JPH08225480A - Production of synthetic intermediate for vitamin d derivative - Google Patents

Abstract

PURPOSE: To obtain an ene-yne compound useful as a synthetic intermediate of an active form of a vitamin D3 derivative in an effective manner by reacting an optically active alcohol derivative with an ethylene metal salt and subsequently reducing the obtained reaction product. CONSTITUTION: An enone compound of formula II is obtained by reacting a compound of formula I (R is H or a blocking group for OH; Y is H or a substituted silyl) with a metal salt of ethylene (e.g. halogenated vinylmagnesium) in a solvent (e.g. THF) at 0-50 deg.C. Subsequently, after blocking or deblocking is optionally carried out for a hydroxy group, the compound of formula II is reduced in a diastereo-selectively by a general method to obtain an ene-yne compound of formula III. Use of a compound of formula III as a raw material enables the easy synthesis of 23-hydroxy(or oxo)vitamin D3 derivative useful as a curing or prophylactic agent to diseases such as osteoporosis and rachitis, which are attributable to abnormalities of absorption, transportation or metabolism of calcium, an anti-tumor agent, etc., without depending on time consuming processes and through such a moderate process as silica gel column chromatography for purification.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an enyne compound useful as an intermediate in the production of various active vitamin D ₃ derivatives. That is, using the enyne compound, which is the object compound of the present invention, as a raw material, for example, the method described in Japanese Patent Laid-Open Publication No. 45249/1988, 23.
- it is possible to produce hydroxy (or oxo) vitamin D ₃ derivatives. The 23-hydroxy (or oxo) vitamin D ₃ derivative has an excellent pharmacological action, that is, a useful physiological action similar to vitamin D, and various diseases caused by abnormal calcium absorption, transport or metabolism, such as rickets, Not only is it useful as a therapeutic or prophylactic agent for bone diseases such as osteomalacia and osteoporosis, it also suppresses the growth of tumor cells such as myeloid leukemia cells and induces differentiation into normal cells. And is useful as an antitumor agent. The same publication, it is described that synthesize 23-hydroxy (or oxo) vitamin D ₃ derivatives in accordance with the following reaction formula.

[Chemical 11]

On the other hand, recently, a method for synthesizing a vitamin D derivative by reacting an enyne compound and a vinyl bromide compound as described in the following formula with a palladium catalyst has been developed (Journal of American Chemical).・ Society (J. Am. Chem. Soc.) Volume 114,
9836 (1992)).

[Chemical 12]

[0003]

2. Description of the Related Art The above-mentioned report describes that an enein compound is synthesized by using propargyl alcohol as a raw material as shown in the following formula.

[Chemical 13]

[0004]

However, the above method requires special equipment in the dimethoxylation step, requires the use of toxic chromic acid in the oxidation step, and requires a synthetic route. In the middle of the process, inefficient high performance liquid chromatography must be used for diastereomer separation, and the charged amount of one batch is very limited, and purification on a large scale becomes very difficult. Further, the racemic resolution step requires 19 days for the reaction. Therefore, when handling a relatively large amount, the above method is not satisfactory from the viewpoint of an efficient manufacturing method.

[0005]

Means for Solving the Problems In order to solve the above problems, the present inventors have made various studies on a method for producing an optically active enyne derivative. As a result, they have found that an enyne derivative can be efficiently produced by using a commercially available optically active epoxide, and completed the present invention. That is, the present invention has the general formula (3)

Embedded image (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, and Y
Represents a hydrogen atom or a substituted silyl group) and an intermediate thereof.

More specifically, the present invention relates to (i) the general formula (1)

[Chemical 15] (Wherein R and Y have the same meanings as described above), the compound represented by the general formula (2) is reacted with a metal salt of ethylene.

Embedded image (Wherein R and Y have the same meanings as described above), the hydroxyl group is protected or deprotected as necessary, and the compound represented by the general formula (2) is subjected to a reduction reaction. A method for producing the enyne compound represented by the general formula (3) by adding to (ii) the general formula (4)

[Chemical 17] A metal salt of acetylene optionally substituted with a substituted silyl group at the 2-position is added to the compound represented by the formula (wherein X represents a leaving group) to give a compound of the general formula (5a)

Embedded image (Wherein, X and Y have the same meanings as described above), and by protecting the hydroxyl group as necessary, the compound represented by the general formula (5)

[Chemical 19] (Wherein R, Y and X have the same meanings as described above), and by reacting the compound represented by the general formula (5) with an alkali metal salt of cyanide, After the compound represented by the general formula (1),
A method for producing the enyne compound represented by the general formula (3) according to the method (i) above, and (iii) useful as a raw material compound or an intermediate in these methods,
The present invention relates to the compound represented by the general formula (1) and the compound represented by the general formula (5).

The functional group in the present invention will be described.
As the hydroxyl-protecting group, any group can be used as long as it can be used under the reaction conditions of the present method. The introduction and removal methods can be carried out by a method known to those skilled in the art (for example, Protective Groups in O).
organicSynthesis, John-Wile
y Sons, New York, pp10-86 (1
981)), a protecting group removed by acid or alkali hydrolysis, especially a substituted silyl group, a methyl group,
Examples thereof include a substituted methyl group, a 2-tetrahydropyranyl group and an acyl group.

Examples of the substituted silyl group include a silyl group trisubstituted with a lower alkyl group or an aryl group, and examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, t-butyl and the like having 6 or less carbon atoms. Examples of the alkyl group and the aryl group include aryl groups having 10 or less carbon atoms such as phenyl. Specific examples of the substituted silyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, t-butyldimethylsilyl group, diphenylmethylsilyl group, t-butyldiphenylsilyl group. And so on.

Examples of the substituent in the substituted methyl group include an alkoxy group, an alkylthio group, an aralkyloxy group, an alkoxyalkoxy group, and the like, and the alkyl portion of these substituents includes an alkyl group such as methyl and ethyl having 4 or less carbon atoms. Examples of the aryl portion of the group include aryl groups having 10 or less carbon atoms such as phenyl. Specific examples of the substituted methyl group include a methoxymethyl group, a methylthiomethyl group, a benzyloxymethyl group and a methoxyethoxymethyl group. Examples of the acyl group include a lower alkanoyl group and an aroyl group, and examples of the lower alkanoyl group include a carbon number of 3 or less substituted with 1 to 3 halogen atoms such as monochloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl. And alkanoyl groups having 6 or less carbon atoms in the alkyl moiety such as acetyl, propionyl, butyryl, butyryl, isobutyryl, pivaloyl, and the like, and aroyl groups having 1 carbon atom in the aryl moiety such as benzoyl.
There may be 0 or less aroyl groups.

Suitable examples of the protective group for the hydroxyl group represented by R include a substituted silyl group. As a more preferable one, a silyl group substituted with a lower alkyl group or an aryl group such as a triisopropylsilyl group, a t-butyldimethylsilyl group or a diphenylmethylsilyl group can be selected. A preferable example of the substituted silyl group represented by Y is a trimethylsilyl group.

Examples of the leaving group include halogen, alkylsulfonyloxy group, arylsulfonyloxy group and aralkylsulfonyloxy group, and examples of halogen include chlorine, bromine and iodine, and alkylsulfonyloxy group and aralkylsulfonyl group. As the alkyl part of the oxy group, an alkyl group having 4 or less carbon atoms such as methyl and ethyl is an aralkylsulfonyloxy group,
Examples of the aryl moiety of the arylsulfonyloxy group include aryl having 10 or less carbon atoms such as phenyl. The aryl portion of the arylsulfonyloxy group may be substituted with an alkyl group having 4 or less carbon atoms such as methyl. Examples of such leaving groups include methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, benzylsulfonyloxy, p-toluenesulfonyloxy and the like.

As the metal salt of acetylene which may be substituted with a substituted silyl group at the 2-position, any metal salt having a nucleophilic property may be used. Specifically, it may be represented by the general formula (10).

Embedded image (Wherein Y represents the same meaning as described above and M ¹ represents an alkali metal). Examples of the alkali metal represented by M ¹ include sodium and lithium. The compound represented by the general formula (10) is preferably a lithium salt of acetylene or a lithium salt of 2-trimethylsilylacetylene. Further, a metal salt of acetylene which may be substituted with a substituted silyl group at the 2-position may form a complex, and an ethylenediamine complex of lithium salt is also preferable. The metal salt of ethylene may be a nucleophilic metal salt, and specifically, the general formula (11)

[Chemical 21] (In the formula, M ² is an alkali metal or a compound represented by MgZ (Z represents a halogen atom)). M ²
Examples of the alkali metal represented by are sodium and lithium. Examples of the halogen atom represented by Z include chlorine, iodine and bromine. A desirable example of the compound represented by the general formula (11) is vinylmagnesium bromide. Examples of the type of alkali metal forming an alkali metal salt of cyan ion include sodium and potassium.

Next, the manufacturing method of the present invention will be described in detail below.

[Chemical formula 22] (In the formula, R ³ represents a hydroxyl-protecting group, and X and Y have the same meanings as described above.) Step A: Acetylene optionally substituted with a substituted silyl group at the 2-position to the compound (4). Addition of commercially available or easily available compound (4)
And a metal salt of acetylene which may be substituted with a substituted silyl group at the 2-position, such as tetrahedron letters (Tetr)
The compound of formula (5a) can be synthesized by a reaction according to a method described in ahedron Letters, Vol. 24, page 391 (1983). For example, 1 equivalent or more, preferably 1.2 to 1.8 equivalents of the lithium salt of acetylene optionally substituted with a substituted silyl group at the 2-position to the compound (4) is used at a reaction temperature of -100 ° C to -50 ° C. Preferably, in an aprotic solvent such as tetrahydrofuran or diethyl ether at −80 ° C. to −70 ° C., for example, n-butyllithium is added to the solvent and then acetylene gas is passed through, or n-butyllithium is added to the solvent. It is prepared by a method such as adding acetylene mono-substituted by a substituted silyl group after addition, and if necessary, 1 equivalent or more, preferably 1.2 to 1.8 equivalents of a Lewis acid, preferably boron trifluoride. Of the compound (5a) by sequentially adding the compound (4) and reacting.
Can be synthesized.

Step B: Addition of acetylene to compound (6) Compound (6) which is commercially available or easily available
By reacting in the same manner as in step A above, the formula (1
It is also possible to synthesize the compound of a). The resulting compound (1a) can be converted to a compound of formula (1b) by protecting the hydroxyl group, if necessary.

Step C: Nitrilation of Compound (5) (Compound (5a) or Compound (5b)) Compound (5) (Compound (5a) or Compound (5b))
Is dissolved in an aprotic solvent such as acetonitrile and, if necessary, 5 to 20% by weight, preferably 10 to 15% by weight, of dicyclohexeno-based on the compound (5).
By reacting with 1 equivalent or more, preferably 3 to 4 equivalents of an alkali metal salt of cyanide such as potassium cyanide in the presence of 18-crown-6 with respect to the compound (5), at a reaction temperature of 30 ° C. or higher, preferably by heating and refluxing, Compound (1) (compound (1a) or compound (1b)) can be synthesized.

Step D: Enonization of Compound (1) (Compound (1a) or Compound (1b)) Compound (1) (Compound (1a) or Compound (1b))
Is dissolved in, for example, an aprotic solvent such as tetrahydrofuran or diethyl ether, and at a reaction temperature of 0 ° C. to 50 ° C., preferably room temperature, at 1 equivalent or more, preferably 1.2 to 1.8 equivalents relative to compound (1). Compound (2) (compound (2a) or compound (2b)) can be synthesized by adding a metal salt of ethylene, preferably vinylmagnesium halide and reacting. Vinylmagnesium halide is, for example, in an ether solvent such as THF, the temperature of vinyl halide and powdered magnesium from room temperature to reflux under heating,
Preferably, it can be synthesized by a method such as reacting under heating under reflux.

Step E: Reduction of Compound (2) (Compound (2a) or Compound (2b)) Compound (2) (Compound (2a) or Compound (2b))
Can be diastereoselectively reduced using a generally known method to synthesize a compound of formula (3) (compound (3a) or compound (3b)). However,
For selective reduction, it is desirable that the hydroxyl group is not protected. For example, compound (2) (compound (2a)
Alternatively, the compound (2b)) is dissolved in a lower saturated fatty acid having 4 or less carbon atoms, of which acetic acid is preferable, and the reaction temperature is 0.
C. to 40.degree. C., preferably in the vicinity of 10.degree. Compound (3) was obtained by reacting with acetylated boron.
(Compound (3a) or compound (3b)) can be synthesized. The alkyl moiety of the tetraalkylammonium salt may be a lower one having 1 to 5 carbon atoms, preferably a methyl group or a butyl group. Further, the compound of the formula (3) can be synthesized by reducing using a usual enone reduction method without using the above method and then separating and purifying by silica gel column chromatography. For example, it is dissolved in an alcohol having 4 or less carbon atoms, preferably ethanol, and the reaction temperature is -20 ° C to 25 ° C, preferably 0 ° C.
At -10 ° C (1 equivalent or more, if necessary, preferably 1.
When 2-1.8 equivalents of cerium chloride are added, the
4 reduction can be prevented) 1 equivalent or more, preferably 1.2 to 1.8 equivalents of sodium borohydride is added to the compound (2) and reacted, and the obtained diastereomeric mixture is subjected to silica gel column chromatography. The compound (3) (compound (3a) or compound (3b)) can be similarly synthesized by separating and purifying with.

Equations (5a), (5b), (1a), (1
Among the compounds represented by b), (2a), (2b), (3a) or (3b), the compound in which Y is a substituted silyl group can be converted into the compound in which Y is a hydrogen atom by a known method. For example, when Y is a trimethylsilyl group, it can be converted to a corresponding compound in which Y is a hydrogen atom by reacting in an alcoholic solvent such as methanol in the presence of an alkali such as potassium carbonate at room temperature. Specifically, for example, 20 mg to 50 mg / 1 ml, preferably 30 m
Examples include a method of treating with a g-40 mg / 1 ml potassium carbonate / methanol suspension. In this reaction, it is desirable that potassium carbonate is in a suspended state because the reaction rate is faster. However, in the case of the compound represented by the formula (5a), it is more preferable to carry out the same reaction as the compound represented by the formula (5b) after protecting the hydroxyl group in advance, rather than performing the desilylation silyl reaction under direct basic conditions. It is desirable because it can prevent the epoxidation reaction.

Compound (3) obtained by the method of the present invention
Is, for example, after protecting the hydroxyl group, and with compound (7) and the literature (Journal of American Chemical Society (J. Am. Chem. Soc. 114, 9836).
Page (1992)), the palladium coupling reaction was carried out under the same conditions as described below, followed by deprotection to obtain the literature (J. Am. Chem. Soc. 11).
4, Vol. 98, page 36 (1992))
Vitamin D ₃ whose position is oxidized and Japanese Patent Laid-Open Publication No. 1988
The compound (8) described in No. 45249 can be used.

[Chemical formula 23] (In the formula, R ⁴ represents a hydrogen atom, a substituted silyl group, a methyl group, a substituted methyl group or a 2-tetrahydropyranyl group,
R ⁵ and R ⁶ are the same or different and each represents a substituted silyl group such as a tert-butyldiphenylsilyl group or a tert-butyldimethylsilyl group, and Q represents a leaving group (for example, a bromine atom or a trifluoromethanesulfonyloxy group). . )

[0020]

INDUSTRIAL APPLICABILITY By the production method and intermediate of the present invention, it has become possible to efficiently synthesize an enyne compound in a large amount. Specifically, there is no time-consuming step, and purification can be performed by a silica gel column chromatography operation.
Further, it is not necessary to use a highly toxic compound. Therefore, the production method and the intermediate of the present invention facilitate the synthesis of the active vitamin D ₃ derivative, which has hitherto been difficult on a relatively large scale.

[0021]

EXAMPLES Next, the present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples. The abbreviations used below have the following meanings. TBS: tert-butyldimethylsilyl group MOM: methoxymethyl group Tf: trifluoromethanesulfonyl group

Example 1

[Chemical formula 24] (1) Synthesis of 1-chloro-2R-hydroxy-pent-4-yne n-butyllithium hexane solution (0.96 ml,
Tetrahydrofuran (2.0 ml)
In addition to, acetylene gas (about 50m
Stirring through l) for 10 minutes. Next, a boron trifluoride diethyl ether complex (0.2 ml) and R-epichlorohydrin (93 mg) were sequentially added, and the mixture was further stirred at -78 ° C for 20 minutes. A saturated aqueous ammonium chloride solution was added dropwise at the same temperature, the mixture was returned to room temperature, and then extracted twice with ethyl acetate. The organic layer was washed with saturated brine to obtain a residue. This was subjected to silica gel column chromatography, and fractions eluted with ethyl acetate: hexane (1: 3) were collected to give 103 mg of the title compound. NMR (CDCl ₃ , δ) 4.00 (1H, m), 3.73 (1H, dd, J =
4.6, 11.2 Hz), 3.65 (1H, dd, J =
6.3, 11.2Hz), 2.57 (1H, dd, J =
2.0, 2.6 Hz), 2.54 (1H, t, J = 2.
6Hz), 2.09 (1H, t, J = 2.6Hz) (2) Synthesis of 1-cyano-2R-hydroxy-pent-4-yne 1-chloro-2R-hydroxy-pent-4-yne (4
Dicyclohexano-18-crown-6 (15 mg) and potassium cyanide (80 mg) were sequentially added to a solution of 7 mg) in acetonitrile (4 ml), and the mixture was heated under reflux for 7 hours. After cooling, the reaction solution was added to ice water and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, and fractions eluted with ethyl acetate: hexane (1: 3) were collected to give the title compound (35 m).
g was obtained. NMR (CDCl ₃ , δ) 4.14 (1H, m), 2.69 (1H, d, J = 3.
0 Hz) 2.67 (1H, d, J = 4.0 Hz), 2.
56 (2H, dd, J = 2.6, 5.9Hz) 2.14
(T, 1H, J = 2.6 Hz) (3) 5R-hydroxy-1-octene-7-in-3
Synthesis of 1-one 1-cyano-2R-hydroxy-pent-4-yn (3
Vinylmagnesium bromide (1.0 M, 0.32 ml) was added to a tetrahydrofuran (1.0 ml) solution of 5 mg), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, and fractions eluted with ethyl acetate: hexane (1: 3) were collected and the title compound 8.9 was obtained.
mg was obtained. NMR (CDCl ₃ , δ) 6.37 (1H, dd, J = 9.6, 17.5 Hz),
6.29 (1H, dd, J = 2.0, 17.5Hz),
5.93 (1H, dd, J = 2.0, 9.6Hz),
4.27 (1H, m), 3.21 (1H, d, J = 4.
0Hz), 2.99 (1H, dd, 3.3, 17.5H
z), 2.48 (1H, ddd, J = 2.6, 3.6,
15.6 Hz), 2.45 (1H, ddd, J = 2.
6, 4.6, 15.6 Hz), 2.06 (1H, t, J
= 2.6 Hz) (4) 3S, 5R-dihydroxy-1-octene-7-
Synthesis of Yin To a solution of 5R-hydroxy-1-octen-7-yn-3-one (50 mg) in acetic acid (2 ml) was added ammonium borohydride (42 mg), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, methanol was added to the reaction solution and concentrated under reduced pressure to obtain a residue. This was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: hexane (1: 3) were collected to give the title compound (37 mg). NMR (CDCl ₃ , δ) 5.91 (1H, ddd, J = 17.2, 10.5,
5.5 Hz), 5.29 (1H, d, J = 17.2H)
z), 5.13 (1H, d, J = 10.5Hz), 4.
46 (1H, m), 4.09 (1H, m), 2.44-
2.39 (2H, m), 2.05 (1H, t, J = 2.
6 Hz), 1.88-1.68 (2H, m) (5) 3S, 5R-di (tert-butyldimethylsilyloxy) -1-octen-7-yne (compound (E
5)) Synthesis 3S, 5R-dihydroxy-1-octene-7-yne (3.0 g) in dimethylformamide (60 ml) was added to imidazole (4.4 g) and tert-butyldimethylsilyl chloride (8.0 g). Were sequentially added and stirred at 50 ° C. for 2 hours. After the reaction is complete, leave it to cool and pour in ice water, 2N
An aqueous HCl solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution were sequentially washed, dried over magnesium sulfate and concentrated under reduced pressure to obtain a residue.
This was subjected to silica gel column chromatography, and the fractions eluted with hexane: ethyl acetate (20: 1) were collected and concentrated to give the title compound (7.1 g). NMR (CDCl ₃ , δ) 5.80 (1H, ddd, J = 17.5, 10.3,
7.3 Hz), 5.03 (1H, d, J = 10.3H
z), 5.14 (1H, d, J = 17.5 Hz), 4.
22 (1H, m), 3.93 (1H, m), 2.37
(2H, m), 1.97 (1H, t, J = 2.6H
z), 1.92-1.83 (1H, m), 1.70-
1.60 (1H, m), 0.89 (9H, s), 0.8
8 (9H, s), 0.09 (3H, s), 0.08 (3
H, s), 0.06 (3H, s), 0.04 (3H,
s)

Reference Example 1

[Chemical 25] (1) Tris- (dibenzylideneacetone) dipalladium (0) chloroform complex (17 mg), triphenylphosphine (44 mg) and triethylamine (2.
0 ml) was added to toluene (2.0 ml), and the mixture was stirred for 10 minutes. Then, the compound (E4) (65 mg) and the compound (E
5) A solution of (62 mg) in toluene (1.0 ml) was added, and the mixture was heated under reflux for 1 hour. After allowing to cool, the reaction solution was directly subjected to silica gel column chromatography, and fractions eluted with ethyl acetate: hexane (1:20) were collected to obtain the target compound (E6) (70 mg). NMR (CDCl ₃ , δ) 6.23 (1H, d, J = 11.1 Hz), 6.02
(1H, d, J = 11.1 Hz) 5.19 (1H,
s), 5.09 (1H, d, J = 6.6Hz), 4.8
6 (1H, d, J = 6.6Hz), 4.86 (1H,
s), 4.66 (1H, d, J = 6.9 Hz), 4.6
1 (1H, d, J = 6.9 Hz), 4.38 (1H,
m), 4.19 (1H, m), 3.94 (1H, br.
t), 3.45 (3H, s) 3.37 (3H, s),
0.88 (18H, m), 0.54 (3H, s), 0.
06 (12H, m) (2) Compound (E6) (70 mg) in methanol (2.
0 ml) solution was added with methanesulfonic acid (0.1 ml) and stirred for 3 hours. The reaction solution was added to water and extracted twice with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Then, it concentrated under reduced pressure and the residue was obtained. This was subjected to silica gel column chromatography, and fractions eluted with ethyl acetate: hexane (3: 2) were collected to obtain compound (E3) (30 mg). NMR (CDCl ₃ , δ) 6.37 (1H, d, J = 11.2 Hz), 6.33
(1H, s), 6.02 (1H, d, J = 11.2H
z) 5.33 (1H, s), 4.99 (1H, s),
4.20 to 4.50 (3H, m), 0.98 (3H,
d, J = 5.6 Hz), 0.57 (3H, s)

Reference Example 2 The starting compound (E4) of Reference Example 1 was synthesized by the following method.

[Chemical formula 26] 1) Synthesis of Compound (E9) Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 40, 16
1α, 3 synthesized by the method described on page 62 (1992)
β-bis [tert-butyldimethylsilyloxy]-
23-formyl-9,10-secopregna-5 (Z),
7 (E), 10 (19) -triene (compound (E8),
A solution of methylmagnesium bromide in tetrahydrofuran (0.96 mol / L, 45.5 ml) was carefully added dropwise to a diethyl ether solution (415 ml) of 19.7 g), and the mixture was stirred under ice cooling for 30 minutes, and then a saturated aqueous ammonium chloride solution was added. Distributed. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue is subjected to silica gel column chromatography, the fractions eluted with ethyl acetate: n-hexane (1: 5) are collected, and the desired 23-alcohol compound (compound (E9), diastereomeric mixture derived from the 23rd position) is collected. 18.4 g (yield 91%) was obtained. IR (neat) cm ⁻¹ : 3353 NMR (CDCl ₃ , δ): 0.05 to 0.06 (1
2H, m), 0.54, 0.56 (3H, s), 3.9
1 (1H, m), 4.20 (1H, m), 4.36 (1
H, m), 4.86 (1H, d, J = 2 Hz), 5.1
7 (1H, s), 6.01 (1H, d, J = 11H
z), 6.24 (1H, d, J = 11Hz)

2) Synthesis of compound (E10) 10.0 g of compound (E9) was added to dichloromethane (133
ml), N-methylmorpholine-N-oxide (2.93 g), powdered molecular sieves 4A (5.0 g),
Tetra-n-propyl ammonium pearl tenate 60
0 mg was sequentially added and the mixture was stirred at room temperature for 15 minutes. The reaction solution was directly subjected to silica gel column chromatography, and the fractions eluted with dichloromethane were collected to obtain 9.12 g (yield 92%) of the desired methyl ketone compound (Compound (E10)). IR (neat) cm ⁻¹ : 1718 NMR (CDCl ₃ , δ): 0.05 to 0.06 (1
2H, m), 0.57 (3H, s), 0.93 (3H,
d, J = 6.5 Hz), 2.12 (3H, s), 4.1
8 (1H, m), 4.36 (1H, m), 4.86 (1
H, d, J = 2.5 Hz), 5.17 (1 H, s),
6.01 (1H, d, J = 11 Hz), 6.23 (1
H, d, J = 11Hz)

3) Synthesis of compound (E11) A solution of 2.55 g of N, N'-hexamethyldisilazane and 30 ml of tetrahydrofuran was cooled to -70 ° C and n-
Butyl lithium in hexane (1.64 mol / l,
9.10 ml) was added dropwise, and then a solution of 6.30 g of compound (E10) and 35 ml of tetrahydrofuran was added dropwise. Hexafluoroacetone gas (obtained by dehydrating hexafluoroacetone trihydrate with sulfuric acid)
Was blown in until the material disappeared. Acetic acid 3.1 in the reaction solution
Add a solution of 5 g and 20 ml of tetrahydrofuran,
The mixture was returned to room temperature and partitioned with water and ethyl acetate. The organic layer was washed successively with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine,
After drying over magnesium sulfate, concentration under reduced pressure gave a residue. The residue was subjected to silica gel chromatography, and fractions eluted with ethyl acetate: n-hexane (1:30) were collected to give 6.56 g of a desired ketone body (compound (E11)).
(Yield 82%) was obtained. IR (neat) cm ⁻¹ : 1709 NMR (CDCl ₃ , δ): 0.04 to 0.06 (1
2H, m), 0.57 (3H, s), 0.96 (3H,
d, J = 6 Hz), 2.88 (3H, s), 4.20
(1H, m), 4.37 (1H, m), 4.85 (1
H, d, J = 2 Hz), 5.18 (1H, s), 6.0
1 (1H, d, J = 12Hz), 6.23 (1H, d,
J = 11 Hz), 6.88 (1H, br.s).

4) Synthesis of compounds (E12a) and (E12b) 7.0 g of compound (E11), 60 m of tetrahydrofuran
To a solution of 1 and 60 ml of methanol was added sodium borohydride (0.514 g) at -10 ° C. After stirring for 10 minutes, 1N-hydrochloric acid water was added to the reaction solution. After returning to room temperature, the mixture was partitioned with ethyl acetate and water, the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: n-hexane (1:20) were collected to collect the compound (E12
a) (Rf = 0.25, hexane / ethyl acetate (10 /
1)) 2.27 g (yield 32%) and compound (E12b)
(Rf = 0.5, hexane / ethyl acetate (10/1))
3.65 g (yield 52%) was obtained.

Compound (E12a) IR (neat) cm ⁻¹ : 3308 NMR (CDCl ₃ , δ): 0.06 (12H,
m), 0.56 (3H, s), 0.98 (3H, d, J
= 6 Hz), 4.20 (1H, m), 4.38 (2H,
m), 4.86 (1H, d, J = 2Hz), 5.18
(1H, s), 6.02 (1H, d, J = 11Hz),
6.23 (1H, d, J = 11Hz), 6.31 (1
H, s) Compound (E12b) IR (neat) cm ⁻¹ : 3326 NMR (CDCl ₃ , δ): 0.06 (12H,
s), 0.56 (3H, s), 1.00 (3H, d, J
= 6 Hz), 4.20 (1H, m), 4.37 (2H,
m), 4.86 (1H, d, J = 2Hz), 5.18
(1H, s), 6.02 (1H, d, J = 11Hz),
6.24 (1H, d, J = 11Hz), 6.28 (1
H, s)

[0029]

[Chemical 27] 5) Synthesis of Compound (E2) Compound (E12a) (1.5 g) in chloroform (20
ml) solution with diisopropylethylamine (14.8 m
1) and chloromethyl methyl ether (4.31 ml) were sequentially added, and the mixture was heated under reflux for 1 hour. After allowing to cool, the reaction solution was added to water and extracted twice with ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Then, it concentrated under reduced pressure and the residue (1.72g) was obtained. This was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: hexane (1: 5) were collected to obtain compound (E2) (1.60 g). NMR (CDCl ₃ , δ) 6.23 (1H, d, J = 11.1 Hz), 6.02
(1H, d, J = 11.1 Hz) 5.19 (1H,
s), 5.09 (1H, d, J = 6.6Hz), 4.8
6 (1H, d, J = 6.6Hz), 4.86 (1H,
s), 4.66 (1H, d, J = 6.9 Hz), 4.6
1 (1H, d, J = 6.9 Hz), 4.38 (1H,
m), 4.19 (1H, m), 3.94 (1H, br.
t), 3.45 (3H, s) 3.37 (3H, s),
0.88 (18H, m), 0.54 (3H, s), 0.
06 (12H, m)

6) Synthesis of compound (E3) Compound (E2) (1.72 g) was added to dichloromethane (15
It was dissolved in a mixed solvent of 0 ml) and methanol (30 ml). This was cooled to −78 ° C. and ozone gas was passed through. After confirming that the reaction solution was colored a pale blue color, excess ozone was removed by passing nitrogen gas through it, and then triphenylphosphine (1.70 g) was added and the reaction solution was returned to room temperature. The reaction mixture was added to water and extracted twice with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Then, it concentrated under reduced pressure and the residue (3.50g) was obtained. This was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: hexane (1: 5) were collected and compound (E3) (4
85 mg) was obtained. NMR (CDCl ₃ , δ) 5.06 (1H, d, J = 6.6Hz), 4.86 (1
H, d, J = 6.6 Hz) 4.65 (1H, d, J =
7.0 Hz), 4.59 (1H, d, J = 7.0H
z), 3.93 (1H, m), 3.42 (3H, s),
3.35 (3H, s), 0.99 (3H, d, J = 6.
3Hz), 0.63 (3H, s)

7) Synthesis of compound (E4) A solution of 1,1,1,3,3,3-hexamethyldisilazane (0.363 ml) in toluene (3.0 ml) was added to-
The mixture was cooled to 78 ° C., a hexane solution of n-butyllithium (0.86 ml, 1.60 M) was added dropwise, and the mixture was stirred for 10 minutes. Subsequently, bromomethyltriphenylphosphonium bromide (748 mg) was added and the temperature was raised to 0 ° C.
Stir for minutes. A solution of the compound (E3) (169 mg) in toluene (0.7 ml) was added dropwise thereto, and the mixture was further stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Then, it concentrated under reduced pressure and the residue was obtained. This was subjected to silica gel column chromatography, ethyl acetate:
Fractions eluted with hexane (1:10) were collected to obtain the target compound (E4) (80 mg).
3) (44 mg) was recovered. NMR (CDCl ₃ , δ) 5.65 (1H, s), 5.09 (1H, d, J = 6.
6Hz), 4.88 (1H, d, J = 6.6Hz),
4.66 (1H, d, J = 6.9Hz), 4.61 (1
H, d, J = 6.9 Hz), 3.95 (1H, br.
t), 3.45 (3H, s), 3.37 (3H, s),
0.99 (3H, d, J = 5.6Hz), 0.57 (3
H, s)

Reference Example 3 A compound in which Q is a trifluoromethanesulfonyloxy group in the above formula (7) can be synthesized as follows.

[0033]

[Chemical 28]

(In the formula, R ⁴ has the same meaning as described above.) (1) Oxidative Cleavage The compound (b) can be prepared by the method described in the literature [Journal of Organic Chemistry (J. Org. Chem.), 48].
Vol. 3, 3477 (1983)]. That is, the compound (a) is dissolved in an alcohol having 1 to 4 carbon atoms, preferably ethanol and an aromatic solvent, preferably a mixed solvent of benzene, and halogen is blown with oxygen in the presence of a sensitizer such as rose bengal. Illuminate the lamp. After removing the sensitizer, it is concentrated, dissolved again in an aromatic solvent, and at 0 to 10 ° C., preferably 3 to
After cooling to 5 ° C., a Lewis acid, preferably boron trifluoride diethyl ether complex, is added at 1 to 1.5 equivalents, preferably 1.2.
The compound (b) can be synthesized by adding ~ 1.3 equivalents and reacting. (2) Protection of Hydroxyl Group The protection of hydroxyl group is carried out by a general method [eg P
rotaryGroups in Organi
c Synthesis, John-Wiley & So
ns, New York, pp10-86 (1981)].
You can follow. For example, to synthesize a compound (c) having a methoxymethyl group introduced, the compound (b)
It can be carried out by adding diisopropylethylamine and chloromethyl methyl ether to the chloroform solution of and reacting. (3) Synthesis of vinyl triflate From the compound (c), the literature [Tetrahedron Letter, 24,
Compound (d) can be synthesized according to the method described on page 979 (1983)]. For example, in an ether solvent, preferably dimethoxyethane, -78 to -60.
A base containing an alkali metal, preferably lithium diisopropylamide, is prepared at a temperature of preferably -75 to -65 ° C, and then compound (c) is added to generate an enolate ion, followed by N-phenyltrifluoromethanesulfonimide. Compound (d) can be synthesized by adding and reacting.

[0035]

[Chemical 29]

1) Synthesis of compound (E14) 314 mg of compound (E13) was dissolved in a mixed solvent of benzene and ethanol (9: 1, 20 ml), and rose bengal (40 mg) was added thereto while bubbling oxygen. The halogen lamp was irradiated for 1 hour. After completion of the reaction, rose bengal was adsorbed on silica gel and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was dissolved again in 20 ml of benzene, boron trifluoride diethyl ether complex (3 drops) was added under ice cooling, and the mixture was stirred for 3 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, the fractions eluted with ethyl acetate: hexane (1: 2) were collected, and the diastereomeric mixture of the desired aldehyde derivative (E14) (mixing ratio, 1: 2) was collected.
9) (50 mg) was obtained. IR (neat) cm ⁻¹ : 3225 (br.), 295
4, 1705 NMR (CDCl ₃ ) δ: 0.62 (3H × 0.9,
s), 0.72 (3H × 0.1, s) 0.90 to 1.0
2 (3H, m), 4.32 (1H, br.t), 6.3
4 to 6.38 (1H, m), 9.54 (1H × 0.
1), 10.00 (1H x 0.9)

2) Synthesis of compound (E15) 50 mg of compound (E14) in chloroform (2.0 m
l) diisopropylethylamine (1.37 m
1) and chloromethyl methyl ether (0.4 ml) were sequentially added, and the mixture was heated under reflux for 1 hour. After allowing to cool, the reaction solution was poured into ice water and extracted twice with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. This was subjected to silica gel column chromatography, ethyl acetate:
Fractions eluted with hexane (1:10) were collected and collected as a diastereomeric mixture of compound (E15) (mixing ratio, 1: 9).
(52 mg) was obtained. IR (neat) cm ⁻¹ : 2947, 1716 NMR (CDCl ₃ ) δ: 0.64 (3H × 0.9,
s), 0.73 (3H × 0.1), 3.37 (3H,
s), 3.47 (3H, s) 4.01 (1H, br.
s), 4.55 (1H, d, J = 7.1 Hz), 4.7
0 (1H, d, J = 7.1Hz), 4.94 (1H,
d, J = 6.3 Hz), 5.00 (1H, d, J = 6.
3Hz), 9.57 (1H x 0.1, s), 10.02
(1H × 0.9, s)

3) Synthesis of compound (E16) 0.047 ml of 1,1,1,3,3,3-hexamethyldisilazane was dissolved in dimethoxyethane (0.5 ml) and n-butyl was added at -78 ° C. Lithium-hexane solution (1.
6M, 0.104 ml) was added dropwise and stirred for 10 minutes.
Subsequently, a solution of compound (E15) (14 mg) in dimethoxyethane (0.3 ml) was added dropwise, and the mixture was further stirred for 1 hour.
N-phenyltrifluoromethanesulfonimide (99
(mg) was added, the reaction temperature was raised to room temperature, and the mixture was stirred overnight. The reaction mixture was directly concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate: hexane (1:10) were collected to give the compound (E1
6) (10 mg) was obtained. IR (neat) cm ⁻¹ : 2954, 1423 NMR (CDCl ₃ ) δ: 0.61 (3H, s), 0.
97 (3H, d, J = 6.6Hz), 3.37 (3H,
s), 3.47 (3H, s), 4.01 (1H, br.
s), 4.55 (1H, d, J = 7.1 Hz), 4.7
1 (1H, d, J = 7.1Hz), 4.95 (1H,
d, J = 6.3 Hz), 5.01 (1H, d, J = 6.
3 Hz) 6.17 (br.s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 41/18 C07C 41/18 C07F 7/18 C07F 7/18 W // C07C 401/00 C07C 401 / 00

Claims (4)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, and Y
Represents a hydrogen atom or a substituted silyl group) and is reacted with a metal salt of ethylene to give a compound represented by the general formula (2): (Wherein R and Y have the same meanings as described above), and if necessary, the hydroxyl group is protected or deprotected, and then reduced to give an enone compound represented by the general formula (3) (In the formula, R and Y have the same meanings as described above.) A method for producing an enyne compound. 2. A compound represented by the general formula (4): A metal salt of acetylene optionally substituted by a substituted silyl group is added to the 2-position of the compound represented by the formula (wherein X represents a leaving group) and the compound represented by the general formula (5a): (Wherein, X represents the same meaning as described above, Y represents a hydrogen atom or a substituted silyl group), the hydroxyl group is protected as necessary, and then a cyanide alkali metal salt is formed. By reacting with general formula (1) (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, and Y
Represents the same meaning as above), and if necessary protects or deprotects the hydroxyl group, and then reacts with a metal salt of ethylene to give a compound of the general formula (2) (Wherein R and Y have the same meanings as described above), and if necessary, the hydroxyl group is protected or deprotected, and then reduced to give the general formula (3) (In the formula, R and Y have the same meanings as described above.) A method for producing an enyne compound. 3. A compound represented by the general formula (1): (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, and Y
Represents a hydrogen atom or a substituted silyl group). 4. A compound represented by the general formula (5): (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group, Y represents a hydrogen atom or a substituted silyl group, and X represents a leaving group.)
The compound represented by.