4-ol having the following physical properties (yield: 78%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 3.66 (br s, 1H), 3.62 (dd, J
= 3.5,9.7Hz, 1H), 3.34 (dd, J = 6.3,9.2Hz, 1H), 0.5-2.58
(m, 13H), 1.0 (d, J = 6.3Hz, 3H), 0.85 (s, 3H)

Reference Example 2 Synthesis of octahydro-7a-methyl-1- (1-tert-butyldimethylsilyloxy-2-propyl) -1H-inden-4-ol Octahydro-7a-methyl-1- (1-hydroxy −
2-Propyl) -1H-inden-4-ol 3.92
g (18.5 mmol), imidazole 3.02 g (4
4.4 mmol) and 3.34 g (22.2 mmol) of tert-butyldimethylsilylchlorosilane were dissolved in 5.1 ml of dry dimethylformamide under a nitrogen atmosphere and stirred at room temperature for 3 hours. The reaction mixture was developed in water and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue is subjected to silica gel column chromatography (developing solution: 2
Octahydro-7a-methyl-1- (1-tert- having the following physical properties, purified by 0% ethyl acetate / hexane solution)
Butyldimethylsilyloxy-2-propyl) -1H-
5.21 g of inden-4-ol was obtained (yield 87
%).

¹ H-NMR spectrum (270 MHz,
CDCl ₃ , TMS standard) δ: 4.08 (br s, 1H), 3.57 (d
d, J = 3.1,9.2Hz, 1H), 3.26 (dd, J = 7.3,9.2Hz, 1H), 1.99 (b
rdt, J = 3.4,13.4Hz, 1H), 1.0-1.85 (m, 12H), 0.97 (d, J = 6.
7Hz, 3H), 0.94 (s, 3H), 0.89 (s, 3H), 0.02 (s, 6H)

Reference Example 3 Synthesis of octahydro-7a-methyl-1- (1-tert-butyldimethylsilyloxy-2-propyl) -4-benzyloxy-1H-indene Octahydro-7a-methyl-1 under nitrogen atmosphere -(1
-Tert-butyldimethylsilyloxy-2-propyl)
-1H-Inden-4-ol 5.21 g (16.0 m
mol) was dissolved in 80 ml of dry dimethylformamide, and 1.92 g (80 mm) of sodium hydride was added to this solution.
ol) and 5.7 ml (48 mmol) of benzyl bromide were sequentially added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C., saturated aqueous ammonium chloride solution was added, the layers were separated, and the aqueous layer was re-extracted with diethyl ether. Mix the organic layers,
The separated organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (developing solution: 1% ethyl acetate / hexane solution), and octahydro-7a-methyl-1- (1-tert-butyldimethylsilyloxy-) having the following physical properties. 2-propyl) -4-benzyloxy-1H
-5.0 g of indene was obtained (77% yield).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 7.33 (br s, 5H), 4.45 (dx2,
J = 12.2Hz, 2H), 3.68 (br s, 1H), 3.54 (dd, J = 4.2,9.8Hz, 1
H), 3.19 (dd, J = 7.0,9.8Hz, 1H), 0.62-2.08 (m, 13H), 0.9
1 (d, J = 6.3Hz, 3H), 0.89 (s, 3H), 0.81 (s, 9H), 0.0 (s, 6H)

Reference Example 4 Synthesis of 2- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) propanal Octahydro-7a-methyl-1- (1-tert-butyldimethylsilyloxy- 5.0 ml (12 mmol) of 2-propyl) -4-benzyloxy-1H-indene in 40 ml of tetrahydrofuran (hereinafter abbreviated as THF)
And was added to this solution at room temperature with 6.28 g (24 mmol) of terrabutylammonium fluoride. The reaction solution was stirred at room temperature for 4 hours, diluted with diethyl ether, washed successively with water and brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, it is concentrated and purified by silica gel column chromatography (developing solution: 20% ethyl acetate / hexane solution) to give 2- (octahydro-7).
a-Methyl-4-benzyloxy-1H-indene-1
3.35 g of -yl) propan-1-ol was obtained (yield 92%). The obtained 2- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) propan-1-ol 3.35 g (11.0 mmo)
l) was dissolved in 70 ml of methylene chloride, 12.5 mg (33.1 mmol) of pyridinium dichromate was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was filtered through a Florisil column, and the filtrate was concentrated and dried. The concentrate is subjected to silica gel column chromatography (developing solution: 10
% Diethyl ether / hexane solution) to obtain 2.36 g of 2- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) propanal having the following physical properties (yield 71%). ).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 9.54 (d, J = 3.5Hz, 1H), 7.27
(br s, 5H), 4.48 (dx2, J = 12.2,2H), 3.74 (br s, 1H), 1.0
-2.77 (m, 13H), 1.1 (d, J = 6.3Hz, 3H), 1.0 (s, 3H)

Reference Example 5 Synthesis of 3- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) -1-butenyl methyl ether methoxymethyltriphenylphosphonium chloride 67
8 mg (1.98 mmol) of THF11 under nitrogen atmosphere
1.2 ml of n-butyl lithium at 0 ° C
(1.61M hexane solution, 1.98 mmol) was added. After stirring for 15 minutes at 0 ° C, cool to -20 ° C,
2- (Octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) propanal 200m
A THF solution (4 ml) of g (0.66 mmol) was added dropwise. The mixture was stirred at -20 ° C for 30 minutes and further at 0 ° C for 30 minutes. Water was added to the reaction solution, and diethyl ether was added for extraction. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and filtered to dryness. The concentrate was purified by silica gel column chromatography (developing solution: 1-5% diethyl ether / hexane solution) to give 3- (octahydro-7a) having the following physical properties.
-Methyl-4-benzyloxy-1H-indene-1-
260 mg of (yl) -1-butenyl methyl ether was obtained (yield 43%, 22-23 olefin geometric isomer mixture).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 6.31 (d, J = 15.7Hz, 1H, 22-23
-E olefin), 5.79 (d, J = 7.0Hz, 1H, 22-23-Z olefin), 4.64 (dd, J = 10.4,15.7Hz, 1H, 22-23-E olefin),
4.52 (dx2, J = 12.2Hz, 4H), 4.21 (dd, J = 7.0,10.4Hz, 1H, 22
-23-Z olefin), 3.75 (br s, 2H), 3.58 (s, 3H, E olefin-MeO), 3.50 (s, 3H, Z olefin-MeO), 0.77-2.27
(m, 18H)

Reference Example 6 Synthesis of 3- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl) -1-butanal 3- (octahydro-7a-methyl-4-benzyloxy-1H- 260 mg (0.79 mmol) of inden-1-yl) -1-butenyl methyl ether was dissolved in 15 ml of an aqueous acetic acid solution (acetic acid: water = 5: 1), and the mixture was allowed to stand at room temperature.
Stir for 6.5 hours. The reaction solution was diluted with an ethyl acetate-hexane mixed solution (ethyl acetate: hexane = 1: 2),
It was washed successively with water, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (developing solution: 10% ethyl acetate / hexane solution), and 3- (octahydro-7a-methyl-4-benzyloxy-1H-inden-1-yl)-having the following physical properties was obtained. 210 mg of 1-butanal was obtained (84% yield).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 9.77 (brs, 1H), 7.35 (br s,
5H), 4.48 (dx2, J = 12.2Hz, 2H), 3.74 (br s, 1H), 0.89-2.
65 (m, 15H), 1.0 (s, 3H), 1.0 (d, J = 5.2Hz, 3H)

Example 1 (1 "S, 3S, 5R) -2" -hydroxy-1 ",
2 ", 2" -triphenylethyl 3-hydroxy-5
Synthesis of-(octahydro-7'a-methyl-4'-benzyloxy-1H-inden-1-yl) hexanoate (2R) -2-acetoxy-1,1,2-triphenylethanol 329 mg (0.99 mmol) THF6
ml suspension, cooled to -78 ° C, diisopropylamine 0.5 ml (3.57 mmol), n-butyllithium 2.2 ml (1.61M hexane solution, 3.57 m)
mol) and lithium diisopropylamide prepared from 3 ml of THF were added. The reaction solution was heated to 0 ° C., and when it became a transparent solution, magnesium 48 mg
(1.98 mmol) and 1,2-dibromoethane 0.1
A suspension of magnesium bromide in diethyl ether prepared by reacting 7 ml (1.98 mmol) at -78 ° C was added, stirred for 1 hour, and cooled to -115 ° C. 3- (octahydro-7a-methyl-4-benzyloxy-1H-
Inden-1-yl) -1-butanal 210 mg
A solution of (0.662 mmol) in THF (2 ml) was added dropwise to this prepared solution and stirred for 40 minutes. Saturated ammonium chloride was added to the reaction solution, the temperature was raised to room temperature, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography (developing solution: 15% ethyl acetate /
Hexane solution), has the following physical properties (1 "S, 3S, 5
R) -2 "-hydroxy-1", 2 ", 2" -triphenylethyl 3-hydroxy-5- (octahydro-
329 mg of a mixture of 7'a-methyl-4'-benzyloxy-1H-inden-1-yl) hexanoate and its diastereomer (target compound: diastereomer = 5.
7: 1) was obtained (yield 76%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 6.8-7.7 (m, 20H), 6.72 (s, 1
H), 4.43 (dx2, J = 12.2Hz, 2H), 3.74-4.08 (m, 1H), 3.66 (b
rs, 1H), 2.25 (d, J = 7.0Hz, 2H), 0.45-2.14 (m, 15H), 0.8
7 (s, 3H), 0.81 (s, 3H)

Reference Example 7 (4S, 6R) -6- (Octahydro-7'a-methyl-4'-benzyloxy-1H-inden-1-yl)
Synthesis of 2-methylheptane-2,4-diol 123.5 mg (5.08 mmol) of magnesium was suspended in ether, and 0.32 ml of methyl iodide was added at 0 ° C.
(5.08 mmol) was added dropwise. After stirring for 20 minutes, (1 "S, 3S, 5R) -2" -hydroxy-
1 ″, 2 ″, 2 ″ -triphenylethyl 3-hydroxy-5- (octahydro-7′a-methyl-4′-benzyloxy-1H-inden-1-yl) hexanoate 329 mg (0.508 mmol) THF Solution 6.
7 ml was added, and the mixture was stirred at 0 ° C. for 30 minutes and further at room temperature for 1 hour. The reaction solution was cooled to 0 ° C., and water and 0.1N dilute hydrochloric acid were added. Diethyl ether was added, washed with brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.
The concentrate is purified by silica gel column chromatography (developing solution: 15% ethyl acetate / hexane solution) and has the following physical properties (4S, 6R) -6- (octahydro-7 ′).
a-Methyl-4'-benzyloxy-1H-indene-
1-yl) -2-methylheptane-2,4-diol 7
9 mg was obtained (yield 35%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 7.25 (br s, 5H), 4.39 (dx2,
J = 12.2Hz, 2H), 3.81-4.19 (m, 1H), 3.64 (br s, 1H), 2.83
(br s, 2H), 0.70-2.08 (m, 17H), 1.24 (s, 3H), 1.21 (s, 3
H), 0.91 (m, 6H)

Reference Example 8 (4S, 6R) -6- (Octahydro-7'a-methyl-4'-benzyloxy-1H-inden-1-yl)
Synthesis of 2-methyl-4- (triethylsilyloxy) heptan-2-ol (4S, 6R) -6- (octahydro-7'a-methyl-4'-benzyloxy-1H-inden-1-yl)
-2-methylheptane-2,4-diol 97 mg
(0.26 mmol) was added to dry dimethylformamide 0.
Dissolve in 24 ml and imidazole 46 mg at 0 ° C
(0.34 mmol) and 0.056 ml (0.34 mmol) of chlorotriethylsilane were added, and the mixture was stirred for 2 hours. Water was added to this reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous solution of ammonium chloride and brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained concentrate was purified by silica gel column chromatography (developing solution: 5% ethyl acetate / hexane solution), and (4S, 6R) -6- (octahydro-
78 mg of 7'a-methyl-4'-benzyloxy-1H-inden-1-yl) -2-methyl-4- (triethylsilyloxy) heptan-2-ol was obtained (61).
%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 7.27 (br s, 5H), 4.46 (dx2,
J = 12.2Hz, 2H), 4.0-4.5 (m, 1H), 3.67 (br s, 1H), 0.46-
2.23 (m, 17H), 1.23 (s, 3H), 1.19 (s, 3H), 0.95 (s, 3H),
0.91 (d, J = 5.2Hz, 9H), 0.66 (s, 3H), 0.66 (br t, J = 9.0Hz,
6H)

Reference Example 9 Synthesis of (4S, 6R) -6- (octahydro-7'a-methyl-4'-hydroxy-1H-indene) -2-methylheptane-2,4-diol (4S, 6R) -6- (octahydro-7'a-methyl-4'-benzyloxy-1H-inden-1-yl)
78 mg of 2-methyl-4- (triethylsilyloxy) heptane-2-ol and Raney-Ni (W-2)
Was suspended in 5 ml of methanol, and the hydrogen gas atmosphere (1
The mixture was stirred for 24 hours (0 atm). The reaction solution was filtered through a Celite column to remove the solvent. The concentrate is purified by silica gel column chromatography (developing solution: 30-50% ethyl acetate / hexane solution) and has the following physical properties (4S, 6
19 mg of R) -6- (octahydro-7′a-methyl-4′-hydroxy-1H-inden-1-yl) -2-methylheptane-2,4-diol was obtained (yield 45).
%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 3.85-4.35 (m, 2H), 2.5-3.2
(m, 1H), 0.7-2.23 (m, 17H), 2.37 (s, 3H), 2.33 (s, 3H), 1.
0 (m, 6H)

Reference Example 10 (4S, 6R) -6- (Octahydro-7'a-methyl-4'-hydroxy-1H-inden-1-yl) -2
-Methyl-4- (triethylsilyloxy) heptane-
Synthesis of 2-ol (4S, 6R) -6- (octahydro-7'a-methyl-4'-hydroxy-1H-inden-1-yl) -2
-Methylheptane-2,4-diol 19 mg (0.0
73 mmol) dry dimethylformamide 0.24 m
l, and imidazole 9.9 mg (0.1
4 mmol) and chlorotriethylsilane 0.012
ml (0.073 mmol) was added, and the mixture was stirred for 2 hours.
Water was added to this reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous solution of ammonium chloride and brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained concentrate is purified by silica gel column chromatography (developing solution: 5% ethyl acetate / hexane solution), and (4S, 6R) -6- (octahydro-7'a-
22 mg of methyl-4′-hydroxy-1H-inden-1-yl) -2-methyl-4- (triethylsilyloxy) heptan-2-ol was obtained (80%).

¹ H-NMR spectrum (90 MHz, C
DCl ₃ , TMS standard) δ: 0.46-2.27 (m, 15H), 1.29
(s, 3H), 1.25 (s, 3H), 1.02 (d, J = 3.5Hz, 3H), 1.0 (d, J = 5.
2Hz, 9H), 0.71 (br t, J = 5.2Hz, 6H)

Reference Example 11 (1'R, 3'S) -1- (1'-methyl-3'-triethylsilyloxy-5'-methyl-5'-trimethylsilyloxy-1-hexyl) octahydro-7a- Synthesis of methyl-1H-inden-4-one (4S, 6R) -6- (octahydro-7'a-methyl-4'-hydroxy-1H-inden-1-yl) -2
-Methyl-4- (triethylsilyloxy) heptane-
2-ol 30 mg (0.075 mmol) was dissolved in methylene chloride 0.5 ml, pyridinium dichromate 85 mg (0.23 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was filtered through a Florisil column, the filtrate was concentrated to dryness, and (1′R, 3 ′S) -1-
(1'-methyl-3'-triethylsilyloxy-5 '
A mixture of -methyl-5'-hydroxy-1-hexyl) octahydro-7a-methyl-1H-inden-4-one was obtained. Dissolve this mixture in 14 ml of methylene chloride and add 0.055 ml of trimethylsilylimidazole.
(0.375 mmol) was added and stirred for 20 hours. Water was added to the reaction solution, stirred for 30 minutes, and extracted with methylene chloride. The organic layer was washed successively with water and brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the obtained concentrate is purified by silica gel column chromatography (developing solution: 15% ethyl acetate / hexane solution) and has the following physical properties (1′R, 3 ′S) -1- (1 ′). -Methyl-3'-
Triethylsilyloxy-5'-methyl-5'-trimethylsilyloxy-1-hexyl) octahydro-7a
30 mg of -methyl-1H-inden-4-one was obtained (yield 2 steps 85%).

(1'R, 3'S) -1- (1'-methyl-3'-triethylsilyloxy-5'-methyl-5 '
-Hydroxy-1-hexyl) octahydro-7a-methyl-1H-inden-4-one ¹ H-NMR spectrum (90 MHz, CDCl ₃ , T
MS standard) δ: 3.92-4.43 (m, 2H), 0.39-3.58 (m, 17H),
1.19 (s, 3H), 0.9 (s, 3H), 0.86 (d, J = 7.7Hz, 9H), 0.61 (br
t, J = 7.7Hz, 6H), 0.56 (s, 3H) (1'R, 3'S) -1- (1'-methyl-3'-triethylsilyloxy-5'-methyl-5'-trimethylsilyl (Oxy-1-hexyl) octahydro-7a-methyl-1H-inden-4-one ¹ H-NMR spectrum (270 MHz, CDCl ₃ ,
TMS standard) δ: 4.01 (br s, 1H), 0.8-2.6 (m, 17H), 1.2
7 (s, 3H), 1.26 (s, 3H), 0.99 (d, J = 4.5Hz, 3H), 0.97 (d, J =
7.5Hz, 9H), 0.65 (s, 3H), 0.6 (br t, J = 7.5Hz, 6H), 0.05
(s, 9H)

[0050]

INDUSTRIAL APPLICABILITY According to the present invention, a hydroindan-4-ol derivative (I) useful as a synthetic intermediate for 23S-vitamin D derivative and a highly stereoselective method for producing the compound are provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 69/675 9546-4H C07C 69/675 69/708 9546-4H 69/708 Z

Claims (2)

[Claims] 1. A compound represented by the following general formula (I) (In the formula, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group, and R ³ represents a hydrogen atom or an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group. Represents a hydroindan-4-ol derivative. 2. The following general formula (II): (Wherein R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group), and a base is allowed to act on the acetic acid ester derivative. The enolates are represented by the following general formula (III): (Wherein R ⁵ represents a hydrogen atom or a hydroxyl-protecting group) is allowed to act on the 3- (4-hydroxyhydroindane) butanal derivative, and the hydroxyl group may be protected or deprotected as necessary. Characterized by the following general formula (I): (In the formula, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group, and R ³ represents a hydrogen atom or an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group. The method for producing a hydroindan-4-ol derivative represented by