JP3410492B2 - 7-Octin-1-ene derivative and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 7-octyne-1
An ene derivative and a method for producing the same. The 7-octyne-1-ene derivative provided by the present invention is said to be effective for the treatment of defective calcium metabolism such as chronic renal failure, hypoparathyroidism, osteomalacia, and osteoporosis.
-Hydroxyvitamin D ₃ , 1α, 25-dihydroxyvitamin D ₃ , 1α-hydroxyvitamin D ₂ , 2
4-epi-1α, 25-dihydroxyvitamin D ₂ ,
For the treatment of 1α-hydroxyvitamin D derivatives such as 2β- (3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D ₃ and skin diseases such as psoriasis and diseases with abnormal cell differentiation functions such as myeloid leukemia 1α, 24-dihydroxyvitamin D expected to be effective
_3, 22-oxa-1 alpha, 25-dihydroxyvitamin _D 3, 22-dehydro-26,27-cyclo -1
It is useful as a synthetic intermediate for 1α-hydroxyvitamin D derivatives such as α, 24-dihydroxyvitamin D ₃ .

[0002]

2. Description of the Related Art In recent years, with the progress of research on vitamin D, many 1α-hydroxyvitamin D derivatives, including the above 1α-hydroxyvitamin D derivative, have been developed as pharmaceuticals. Convergent synthetic methods are useful not only for producing derivatives, but also for synthesizing metabolites, degradation products or labeled compounds necessary for developing them as pharmaceuticals.

The A-ring constituents of the 1α-hydroxyvitamin D derivative were synthesized and the CD-ring constituents (CD-ring synthesis) were synthesized.
As a method for synthesizing a convergent 1α-hydroxyvitamin D derivative to be bound with s), for example, (S)-
Method using (+)-carvone as a raw material (Journal of Organic Chemistry)
Organic Chemistry), Volume 54,
Pp. 3098 (1986)), (R)-(-)-
Method of using carvone as a raw material (Journal of Organic Chemistry)
anic Chemistry), Volume 54, Volume 351
P. 5 (1986)), using cyclohexene dicarboxylic acid ester (Tetrahedron Letters, No. 31).
Vol., P. 1577 (1990)) and the like.

Further, as a method for synthesizing the A ring constituent part, 5
-A method for synthesizing hexyne-1-ol via iodoalkene (Tetrahedrone Letters)
dron Letters), Vol. 33, p. 4365 (1992)).

[0005]

However, these methods for synthesizing the ring A constituents have drawbacks such as high cost of starting materials and long reaction steps to the key intermediate, and moreover, cyclohexyl. Since the steric structure of the den moiety cannot be controlled, it was necessary to isomerize to the Z-form using a photoreaction, which is not always satisfactory in industrial practice. Moreover, all of the methods described in the above-mentioned documents relate to the synthesis of 1α-hydroxyvitamin D derivatives having no substituent at the 2-position, and conventionally, 2β-
1 having a substituent at the 2-position such as (3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D ₃
A adaptable to the synthesis of α-hydroxyvitamin D derivatives
The ring component has not been previously known.

Therefore, an object of the present invention is to use an easily available and inexpensive raw material as a starting material, and to use 1α-
It is an object of the present invention to provide a novel 7-octin-1-ene derivative useful in the synthesis of a hydroxyvitamin D derivative, particularly a 1α-hydroxyvitamin D derivative having a substituent at the 2-position, and a method for producing the same.

[0007]

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

[0008]

[Chemical 4]

(In the formula, R ¹ , R ² and R ³ each represent a hydrogen atom or a hydroxyl-protecting group, R ⁴ represents a hydrogen atom, —CO ₂ R ⁵ or —CH ₂ OR ⁶ , and R ⁵ represents A 7-octyne-1-ene derivative represented by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁶ represents a hydrogen atom or a hydroxyl-protecting group (hereinafter referred to as 7-octyne-1- This is achieved by providing an ene derivative (I).

[0010]

[Chemical 5]

(In the formula, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group.) And an oxirane derivative (hereinafter abbreviated as oxirane derivative (II)) and a general formula (III).

[0012]

[Chemical 6]

(In the formula, R ⁴ is a hydrogen atom, --CO ₂ R ⁵
Or an _-CH 2 OR ^{6, R 5} represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, ^{R 6} represents a hydrogen atom or a protective group for a hydroxyl group. ), The acetylene derivative (hereinafter abbreviated as acetylene derivative (III)) is reacted in the presence of a basic substance or a Grignard reagent, and the hydroxyl group is protected or deprotected as necessary. , 7-octyne-1-ene derivative (I).

The hydroxyl-protecting group represented by R ¹ , R ² , R ³ and R ⁶ may be any substituent as long as it is a substituent capable of protecting the hydroxyl group, and examples thereof include a trimethylsilyl group and triethyl. Silyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, te
Trisubstituted silyl groups such as rt-butyldiphenylsilyl group; methoxymethyl group, methoxyethoxymethyl group, 1
Examples thereof include a 1- (alkoxy) alkyl group such as a-(ethoxy) ethyl group and a methoxyisopropyl group; a 2-oxacycloalkyl group such as a tetrahydrofuranyl group and a tetrahydropyranyl group. Further, R ¹ and R ² or R ² and R ³ may be taken together to form a cyclic acetal with an optionally substituted methylene group such as an ethylidene group, an isopropylidene group and a benzylidene group. Further, as the hydroxyl-protecting group represented by R ² , an acyl group such as an acetyl group, a propanoyl group, a butyryl group, a benzoyl group; an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group and an allyloxycarbonyl group. Also included.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ⁵ are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group,
Examples thereof include a pentyl group and a hexyl group.

The 7-octyne-1-ene derivative (I) of the present invention has the following three groups depending on the kind of the substituent.
Can be roughly divided into groups.

Group 1: a compound represented by the general formula (I) when R ⁴ is a hydrogen atom, that is, the following general formula (Ia)

[0018]

[Chemical 7]

(Wherein R ¹ , R ² and R ³ are as defined above, and R ⁷ represents a hydrogen atom).

Group 2: a compound represented by the general formula (I) when R ⁴ is —CO ₂ R ^5, that is, the following general formula (Ib)

[0021]

[Chemical 8]

(Wherein R ¹ , R ² , R ³ and R ⁵
Is as defined above. ) The compound shown by these.

Group 3: a compound represented by the general formula (I) when R ⁴ is —CH ₂ OR ^6, that is, the following general formula (Ic)

[0024]

[Chemical 9]

(Wherein R ¹ , R ² , R ³ and R ⁶
Is as defined above. ) The compound shown by these.

The reaction between the oxirane derivative (II) and the acetylene derivative (III) is carried out in the presence of a basic substance or a Grignard reagent. As the basic substance to be used, alkyl lithium such as butyl lithium and methyl lithium; alkali metal such as lithium and sodium;
Alkali metal amides such as sodium amide, lithium diisopropylamide, lithium dicyclohexylamide and lithium bistrimethylsilylamide; alkali hydroxides such as potassium hydroxide and sodium hydroxide;
A lithium acetylide ethylenediamine complex prepared in advance with a basic substance can also be used. As the Grignard reagent, an alkyl magnesium halide such as ethyl magnesium bromide or ethyl magnesium iodide is used. The amount of the basic substance or Grignard reagent used is usually about 0.5 to 1 mol with respect to 1 mol of the acetylene derivative.
It is 1.0 mol. In the case of alkyl lithium and Grignard reagent, an acetylene metal derivative is prepared by reacting with an acetylene derivative in an ether solvent such as tetrahydrofuran according to a conventional method, and in the case of alkali metal, alkali metal amide and alkali hydroxide, a conventional method is used. To react with an acetylene derivative in liquid ammonia or dimethylsulfoxide according to the procedure described above to prepare an acetylene metal derivative, and then at -80 ° C to 80 ° C with about 0.5 to 1.0 mol of an oxirane derivative based on the acetylene metal derivative. Thus, the 7-octyne-1-ene derivative (I) can be obtained. In addition, hexamethylphosphoric triamide, boron trifluoride diethyl ether complex, or the like can be used to accelerate the reaction.
The obtained octyne derivative is treated with dilute hydrochloric acid, ammonium chloride aqueous solution, etc. by a conventional method, extracted with ethyl ether, ethyl acetate, etc., washed with sodium bicarbonate solution, saline solution, etc., and dried with anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. After that, it can be concentrated and isolated and purified by means such as chromatography.

The obtained 7-octyne-1-ene derivative (I) is, if necessary, deprotected by a conventional method,
Can be protected.

The oxirane derivative (II) as a raw material is
Reaction process A shown below using inexpensive mannitol as a raw material
Can be manufactured according to.

[0029]

[Chemical 10]

In the above formulas, R ¹ , R ² , R ³ and R
⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, R represents a hydroxyl-protecting group, and R ′ represents a lower alkyl group or an aryl group.

The reaction of each step shown in the above reaction step A will be described in more detail below.

That is, a diol (XII) in which hydroxyl groups at the 3-position, 4-position, 5-position and 6-position were protected from mannitol (XIII) was synthesized according to a conventional method, and then the diol and the diol were prepared. Cyclic orthoesters are obtained by heating 1 to 20 times moles of dimethylformamide dimethyl acetal, methyl orthoformate, ethyl orthoformate and the like in the presence or absence of an acid catalyst at room temperature to 200 ° C. 5-Hexene-1,2,3,4-tetraol having a hydroxyl group protected by adding acid anhydride such as acetic anhydride or propionic anhydride in an amount of 1 to 10 times and heating the mixture at room temperature to 200 ° C. The derivative (XI) is obtained.

5-hexene-1,2, having a protected hydroxyl group,
The 3,4-tetraol derivative (XI) is subjected to a deprotection reaction according to a conventional method to protect the 3- and 4-positions of 5-hexene-1,2,3,4-tetraol derivative (X). To get

The 5-hexene-1,2,3,4-tetraol derivative (X) in which the 3-position and the 4-position are protected can be used in the presence of a base such as pyridine or triethylamine in the presence of 1-5.
By reacting with a sulfonylating agent such as p-toluenesulfonyl chloride or methanesulfonyl chloride in a double mole at about -30 to about 80 ° C in the presence or absence of an inert solvent, 3-position and 4-position are converted. Protected 2,3
Convert to 4-trihydroxy-5-hexen-1-ylsulfonate derivative (IX).

Protected 3- and 4-positions 2,3
The 4-trihydroxy-5-hexen-1-ylsulfonate derivative (IX) is converted into the oxirane derivative (II) according to a conventional method. For example, the oxirane derivative (II) can be obtained by dissolving the sulfonate in an inert solvent such as methanol, ethanol or tetrahydrofuran and allowing it to react with a base such as sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride. it can.

The oxirane derivative (II) can be converted into the 7-octyne-1-ene derivative (Ia) and (I-
b) and (Ic) can be led.

Further, the 7-octyne-1-ene derivative (Ia) in which R ⁷ is a hydrogen atom is reacted with formaldehyde in the presence of a basic substance or a Grignard reagent to protect the hydroxyl group, if necessary. Alternatively, deprotection can lead to the 7-octyne-1-ene derivative (Ic).

Further, a 7-octyne-1-ene derivative (I
-A) in which R ⁷ is a hydrogen atom is butyllithium,
A 7-octyne-1-ene derivative (Ib) is obtained by reacting with methyl formate, ethyl chloroformate, halogenated formate such as methyl bromoformate or carbon dioxide in the presence of alkyl lithium such as methyl lithium. Can be converted.

7-Octyn-1-ene derivative (Ib)
The lithium aluminum hydride, aluminum hydride,
The 7-octyne-1-ene derivative (Ic) can be obtained by reducing with diisobutylaluminum hydride, lithium trimethoxyaluminum hydride or the like, and protecting the hydroxyl group if necessary.

7-octyne-1 thus obtained
The -ene derivative (Ic) can be introduced into the A ring constituent part for producing a vitamin D derivative by, for example, the method shown below.

7-octyne-1-ene derivative (Ic)
Can be hydroaluminated with lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, etc., and then iodinated with iodine to obtain iodoalkene (IV).

Then, iodoalkene (IV) is cyclized by using tetrakistriphenylphosphinopalladium or a palladium catalyst prepared from palladium acetate and triphenylphosphine in the presence of a base such as silver carbonate or triethylamine. A cyclohexanetriol derivative (V) can be obtained.

The cyclohexanetriol derivative (V) thus obtained is sulfonylated at the 2-position hydroxyl group with methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride or the like in the presence of triethylamine, pyridine or the like. , Lithium aluminum hydride, lithium triethylborohydride, etc. to give a cyclohexanediol derivative (VI)
Can be Of these cyclohexanediol derivatives, compounds in which R ⁶ is a hydroxyl group or a protected hydroxyl group are known as A-ring constituent moieties for the production of 1α-hydroxyvitamin D compounds, and methods known per se (for example, Journal of American
Chemical Society (J. Am. Chem. So
c. ), 104, 2945 (1982)), and various 1α as described above having pharmacological activity.
It can lead to hydroxyvitamin D derivatives.

Moreover, since the cyclohexanetriol derivative of the present invention has a hydroxyl group at the 2-position as well as at the 1-position and the 3-position, the 2-position hydroxyl group is utilized to make the 2-position. 1α-hydroxyvitamin D having a substituent
It can be advantageously used as an A ring constituent part for producing a derivative. For example, by introducing a 3-hydroxypropyl group into the 2-position hydroxyl group of the cyclohexanetriol derivative (V) of the present invention, the following formula (VII)

[0045]

[Chemical 11]

(Wherein R ¹ , R ³ and R ⁶ are as defined above), the compound is synthesized, and then the hydroxyl group of this compound is optionally protected, followed by a method known per se (eg, , Journal of American Chemical Society (J. Am. Chem. So
c. ), 104, 2945 (1982)).
By linking the CD ring portion of _{3 with} the formula (VIII) below, which is expected to be put into practical use as a therapeutic drug for osteoporosis having high blood durability as described above.

[0047]

[Chemical 12]

It is possible to produce 2β- (3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D _{3 represented} by

[0049]

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

Reference Example 1 [Synthesis of 1,2: 3,4-O-diisopropylidene-5-hexene] 3,4: 5,6-O-diisopropylidene-D-mannitol 128.5 g with N, 200 ml of N-dimethylformamide dimethyl acetal was added, and the mixture was heated to 100 ° C. to distill off methanol. After heating at 100 ° C for 1 hour and confirming that almost all the raw materials had disappeared by thin layer chromatography, heating to 170 ° C was performed to remove excess N,
N-dimethylformamide dimethyl acetal was distilled off over about 1 hour. After the distillate was gone, the temperature was raised to 150 ° C, 100 ml of acetic anhydride was added little by little, and the distillation temperature was about 9
The distillate around 0 ° C. was distilled off. The obtained reaction solution was cooled to room temperature, diethyl ether was added, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 1,
60.7 g of 2: 3,4-O-diisopropylidene-5-hexene was obtained (yield 54%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ ) δ: 5.90 (ddd, 1H, J = 5.7,
10.2, 17.2 Hz), 5.13 to 5.52 (m,
2H), 4.37 (ddt, 1H, J = 0.9, 5.
7, 7.6 Hz), 3.8 to 4.2 (m, 3H), 3.
70 (dd, 1H, J = 6.6, 7.6 Hz), 1.4
1 (s, 9H), 1.34 (s, 3H) IR spectrum (neat, cm ^-1 ) 2984, 2932, 288
0, 1455, 1378, 1250, 1214, 115
4,1120,1065,993,924,846,5
12 Specific rotation [α] _D = + 4.18 ° (c = 2.00, CHCl
₃ )

Reference Example 2 [3,4-O-isopropylidene-5-hexene-1,
Synthesis of 2-diol] 1, 2 obtained in Reference Example 1:
3,4-O-isopropylidene-5-hexene 36.8
After adding 300 ml of glacial acetic acid and 60 ml of water to g and stirring for 14 hours at room temperature, the reaction solution was added little by little to 500 ml of 50% aqueous sodium hydroxide solution containing ice. The formed sodium acetate crystals were filtered, and the crystals were washed with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography to give 3,4-
13.5 g of O-isopropylidene-5-hexene-1,2-diol was obtained (yield 44%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ ) δ: 5.93 (ddd, 1H, J = 5.9,
9.1, 15.3 Hz), 5.17 to 5.52 (m, 2
H), 4.42 (dd, 1H, J = 5.9, 6.4H
z), 3.5 to 3.9 (m, 4H), 3.0 to 3.4.
(Brs, 2H), 1.42 (s, 6H) IR spectrum (neat, cm ⁻¹ ) 3414, 2984, 293
0,2878,1727,1645,1455,142
8, 1407, 1371, 1250, 1214, 116
8, 1120, 1055, 925, 874, 812, 7
79,734,664,621,511 Specific optical rotation [α] _D = + 4.66 ° (c = 1.07, CHCl
₃ )

Reference Example 3 [3,4-O-isopropylidene-2-hydroxy-5]
-Synthesis of hexen-1-yl p-toluenesulfonate] 3,4-O-isopropylidene-5-hexene-1,2
9.77 g of diol was mixed with 155 ml of pyridine and 52 ml of chloroform, and 11.39 g of p-toluenesulfonyl chloride was added little by little at 0 ° C. in 4 portions. 0 ° C
After stirring for 6 hours, the mixture was poured into 6N hydrochloric acid containing ice and extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and
After concentrating under reduced pressure, 17.88 g of 3,4-O-isopropylidene-2-hydroxy-5-hexen-1-yl p-toluenesulfonate having the following physical properties was obtained (yield 100%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ ) δ: 7.80 (d, 2H, J = 8.2H)
z), 7.35 (d, 2H, J = 8.2 Hz), 5.8
7 (ddd, 1H, J = 6.4, 8.9, 17.3H
z), 5.15 to 5.49 (m, 2H), 3.58 to
4.50 (m, 5H), 2.45 (s, 3H), 1.3
7 (s, 6H) IR spectrum (neat, cm ^-1 )
3508, 3084, 3064, 2984, 2932,
2882, 1647, 1597, 1494, 1453,
1369, 1308, 1291, 1213, 1174,
1118, 1096, 1063, 980, 930, 89
6,873,834,814,691,664,55
2,514

Reference Example 4 [1,2-Epoxy-3,4-O-isopropylidene-
Synthesis of 5-hexene] 3,4-O-isopropylidene-2-hydroxy-5-
Hexen-1-yl p-toluene sulfonate 17.8
8 g was dissolved in 80 ml of methanol, 17.11 g of anhydrous sodium carbonate was added at room temperature, and the mixture was stirred for 15 minutes. The reaction solution was filtered through Celite, and the crystals were washed with diethyl ether. After concentrating the filtrate, the solid matter was removed through a silica gel column. After concentration under reduced pressure, 7.87 g of 1,2-epoxy-3,4-O-isopropylidene-5-hexene having the following physical properties was obtained (yield 89%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ ) δ: 5.90 (ddd, 1H, J = 6.7,
9.8, 17.2 Hz), 5.22 to 5.52 (m, 2
H), 4.36 (dd, 1H, J = 5.4, 6.7H)
z), 3.61 (dd, 1H, J = 5.1, 5.4H
z), 3.09 (ddd, 1H, J = 2.6, 4.1,
4.9 Hz), 2.83 (dd, 1H, J = 4.1,
4.9 Hz), 2.70 (dd, 1H, J = 2.6)
4.9 Hz), 1.44 (s, 6 Hz) IR spectrum (neat, cm ⁻¹ ) 3520, 2984, 292
8, 1725, 1659, 1597, 1494, 145
4,1358,1306,1290,1250,121
2,1188, 1176, 1120, 1095, 107
1,1003,919,876,836,816,77
8,713,690,663,571,554

Example 1 Under a nitrogen atmosphere, a solution of 0.16 ml of tetrahydro-2- (2-propynyloxy) -2H-pyran and 4 ml of tetrahydrofuran was added at -78 ° C. to 0.68 ml of n-butyllithium (1.63N, 1). 0.11 mmol, hexane solution) was added dropwise, and the mixture was stirred for 25 minutes. To the reaction mixture was added boron trifluoride diethyl ether complex 0.15 ml, and the mixture was stirred at -78 ° C for 20 minutes. (2R, 3R, 4
S) -1,2-epoxy-3,4-O-isopropylidene-5-hexene 94 mg was added to tetrahydrofuran 4 ml.
Was added to the above solution, and the mixture was stirred for 40 minutes while being cooled. The reaction mixture was poured into a mixture of ice and a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, it has the following physical properties (5
R, 6R, 7S) -Tetrahydro-2- (5-hydroxy-6,7-O-isopropylidene-8-nonene-2-
165 mg of in-1-yloxy) -2H-pyran was obtained (yield 96%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 5.90 (ddd, J = 6.5)
9, 9.9, 17.19Hz, 1H), 5.40 (dd
d, J = 0.88, 1.98, 17.19 Hz, 1
H), 5.27 (ddd, J = 0.88, 1.98,
9.9Hz, 1H), 4.79 (m, 1H), 4.45
(Dddd, J = 0.88, 0.88, 6.59, 7.
46Hz, 1H), 4.26 (m, 2H), 3.7 ~
4.1 (m, 1H), 3.5 to 3.7 (m, 1H),
2.54 (ddd, J = 2.16, 2.16, 6.1
7, 2H), 2.39 (1H), 1.5 to 2.0 (m,
6H), 1.42 (s, 6H) IR spectrum (nea
t, cm ⁻¹ ) 3438, 3084, 2980, 293.
6,2286, 2224, 1727, 1644, 144
0,1378,1346,1322,1250,121
1,1165,1117,1055,1022,97
2,944,929,902,873,813,511

Example 2 (5R, 6R, 7S) -Tetrahydro-under a nitrogen atmosphere
2- (5-Hydroxy-6,7-O-isopropylidene-8-nonen-2-yn-1-yloxy) -2H-pyran (146 mg) was dissolved in N, N-diisopropylethylamine (0.5 ml) and the mixture was stirred at 0 ° C. It was stirred. 0.07 ml of distilled chloromethyl methyl ether was added to the obtained solution, and the mixture was stirred for 48 hours. Ice and 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, (5R, 6R, 7S) -tetrahydro-2- (5 having the following physical properties is obtained.
-Methoxymethoxy-6,7-O-isopropylidene-
125 mg of 8-nonene-2-yn-1-yloxy) -2H-pyran was obtained (yield 68%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 5.88 (ddd, J = 6.5)
9, 9.9, 17.19 Hz, 1H), 5.40 (d
d, J = 0.9, 17.19 Hz, 1H), 5.24
(Ddd, J = 0.9, 2.0, 9.9 Hz, 1H),
4.7-4.88 (m, 1H), 4.77 (AB, J =
4.86 Hz, 1H), 4.72 (AB, J = 4.86)
Hz, 1H), 4.46 (dd, J = 6.59, 6.6)
9 Hz, 1H), 4.24 (m, 2H), 3.5-4.
05 (m, 3H), 3.4 to 3.5 (m, 1H), 3.
40 (s, 3H), 2.56 (ddd, J = 2.66,
2.66, 5.76 Hz, 2H), 1.4 to 1.8
(M, 6H), 1.41 (s, 6H) IR spectrum (neat, cm ⁻¹ ) 2980, 1452, 144
2,1378, 1369, 1246, 1212, 115
1,1117,1023,920,902,873,8
14,512

Example 3 (5R, 6R, 7S) -Tetrahydro-2- (5-methoxymethoxy-6,7-O-isopropylidene-8-nonen-2-yn-1-yloxy) -2H-pyran 12
Dissolve 5 mg in methanol, catalytic amount of pyridinium
p-Toluenesulfonate was added, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over sodium sulfate. After concentrating under reduced pressure, it was purified using silica gel column chromatography and had the following physical properties (5
R, 6R, 7S) -5-Methoxymethoxy-6,7-O
38 mg of isopropylidene-8-nonen-2-yn-1-ol was obtained (yield 44%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 5.94 (ddd, J = 6.4)
3, 10.02, 16.97 Hz, 1H), 5.40
(Ddd, J = 0.77, 2.06, 16.97 Hz,
1H), 5.28 (ddd, J = 0.77, 2.06,
16.97 Hz, 1H), 4.77 (AB, J = 6.8)
1Hz, 1H), 4.75 (AB, J = 6.81Hz,
1H), 4.46 (dddd, J = 0.77, 0.7
7,6.43,7.46Hz, 1H), 4.24 (t,
J = 2.06, 2H), 3.78 to 4.05 (m, 2
H), 3.42 (s, 3H), 2.58 (dt, J =
2.06, 5.49 Hz, 2H), 1.82 (bs, 1
H), 1.42 (s, 6H) ¹³ C-NMR spectrum (75 MHz) δ: 136.16, 118.44, 10
9.33, 96.35, 82.18, 81.12, 8
0.40, 79.07, 75.39, 55.95, 5
1.27, 27.04, 26.93, 21.80 IR spectrum (neat, cm ⁻¹ ) 3432, 3080,
2984, 2930, 2600, 2450, 1644,
1453, 1427, 1380, 1371, 1264,
1212, 1152, 1103, 1030, 921, 8
75,812,755 Specific optical rotation [α] _D = + 16.4 ° (c = 0.388, CHCl 3
₃ )

Example 4 4.2 g of a lithium acetylide ethylenediamine complex was dissolved in 50 ml of dimethyl sulfoxide under a nitrogen atmosphere.
Stir at room temperature. A solution prepared by dissolving 3.4 g of (2R, 3R, 4S) -1,2-epoxy-3,4-O-isopropylidene-5-hexene in 5 ml of dimethyl sulfoxide was added to the above solution, and the mixture was stirred under water cooling for 2 hours. . The reaction solution was poured into ice-cooled dilute hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, (3S, 4R, 5R) -3,4-O-isopropylidene-7-octyne-1-en-5-ol 3 having the following physical properties is obtained. .3
3 g was obtained (yield 85%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 5.92 (ddd, J = 6.9)
6,10.25, 16.39 Hz, 1H), 5.43
(Dd, J = 1.10, 16.39 Hz, 1H), 5.
26 (dd, J = 1.10, 10.25 Hz, 1H),
4.45 (t, J = 6.96Hz, 1H), 3.90 ~
3.96 (m, 1H), 3.81 to 3.85 (m, 1
H), 2.49 (dd, J = 2.57, 6.22 Hz,
2H), 2.30 (brs, 1H), 2.06 (t, J
= 2.57 Hz, 1H), 1.42 (s, 6H)

Example 5 In a nitrogen atmosphere, 3.33 g of (3S, 4R, 5R) -3,4-O-isopropylidene-7-octyne-1-en-5-ol was dissolved in 50 ml of methylene chloride, and imidazole 1 was added. 0.73 g and tert-butyldiphenylsilyl chloride 6.07 g were added, and the mixture was stirred at room temperature for 1 hour.
Water was added to the reaction solution, the layers were separated, and the organic layer was dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, (3S, 4R, 5R) -5- (t-butyldiphenylsilyloxy) -3,4-O-isopropylidene-7 having the following physical properties was obtained.
4.79 g of -octyne-1-ene was obtained (yield 65
%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 7.35 to 7.75 (m, 10
H), 5.78 (ddd, J = 6.96, 10.26.
16.86 Hz, 1H), 5.32 (dd, J = 1.1)
0, 16.86 Hz, 1 H), 5.16 (dd, J =
1.10, 10.26Hz, 1H), 4.49 (t, J
= 7.33 Hz, 1H), 4.02 to 4.21 (m, 2)
H), 2.27 to 2.31 (m, 2H), 1.93.
(T, J = 2.75 Hz, 1H), 1.40 (s, 3
H), 1.39 (s, 3H), 1.08 (s, 9H)

Example 6 Under a nitrogen atmosphere, 0.80 ml of n-butyllithium (1.63N, hexane solution) was added dropwise to a solution of 200 mg of methyl propiolate and 4 ml of tetrahydrofuran at -78 ° C, and the mixture was stirred for 5 minutes. To the reaction mixture was added boron trifluoride diethyl ether complex 0.15 ml, -7
Stir for 5 minutes at 8 ° C. (2R, 3R, 4S) -1,2
A solution of 102 mg of epoxy-3,4-O-isopropylidene-5-hexene in 4 ml of tetrahydrofuran was added to the above solution, and the mixture was stirred for 20 minutes while being cooled. The reaction mixture was poured into a mixture of ice and a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, it has the following physical properties (5R, 6R,
61 mg of 7S) -5-hydroxy-6,7-O-isopropylidene-8-nonene-2-ynoate was obtained (yield 38%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 5.91 (ddd, J = 6.9)
5,10.25, 16.88Hz, 1H), 5.41
(Dd, J = 1.10, 16.88 Hz, 1H), 5.
25 (dd, J = 1.10, 10.25 Hz, 1H),
4.45 (t, J = 6.95 Hz, 1H), 3.81
4.22 (m, 4H), 2.40 (d, J = 6.23H
z, 1H), 2.25 (brs, 1H), 1.41
(S, 6H), 1.26 (t, J = 7.1Hz, 3H)

Example 7 Under a nitrogen atmosphere, 61 mg of methyl (5R, 6R, 7S) -5-hydroxy-6,7-O-isopropylidene-8-nonene-2-inate was dissolved in 2 ml of methylene chloride to give 36 mg of imidazole. And tert-butyldiphenylsilyl chloride (69 mg) were added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, the layers were separated, and the organic layer was dried over magnesium sulfate. By concentrating under reduced pressure and purifying by silica gel column chromatography, (5R, 6R, 7S) -5- (t-butyldiphenylsilyloxy) -6,7-O-isopropylidene-8 having the following physical properties was obtained. 95 mg of methyl nonen-2-ynoate was obtained (yield 83%).

¹ H-NMR spectrum (90 MHz, C
Cl ₄ , TMS) δ: 7.33 to 7.75 (m, 10
H), 5.84 (ddd, J = 6.99, 10.20,
16.98 Hz, 1H), 5.36 (dd, J = 1.0)
8,16.98Hz, 1H), 5.20 (dd, J =
1.08, 10.20 Hz, 1H), 4.48 (t, J
= 6.99 Hz, 1H), 4.01 to 4.23 (m, 4
H), 2.18 to 2.30 (m, 2H), 1.40
(S, 6H), 1.28 (t, J = 7.0Hz, 3
H), 1.02 (s, 9H)

Reference Example 5 [2Z- (5R, 6R, 7S) -3-iodo-5-methoxymethoxy-6,7-O-isopropylidene-2,8
-Synthesis of nonanedien-1-ol] In a nitrogen atmosphere, a solution of 43.2 mg of sodium methylate suspended in 4 ml of tetrahydrofuran was added (5R, 6).
R, 7S) -5-Methoxymethoxy-6,7-O-isopropylidene-8-nonen-2-yn-1-ol 10
A solution of 7 mg dissolved in 13 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. To the resulting solution, a solution of lithium aluminum hydride in tetrahydrofuran 0.4
4 ml (0.37 mol / l) was added dropwise at 0 ° C,
Then, it heated at 80 degreeC and stirred for 1 hour. The obtained solution was cooled to −78 ° C., a solution of 1.07 g of iodine in 1 ml of tetrahydrofuran was added, and the mixture was stirred at −78 ° C. for 2 hours and at −40 ° C. for 3 hours. The resulting mixture was poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over magnesium sulfate. After being concentrated under reduced pressure, it was purified using silica gel column chromatography and 2Z- (5R, 6R, 7S) having the following physical properties.
-3-iodo-5-methoxymethoxy-6,7-O-isopropylidene-2,8-nonadiene-1-ol 64
mg was obtained (41% yield).

¹ H-NMR spectrum (300 MHz,
CCl ₄ , TMS) δ: 5.985 (t, J = 5.7).
Hz, 1H), 5.865 (ddd, J = 7.49, 1
0.17, 17.22 Hz, 1H), 5.448 (dd
d, J = 0.76, 1.53, 17.22 Hz, 1
H), 5.303 (ddd, J = 0.76, 1.53,
10.17 Hz, 1 H), 4.739 (AB, J = 6.
78Hz, 1H), 4.675 (AB, J = 6.78H)
z, 1H), 4.402 (dd, J = 7.49, 8.1)
5Hz, 1H), 4.184 (dd, J = 3.00,
5.7 Hz, 2H), 4.010 (ddd, J = 3.0)
2,4.13,8.09Hz, 1H), 3.870 (d
d, J = 3.02, 8.15 Hz, 1H), 3.366
(S, 3H), 2.794 (dd, J = 8.09, 1
4.39 Hz, 1 H), 2.680 (ddd, J = 1.
21, 4.13, 14.39 Hz, 1H), 2.136
(Bs, 1H), 1.431 (s, 3H), 1.422
(S, 3H) ¹³ C-NMR spectrum (75 MHz)
δ: 137.24, 136.01, 119.45, 10
9.35, 104.94, 96.93, 81.98, 7
8.47, 74.69, 67.25, 56.00, 4
7.12, 26.96 (2) IR spectrum (nea
t, cm ⁻¹ ) 3424, 3080, 2980, 293.
0,1712,1644,1450,1378,124
0,1216,1151,1098,1032,92
0,876, 811, 732, 511 Specific optical rotation [α] _D = + 31.0 ° (c = 0.2, CHCl ₃ ).

Reference Example 6 [Synthesis of (5R, 3S, 4R) -2- (5-methoxymethoxy-3,4-O-isopropylidene-2-methylene-cyclohexylidene) -ethanol] Palladium acetate 3.4 mg , Triphenylphosphine (4.4 mg) and potassium carbonate (54 mg) were suspended in acetonitrile (2 ml), and 2Z- (5R, 6R, 7 was added thereto.
S) -3-Iodo-5-methoxymethoxy-6,7-O
A solution of 60 mg of isopropylidene-2,8-nonadiene-1-ol in acetonitrile was added at room temperature. After stirring at 80 ° C. for 5 hours, ice water and ethyl acetate were added for extraction, and the mixture was washed with saturated aqueous sodium thiosulfate solution and then saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline and then dried over magnesium sulfate. After being concentrated under reduced pressure, it was purified using silica gel column chromatography and has the following physical properties (5R, 3S, 4R) -2-
23.4 mg of (5-methoxymethoxy-3,4-O-isopropylidene-2-methylene-cyclohexylidene) -ethanol was obtained (yield 58%).

¹ H-NMR spectrum (300 MHz,
CCl ₄ , TMS) δ: 5.691 (ddd, J =
2.29, 5.35, 7.8Hz, 1H), 5.277
(T, J = 1.86 Hz, 1H), 4.829 (t, J
= 1.86 Hz, 1 H), 4.827 (AB, J = 6.
77Hz, 1H), 4.704 (AB, J = 6.77H)
z, 1H), 4.410 (dd, J = 7.8, 12.3)
5Hz, 1H), 4.407 (ddd, J = 1.86,
1.86, 9.89 Hz, 1H), 4.329 (dd
d, J = 2.03, 2.41, 2.74 Hz, 1H),
4.183 (bd, J = 12.35 Hz, 1H), 3.
583 (dd, J = 2.41, 9.89 Hz, 1H),
3.399 (s, 3H), 2.547 (dd, J = 2.
74, 15.28Hz, 1H), 2.484 (bd, J
= 15.28 Hz, 1H), 1.474 (s, 6H)
¹³ C-NMR spectrum (125 MHz) δ: 14
1.88, 136.10, 130.39, 110.9
3,108.11, 96.25, 82.43, 75.6.
5,70.94,59.74,55.51,40.3
3, 27.05, 26.90 IR spectrum (nea
t, cm ⁻¹ ) 3436, 2982, 2924, 173
0, 1695, 1649, 1453, 1370, 122
9,1151,1089,1063,1040,96
5,916,867,837,808,773 Specific optical rotation [α] _D = -109.2 ° (c = 0.0293, CH
Cl ₃ )

[0076]

INDUSTRIAL APPLICABILITY According to the present invention, available and inexpensive raw materials are used as starting materials, and a novel synthetic intermediate useful for the synthesis of 1α-hydroxyvitamin D derivative is provided in a relatively short step, And a method for producing the compound is provided.

─────────────────────────────────────────────────── ─── Continued Front Page (56) References US Patent 5086191 (US, A) Jose L. Mascarenas, A Short, Efficient Route to 1-Hydroxy xylated Vitamin D Ring A Fragments, T etrahedron Letters, July 21, 1992, Vol. 33 / N o. 30, p. 4365-4368 Chemical Society of Japan, Experimental Chemistry Lecture (Vol. 25) Organic Synthesis VII Synthesis with Organometallic Reagents, Japan, Maruzen Co., Ltd., September 5, 1991, p. 69 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07C 33/048 C07C 29/36-29/42 C07C 67/343-67/347 C07C 69/732-69/738 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The following general formula (I): (In the formula, R ¹ , R ² and R ³ each represent a hydrogen atom or a hydroxyl-protecting group, R ⁴ represents a hydrogen atom, —C
O ₂ R ⁵ or represents _-CH 2 OR ^{6, R 5} represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, ^{R 6} represents a hydrogen atom or a protective group for a hydroxyl group. ) 7
-Octyn-1-ene derivatives. 2. The following general formula (II): (In the formula, R ¹ and R ² each represent a hydrogen atom or a hydroxyl-protecting group.) And an oxirane derivative represented by the following general formula (III): (Wherein R ⁴ is as defined above), the acetylene derivative is reacted in the presence of a basic substance or a Grignard reagent, and the hydroxyl group is protected or deprotected as necessary. The method for producing a 7-octyne-1-ene derivative according to claim 1.