JP2002030097A - Method for producing steroid derivative - Google Patents

Abstract

(57) [Problem] To provide an efficient method for producing dictyosterol and its derivatives. SOLUTION: General formula (I) [Wherein R _1, the R ₂ is a hydrogen atom or a lower alkyl group, R ₃
Represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ₄ represents a hydroxyl-protecting group. Wherein the 5-ene part of the steroid derivative represented by the formula (1) is regio- and stereoselectively hydroxylated, subsequently eliminated, and then the hydroxyl-protecting group at the 3- or 25-position is removed. IV) [R ₁ , R ₂ and R ₃ are the same as defined above. A method for producing a steroid derivative represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing a steroid derivative which has a strong neurite regenerating action and is effective for treating Alzheimer's disease, senile dementia, Parkinson's disease and various movement disorders.

[0002]

2. Description of the Related Art Lactacystin (J. Antibiotics, 44, 11) has been used as a compound having a neurite outgrowth action.
3 (1991), epolactaene (J. Antibiotics, 48, 733 (19
95), staurosporine (Neuroscience, 26, 299 (1987)) and the like are known and are being actively studied.

On the other hand, some steroid derivatives have been found to have a similar effect. That is, the general formula (IV)

[0004]

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The compound wherein R ₁ is an ethyl group and R ₂ and R ₃ are hydrogen atoms is dictyostol (dictyostol).
erol, (24R) -24-ethylcholest-trans-22-en-3β-o
l) and is known as a natural steroid found in marine organisms (Biochim. Biophys. Acta, 834, 30
1 (1985), Proc. Natl. Acad. Sci. USA, 87, 7565 (199
0). ). This dictyosterol has recently been found as a component in slime molds, has an excellent neurite regenerating effect on central nervous cells, especially on mature central nervous cells, and is used as a therapeutic agent for neurodegenerative diseases including anti-dementia drugs. (Japanese Patent Application No. 11-207263).

Hitherto, as a method for producing the compound represented by the general formula (IV), C-20 aldehyde (V) obtained by the ozone oxidation of stigmasterol is reduced, and then the obtained C-2
2 Alcohol (VI) was hydrogenated (VII), and then re-oxidized to prepare a side chain on C-20 aldehyde (VIII) (Scheme 1) (Chem. Ber., 108, 110 (197
Five).). Since this method is not an asymmetric synthesis, it is necessary to separate each enantiomer which is difficult to separate in each step, and the operation is complicated. In addition, it has various disadvantages such as the need to use expensive reagents such as platinum oxide and rhodium complex, low stereoselectivity, lack of versatility, and the like.

[0007]

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[0008]

DISCLOSURE OF THE INVENTION Dictiosterol, which exhibits an excellent neurite regenerating activity on mature central nervous cells and is expected to be useful as a therapeutic drug for neurodegenerative diseases including anti-dementia drugs, and dictiosterol There is a need for an efficient method for producing a steroid derivative as a derivative.

An object of the present invention is to provide a method for efficiently producing a steroid derivative.

[0010]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, a stigmasterol derivative was used as a starting material, and the stigmasterol derivative was used as a starting material.
The inventors have found that a steroid derivative can be produced by removing the hydroxyl group at the 5-position after hydroxylation of the ene portion in a regio- and stereoselective manner, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (I)

[0012]

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[Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ₄ represents a hydroxyl-protecting group. General formula (II) obtained by regio- and stereoselectively hydroxylating the 5-ene part of the steroid derivative represented by

[0014]

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[Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above. ] Represented by the general formula (III)

[0016]

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[Wherein, R ₅ represents a tosyloxy group, a mesyloxy group, a phenylthio or a halogen atom, and R ₁ ,
R ₂ , R ₃ and R ₄ are the same as defined above. Wherein R ₅ is subsequently eliminated, and if necessary, the protecting group for the hydroxyl group at the 3- or 25-position is removed.

[0018]

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[R ₁ , R ₂ and R ₃ are the same as defined above. And a method for producing a steroid derivative represented by the formula:

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The starting material of the present invention is represented by the general formula (I)

[0021]

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[Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ₄ represents a hydroxyl-protecting group. ] Is a known C-20 aldehyde compound (V:
(Scheme 1) and general formula (IX)

[0023]

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Wherein R ₁ , R ₂ and R ₃ are as defined above. ], And easily prepared by removing the 23-phenylsulfonyl group and then deprotecting the 3-position hydroxyl group. it can. Furthermore, the method of the present invention is abundant in nature, can use stigmasterol and the like which are easily available at low cost as a raw material, and is easy to convert to the corresponding steroid derivative, and is excellent in versatility and high versatility. It provides a method.

The lower alkyl group represented by R ₁ and R ₂ in the general formula (I) represents a hydrocarbon group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group and an n-butyl group.

The protecting group R ₄ for the hydroxyl group at the 3-position in the general formula (I) has a basic property due to coupling with a phenylsulfone derivative in the next step and further a reaction with a borane derivative or LiAlH _4. Those that are stable under reducing conditions are desirable. As such a substance, for example, a tetrahydropyranyl (THP) group, various silyl groups and the like are used.

The compound of the general formula (I) comprises the compound (V) and the compound (I
X), usually performed using LDA or n-BuLi in tetrahydrofuran (THF).

The compounds of general formula (II), the general formula (I) stereo and regioselective hydroxide hydroboration of the compound, ie a BH ₃ · Me ₂ S or BH ₃ · THF, such as borane derivatives reaction To be obtained. The 6-hydroxyl group of the compound of the general formula (II) thus obtained is then converted into a derivative represented by the general formula (III) which is easily removed by reduction.

R _{5 in the} general formula (III) includes a tosyloxy group, a mesyloxy group, phenylthio or a halogen atom, and examples of the halogen atom include an iodine atom and a bromine atom. The derivative of the general formula (III) having R ₅ which is easily reductively removed includes the corresponding compound obtained by reacting the hydroxyl group of the compound of the general formula (II) with tosyl chloride and methanesulfonyl chloride under basic conditions. Esters, or phenylthio derivatives obtained by further reacting with thiophenol, or NaI
Alternatively, a halogen derivative obtained by reacting with an alkali metal halide such as NaBr can be mentioned.

The subsequent reductive removal reaction can be performed using a metal hydride, for example, LiAlH ₄ or Bu ₃ SnH in the presence of AIBN. In the case of tetrahydropyranyl (THP) group, deprotection of the hydroxyl group at the 3-position and 25-position is carried out by using p-toluenesulfonic acid (p-TsOH) or pyridinium-p-toluenesulfonium (PPTS) in alcohol. In the case of a group, the reaction can be performed using tetrabutylammonium fluoride or the like. Na- for 23-phenylsulfonyl group
It can be performed using Hg. Scheme 2 shows an example of the production of dictyosterol using actual reagents. On the other hand, to produce the 24-position epimer of dictyosterol, a similar reaction can be obtained from stegmasterol (Scheme 3).

[0031]

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[0032]

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[0033]

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 (24R) -24-ethyl-3β-tetrahydropyranyloxy-cholesta-5,22-diene (Ia: R ₁ =
_{C 2 H 5, R 2 =} R 3 = H, R 4 = THP) sulfone derivative _{(IXa: R 1 = C 2} H 5, R 2 = R 3 = H) (3.5
g) was cooled to -78 ⁰ C dissolved in THF (100 mL). LD under nitrogen
A THF solution of A (1.5 mol / L, 27 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. A THF solution (100 mL) of C-20 aldehyde (V) (10 g) was added dropwise at the same temperature, and the mixture was stirred for 30 minutes. A saturated ammonium chloride solution was added, extracted with ethyl acetate, washed with saturated saline, dried and concentrated. Methanol (100 mL) and THF (100
mL), Na ₂ HPO ₄ (40 g) and 5% Na-Hg (60 g) were added, and the mixture was stirred at room temperature overnight. It was concentrated except for mercury. The residue was extracted with ethyl acetate, washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate / chloroform = 7/2/1). Purified product (4
g) was added to dichloromethane (100 mL) with 3,4-dihydro-2H-pyran (DHP) (2 g) and PPTS (0.5 g), and the mixture was stirred for 1 hour.
After washing with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, the mixture was concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1) to give the title compound (5).
g obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.66 (3H, s, 18-C
H ₃ ), 0.80 (3H, s, 19-CH ₃ ), 0.84-0.86 (9H, m, 26-CH
₃ , 27-CH ₃ , 29-CH ₃ ), 0.99 (3H, d, J = 6.8 Hz, 21-C
H ₃ ), 3.49 (1H, m, 3-H), 5.25 (2H, m, 22-H, 23-H),
6.15 (1H, m, 6-H).

Example 2 (6S), (24R) -24-ethyl-6-hydr
Roxy-3β-tetrahydropyranyloxy-cholesta-22-
En (IIa: R₁= C_TwoH_Five, R_Two= R_Three= H, R_Four= THP) Compound (Ia) (5 g) obtained in Example 1 was dissolved in THF (60 mL),
0-5⁰1mol / L BH at C _Three・ Add THF solution (15 mL)
And stirred for 2 hours. Then, 3 mol / L sodium hydroxide
Solution (15 mL), 30% H_TwoO_Two(15 mL) and add 30 minutes at room temperature
Stirred. Add water, extract with ethyl acetate, and with saturated saline
After washing, it was dried and concentrated. Silica gel chromatography of the residue
Purified by chromatography (hexane / ethyl acetate = 9/1)
3 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.66 (3H, s, 18-C
H ₃ ), 0.80 (3H, s, 19-CH ₃ ), 0.84-0.86 (9H, m, 26-CH
₃ , 27-CH ₃ , 29-CH ₃ ), 1.01 (3H, d, J = 6.8 Hz, 21-C
H ₃ ), 3.32 (1H, m, 6-H), 3.41 (1H, m, 3-H), 5.10-5.2
4 (2H, m, 22-H, 23-H).

Example 3 (24R) -24-Ethyl-cholesta-22-
Ene-3β-ol (IVa: R ₁ ＣC ₂ H ₅ , R ₂ ＲR ₃化合物 H) The compound (IIa) (2 g) obtained in Example 2 was dissolved in pyridine (20 mL), and tosyl chloride ( 3 g) was added and the mixture was stirred at room temperature overnight. A saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After washing with saturated saline, the solvent was concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 95/5) to give the tosyl form (IIIa: R ₁ = C ₂ H ₅ ,
R ₂ = R ₃ = H, R ₄ = THP, R ₅ = OTs).

¹ H-NMR (CDCl ₃ ) δ: 0.71 (3H, s, 18-C
H ₃ ), 0.81-0.92 (12H, m, 19-CH ₃ , 26-CH ₃ , 27-CH ₃ , 29
-CH ₃ ), 1.03 (3H, d, J = 6.4 Hz, 21-CH ₃ ), 3.41 (1H,
m, 3-H), 4.36 (1H, m, 6-H), 5.02-5.21 (2H, m, 22-
H, 23-H). To an ether (100 mL) containing LiAlH ₄ (1.5 g) was added an ether solution (100 mL) of the tosyl compound (IIIa) (2.5 g), and the mixture was heated under reflux overnight. After adding a small amount of water, magnesium sulfate was added and the mixture was filtered. The solvent was concentrated, and the residue was dissolved in THF (25 mL). Methanol (25 mL) and p-TsOH (250 mg) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added, and the mixture was washed with a saturated sodium hydrogen carbonate solution and saturated saline, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1). The product was crystallized from acetone to give 1.1 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.66 (3H, s, 18-C
H ₃ ), 0.80-0.85 (12H, m, 19-CH ₃ , 26-CH ₃ , 27-CH ₃ , 29
-CH ₃ ), 0.96 (3H, d, J = 6.3 Hz, 21-CH ₃ ), 3.60 (1H,
m, 3-H), 5.18 (2H, m, 22-H, 23-H).

Example 4 (24S) -24-Ethyl-cholesta-22-
Ene-3β, 25-diol (IVc: R ₁ = R ₃ = H, R ₂ = C ₂ H
₅ , R ₃ OHOH) phenylsulfone derivative (IXb: R ₁ ＣC ₂ H ₅ , R ₂ ＨH,
R ₃ = OTHP) (1 g) and C-20 aldehyde (V) (1 g) were prepared in Example 1.
(Ic: R ₁ = C ₂ H ₅ , R ₂ = H, R ₃ = OTH
520 mg of P) were obtained. (Ic) (520 mg) was treated in the same manner as in Examples 1, 2 and 3 to obtain 360 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.67 (3H, 18-CH ₃ ),
0.80 (3H, s, 19-CH ₃ ), 0.84 (3H, t, J = 6.3 Hz, 29-C
H ₃ ), 1.03 (3H, d, J = 6.3 hz, 21-CH ₃ ), 1.16, 1.17
(Each _{3H, s, 26-CH 3} , 27-CH 3), 3.59 (1H, m, 3H), 5.14-
5.39 (2H, m, 22-H, 23-H).

Example 5 (24S) -24-Ethyl-cholesta-22
-Ene-3β-ol ((IVb: R ₁ = H, R ₂ = C ₂ H ₅ , R ₃ =
H) Stigmasterol derivative (Ib: R ₁ = H, R ₂ = C
_{2 H 5, R 3 = H} , R 4 = THP) (3 g) and THF (30 mL) under ice-cooling _{1 mol / L BH 3 · THF} (10 mL) was dissolved was added, stirred for 2 hours at the same temperature did. Then, a 3 mol / L sodium hydroxide aqueous solution (8
mL) and 30% H ₂ O ₂ (8 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Water was added, extracted with ethyl acetate, washed with saturated saline, and the solvent was concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1). Purified product (1.6 g)
Was treated in the same manner as in Example 3 to obtain 750 mg of the title compound.

[0044]¹H-NMR (CDCl_Three): δ: 0.66 (3H, s, 18-C
H_Three), 0.80-0.84 (12H, 19-CH_Three, 26-CH _Three, 27-CH_Three, 29-CH
_Three), 0.98 (3H, d, J = 6.3 Hz, 21-CH_Three), 3.62 (1H, m,
3-H), 5.20 (2H, m, 22-H, 23-H).

[0045]

Industrial Applicability According to the present invention, dictyosterol and its derivatives can be efficiently produced, and as a therapeutic agent for neurodegenerative diseases of steroid derivatives having an excellent neurite projection regenerating action on mature central nervous cells. Development became possible.

Claims (1)

[Claims] 1. A compound of the general formula (I) [In the formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R ₄ represents a hydroxyl-protecting group. A steroid derivative represented by the general formula (II) obtained by regio- and stereoselectively hydroxylating the 5-ene part: [Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above. The steroid derivative represented by the general formula (III): [Wherein, R ₅ represents a tosyloxy group, a mesyloxy group, a phenylthio or a halogen atom, and R ₁ , R ₂ , R ₃ and R ₄
Is the same as defined above. Wherein R ₅ is eliminated, and if necessary, the protecting group for the hydroxyl group at the 3- or 25-position is removed.
V) [R ₁ , R ₂ and R ₃ are the same as defined above. A method for producing a steroid derivative represented by the formula: