JPH08325211A - Indene compound and production of its derivative - Google Patents

Abstract

PURPOSE: To efficiently obtain an indene derivative expressed by a specific formula and useful as a synthetic intermediate for CD ring part in simple synthesis of 1α,25-dihydroxyvitamine D3 in a short process. CONSTITUTION: This derivative is expressed by formula I [R is H, a 2-8C acyl or a tri(1-6C hydrocarbon)-substituted silyl, e.g. (6R)-6-[(4S, 7aS)-4-benzoyloxy-7a- methylinden-1-yl]-2-nitro-3-heptanol. Furthermore, the compound is preferably obtained by reacting a compound of formula II in the presence of a basic catalyst such as triethylamine in an organic solvent such as nitroethane or tetrahydrofuran or a mixed solvent of an organic solvent with water at 0 deg.C to ambient temperature. The compound of formula I is used as a raw material and successively reacted and converted into a compound of formula III, which is then reacted with a methylating agent (e.g. methyllithium) and as necessary, an OH-protecting group is removed. Thereby, a compound of formula IV is preferably obtained.

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL FIELD OF USE The present invention is useful as a medicine.
The present invention relates to a synthetic intermediate of α, 25-dihydroxyvitamin D ₃ . More particularly, it relates to a method for producing an indene compound useful as a synthetic intermediate for the CD ring portion in the synthesis of 1α, 25-dihydroxyvitamin D ₃ by a convergent method of linking the A ring portion and the CD ring portion, and a derivative thereof. .

[0002]

PRIOR ART The following formula (V)

[0003]

[Chemical 7]

For the compound represented by, for example, synthetic examples have been reported by the following route (Isao Shimizu e
Tal, J. Org. Chem., 1993, 58, 1483).

[0005]

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[0006] However, this route requires a very long number of steps of 25 steps compared with the easily available starting material.

[0007]

Therefore, if the compound represented by the above formula (V) can be obtained in a shorter step, the synthesis of 1α, 25-dihydroxyvitamin D ₃ will be further simplified.

[0008]

As a result of intensive studies, the inventors of the present invention have found that a compound represented by the following formula (VI) obtained in 9 steps from readily available vitamin D ₂ can be prepared in 6 steps by the above formula (V). The present invention has been achieved by succeeding in inducing a compound represented by

That is, the following formula (I)

[0010]

[Chemical 9]

[In the formula, R represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group. ] The indene compound represented by the following formula (II) as a raw material,

[0012]

[Chemical 10]

[In the formula, R has the same definition as in the above formula (I). ] An indene compound represented by the following formula (III),

[0014]

[Chemical 11]

[In the formula, R has the same definition as in the above formula (I). ] Through the following formula (IV)

[0016]

[Chemical 12]

[In the formula, R has the same definition as in the above formula (I). ] The following formula (V) is characterized by reacting with a methylating agent after conversion into an indene compound represented by

[0018]

[Chemical 13]

[In the formula, R'represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group. ] The manufacturing method of the indene derivative represented by this was discovered. Therefore, the present invention provides the above formula (I
An indene compound represented by I) or (III)
A method for producing an indene derivative represented by the above formula (V), which comprises converting to a compound represented by the above formula (IV) and then reacting with a methylating agent to remove a protective group for a hydroxyl group if necessary. Is.

The present invention also provides the above formulas (I) and (I
It is an indene compound represented by I) or (III).

Examples of the acyl group having 2 to 8 carbon atoms of R in the above formula (I) include an acetyl group, a pivaloyl group, a hexanoyl group, a benzoyl group and an ethoxycarbonyl group, preferably a benzoyl group. .

In the above-mentioned formula (I), R of R (1 carbon atom)
Examples of the (hydrocarbon group) to (6) -substituted silyl group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group, and a t-butyldimethylsilyl group is preferable. .

The indene compound represented by the above formula (I) is represented by the following formula (VI)

[0024]

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[In the formula, R has the same definition as in the above formula (I). ] The indene compound represented by the formula [1] can be obtained by reacting nitroethane with an organic solvent or a mixed solvent of an organic solvent and water in the presence of a base catalyst. Suitable bases include sodium hydroxide, potassium hydroxide,
Examples thereof include sodium alkoxide, potassium alkoxide, triethylamine, alumina, and butyllithium. Among them, it is preferable to use t-butyldimethylsilyl chloride and tetrabutylammonium fluoride in addition to triethylamine. Examples of the organic solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and diethyl ether, and it is preferable to use tetrahydrofuran. This reaction is usually carried out in the temperature range of -70 ° C to 60 ° C, preferably 0 ° C to room temperature.

The indene compound represented by the above formula (II) can be obtained by reacting the indene compound represented by the above formula (I) with a dehydrating agent in an organic solvent. As the dehydrating agent, phthalic anhydride, dicyclohexylcarbodiimide, or a combination of methanesulfonyl chloride and triethylamine is used, but a combination of methanesulfonyl chloride and triethylamine is preferable. As the organic solvent, a hydrocarbon solvent such as hexane or benzene,
Examples include ether solvents such as tetrahydrofuran and diethyl ether, and halogen solvents such as dichloromethane and chloroform, with dichloromethane being preferred. This reaction is usually carried out in a temperature range of 0 ° C to 120 ° C, but a temperature range of 0 ° C to room temperature is preferable.

The indene compound represented by the above formula (III) is obtained by reacting the double bond of the indene compound represented by the above formula (II) with an appropriate reducing agent in an organic solvent or a mixed solvent of an organic solvent and water. It is obtained by Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, tris-butyllithium borohydride, and triethyllithium borohydride.
Of these, sodium borohydride is preferable. Examples of the organic solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and dioxane, and among them, a mixed solvent of ethanol and dioxane is preferable. This reaction is usually from 0 ° C to 1
It is carried out in a temperature range of 00 ° C, but a temperature range of room temperature to 40 ° C is preferable.

The indene compound represented by the above formula (IV) can be obtained by treating the indene compound represented by the above formula (III) with a reagent capable of converting a nitro compound into a ketone. Reagents capable of converting nitro compounds to ketones include strong bases such as sodium hydroxide and sodium ethoxide in combination with acids such as sulfuric acid and hydrochloric acid, oxidizing agents such as potassium permanganate in the presence of potassium hydroxide, sodium sulfite. Examples thereof include ozone, n-propyl nitrite, ozone, basic silica gel, and titanium trichloride. Among them, potassium permanganate in the presence of potassium hydroxide is preferable. The solvent and temperature of this reaction are selected depending on the type of reagent, but when potassium permanganate in the presence of potassium hydroxide is used, it is usually used in a mixed solvent of water and an alcohol solvent such as methanol and ethanol, The temperature is in the range of 20 ° C to 50 ° C, preferably 0 ° C to room temperature.

The indene compound represented by the above formula (III) can also be obtained by treating the indene compound represented by the above formula (II) with a reagent capable of converting a nitroolefin into a ketone. Examples of reagents that can convert nitroolefins to ketones include zinc in acetic acid, iron in hydrochloric acid, Raney nickel, a combination of lithium tris-butyl borohydride and dilute sulfuric acid.

The indene derivative represented by the above formula (V) is prepared by reacting the indene compound represented by the above formula (IV) with a methylating agent such as methyllithium or methylmagnesium bromide, and then, if necessary, a hydroxyl-protecting group. Is obtained by removing. The reaction with the methylating agent is carried out in an ether solvent such as tetrahydrofuran or diethyl ether, usually in the temperature range of -70 ° C to 80 ° C, preferably in the temperature range of about 0 ° C to room temperature. Removal of the hydroxyl-protecting group is performed by a general method depending on the type of the protecting group.

With respect to R'in the above formula (V), the same groups as those mentioned above for R can be mentioned.

The compound represented by the above formula (VI) can be obtained from vitamin D ₂ by the following route, for example (JP-A-6-263667). R ⁰ in the following reaction formula represents an alkyl group having 1 to 8 carbon atoms.

[0033]

[Chemical 15]

[0034]

The present invention will be described in more detail with reference to the following examples.

[Example 1]

[0036]

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Tetrabutylammonium fluoride 3
The hydrate (450 mg, 1.40 mmol) was added to THF (1
0 ml), and under ice cooling, nitroethane (0.35 m
1, 4.90 mmol), (4R) -4-[(4S, 7
aS) -4-benzoyloxy-7a-methylinden-1-yl] -pentanal (1) (1.00 g, 2.
90 mmol) in THF (5 ml), triethylamine (0.40 ml, 2.90 mmol), t-butyldimethylsilyl chloride (750 mg, 5.00 mm).
ol) in THF (5 ml) was added sequentially, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water and saturated saline (200 ml each), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. Using silica gel (50 g), hexane: ethyl acetate (40:
The target product (6R) -6-[(4S, 7aS) -4-benzoyloxy-7a-methylinden-1-yl] -2-nitro-3--is obtained by column purification with 1 → 10: 1). Heptanol (2) (1.26g, 2.90m)
mol, 100%) was obtained.

¹ H NMR (CDCl ₃ , ppm) δ;
0.94 (3H, d, J = 6Hz), 1.05 (3H,
s), 1.05 to 2.35 (20H, m), 3.75 to
4.20 (1H, m), 4.45 to 4.65 (1H,
m), 5.35-5.45 (1H, m), 7.40-
7.60 (3H, m), 8.00-8.10 (2H,
m) [Example 2]

[0039]

[Chemical 17]

(6R) -6-[(4S, 7aS) -4-
Benzoyloxy-7a-methylinden-1-yl]
-2-Nitro-3-heptanol (2) (1.12 g,
2.67 mmol) was dissolved in dichloromethane (10 ml) and triethylamine (2.5 ml, 18.ml) under ice cooling.
1 mmol) was added, and methanesulfonyl chloride (0.33
(ml, 4.26 mmol) was slowly added dropwise, and the mixture was stirred as it was for 1 hour. After completion of the reaction, 1N hydrochloric acid (200 m
1) was added, and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated saline (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified with silica gel (50 g) using hexane: ethyl acetate (30: 1 → 15: 1) to obtain the desired product (6R) -6-[(4S, 7a
S) -4-Benzoyloxy-7a-methylindene-
1-yl] -2-nitro-2-heptene (3) (618
mg, 1.54 mmol, 58%) was obtained.

¹ H NMR (CDCl ₃ , ppm) δ;
0.97 (3H, d, J = 6Hz), 1.06 (3H,
s), 1.10 to 2.40 (20H, m), 5.35
5.45 (1H, m), 7.12 (1H, t, J = 8H
z), 7.40 to 7.60 (3H, m), 8.00
8.10 (2H, m) [Example 3]

[0042]

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Sodium borohydride (240 mg,
6.31 mmol) was dissolved in dioxane (5 ml) and ethanol (5 ml), and (6R) -6-[(4S, 7a
S) -4-Benzoyloxy-7a-methylindene-
1-yl] -2-nitro-2-heptene (3) (522
Dioxane (10 ml) solution of mg, 1.30 mmol) was slowly added dropwise at 30 ° C., and the mixture was stirred as it was for 1 hour. After completion of the reaction, add acetic acid until foaming disappears,
Water (200 ml) was added, and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine (200 ml each), dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product.
The target product (6R) -6-[(4S, 7aS) -4-benzoyloxy-7a-methyl was obtained by purifying with hexane: ethyl acetate (30: 1 → 20: 1) using silica gel (50 g). Inden-1-yl] -2-nitroheptane (4) (493 mg, 1.22 mmol,
94%).

¹ H NMR (CDCl ₃ , ppm) δ;
0.92 (3H, d, J = 6Hz), 1.03 (3H,
s), 1.05 to 2.15 (22H, m), 4.45 to
4.65 (1H, m), 5.35 to 5.45 (1H,
m), 7.40 to 7.60 (3H, m), 8.00
8.10 (2H, m) [Example 4]

[0045]

[Chemical 19]

(6R) -6-[(4S, 7aS) -4-
Benzoyloxy-7a-methylinden-1-yl]
-2-Nitroheptane (4) (450mg, 1.12m
(mol) in methanol (23 ml), and under ice cooling,
0.1N potassium hydroxide in methanol (23m
1) was slowly added dropwise, and the mixture was stirred as it was for 1 hour. Potassium permanganate (120 mg, 0.76 mm) in the reaction solution
ol) and anhydrous magnesium sulfate (120 mg, 1.
(00 mmol) aqueous solution (23 ml) was added dropwise, and the mixture was further stirred for 2 hours. After completion of the reaction, water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated saline (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. The crude product was subjected to column purification with silica gel (50 g) using hexane: ethyl acetate (30: 1 → 20: 1) to obtain the desired product (6R) -6-[(4S, 7aS)-
4-benzoyloxy-7a-methylinden-1-yl] -2-oxoheptane (5) (298 mg, 0.8
0 mmol, 71%) was obtained.

¹ H NMR (CDCl ₃ , ppm) δ;
0.95 (3H, d, J = 6Hz), 1.04 (3H,
s), 1.05 to 2.15 (16H, m), 2.14
(3H, s), 2.30 to 2.50 (2H, m), 5.
35 to 5.45 (1H, m), 7.40 to 7.60 (3
H, m), 8.00-8.10 (2H, m) [Example 5]

[0048]

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(6R) -6-[(4S, 7aS) -4-
Benzoyloxy-7a-methylinden-1-yl]
-2-Oxoheptane (5) (40mg, 0.11mm
ol) was dissolved in THF (1 ml), and a 0.93 M THF solution of methyl magnesium bromide (0.8
ml, 0.74 mmol) was added dropwise. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution (20 ml) was added, and the mixture was extracted with ethyl acetate (15 ml × 2). The organic layer was washed with saturated saline (200 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. To the obtained crude product was added 4N potassium hydroxide in methanol (4.5 ml) and water (0.5 ml),
Heated to reflux for hours. After allowing to cool, water (35 ml) was added, and the mixture was extracted with ethyl acetate (35 ml × 2). The organic layer is a saturated aqueous solution of potassium hydrogen sulfate and saturated saline (70 ml each).
The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. Using silica gel (50 g),
By purifying the column with hexane: ethyl acetate (30: 1 → 20: 1), the desired product (6R) -6-[(4
S, 7aS) -4-Hydroxy-7a-methylinden-1-yl] -2-methylheptan-2-ol (6)
(23 mg, 0.08 mmol, 75%) was obtained.

¹ H NMR (CDCl ₃ , ppm) δ;
0.89 (3H, d, J = 6Hz), 0.92 (3H,
s), 1.00 to 2.05 (18H, m), 1.19
(6H, s), 4.05 to 4.10 (3H, m)

[0051]

INDUSTRIAL APPLICABILITY All the above-mentioned reactions are easy to operate and the yield is relatively high. Therefore, the present invention provides a method for producing a synthetic intermediate for the CD ring portion in the synthesis of 1α, 25-dihydroxyvitamin D ₃ which is short, efficient and convenient. In addition, the indene compound described in the present specification can be used as a synthetic intermediate for other vitamin D ₃ derivatives.

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Claims (10)

[Claims] 1. The following formula (I): [In the formula, R represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon) -substituted silyl group. ] The indene compound represented by this. 2. The indene compound according to claim 1, wherein in the formula (I), R is a benzoyl group. 3. The following formula (II): [In the formula, R has the same definition as in the above formula (I). ] The indene compound represented by this. 4. The indene compound according to claim 3, wherein in the formula (II), R is a benzoyl group. 5. The following formula (III): [In the formula, R has the same definition as in the above formula (I). ] The indene compound represented by this. 6. The indene compound according to claim 5, wherein in the formula (III), R is a benzoyl group. 7. An indene compound represented by the above formula (II) or (III) is replaced by the following formula (IV): [In the formula, R has the same definition as in the above formula (I). ] After being converted to a compound represented by the formula, a methylating agent is allowed to act on the compound to remove a hydroxyl-protecting group if necessary, and the following formula (V): [In the formula, R ′ represents a hydrogen atom, an acyl group having 2 to 8 carbon atoms, or a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group. ] The manufacturing method of the indene derivative represented by these. 8. R in the above formula (II) or (III), and (IV) is a benzoyl group, and the above formula (V)
The method for producing an indene derivative according to claim 7, wherein R ′ in is a hydrogen atom. 9. The following formula (VI): [In the formula, R has the same definition as in the above formula (I). ] The manufacturing method of the indene compound represented by the said formula (I) characterized by reacting the compound represented by this with nitroethane. 10. R in the above formulas (I) and (VI)
The method for producing an indene compound according to claim 9, wherein is a benzoyl group.