JPH11116551A - Vitamin d3 derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative bearing methyl group on the 2 site, and useful as a therapeutic agent for osteoporosis. SOLUTION: This new derivative is a 1,25-dihydroxy-2-methyl vitamin D3 derivative of formula I [R<1> and R<2> are each H or a tri(l-7C alkyl)silyl; the configuration of 1-3 site asymmetric carbon atoms represents α,β coordination], e.g. 1β,25-dihydroxy-2β-methyl-3β-β-vitamin D3 . The compound of formula I is obtained by reaction of % an exomethylene compound of formula II (X is Br or I) with an ene-yne compound [e.g. (3R,4R,5R)-3,5-dihydroxy-4-methyl-1- octen-7-yne] in a molar ratio of (1:5) to (5:1) in the presence of a palladium catalyst [e.g. composed of tris(dibenzylideneacetone)palladium and triphenylphosphine] followed by, as necessary, deprotection of tri(1-7C hydrocarbon)silyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel vitamin D ₃ derivative having a methyl group at the 2-position and a method for producing the same. More specifically, the present invention relates to a 1,25-dihydroxy-2-methylvitamin D ₃ derivative useful as a therapeutic agent for osteoporosis, a method for producing the derivative, a key intermediate thereof, and a method for producing the key intermediate.

[0002]

BACKGROUND OF THE INVENTION active vitamin D ₃ is a substance that controls metabolism such as calcium and phosphate in the body, very important to act is widely recognized throughout the scientific literature of patents and general ever Have been. It is also a well-known fact that various vitamin D derivatives are used as remedies for vitamin D metabolism disorders such as osteoporosis and rickets.

[0003] In addition, calcium-modulating action and various other biological activities observed in vitamin D ₃ exhibit various action selectivities due to differences in binding affinity to vitamin D receptor and binding affinity to vitamin D binding protein. Some have interpreted that it is due to

[0004] Known 2-substituted vitamin D ₃ derivatives include a hydroxyl group at the 1-position having an α-coordinate and a β-coordinate substituent at the 2-position (unsubstituted or substituted C ₁ -C 3 -substituted hydroxyl group). ₆
Linear alkyl group, C _1-
1,25-dihydroxyvitamin D ₃ derivatives having a C ₆ linear alkyloxy group, a C ₁ -C ₅ alkenyl group, or a hydroxyl group have been reported (Kobayashi et al., The 116th Annual Meeting of the Pharmaceutical Society of Japan ( 1996), Abstracts of Lectures 3, p8
8).

A 1,25-dihydroxyvitamin D ₃ derivative in which the hydroxyl group at the 1-position is α-coordinate and the α-position at the 2-position has a substituent (3-hydroxypropyl group or 3-fluoropropyl group) Is known (Posner, G.
H., J. Org. Chem., 1995, 60, 4617) is 1,25 for dihydroxy-2-methyl-vitamin D ₃ derivatives,
There are no reports that various stereoisomers related to the asymmetric carbon at the 1-, 2-, and 3-positions were obtained.

[0006] Methods for producing these 2-substituted vitamin D ₃ derivatives are also disclosed in the above-mentioned documents, but all of them are in the 1-position and 2-position.
Among the stereoisomers for the asymmetric carbon at the 3-position and the 3-position, only a specific combination of isomers can be produced, and no method for efficiently producing an arbitrary combination of isomers is disclosed.

In recent years, the general formula (II)

[0008]

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[Wherein, X represents a bromine atom or an iodine atom. And an exomethylene compound represented by the general formula (II
I)

[0010]

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Wherein R ₃ and R ₄ are each independently:
Represents a hydrogen atom or a tri (C ₁ -C ₇ hydrocarbon) silyl group. 4-position unsubstituted ene in - novel methods of synthesizing the activated vitamin D ₃ by reacting an in-compound was announced. (Trost, BM; J. Am. Chem. So
c., 1992, 114 , 9836). However, there is no known example using an ene-yne compound having a substituent such as a methyl group at the 4-position.

In addition, 4-substituted unsubstituted ene-yne compounds have been synthesized by various methods in optically pure form (Tros
t, BM; J. Am. Chem. Soc., 1992, 114 , 9836, Tros
t, BM; Tetrahedron Lett., 1994, 35 , 8119, Moriar
ty, RM; Tetrahedron Lett., 1995, 36 , 51, Vandewa
lle, M .; Tetrahedron Lett., 1995, 36 , 9023).

However, the ene-yne compound (III) is not known even though the 4-position is substituted with a methyl group and has a hydroxyl group which may be protected at the 3- and 5-positions. There is no disclosure of a method for optically pure synthesis of stereoisomers derived from consecutive asymmetric carbons at the 3-, 4-, and 5-positions.

[0014]

An object of the present invention is to provide a novel 1,25-dihydroxy-2-methylvitamin D ₃ derivative having biological activity, a method for producing the same, and a process for producing the same. Key intermediate used,
Another object of the present invention is to provide a method for producing the same.

[0015]

Means for Solving the Problems The present inventors have intensively studied for the above-mentioned object, and as a result, have reached the following invention. That is, the present invention provides a compound represented by the general formula (I)

[0016]

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Wherein R ₁ and R ₂ are each independently
Represents a hydrogen atom or a tri (C ₁ -C ₇ alkyl) silyl group. Here, the steric configurations of the asymmetric carbons at the first, second, and third positions are each independently α-configuration or β-configuration (provided that 1-position is α-configuration and 2-position is β-coordination, excluding stereoisomers where the 3-position is β-coordination). 1,25-dihydroxy-2-methylvitamin D represented by the formula:
₃ derivatives.

Accordingly, the vitamin D ₃ derivative of the present invention has three configurations at the first, second, and third positions, respectively: (1) α configuration, α configuration, and a combination of α configuration (2) ) Combination of α coordination, α coordination and β coordination (3) Combination of α coordination, β coordination and α coordination (4) Combination of β coordination, α coordination and α coordination (5) β Combination of coordination, α coordination and β coordination (6) Combination of β coordination, β coordination and α coordination Are included. Further, a mixture containing a plurality of any of these seven types of stereoisomers in an arbitrary ratio is also included in the scope of the present invention.

The notation of the configuration of vitamin D is in accordance with a common practice. That is, the term “α-coordinate” means a bond from above the paper surface, and the term “β-coordinate” means a bond from below the paper surface.

The present invention also includes a method for producing the vitamin D ₃ derivative represented by the above formula (I). That is, the general formula (II)

[0021]

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[Wherein, X represents a bromine atom or an iodine atom. And an exomethylene compound represented by the general formula (II
I)

[0023]

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Wherein R ₃ and R ₄ are each independently:
Represents a hydrogen atom or a tri (C ₁ -C ₇ hydrocarbon) silyl group. With an ene-yne compound represented by the formula (I) by deprotecting the tri (C ₁ -C ₇ hydrocarbon) silyl group if necessary. To produce a 1,25-dihydroxy-2-methylvitamin D ₃ derivative.

In addition, the present invention provides a compound of the general formula (III)

[0026]

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Wherein R ₃ and R ₄ are each independently:
Represents a hydrogen atom or a tri (C ₁ -C ₇ hydrocarbon) silyl group. Here, the configurations of the asymmetric carbons at the 3-, 4- and 5-positions are each independently R configuration or S configuration. And an ene-yne compound represented by the formula: Further, a mixture containing a plurality of any of these eight stereoisomers at an arbitrary ratio is also included in the scope of the present invention.

Further, the present invention provides the following reaction formula (Scheme 1)

[0029]

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Wherein R ₁₁ is tri (C ₁ -C ₇ alkyl)
Represents a silyl group or a (C ₁ -C ₇ alkyl) di (C ₆ -C ₁₀ aryl) silyl group, R ₁₂ represents a protecting group which forms an acetal together with a bonding oxygen atom, and TMS represents a trimethylsilyl group. [II]
This is a method for producing the ene-yne compound represented by I) optically pure.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a tri (C ₁ -C ₇ alkyl) silyl group is substituted by three independent linear or branched C ₁ -C ₇ alkyl groups. A trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, or a t-butyldiphenylsilyl group. Also, (C
The ₁ -C ₇ alkyl) di (C ₆ -C ₁₀ aryl) silyl group, substituted by one straight or branched C ₁ -C ₇ alkyl groups and two C ₆ -C ₁₀ aryl group Represents a silyl group, and among them, a t-butyldiphenylsilyl group is preferable.

Preferable specific examples of the 1,25-dihydroxy-2-methylvitamin D ₃ derivative represented by the general formula (I) include 1β, 25-dihydroxy-2β-methyl-3β-vitamin D ₃ (1 ) 1α, 25-dihydroxy-2β-methyl-3α-vitamin D ₃ (2) 1β, 25-dihydroxy-2β-methyl-3α-vitamin D ₃ (3) 1α, 25-dihydroxy-2α-methyl-3β-vitamin D ₃ (4) 1β, 25-dihydroxy-2α-methyl-3β-vitamin D ₃ (5) 1α, 25-dihydroxy-2α-methyl-3α-vitamin D ₃ (6) 1β, 25-dihydroxy-2α-methyl -3α- vitamin D ₃ (7) 1β, 25- dihydroxy -2β- methyl -3β- vitamin D _3-1,3-bis (trimethylsilyl) ether (8) l [alpha], 25- Hydroxy -2β- methyl -3α- vitamin D _3-1,3-bis (trimethylsilyl) ether (9) l [beta], 25-dihydroxy--2β- methyl -3α- vitamin D _3-1,3-bis (trimethylsilyl) ether ( 10) l [alpha], 25-dihydroxy--2α- methyl -3β- vitamin D _3-1,3-bis (trimethylsilyl) ether (11) l [beta], 25-dihydroxy--2α- methyl -3β- vitamin D _3-1,3- bis (trimethylsilyl) ether (12) l [alpha], 25-dihydroxy--2α- methyl -3α- vitamin D _3-1,3-bis (trimethylsilyl) ether (13) l [beta], 25-dihydroxy--2α- methyl -3α- vitamin D _3-1,3-bis (trimethylsilyl) ether (14) l [beta], 25-dihydroxy -2β- main Chill -3β- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether (15) 1α, 25- dihydroxy -2β- methyl -3α- vitamin D _3-1,3-bis (t-butyldimethyl silyl) ether (16) l [beta], 25-dihydroxy--2β- methyl -3α- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether (17) 1α, 25- dihydroxy -2α- methyl -3β- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether (18) l [beta], 25-dihydroxy--2α- methyl -3β- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether ( 19) l [alpha], 25-dihydroxy--2α- methyl -3α- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether (20) l [beta] , 25-dihydroxy -2α- methyl -3α- vitamin D _3-1,3-bis (t-butyldimethylsilyl) ether (21), and the like.

The vitamin D represented by the above formula (I)
_{In the} method for producing the _three derivatives, the starting material represented by the above formula (II
The ene-yne compound represented by I) has the 3-position, 4-position,
And all stereoisomers derived from the asymmetric carbon at position 5,
Alternatively, they may be a mixture of any ratio thereof, but their configuration is preserved during the reaction, and a 1,25-dihydroxy-2-methylvitamin D ₃ derivative having a corresponding configuration is produced.

The palladium catalyst used in this production method is 0
It is a combination of a divalent or divalent organic palladium compound and a trisubstituted phosphorus compound. Examples of such an organic palladium compound include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) palladium chloroform, and palladium acetate. Examples of the trisubstituted phosphorus compound include triphenylphosphine and tributylphosphine. As a palladium catalyst combining both, tris (dibenzylideneacetone) palladium and triphenylphosphine, tris (dibenzylideneacetone)
Palladium chloroform and triphenylphosphine are preferred, and the mixing ratio is preferably 1: 1 to 1:10.

Here, the molar ratio of the exomethylene compound represented by the above formula (II) to the ene-yne compound represented by the above formula (III) is in the range of 1: 5 to 5: 1. Is desirable. The palladium catalyst is used in an amount of 0.1 to 100 mol%, preferably 1 to 20 mol%, based on the exomethylene compound.
It is used in the range of mol%.

In the reaction between the exomethylene compound represented by the above formula (II) and the ene-yne compound represented by the above formula (III), the reaction solvent is a non-polar solvent such as hexane, heptane, toluene and the like. Examples of the solvent include polar solvents such as a solvent, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, and acetonitrile, and a mixed solvent thereof. Of these, heptane and toluene are preferred. Further, when these solvents are used in the reaction, it is desirable to carry out a treatment such as distillation or nitrogen substitution in advance. The reaction is carried out at a temperature ranging from room temperature to the boiling point of the solvent.

Further, in order to capture an acid such as hydrogen halide generated in the reaction system, it is preferable to add a base such as triethylamine or diisopropylethylamine for the reaction. As the amount of the base to be added, it is preferable to use at least one equivalent of the reactant represented by the above formula (II) or the above formula (III) which is used in excess.

The vitamin D ₃ derivative of the general formula (I) obtained by the above reaction is further subjected to a deprotection reaction, if necessary. As such a deprotection reaction, known methods (for example, Calveley, MJ; Tetrahedron, 20, 4609, 1987,
Ho, PT; Tetrahedron letters, 1623, 1978). In this case, examples of the deprotecting agent include tetrabutylammonium fluoride, lithium tetrafluoroborate, pyridium-P-troen sulfonate and camphorsulfonic acid.

The exomethylene compound represented by the general formula (II) is synthesized by a known method (Yamada et al., J. Org. Chem., 1995, 60 , 1828).

On the other hand, preferred specific examples of the ene-yne compound represented by the above formula (III) include (3R, 4R, 5R) -3,5-dihydroxy-4-methyl-1-octene-7- In (22) (3S, 4R, 5R) -3,5-dihydroxy-4-methyl-1-octene-7-yne (23) (3R, 4R, 5S) -3,5-dihydroxy-4-methyl- 1-octen-7-yne (24) (3S, 4R, 5S) -3,5-dihydroxy-4-methyl-1-octen-7-yne (25) (3R, 4S, 5R) -3,5- Dihydroxy-4-methyl-1-octen-7-yne (26) (3S, 4S, 5R) -3,5-dihydroxy-4-methyl-1-octen-7-yne (27) (3R, 4S, 5S ) -3,5-Dihydroxy-4-methyl-1 -Octen-7-yne (28) (3S, 4S, 5S) -3,5-dihydroxy-4-methyl-1-octen-7-yne (29) (3R, 4R, 5R) -3,5-bis (Trimethylsilyloxy) -4-methyl-1-octene-7-yne (30) (3S, 4R, 5R) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octene-7-yne (31) ) (3R, 4R, 5S) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octene-7-yne (32) (3S, 4R, 5S) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octen-7-yne (33) (3R, 4S, 5R) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octen-7-yne (34) (3S, 4S, 5R -3,5-bis (trimethylsilyloxy) -4-methyl-1-octene-7-yne (35) (3R, 4S, 5S) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octene -7-yne (36) (3S, 4S, 5S) -3,5-bis (trimethylsilyloxy) -4-methyl-1-octen-7-yne (37) (3R, 4R, 5R) -3,5 -Bis (t-butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (38) (3S, 4R, 5R) -3,5-bis (t-butyldimethylsilyloxy) -4-methyl -1-octen-7-yne (39) (3R, 4R, 5S) -3,5-bis (t-butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (40) (3S, 4R, 5S) -3 5-bis (t-butyldimethylsilyloxy) -4-methyl-1-octene-7-yne (41) (3R, 4S, 5R) -3,5-bis (t-butyldimethylsilyloxy) -4- Methyl-1-octen-7-yne (42) (3S, 4S, 5R) -3,5-bis (t-butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (43) (3R 4,4S, 5S) -3,5-bis (t-butyldimethylsilyloxy) -4-methyl-1-octene-7-yne (44) (3S, 4S, 5S) -3,5-bis (t- Butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (45).

Further, the present invention is a method for producing the ene-yne compound represented by the formula (III) optically pure. In the above scheme 1, R ₁₁ is a tri (C ₁ -C ₇ alkyl) silyl group or (C ₁ -C ₇ alkyl) di (C
Represents a ₆ -C ₁₀ aryl) silyl group, preferred examples are trimethylsilyl group, triethylsilyl group, t- butyl dimethyl silyl group, and a t-butyldiphenylsilyl group. R ₁₂ represents a protecting group that forms an acetal together with a bonding oxygen atom, and a methoxymethyl group,
A methoxyethoxymethyl group and a tetrahydropyranyl group are preferred.

This production method can be carried out as follows. That is, the hydroxyl group of a commercially available optically active ester compound (IV) is silyl protected in the presence of a base to obtain a compound (V). Here, as the silylating agent, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl triflate, t-butyldimethylsilyl triflate and the like are preferably used. As the base, a usual base such as triethylamine, 2,6-lutidine and imidazole is used.

Next, the compound (V) is reduced with a hydride reducing agent to obtain an alcohol (VI). As the hydride reducing agent, lithium aluminum hydride, diisobutyl aluminum hydride and the like are preferable. Further, the generated hydroxyl group is converted to dimethyl sulfoxide / oxalyl chloride or TPAP.
(Tetrapropylammonium pentaruthenate) / N
Oxidation with -methylmorpholine-N-oxide or the like to give the aldehyde (VII), followed by the usual Wittig reaction to give the methylene form (VIII).

Next, the double bond is converted into an epoxide compound (IX) using a peroxide reagent such as hydrogen peroxide or metachloroperbenzoic acid, and then reacted with an acetylene derivative shown in the scheme in the presence of a base such as alkyllithium. Compound (X) is obtained. Compound (X) is produced as a mixture (1: 1) of two diastereomers based on the stereoisomerism of the hydroxyl group, and these can be easily separated and purified by ordinary separation operations such as column chromatography. The configuration of the hydroxyl group of the separated diastereomer is represented by (R)
It can be determined by measuring < ¹ > H NMR using the-and (S)-MTPA esters (Kusumi et al., Journal of Synthetic Organic Chemistry, 1996, 51 , 462).

Further, by subjecting the separated compound (X) to the following reaction, the desired ene-yne compound represented by the general formula (III) can be produced optically pure. That is, the hydroxyl group of compound (X) is protected with acetal to obtain compound (XI). As the acetalizing agent, methoxymethyl chloride, methoxyethoxymethyl chloride, dihydropyran and the like are used. Next, after desilylation with a fluoride reagent such as tetrabutylammonium fluoride to give compound (XII), the generated primary hydroxyl group is converted to dimethylsulfoxide / oxalyl chloride or TPAP (tetrapropylammonium pentaruthenate) / N-methylmorpholine. -N-
Oxidized with an oxide or the like to form aldehyde (XIII). Further, the aldehyde group is reacted with a vinyl Grignard reagent to obtain a compound (XIV). Finally, the target en-yne compound (III) can be obtained by removing the acetal protecting group at the 5-position hydroxyl group under acidic conditions.

This compound (III) is a mixture of two diastereomers based on the stereoisomer of the hydroxyl group at the 3-position (1:
These are produced as 1) and can be easily separated and purified by ordinary separation operations such as column chromatography. The configuration of the hydroxyl group of the separated diastereomer is
Each is converted to an acetonide with a hydroxyl group at position 3 or 5,
It can be determined by measuring ¹³ C NMR (Ry
chnovsky, SD; J. Org. Chem., 1993, 58 , 3511).
Furthermore, it can be led to a protected silyl group at the 3- or 5-position hydroxyl group, if necessary.

The silylating agent used here includes trimethylsilyl chloride, triethylsilyl chloride, t-
Butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl triflate, t-
Butyldimethylsilyl triflate and the like are preferably used, and as the base, ordinary bases such as triethylamine, 2,6-lutidine and imidazole are used. As a reaction condition such as a solvent and a reaction temperature in each reaction step of the above reaction formula, a condition usually used for each reaction is applied.

In this production method, the steric configuration of the 4-position methyl group of the desired ene-yne compound (III) is derived from the optically active ester compound (IV) used as a starting material. Maintains this configuration throughout the entire reaction. That is, the present invention uses an optically active ester compound (IV) as a starting material, and consistently employs a reaction for maintaining its steric configuration, whereby vitamin D ₃
A process for the optically pure preparation of key intermediates (III) of the class of syntheses is provided.

As an example of the production of an optically pure ene-yne compound according to the present method, (3R, 4R, 5R) -3,5-
Bis (t-butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (38) and (3S, 4
R, 5R) -3,5-bis (t-butyldimethylsilyloxy) -4-methyl-1-octen-7-yne (3
The synthesis method of 9) is shown in the following schemes 2 and 3.

[0050]

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[0051]

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[In the above scheme, TBDPSCl is t-
Butyldiphenylsilyl chloride, DIBAL-H is diisobutylaluminum hydride, TPAP is tetrapropylammonium pentaruthenate, NMO is N-methylmorpholine-N-oxide, mCPBA is metachloroperbenzoic acid, MTPACl is α-methoxy-α- ( Trifluoromethyl) phenylacetyl chloride, DMAP
Is 4-dimethylaminopyridine, DHP is dihydropyran, TsOH is tosylic acid, TBAF is tetrabutylammonium fluoride, TBSOTf is t-butyldimethylsilyl triflate, TBDPS is t-butyldiphenylsilyl group, and TBS is t-butyl. A dimethylsilyl group and THP represent a tetrahydropyranyl group. ]

In addition to this example, for example, the (4R, 5S) series is prepared by a similar production method using the compound (52) obtained in the above-mentioned scheme 2, and the (4S) series is obtained by using the following optically active ester compound (64) as a starting material. ) Can be synthesized by a similar production method.

[0054]

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[0055]

【Example】

Example 1 Methyl- (S) -3- (t-butyldiffee)
Nylsilyloxy) -2-methylpropionate (4
Synthesis of 7)

[0056]

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Under an argon atmosphere, methyl- (S) -3-
Hydroxy-2-methyl propionate (46) (1.
9 ml, 2.0 g, 16.9 mmol) was dissolved in 100 ml of dichloromethane, and imidazole (2.3 g, 3
2.5 mmol), TBDPSCl (4.3 ml, 1
6.9 mmol) and stirred for 5 minutes. H ₂ O was added and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off. The crude product was subjected to column chromatography (60 g, 2
% AcOEt-hexane) to give a colorless oil (4%).
7) (6.5 g, quant) was obtained. ¹ H NMR (400 MHz, CDCl ₃ / TMS)
δ: 1.04 (9H, s), 1.15 (3H, d, J
= 7.0 Hz), 2.72 (1H, dquin, J =
5.8, 7.0 Hz), 3.67 (3H, s),
3.73 (1H, dd, J = 6.4, 9.8 Hz),
3.83 (1H, dd, J = 9.8, 6.4 Hz),
7.35-7.44 (6H, m), 7.64-7.6
8 (4H, m) MS m / z 325 (M ^<+> -Me-Me), 299.
(M ⁺ -tBu)

Example 2 (R) -3- (t-butyldiphenylsilyloxy)-
Synthesis of 2-methylpropanol (48)

[0059]

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Under an argon atmosphere, methyl- (S) -3-
(T-Butyldiphenylsilyloxy) -2-methylpropionate (47) (1.0 g, 2.7 mmol) was dissolved in 50 ml of dry toluene, and the solution was dissolved in 1M DIBA at 0 ° C.
LH / hexane (5.7 ml, 5.7 mmol) was added, and the mixture was stirred for 15 minutes, returned to room temperature, and stirred for 45 minutes.
Ethyl acetate was added to the reaction solution to decompose excess DIBAL-H, and the reaction solution was extracted with 0.5N HCl. The ethyl acetate layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off. The crude product was purified by column chromatography (30 g, 4-10% AcOEt-hexane) to give (48) as a colorless oil (968 mg, quant).
I got ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.83 (3H, d, J = 7.0 Hz), 1.06
(9H, s), 1.99 (1H, dddddq, J =
4.6, 5.2, 6.2, 7.0 Hz), 2.58
(1H, bs), 3.60 (1H, dd, J = 7.
6, 10.1 Hz), 3.97 (2H, d, J = 6.
4Hz), 3.72 (1H, dd, J = 4.6, 1)
0.1Hz), 7.37-7.46 (6H, m),
7.67-7.69 (4H, m) MS m / z 328 (M ⁺ ), 271 (M ⁺ -tB
u)

Example 3 (S) -3- (t-butyldiphenylsilyloxy)-
Synthesis of 2-methylpropanal (49)

[0062]

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Under an argon atmosphere, (R) -3- (t-butyldiphenylsilyloxy) -2-methylpropanol (48) (725 mg, 2.2 mmol) was dissolved in 40 ml of dry dichloromethane, and MS-4A (0 ° C.) was dissolved at 0 ° C. 30m
g), NMO (862 mg, 11.1 mmol), TP
AP (cat) was added, and the mixture was stirred for 15 minutes, returned to room temperature, and stirred overnight. Next, H ₂ O was added, and the mixture was extracted with ethyl acetate. This was washed with a saturated sodium chloride solution in an ethyl acetate layer, dried over magnesium sulfate, and the solvent was distilled off. The crude product was purified by column chromatography (21 g, 4% AcOEt-hexane) to give colorless oil (49) (700 mg,
97%). ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
1.04 (9H, s), 1.10 (3H, d, J =
7.0 Hz), 2.56 (1H, ddddq, J =
1.3, 4.8, 6.1, 7.0 Hz), 3.87
(2H, ddd, J = 4.8, 6.1, 10.0H
z), 7.36-7.46 (6H, m), 7.63-
7.67 (4H, m), 9.77 (1H, d, J =
1.5 Hz) MS m / z 325 (M ⁺ -H), 269 (M ⁺ -t
Bu)

Example 4 (S) -4- (t-butyldiphenylsilyloxy)-
Synthesis of 3-methyl-1-butene (50)

[0065]

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Under an argon atmosphere, Ph ₃ P ⁺ CH ₃ Br
^- (2.2 g, 7.4 mmol) was suspended in 15 ml of THF, and butyllithium (5.2 ml, 9.3 mm) was added at 0 ° C.
ol) and stirred for 20 minutes. This is called (S) -3-
T of (t-butyldiphenylsilyloxy) -2-methylpropanal (49) (1.2 g, 3.7 mmol)
It was added to 15 ml of the HF solution at 0 ° C., stirred for 15 minutes, returned to room temperature, and stirred for 45 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off. The crude product was subjected to column chromatography (12
g, 2% AcOEt-hexane) to give (50) (1.1 g, 92%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
1.03 (3H, d, J = 7.0 Hz), 1.05
(9H, s), 2.39 (1H, ddq, J = 6.
0, 6.7, 7.0 Hz), 3.49 (1H, d
d, J = 6.7, 9.7 Hz), 3.57 (1H, d
d, J = 6.1, 9.7 Hz), 5.01 (3H,
m), 7.35-7.44 (6H, m), 7.65-
7.68 (4H, m), 9.77 (1H, d, J =
1.5 Hz) MS m / z 267 (M ⁺ -tBu)

Example 5 (3S) -4- (t-butyldiphenylsilyloxy)
Synthesis of -3-methyl-1-butene oxide (51)

[0068]

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Under an argon atmosphere (50) (1.0 g,
3.1 mmol) was dissolved in 25 ml of dry dichloromethane, mCPBA (1.4 g, 7.4 mmol) was added at 0 ° C., and the mixture was stirred for 15 minutes. This was returned to room temperature and further stirred overnight. H ₂ O was added and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution and dried over magnesium sulfate. The crude product was subjected to column chromatography (3
0 g, and purified by 2% Et ₂ O-hexane) to afford a colorless oil (51) (1.1g, quant) . ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.99 (3H, d, J = 6.8 Hz), 1.05
(5H, s), 1.07 (4H, s), 1.58 (1
H, dtq, J = 5.0, 6.7, 7.0 Hz),
2.57 (4 / 9H, m), 2.60 (8 / 9H, d)
d, J = 2.7, 5.0 Hz), 2.73 (4/9
H, dd, J = 4.3, 5.0 Hz), 2.76 (5
/ 9H, dd, J = 4.3, 5.0Hz), 2.85
(5 / 9H, ddd, J = 2.7, 4.3, 7.0H
z), 2.97 (4 / 9H, ddd, J = 2.7,
4.3, 7.0 Hz), 3.49 (1H, dd, J =
6.7, 9.7 Hz), 3.62 (1H, dd, J =
7.0, 9.7 Hz), 3.70 (1H, dd, J =
5.0, 9.7 Hz), 4.02 (3H, m),
7.39 (6H, m), 7.67 (4H, m) MS m / z 283 (M ⁺ -tBu)

Example 6 (2S, 3S) -1- (t-butyldiphenylsilylthio)
Xy) -2-methyl-6-trimethylsilyl-5-hex
Syn-3-ol (52) and (2S, 3R) -1-
(T-butyldiphenylsilyloxy) -2-methyl-
6-trimethylsilyl-5-hexyn-3-ol (5
Synthesis of 3)

[0071]

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Under an argon atmosphere, ethynyltrimethylsilane (780 ml, 5.0 mmol) was added to 40 ml of THF.
Butyllithium (4.5 ml, 5.0 ml) at 0 ° C.
mmol) and stirred for 20 minutes. This is -78 ° C
The compound (51) (1.7 g, 5.0 mmol)
l) in 40 ml of THF solution, and add BF ₃ .Et ₂ O
(9.5 ml, 5.0 mmol), and the mixture was stirred for 15 minutes. After returning to room temperature, the mixture was further stirred for 2 hours. To this was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The crude product was purified by column chromatography (51 g, 2% Et ₂ O-hexane) to give (52) (1.2 g, 52%), (5
3) (1.1 g, 49%) were obtained as colorless oils. (52) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.14 (9H, s), 1.00 (3H, d, J =
7.0Hz), 1.06 (9H, s), 1.92-
1.99 (1H, m), 2.42 (1H, dd, J =
7.0, 10.1 Hz), 2.50 (1H, dd, J
= 6.7, 10.1 Hz), 2.84 (1H, d, J)
= 3.1 Hz), 3.67 (1H, dd, J = 6.
4, 10.2 Hz), 3.75 (1H, dd, J =
4.2, 10.2 Hz), 3.79 (1H, dd, J
= 4.3, 10.4 Hz), 7.37-7.46 (6
H, m), 7.65-7.68 (4H, m) MS m / z 381 (M ⁺ -tBu), 269 (M ⁺
-Me-2Ph), 239 (M ⁺ -2Ph-3Me) (53) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.15 (9H, s), 0.91 (3H, d, J =
7.1 Hz), 1.07 (9H, s), 1.93-
1.99 (1H, m), 2.46 (1H, dd, J =
6.4, 10.6 Hz), 2.54 (1H, dd, J
= 6.4, 10.6 Hz), 2.84 (1H, d, J)
= 3.1 Hz), 3.67 (1H, dd, J = 6.
4, 10.4 Hz), 3.74-3.76 (1H,
m), 3.79 (1H, dd, J = 4.3, 10.4)
Hz), 7.37-7.46 (6H, m), 7.65
-7.68 (4H, m) MS m / z 423 (M ⁺ -Me), 365 (M ⁺ -
TMS), 308 (M ⁺ -TMS-tBu)

Example 7 Synthesis of MTPA Ester (Absolute Structure of Alcohol (X))
Determination) Under an argon atmosphere, each of the above alcohols was dissolved in dry dichloromethane, DMAP (2 equivalents), (R)-or (S) -MTPACl (2 equivalents) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly used in TLC (10% Ac
OEt-hexane) to give MTPA ester.

Compounds (52) to (54), (5
Synthesis of 5)

[0075]

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(54) (R) Yield: 30% (colorless oil) ¹ HNMR (400 MHz, CDCl ₃ / TMS) δ:
0.12 (9H, s), 0.80 (3H, d, J =
6.7 Hz), 1.06 (9H, s), 2.17 (1
H, q, J = 6.7 Hz), 2.68 (1H, t, J)
= 6.7 Hz), 3.41 (2H, dd, J = 3.
0, 10.3 Hz), 3.58 (3H, s), 5.4
6. (1H, dd, J = 6.1, 10.3 Hz);
28-7.46 (9H, m), 7.49-7.55
(2H, m), 7.61-7.65 (4H, m) (55) (S) Yield: 25% (colorless oil) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.12 (9H, s), 0.86 (3H, d, J =
7.0 Hz), 1.07 (9H, s), 2.28 (1
H, q, J = 6.1 Hz), 2.57 (1H, dd,
J = 5.8, 10.6 Hz), 2.71 (1H, d
d, J = 6.1, 10.6 Hz), 3.46 (3H,
s), 3.48 (2H, m), 5.49 (1H, d
d, J = 5.8, 9.8 Hz), 7.28-7.46
(9H, m), 7.49-7.56 (3H, m),
7.60-7.69 (4H, m) Synthesis of Compounds (56) and (57) from Compound (53)

[0077]

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(56) (R) Yield: 13% (colorless oil) ¹ HNMR (400 MHz, CDCl ₃ / TMS) δ:
0.07 (9H, s), 0.95 (3H, d, J =
7.0 Hz), 1.05 (9H, s), 2.26 (1
H, q, J = 6.7 Hz), 2.55 (1H, dd,
J = 6.1, 11.6 Hz), 2.75 (1H, d
d, J = 5.2, 11.6 Hz), 3.42 (3H,
s), 3.56 (1H, dd, J = 5.8, 10.7
Hz), 3.64 (1H, dd, J = 6.5, 10.
7 Hz), 5.27 (1H, dd, J = 5.8, 1
1.6Hz), 7.28-7.45 (9H, m),
7.50-7.56 (2H, m), 7.59-7.6
5 (4H, m) (57) (S) Yield: 17% (colorless oil) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.11 (9H, s), 0.82 (3H, d, J =
7.0 Hz), 1.05 (9H, s), 2.19 (1
H, q, J = 6.1 Hz), 2.58 (1H, dd,
J = 6.7, 11.0 Hz), 2.75 (1H, d
d, J = 6.7, 11.0 Hz), 3.49 (1H,
dd, J = 5.4, 10.3 Hz), 3.54 (1
H, dd, J = 5.8, 10.3 Hz), 3.57
(3H, s), 5.32 (1H, dd, J = 6.7,
10.3 Hz), 7.28-7.45 (9H, m),
7.59-7.54 (2H, m), 7.59-7.6
5 (4H, m)

Example 8 (4R, 5S) -6- (t-butyldiphenylsilylthio)
Xy) -5 methyl-4-tetrahydropyranyloxy-
Synthesis of 1-trimethylsilyl-1-hexyne (58)

[0080]

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Alcohol (53) (1.07 g, 2.5
0 mmol) in a dichloromethane solution (10 ml).
P (0.34 ml, 3.75 mmol, 1.05 equivalent)
And TsOH (72 mg, 0.375 mmol, 0.15
Equivalent) and left at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off.
The obtained crude product was purified by silica gel column chromatography (100 g, 1% AcOEt-hexane) to obtain colorless oil (58) (1.26 g, 98%). ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.127 (9 / 2H, s), 0.135 (9/2
H, s), 0.95 (3H, d, J = 7.0 Hz),
1.058 (9 / 2H, s), 1.061 (9/2
H, s), 1.41-1.62 (4H, m), 1.6.
9-1.81 (2H, m), 2.09-2.17 (1
H, m), 2.38 (1 / 2H, dd, J = 7.3,
17.1 Hz), 2.46 (1 / 2H, dd, J =
4.6, 17.1 Hz), 2.54 (1 / 2H, d
d, J = 5.5, 17.1 Hz), 2.66 (1/2)
H, dd, J = 5.8, 17.1 Hz), 3.38−
3.49 (1H, m), 3.58-3.71 (2H,
m), 3.75-3.81 (1H, m), 3.88-
3.91 (1 / 2H, m), 3.92-4.06 (1
/ 2H, m), 4.66 (1 / 2H, dd, J = 3.
1, 3.4 Hz), 4.86 (1 / 2H, dd, J =
2.7, 4.3 Hz), 7.35-7.44 (6H,
m), 7.65-7.70 (4H, m)

Example 9 (2S, 3R) -2-methyl-3-tetrahydropyrani
Synthesis of Luoxy-5-hexyn-1-ol (59)

[0083]

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Compound (58) (1.13 g, 2.20 m)
mol) in a THF solution (20 ml) in 1M nBu ₄ NF.
/ THF (8.8 ml, 8.80 mmol, 4 equivalents) was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The resulting crude product was subjected to silica gel column chromatography (35 g, 20 g).
% AcOEt-hexane) to give a colorless oil (5%).
9) (450 mg, 96%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.99 (3 / 2H, d, J = 6.7 Hz), 1.0
1 (3 / 2H, d, J = 7.0 Hz), 1.41-
1.89 (6H + 1 / 2H, m), 1.99 (1/2)
H, t, J = 2.7 Hz), 2.00 (1 / 2H,
t, J = 2.7 Hz), 2.13 to 2.19 (1/2)
H, m), 2.33 (1 / 2H, bs), 2.38
(1 / 2H, ddd, J = 2.4, 6.1, 17.1)
Hz), 2.57 (1 / 2H, ddd, J = 2.4,
4.0, 17.1 Hz), 2.63 (1 / 2H, dd)
d, J = 2.8, 4.0, 17.1 Hz), 2.7
2 (1 / 2H, ddd, J = 2.8, 7.0, 17.
1Hz), 3.30-3.31 (1 / 2H, m),
3.41-3.56 (3 / 2H, m), 3.60-
3.81 (2H, m), 3.95-4.01 (3/2
H, m), 4.69-4.71 (1H, m)

Example 10 (4R, 5R) -3-Hydroxy-4-methyl-5-te
Tiger Synthesis of tetrahydropyranyl-1-oct emissions 7--in (61)

[0086]

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DMSO (0.92 ml, 12.5 mmol
Oxalyl chloride (0.56 ml, 6.30 mmol, 3 equivalents) was added to a dichloromethane solution (4 ml) of 1,6 equivalents), and the mixture was stirred at -78 ° C for 1 hour under an argon atmosphere. Compound (59) (440 mg,
2.08 mmol) in dichloromethane solution (10 ml)
Was added at −78 ° C. and stirred for 30 minutes, and then Et ₃ N (3.2 m) was added.
1, 24 mmol, 12 equivalents) and stirred at -78 to 0 ° C for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The crude product was filtered through a small amount of silica gel, and the solvent was distilled off to obtain aldehyde (60) as a colorless oil. This product was used for the next reaction without further purification.

Aldehyde (60) (426 mg, 2.0
2 mmol) in THF (10 ml) at 0 ° C. at 1M
Vinylmagnesium bromide / THF (4.0 ml,
4.00 mmol, 2 equivalents) and stirred at 0 ° C. for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (55 g, 20% AcOEt-hexane) to obtain a colorless oily allyl alcohol (61).
(329 mg, 68%). ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.85 (3 / 4H, d, J = 7.0 Hz), 0.8
8 (3 / 4H, d, J = 7.3 Hz), 0.90 (3
/ 4H, d, J = 7.0 Hz), 0.93 (3/4
H, d, J = 7.0 Hz), 1.47-1.87 (6
H, m), 1.98-2.05 (1H, m), 2.1
5-2.19 (1H, m), 2.37-1.89 (2
H, m), 3.37-4.15 (4.5H, m),
4.51-4.84 (1.5H, m), 5.13-
5.35 (2H, m), 5.83-5.94 (1H,
m)

Example 11 (3R, 4R, 5R) -3,5-dihydroxy-4-meth
Cyl-1-octen-7-yne (22) and (3S,
4R, 5R) -3,5-dihydroxy-4-methyl-1
Synthesis of octen-7-yne (23)

[0090]

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Allyl alcohol (61) (315 mg,
1.32 mmol) in 10 ml of methanol solution
H (25 mg, 0.13 mmol, 0.1 eq) was added and left at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with Et ₂ O. Wash the extract with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off. The obtained crude product is subjected to silica gel column chromatography (55
g, 10% AcOEt-hexane) to give a colorless oily en-yne compound (22) (79 mg, 39%),
(23) (75 mg, 37%) was obtained. (22) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.90 (3H, d, J = 7.0 Hz), 1.95
(1H, dquin, J = 2.8, 7.0 Hz),
2.08 (1H, t, J = 2.8 Hz), 2.43
(1H, ddd, J = 2.8, 7.0, 17.1H
z), 2.54 (1H, ddd, J = 2.8, 4.
6, 17.1 Hz), 2.72 (1H, d, J = 5.
5 Hz), 2.96 (1H, d, J = 4.6 Hz),
3.79 (1H, tt, J = 4.6, 7.0 Hz),
4.44 (1H, dtt, J = 7.0, 1.5, 5.
5Hz), 5.23 (1H, dt, J = 10.7,
1.5Hz), 5.32 (1H, dt, J = 17.1,
1.5 Hz), 5.94 (1H, ddd, J = 5.
5, 10.7, 17.1 Hz) (23) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.83 (3H, d, J = 7.0 Hz), 1.83
(1H, dquin, J = 7.0, 7.9 Hz),
2.07 (1H, t, J = 2.8 Hz), 2.41
(1H, ddd, J = 2.8, 6.7, 16.8H
z), 2.58 (1H, ddd, J = 2.8, 4.
0, 16.8 Hz), 2.88 (1H, bs), 3.
41 (1H, bs), 3.74 (1H, m), 4.1
4 (1H, tt, J = 1.2, 7.3 Hz), 5.1
4. 9 (1H, dt, J = 10.4, 1.2 Hz);
27 (1H, dt, J = 17.1, 1.2 Hz),
5.88 (1H, ddd, J = 7.3, 10.4, 1
7.1 Hz)

Example 12 (3R, 4R, 5R) -3,5-di (t-butyl dimethyl)
Lucylyloxy) -4-methyl-1-octene-7-i
Synthesis of (38)

[0093]

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Compound (22) (58 mg, 0.376 m
mol) in dichloromethane solution (5 ml), 2,6-lutidine (0.18 ml, 1.5 mmol, 4 equiv.) followed by TBSOTf (0.34 ml, 1.5 mmol, 4 equivalents).
Was added and stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (10 g, 2% AcOEt-hexane).
A colorless oil (38) (141 mg, 98%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.01 (3H, s), 0.5 (3H, s), 0.0
7 (3H, s), 0.11 (3H, s), 0.89
(9H, s), 0.90 (9H, s), 0.90 (3
H, d, J = 7.0 Hz), 1.78 (1H, dqu)
in, J = 4.9, 7.0 Hz), 1.93 (1H,
t, J = 2.8 Hz), 2.26 (1H, ddd, J)
= 2.8, 7.0, 16.8 Hz), 2.40 (1
H, ddd, J = 2.8, 4.3, 16.8 Hz),
3.86 (1H, dtJ = 7.0, 4.3 Hz),
4.11 (1H, ddt, J = 5.8, 7.3, 1.
8 Hz), 5.09 (1H, dt, J = 10.1,
1.8 Hz), 5.14 (1H, dt, J = 17.
4, 1.8 Hz), 5.84 (1H, ddd, J =
7.3, 10.1, 17.4 Hz)

Example 13 Synthesis of acetonide (absolute configuration of ene-yne compound (III)
Determination of the position) The above ene-yne compound (5 mg) was dissolved in acetone (0.4 ml), dimethoxypropane (0.1 ml) and CSA (1.5 mg, 0.2 equivalent) were added, and the mixture was allowed to stand at room temperature for 5 hours. The solvent was distilled off, and the obtained crude product was subjected to silica gel column chromatography (6 g, 5% AcOEt-
Hexane) to give acetonide.

Synthesis of Compound (62) from Compound (22)

[0097]

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Yield: 80% (colorless oil) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.90 (3H, d, J = 7.0 Hz), 1.39
(3H, s), 1.40 (3H, s), 1.86-
1.92 (1H, m), 2.01 (1H, t, J =
2.8 Hz), 2.44 (1H, ddd, J = 2.
8, 6.1, 17.4 Hz), 2.48 (1H, d
dd, J = 2.8, 5.5, 17.4 Hz);
3. 49 (1H, dt, J = 7.6, 5.8 Hz);
43 (1H, ddt, J = 6.1, 5.2, 1.5H
z), 5.17 (1H, dt, J = 10.7, 1.2
Hz), 5.26 (1H, dt, J = 17.4, 1.
2 Hz), 5.79 (1H, ddd, J = 6.1, 1
0.7, 17.4 Hz) ¹³ C NMR (100 MHz, CDCl ₃ / TMS) δ:
12.89 (q), 24.10 (q), 25.24
(Q), 29.70 (t), 39.76 (d), 6
9.66 (s), 70.61 (d), 73.02
(D), 80.96 (d), 100.88 (s),
115.77 (t), 135.59 (t) Synthesis of compound (63) from compound (23)

[0099]

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Yield: 80% (colorless oil) ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.82 (3H, d, J = 6.7 Hz), 1.45
(3H, s), 1.49 (3H, s), 1.51-
1.61 (1H, m), 2.01 (1H, t, J =
2.7 Hz), 2.42 (1H, ddd, J = 2.
7, 5.5, 17.4 Hz), 2.52 (1H, d
dd, J = 2.7, 4.0, 17.4 Hz);
68 (1H, ddd, J = 4.0, 5.8, 10.1)
Hz), 3.91 (1H, ddt, J = 7.3, 1
0.1, 1.5 Hz), 5.24 (1H, dd, J =
1.5, 7.3 Hz), 5.29 (1H, dd, J =
1.5, 17.4 Hz), 5.76 (1H, ddd,
J = 7.3, 10.1, 17.4 Hz) ¹³ C NMR (100 MHz, CDCl ₃ / TMS)
δ: 12.15 (q), 19.71 (q), 29.7
0 (t), 30.04 (q), 39.76 (d),
69.66 (s), 70.61 (d), 73.02
(D), 80.96 (d), 100.88 (s),
115.77 (t), 135.59 (t)

The following en-yne compounds were synthesized by using a suitable raw material and applying the same production method.

Example 14 (3S, 4R, 5R) -3,5-bis (t-butyldimethyl)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (39)

[0103]

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¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.02 (3H, s), 0.057 (3
H, s), 0.063 (3H, s), 0.11 (3
H, s), 0.78 (3H, d, J = 7.0 Hz),
0.86 (9H, s), 0.90 (9H, s),
89 (1H, dquin, J = 5.5, 7.0H
z), 1.93 (1H, t, J = 2.8 Hz), 2.
26 (1H, ddd, J = 2.8, 7.0, 16.8
Hz), 2.39 (1H, ddd, J = 2.8, 4.
0, 16.8 Hz), 3.97 (1H, ddd, J =
4.0, 5.2, 6.7 Hz), 4.12 (1H,
ddt, J = 6.4, 6.7, 1.2 Hz), 5.0
4. 9 (1H, dt, J = 10.4, 1.2 Hz);
16 (1H, dt, J = 17.1, 1.2 Hz),
5.75 (1H, ddd, J = 6.1, 10.4, 1
7.1 Hz) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Example 15 (3R, 4R, 5S) -3,5-bis (t-butyldimethyl)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (40)

[0106]

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¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.01 (3H, s), 0.049 (3
H, s), 0.051 (3H, s), 0.08 (3
H, s), 0.89 (18H, s), 0.92 (3
H, d, J = 7.0 Hz), 1.86 (1H, dqu)
in, J = 4.0, 6.7 Hz), 1.95 (1H,
t, J = 2.8 Hz), 2.38 (2H, dd, J =
2.7, 5.8 Hz), 3.88 (1H, ddd, J)
= 4.0, 6.1, 6.4 Hz), 4.09 (1
H, t, 7.0), 5.10 (1H, dt, J = 1)
0.4, 1.5 Hz), 5.14 (1H, dt, J =
17.4, 1.5 Hz), 5.81 (1H, ddd,
J = 7.0, 10.4, 17.4) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Example 16 ( 3S, 4R, 5S) -3,5-bis (t-butyldimethyl)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (41)

[0109]

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¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.03 (3H, s), 0.06 (3
H, s), 0.07 (3H, s), 0.08 (3H,
s), 0.76 (3H, d, J = 7.0 Hz), 0.
889 (9H, s), 0.892 (9H, s),
91 (1H, dquin, J = 3.7, 7.0H
z), 1.97 (1H, t, J = 2.8 Hz), 2.
36-2.40 (2H, m), 3.99-4.05
(2H, m), 5.09 (1H, dt, J = 10.
4, 0.9 Hz), 5.13 (1H, dt, J = 1)
7.1, 0.9 Hz), 5.73 (1H, ddd, J
= 7.6, 10.1, 17.1 Hz) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Example 17 (3R, 4S, 5R) -3,5-bis (t-butyldimene)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (42)

[0112]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.03 (3H, s), 0.06 (3
H, s), 0.07 (3H, s), 0.08 (3H,
s), 0.76 (3H, d, J = 7.0 Hz), 0.
889 (9H, s), 0.891 (9H, s),
91 (1H, dquin, J = 3.7, 7.0H
z), 1.97 (1H, t, J = 2.8 Hz), 2.
31-2.43 (2H, m), 3.98-4.04
(2H, m), 5.10 (1H, dt, J = 10.
1, 1.5 Hz), 5.13 (1H, dt, J = 1
7.1, 1.5 Hz), 5.74 (1H, ddd, J
= 7.6, 10.1, 17.1 Hz) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Example 18 (3S, 4S, 5R) -3,5-bis (t-butyldimene)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (43)

[0115]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.01 (3H, s), 0.049 (3
H, s), 0.051 (3H, s), 0.08 (3
H, s), 0.89 (18H, s), 0.92 (3
H, d, J = 7.0 Hz), 1.85 (1H, dqu)
in, J = 3.7, 6.7 Hz), 1.96 (1H,
t, J = 2.8 Hz), 2.39 (2H, dd, J =
2.8, 6.7 Hz), 3.88 (1H, ddd, J)
= 4.0, 6.1, 6.4 Hz), 4.07 (1
H, t, J = 6.7 Hz), 5.10 (1H, dt,
J = 10.1, 1.8 Hz), 5.14 (1H, d
t, J = 18.3, 1.8 Hz), 5.81 (1H,
ddd, J = 7.0, 10.4, 17.4 Hz) MS m / z 367 (M ⁺ -Me), 325 (M ⁺ -
tBu)

Example 19 (3R, 4S, 5S) -3,5-bis (t-butyldimene)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (44)

[0118]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.01 (3H, s), 0.057 (3
H, s), 0.063 (3H, s), 0.11 (3
H, s), 0.78 (3H, d, J = 7.0 Hz),
0.86 (9H, s), 0.90 (9H, s),
88 (1H, dquin, J = 5.5, 6.7H
z), 1.93 (1H, t, J = 2.8 Hz), 2.
26 (1H, ddd, J = 2.8, 7.0, 16.8
Hz), 2.39 (1H, ddd, J = 2.8, 4.
0, 16.8 Hz), 3.97 (1H, dt, J =
4.0, 5.5 Hz), 4.12 (1H, ddt, J
= 5.2, 6.7, 1.2 Hz), 5.09 (1
H, dt, J = 10.4, 1.2 Hz), 5.15
(1H, dt, J = 17.1, 1.2 Hz), 5.7
5 (1H, ddd, J = 6.7, 10.4, 17.4)
Hz) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Example 20 (3S, 4S, 5S) -3,5-bis (t-butyldimethyl)
Tylsilyloxy) -4-methyl-1-octene-7-
Inn (45)

[0121]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.01 (3H, s), 0.05 (3
H, s), 0.07 (3H, s), 0.10 (3H,
s), 0.88 (3H, d, J = 7.0 Hz), 0.
89 (9H, s), 0.90 (9H, s), 1.76
-1.80 (1H, m), 1.93 (1H, t, J =
2.8 Hz), 2.26 (1H, ddd, J = 2.
7, 7.0, 16.8 Hz), 2.40 (1H, dd)
d, J = 2.7, 4.3, 16.8 Hz), 3.85
(1H, dt, J = 7.0, 4.3 Hz), 4.11
(1H, ddt, J = 5.8, 7.3, 1.8H
z), 5.10 (1H, dt, J = 10.1, 1.8
Hz), 5.14 (1H, dt, J = 17.4, 1.
8 Hz), 5.84 (1H, ddd, J = 7.3, 1
0.1, 17.4 Hz) MS m / z 382 (M ⁺ ), 367 (M ⁺ -Me),
325 (M ⁺ -tBu)

Reference Example 1 1α, 25-dihydroxy-2β-methyl-3β-vita
Synthesis of Min D ₃ (65)

[0124]

Embedded image

Exomethylene compound (66) (44 m
g) and 3 ml of a toluene solution of the ene-yne compound (38) (61 mg, 1.5 equivalents) in Pd ₂ (dba) ₃ . CHC
l ₃ (13mg, 0.1 equiv), PPh ₃ (30mg, 1
Eq.) And Et ₃ N (1.5 ml) were added, and the mixture was stirred at room temperature for 10 minutes and then reacted at 120 ° C. for 6 hours. After cooling, the reaction mixture was poured into water and extracted with Et ₂ O. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel chromatography (10% AcOEt-hexane) to obtain compound (67).

The obtained compound (67) was treated with methanol 3m
, and added CSA (28 mg, 1 equivalent), and reacted at room temperature for 16 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate,
and extracted with t ₂ O. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude product is subjected to silica gel chromatography (10 g, 50% Ac
OEt-hexane).
PLC (Lichrosorb RP-18, 70%
(MeCN / H ₂ O) to give a white solid (65) (20
mg, 41%). ¹ H NMR (400 MHz, CDCl ₃ / TMS) δ:
0.55 (3H, s), 0.94 (3H, d, J =
6.3 Hz), 1.15 (3H, d, J = 7.0H)
z), 1.22 (6H, s), 2.42 (1H, d
d, J = 4.9, 14.0 Hz), 2.52 (1H,
d, J = 14.0 Hz), 2.82 (1H, dd, J =
3.7, 11.9 Hz), 3.99-4.04 (2
H, m), 5.02 (1H, t, J = 1.8 Hz),
5.37 (1H, t, J = 1.8 Hz), 6.03
(1H, d, J = 11.6 Hz), 6.35 (1H,
d, J = 11.6Hz) UV ( EtOH) λmax 263nm MS m / z 430 (M +), 412 (M + -H 2 O) 394 (M + -2H 2 O), 376 (M + -3H 2 O) By using the same reaction conditions as in Reference Example 1,
It was prepared 25-dihydroxy-2-methyl-vitamin D ₃ derivatives.

Example 21 1β, 25-dihydroxy-2β-methyl-3β-bita
Min D ₃ (1)

[0128]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.56 (3H, s), 0.94 (3
H, d, J = 6.2 Hz), 1.22 (6H, s),
1.24 (3H, d, J = 7.0 Hz), 2.49
(1H, d, J = 14.0 Hz), 2.57 (1H,
dd, J = 3.4, 14.0 Hz), 2.85 (1
H, dd, J = 7.2, 14.0 Hz), 3.91
(1H, m), 4.17 (1H, bs), 5.01
(1H, d, J = 2.1 Hz), 5.25 (1H,
d, J = 2.1 Hz), 6.01 (1H, d, J = 1)
1.3 Hz), 6.48 (1H, d, J = 11.3H)
z) UV (EtOH) λmax 264nm MS m / z 430 (M +), 412 (M + -H 2 O) 394 (M + -2H 2 O), 376 (M + -3H 2 O)

Example 22 1α, 25-dihydroxy-2β-methyl-3α-bita
Min D ₃ (2)

[0131]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.54 (3H, s), 0.94 (3
H, d, J = 6.4 Hz), 1.06 (3H, d, J
= 7.0 Hz), 1.22 (6H, s), 2.34
(1H, dd, J = 6.4, 13.7 Hz), 2.6
4 (1H, dd, J = 3.7, 13.7 Hz);
83 (1H, dd, J = 4.0, 12.2 Hz),
3.65 (1H, quin, J = 6.1 Hz);
90 (1H, t, J = 5.5 Hz), 5.05 (1
H, d, J = 1.2 Hz), 5.30 (1H, d, J)
= 1.2 Hz), 6.02 (1H, d, J = 11.3)
Hz), 6.41 (1H, d, J = 11.3 Hz) UV (EtOH) λmax 261 nm MS m / z 430 (M ⁺ ), 412 (M ⁺ -H ₂ O) 394 (M ⁺ -2H ₂ O) _{^{), 376 (M + -3H 2}} O)

Example 23 1β, 25-dihydroxy-2β-methyl-3α-vita
Min D ₃ (3)

[0134]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.54 (3H, s), 0.94 (3
H, d, J = 6.4 Hz), 1.10 (3H, d, J)
= 7.2 Hz), 1.22 (6H, s), 2.24
(1H, dd, J = 8.9, 13.3 Hz), 2.6
6 (1H, dd, J = 4.4, 13.3 Hz);
82 (1H, dd, J = 4.1, 13.1 Hz),
3.82 (1H, dq, J = 8.5, 4.3 Hz),
4.27 (1H, bs), 5.01 (1H, d, J =
1.7Hz), 5.28 (1H, d, J = 1.7H)
z), 6.01 (1H, d, J = 11.3 Hz),
6.40 (1H, d, J = 11.3 Hz) UV (EtOH) λmax 265 nm MS m / z 430 (M ⁺ ), 412 (M ⁺ -H ₂ O) 394 (M ⁺ -2H ₂ O), 376 (M ⁺ -3H ₂ O)

Example 24 1α, 25-dihydroxy-2α-methyl-3β-bita
Min D ₃ (4)

[0137]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.53 (3H, s), 0.93 (3
H, d, J = 6.4 Hz), 1.08 (3H, d, J
= 6.7 Hz), 1.22 (6H, s), 2.23
(1H, dd, J = 7.6, 13.4 Hz), 2.6
7 (1H, dd, J = 4.0, 13.4 Hz);
82 (1H, dd, J = 4.0, 12.5 Hz),
3.84 (1H, bs), 4.30 (1H, bs),
5.01 (1H, d, J = 1.4 Hz), 5.28
(1H, d, J = 1.4 Hz), 6.01 (1H,
d, J = 11.3 Hz), 6.39 (1H, d, J =
11.3Hz) UV (EtOH) λmax 265nm MS m / z 430 (M +), 412 (M + -H 2 O) 394 (M + -2H 2 O), 376 (M + -3H 2 O) 376 ( M ⁺ -3H ₂ O-Me)

Example 25 1β, 25-dihydroxy-2α-methyl-3β-bita
Min D ₃ (5)

[0140]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.55 (3H, s), 0.94 (3
H, d, J = 6.4 Hz), 1.02 (3H, d, J
= 7.0 Hz), 1.22 (6H, s), 2.36
(1H, dd, J = 5.5, 14.1 Hz), 2.6
5 (1H, dd, J = 2.8, 14.1 Hz);
83 (1H, dd, J = 4.3, 12.5 Hz),
3.72 (1H, bs), 3.97 (1H, d, J =
3.0 Hz), 5.07 (1H, d, J = 1.8H)
z), 5.30 (1H, d, J = 1.8 Hz), 6.
05 (1H, d, J = 11.3 Hz), 6.43 (1
H, d, J = 11.3 Hz) UV (EtOH) λmax
262nm MS m / z 430 (M +), 412 (M + -H 2 O) 394 (M + -2H 2 O), 376 (M + -3H 2 O) 361 (M + -3H 2 O-Me) HR-MS m / z 430.3447 calcd
for C ₂₈ H ₄₆ O ₃ 430.3447

Example 26 1α, 25-dihydroxy-2α-methyl-3α-bita
Min D ₃ (6)

[0143]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.54 (3H, s), 0.93 (3
H, d, J = 6.4 Hz), 1.22 (6H, s),
1.24 (3H, d, J = 7.0 Hz), 2.50
(1H, d, J = 14.2 Hz), 2.56 (1H,
dd, J = 3.7, 14.2 Hz), 2.85 (1
H, dd, J = 3.4, 12.2 Hz), 3.90 −
3.93 (1H, m), 4.17 (1H, bs),
4.98 (1H, d, J = 1.8 Hz), 5.23
(1H, d, J = 1.8 Hz), 6.03 (1H,
d, J = 11.6 Hz), 6.48 (1H, d, J =
11.6Hz) UV (EtOH) λmax 265nm MS m / z 430 (M +), 412 (M + -H 2 O) 394 (M + -2H 2 O), 376 (M + -3H 2 O)

Example 27 1β, 25-dihydroxy-2α-methyl-3α-bita
Min D ₃ (7)

[0146]

Embedded image

¹ H NMR (400 MHz, CDCl ₃ / T
MS) δ: 0.54 (3H, s), 0.93 (3
H, d, J = 6.4 Hz), 1.12 (3H, d, J)
= 6.7 Hz), 1.22 (6H, s), 2.42
(1H, dd, J = 5.5, 13.7 Hz), 2.5
2 (1H, dd, J = 2.8, 13.7 Hz);
82 (1H, dd, J = 2.4, 12.2 Hz),
4.03-4.08 (2H, m), 5.01 (1H,
t, J = 1.8 Hz), 5.35 (1H, t, J =
1.8 Hz), 6.01 (1H, d, J = 11.3H)
z), 6.36 (1H, d, J = 11.3 Hz) UV (EtOH) λmax 264 nm MS m / z 430 (M ⁺ ), 412 (M ⁺ -H ₂ O) 394 (M ⁺ -2H ₂ O) )

[Example 28] Bovine thymus 1α, 25-dihydroxyvitamin D ₃ receptor
Affinity of the Compound of the Present Invention for VDR (Bottle Thymus Vitamin D Receptor Kit 1 ampoule (about 25 mg) manufactured by Yamasa Shoyu Co., Ltd.) in 0.05M phosphoric acid.
It was dissolved in 55 ml of a 5M potassium buffer (pH 7.4). After pre-incubating 50 μl of an ethanol solution of the test compound and 500 μl of the receptor solution for 1 hour at room temperature, 50 μl of [26,27-methyl- ³ H] 1α, 25-dihydroxyvitamin D ₃ solution (131 Ci / mmo)
l, 16,000 dpm) to a final concentration of 0.1 nM and incubated overnight at 4 ° C. Binding and non-binding of [26,27- methyl - ³ H] 1α, 25- dihydroxyvitamin D ₃ is dextran 200 [mu] l - Kotedo - adding charcoal was centrifuged, liquid scintillation cocktail (ACS-I in 500μl of supernatant
I) 9.5 ml was added, and the radioactivity was measured with a liquid scintillation counter.

[0149] The binding affinity for the D ₃ receptor of the test compound (VDR) is [26,27- methyl - ³ H] 1
The concentration that inhibits the binding of α, 25-dihydroxyvitamin D ₃ by 50% was determined and expressed as a relative intensity ratio when 1α, 25-dihydroxyvitamin D ₃ was taken as 100. Table 1 shows the results.

[0150]

[Table 1]

[Example 29] The effect of the compound of the present invention on the differentiation inducing action of HL-60 cells
The effect of HL-60 cells is a cell bank (Japanese Cancer Research Resource Bank, cell number: JCB0).
085). The cells were used as cryopreserved stocks to prevent changes in cell characteristics due to subculture, and thawed before the start of the experiment to start subculture. For the experiment, a passage from one month to half a year was used. For the subculture, cells in a suspension culture are collected by centrifugation and added to a fresh culture solution at about 1/100 (1-2 × 10 ⁻⁵ cells
/ Ml). RPMI-1640 medium containing 10% fetal calf serum was used as a culture solution. The subcultured cells are collected by centrifugation and added to the culture solution.
The cells were dispersed in x10 ⁴ cells / ml and seeded at 1 ml / well in a 24-well culture dish. In this system, an ethanol solution of the compound of the present invention (1 × 10 ⁻⁷ M to 1 × 10 ^7
-4 M) was added at 1 ml per well. As a control, ethanol was added at 1 ml per well. 37
After culturing at 5 ° C. under 5% CO ₂ for 4 days, the cells were collected by centrifugation. The measurement of nitro blue tetrazolium (hereinafter NBT) reducing activity was carried out according to the following procedure. That is, after the cells collected by centrifugation are suspended in a fresh culture solution, NBT
0.1%, 12-O-tetradecanoylphorbol-
13-acetate (TPO) was added to 100 nM and incubated at 37 ° C. for 25 minutes.
A cytospin specimen was prepared. After air-drying, the cells were stained with Kernetchroth, and the ratio of NBT-reducing activity-positive cells was determined under an optical microscope. Table 2 shows the results.

[0152]

[Table 2]

[0153]

The 1,25-dihydroxy-2-methylvitamin D ₃ derivative represented by the above formula (I) provided by the present invention has a stereoisomer derived from the 1-, 2- and 3-positions. Depending on the body type, some isomers have high affinity for vitamin D receptor and also have high affinity for vitamin D binding protein, and some isomers have high affinity for vitamin D receptor and vitamin D binding protein. It shows a difference in affinity for both proteins, such as low affinity, and can be used as a therapeutic drug for vitamin D metabolism disorder suitable for each action characteristic.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // A61K 31/59 A61K 31/59 C07B 61/00 300 C07B 61/00 300

Claims (4)

[Claims] 1. A compound of the general formula (I) [Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a tri (C ₁ -C ₇ alkyl) silyl group. here,
The configuration of the asymmetric carbon at the 1-, 2-, and 3-positions is independently α-configuration or β-configuration (provided that the 1-position is α-configuration and the 2-position is β-configuration). And the stereoisomer where the 3-position is β-coordinate is excluded). 1, 2
5-dihydroxy-2-methyl-vitamin D ₃ derivatives. 2. A compound of the general formula (II) [In the formula, X represents a bromine atom or an iodine atom. And an exomethylene compound represented by the general formula (III): [Wherein, R ₃ and R ₄ each independently represent a hydrogen atom or a tri (C ₁ -C ₇ hydrocarbon) silyl group. Wherein the tri (C ₁ -C ₇ hydrocarbon) silyl group is deprotected, if necessary, with an ene-yne compound represented by the following formula: A method for producing the vitamin D ₃ derivative according to the above. 3. A compound of the general formula (III) [Wherein, R ₃ and R ₄ each independently represent a hydrogen atom or a tri (C ₁ -C ₇ hydrocarbon) silyl group. here,
The configurations for the asymmetric carbons at the 3-, 4-, and 5-positions are each independently an R configuration or an S configuration. And an ene-yne compound represented by the formula: 4. The following reaction formula: [In the formula, R ₁₁ represents a tri (C ₁ -C ₇ alkyl) silyl group or a (C ₁ -C ₇ alkyl) di (C ₆ -C ₁₀ aryl) silyl group, and R ₁₂ is an acetal together with a bonding oxygen atom. And TMS represents a trimethylsilyl group. ] The method of producing an ene-yne compound represented by the above formula (III) optically pure by the route shown in the above [1].