JPH0672928A - 7-octyn-1-ene derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new 7-octyn-1-ene derivative useful as a synthetic intermediate for la-hydroxyvitamin D derivative having a substituent at 2-site by a relatively short reaction process using an easily available inexpensive raw material as a starting material. CONSTITUTION:The 7-octyn-1-ene of formula I [R<1> to R<3> are H or OH-protecting group; R<4> is H, trisubstituted silyl, CO2R<5> or CH2OR<6> (R<5> is H or alkyl; R<6> is H or OH-protecting group), e.g. (5R, 6R, 7S)-tetrahydro-2-(5-hydroxy-6,7-O- isopropylidene-8-nonen-2-yn-1-yloxy)-2H-pyran. The compound of formula I can be produced by reacting an oxysilane derivative of formula II with an acetylene derivative of formula III in the presence of a basic substance or a Grignard reagent and optionally protecting or deprotecting the hydroxyl group of the product.

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,
24-Epi-1α, 25-dihydroxyvitamin D ↓ 2
2β- (3-hydroxypropoxy) -1α, 25
-1α-hydroxyvitamin D derivatives such as dihydroxyvitamin D ↓ 3, and 1α, 24-dihydroxy, which are expected to be effective for the treatment of skin diseases such as psoriasis and diseases with abnormal cell differentiation functions such as myeloid leukemia Vitamin D ↓ 3,22-oxa-1α, 25-dihydroxyvitamin D ↓ 3,22-dehydro-26,27-cyclo-
1α-, such as 1α, 24-dihydroxyvitamin D ↓ 3
It is useful as a synthetic intermediate for hydroxyvitamin D derivatives.

[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.

[0003] A-ring synthons of 1α-hydroxyvitamin D derivative were synthesized to obtain a CD-ring component.
Convergent 1 to combine with (CD-ring synthons)
As a method for synthesizing an α-hydroxyvitamin D derivative, for example, a method using (S)-(+)-carvone as a raw material (Journa of Organic Chemistry (Journa
l of Organic Chemistry), Vol. 54, p. 3098 (1986)), a method of using (R)-(-)-carvone as a raw material (Journal of Organic Chemistry), 54
Vol. 3515 (1986)), using cyclohexenedicarboxylic acid esters (Tetrahedron Letters, vol. 31, vol. 1).
577 (see 1990)) and the like are known.

Further, as a method for synthesizing the A ring constituent part, 5
-A method for synthesizing hexyne-1-ol via iodoalkene (Tetrahedron Le
tters), 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-
(3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D 1 having a substituent at the 2-position such as 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]

(Wherein R ↑ 1, R ↑ 2 and R ↑ 3 each represent a hydrogen atom or a hydroxyl-protecting group, and R ↑ 4 represents a hydrogen atom, a trisubstituted silyl group, --CO ↓ 2 R ↑ 5 or −
CH ↓ 2OR ↑ 6, R ↑ 5 represents a hydrogen atom or a lower alkyl group, and R ↑ 6 represents a hydrogen atom or a hydroxyl-protecting group. ) 7-octyne-1-ene derivative (hereinafter, referred to as 7-octyne-1-ene derivative (I))
Is abbreviated. ) And also has the general formula (II)

[0010]

[Chemical 5]

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

[0012]

[Chemical 6]

(Wherein R ↑ 4 represents a hydrogen atom, a trisubstituted silyl group, --CO ↓ 2 R ↑ 5 or --CH ↓ 2 OR ↑ 6, and R ↑ 5 represents a hydrogen atom or a lower alkyl group, R
↑ 6 represents a hydrogen atom or a hydroxyl-protecting group. ) The acetylene derivative represented by
It is abbreviated as I). 7-octyne-1 characterized in that it is reacted in the presence of a basic substance or a Grignard reagent to protect or deprotect the hydroxyl group as necessary.
-Achieved by providing a process for the preparation of 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.
Trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert
-Trisubstituted silyl group such as butyldiphenylsilyl group; 1-such as methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group, methoxyisopropyl group
(Alkoxy) alkyl group; tetrahydrofuranyl group,
A 2-oxacycloalkyl group such as a tetrahydropyranyl group can be exemplified. Also, R ↑ 1 and R ↑ 2
Alternatively, 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 a protective group for the hydroxyl group represented by R ↑ 2,
It also includes an acyl group such as an acetyl group, a propanoyl group, a butyryl group and a benzoyl group; and an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group and an allyloxycarbonyl group.

The trisubstituted silyl group represented by R ↑ 4 is trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-
Examples thereof include a butyldiphenylsilyl group.

Examples of the lower alkyl group represented by R ↑ 5 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, 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 or a trisubstituted silyl group, that is, the following general formula (Ia)

[0019]

[Chemical 7]

(Wherein R ↑ 1, R ↑ 2 and R ↑ 3 are as defined above, and R ↑ 7 represents a hydrogen atom or a tri-substituted silyl group).

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)

[0022]

[Chemical 8]

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

Group 3: R ↑ 4 is -CH ↓ 2 OR ↑ 6
When the compound is represented by the general formula (I), that is, the following general formula (Ic)

[0025]

[Chemical 9]

(Where 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 per 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.

[0030]

[Chemical 10]

In the above equations, R ↑ 1, R ↑ 2, R ↑ 3, 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 are protected from mannitol (XIII) was synthesized according to a conventional method, and then the diol and the diol were prepared. A cyclic orthoester is obtained by heating 1 to 20 times mol of dimethylformamide dimethyl acetal, methyl orthoformate, ethyl orthoformate or 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 hydroxyl group protected,
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 is 1-5 in the presence of a base such as pyridine and triethylamine.
3-position and 4-position by reacting with a sulfonylating agent such as p-toluenesulfonyl chloride, methanesulfonyl chloride and the like in a double mole at about -30 to about 80 ° C in the presence or absence of an inert solvent. Is protected 2,
Convert to 3,4-trihydroxy-5-hexen-1-yl sulfonate derivative (IX).

Protected at the 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 sulfonate derivative (II) can be obtained by dissolving the sulfonate in an inert solvent such as methanol, ethanol, or tetrahydrofuran and reacting it with a base such as sodium carbonate, potassium carbonate, sodium hydroxide, or sodium hydride. .

The oxirane derivative (II) was 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 and, if necessary, a hydroxyl group By protection or deprotection, a 7-octin-1-ene derivative (Ic) can be obtained.

The 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.

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

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 in the presence of a base such as silver carbonate or triethylamine using a palladium catalyst prepared from tetrakistriphenylphosphinopalladium or palladium acetate and triphenylphosphine. 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 Among the cyclohexanediol derivatives, compounds in which R ↑ 6 is a hydroxyl group or a protected hydroxyl group are known as A-ring constituents for the production of 1α-hydroxyvitamin D compounds, and methods known per se (eg, , Journal of American
The Chemical Society (J. Am. Chem. Soc.), 10th
Vol. 4, p. 2945 (1982)) can lead to various 1α-hydroxyvitamin D derivatives having pharmacological activity as described above.

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)

[0046]

[Chemical 11]

(In the formula, R ↑ 1, R ↑ 3 and R ↑ 6 are as defined above), a compound represented by the above is synthesized, and then the hydroxyl group is protected as necessary. Method (eg, Journal of American
Chemical Society (J. Am. Chem. Soc.), No. 104
Vol. 2, pp. 2945 (1982)), the CD ring portion of 1α-hydroxyvitamin D ↓ 3 is bound by a method according to the method, and as described above, its practical use as a therapeutic agent for osteoporosis having high blood durability. Formula (VIII) expected to be realized

[0048]

[Chemical 12]

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

[0050]

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 of N, Add 200 ml of N-dimethylformamide dimethylacetal and add 10.
It was heated to 0 ° C. and the methanol was distilled off. 100 ° C for 1 hour
After continuing to heat, the thin layer chromatography confirmed that almost all the raw materials had disappeared, and then heating to 170 ° C., an excess amount of N, N-dimethylformamide dimethyl acetal was distilled off over about 1 hour. After the distillate is gone,
The temperature was raised to 150 ° C., 100 ml of acetic anhydride was added little by little, and the distillate at a distillation temperature of about 90 ° 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 1,2,3,4-O-diisopropylidene-5- having the following physical properties. 60.7 g of hexene was obtained (yield 54%).

NMR spectrum (90 MHz, CCl ↓
4) δ: 5.90 (ddd, 1H, J = 5.7, 10.
2,17.2 Hz), 5.13 to 5.52 (m, 2
H), 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), 1.41
(S, 9H), 1.34 (s, 3H) IR spectrum (neat, cm ↑ -1) 2984, 2932, 2880, 1455, 1378,
1250, 1214, 1154, 1120, 1065
993, 924, 846, 512 Optical 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
300 ml of glacial acetic acid and 60 ml of water were added to g, and the mixture was stirred at room temperature for 1
After stirring for 4 hours, 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 was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 3,4-O having the following physical properties.
13.5 g of -isopropylidene-5-hexene-1,2-diol was obtained (yield 44%).

NMR spectrum (90 MHz, CCl ↓
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, 2930, 2878, 1727,
1645, 1455, 1428, 1407, 1371,
1250, 1214, 1168, 1120, 1055
925, 874, 812, 779, 734, 664, 6
21,511 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-
9.77 g of 1,2-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. The mixture was stirred at 0 ° C for 6 hours, 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 concentrated under reduced pressure to give the following physical properties 3,
4-O-isopropylidene-2-hydroxy-5-hexen-1-yl p-toluenesulfonate was added to 17.8.
8 g was obtained (yield 100%).

NMR spectrum (90 MHz, CCl ↓
4) δ: 7.80 (d, 2H, J = 8.2Hz), 7.
35 (d, 2H, J = 8.2 Hz), 5.87 (dd
d, 1H, J = 6.4, 8.9, 17.3 Hz), 5.
15-5.49 (m, 2H), 3.58-4.50
(M, 5H), 2.45 (s, 3H), 1.37 (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-
17.88 g of 2-hydroxy-5-hexen-1-yl p-toluenesulfonate is dissolved in 80 ml of methanol, and 17.11 g of anhydrous sodium carbonate is added at room temperature to give 1
Stir for 5 minutes. The reaction solution was filtered through Celite, and the crystals were washed with diethyl ether. After concentrating the filtrate,
Solids were removed through a silica gel column. 1,2-epoxy-3,4 having the following physical properties when concentrated under reduced pressure
7.87 g of -O-isopropylidene-5-hexene was obtained (yield 89%).

NMR spectrum (90 MHz, CCl ↓
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, 2928, 1725, 1659,
1597, 1494, 1454, 1358, 1306
1290, 1250, 1212, 1188, 1176,
1120, 1095, 1071, 1003, 919, 8
76, 836, 816, 778, 713, 690, 66
3,571,554

Example 1 In 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,
CCl ↓ 4, TMS) δ: 5.90 (ddd, J = 6.
59, 9.9, 17.19 Hz, 1H), 5.40 (d
dd, 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 (neat, cm ↑ -1) 3438, 3084, 2980, 2936, 2286,
2224, 1727, 1644, 1440, 1378,
1346, 1322, 1250, 1211, 1165,
1117, 1055, 1022, 972, 944, 92
9,902,873,813,511

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 stirred at 0 ° C. did. 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-methoxymethoxy-6,7-O-isopropylidene-8-) having the following physical properties is obtained. Nonen-2-yn-1-yloxy) -2H-pyran 12
5 mg was obtained (68% yield).

↑ 1 H-NMR spectrum (90 MHz,
CCl ↓ 4, TMS) δ: 5.88 (ddd, J = 6.
59, 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, 1442, 1378, 1369,
1246, 1212, 1151, 1117, 1023
920,902,873,814,512

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, saturated aqueous sodium hydrogen carbonate,
Then, it was washed with saturated saline and dried over sodium sulfate. After concentrating under reduced pressure, it was purified using silica gel column chromatography and has the following physical properties (5R, 6
R, 7S) -5-Methoxymethoxy-6,7-O-isopropylidene-8-nonen-2-yn-1-ol 38
mg was obtained (yield 44%).

↑ 1H-NMR spectrum (90 MHz,
CCl ↓ 4, TMS) δ: 5.94 (ddd, J = 6.
43, 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, 109.33, 96.35, 8
2.18, 81.12, 80.40, 79.07, 7
5.39, 55.95, 51.27, 27.04, 2
6.93, 21.80 IR spectrum (neat, cm ↑ -1) 3432, 3080, 2984, 2930, 2600,
2450, 1644, 1453, 1427, 1380,
1371, 1264, 1212, 1152, 1103
1030, 921, 875, 812, 755 Specific rotation +16.4 (c = 0.388, CHCl ↓ 3)

Example 4 4.2 g of 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,
CCl ↓ 4, TMS) δ: 5.92 (ddd, J = 6.
96, 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. -Octin-1-ene 4.79 g was obtained (yield 65%).

↑ 1 H-NMR spectrum (90 MHz,
CCl ↓ 4, TMS) δ: 7.35 to 7.75 (m, 1
0H), 5.78 (ddd, J = 6.96, 10.2)
6, 16.86 Hz, 1H), 5.32 (dd, J =
1.10, 16.86 Hz, 1H), 5.16 (dd,
J = 1.10, 10.26 Hz, 1H), 4.49
(T, J = 7.33 Hz, 1H), 4.02 to 4.21
(M, 2H), 2.27 to 2.31 (m, 2H), 1.
93 (t, J = 2.75 Hz, 1H), 1.40 (s,
3H), 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
The mixture was stirred at 8 ° C for 5 minutes. (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,
CCl ↓ 4, TMS) δ: 5.91 (ddd, J = 6.
95, 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 nonene-2-ynoate was obtained (yield 83
%).

↑ 1 H-NMR spectrum (90 MHz,
CCl ↓ 4, TMS) δ: 7.33 to 7.75 (m, 1
0H), 5.84 (ddd, J = 6.99, 10.2)
0, 16.98 Hz, 1H), 5.36 (dd, J =
1.08, 16.98 Hz, 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, 4H), 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] (5R, 6R, 7S) -5 in a solution of 43.2 mg of sodium methylate suspended in 4 ml of tetrahydrofuran under a nitrogen atmosphere.
Methoxymethoxy-6,7-O-isopropylidene-8
A solution of 107 mg of nonen-2-yn-1-ol in 13 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hour. 0.44 ml of a solution of lithium aluminum hydride in tetrahydrofuran (0.37
(mol / l) was added dropwise at 0 ° C, then heated to 80 ° C 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) -3-iodo-5 having the following physical properties was obtained.
Methoxymethoxy-6,7-O-isopropylidene-
64 mg of 2,8-nonadiene-1-ol was obtained (41% yield).

↑ 1H-NMR spectrum (300MH
z, CCl ↓ 4, TMS) δ: 5.985 (t, J =
5.7 Hz, 1 H), 5.865 (ddd, J = 7.4)
9, 10.17, 17.22Hz, 1H), 5.448
(Ddd, J = 0.76, 1.53, 17.22 Hz,
1H), 5.303 (ddd, J = 0.76, 1.5
3,10.17Hz, 1H), 4.739 (AB, J =
6.78 Hz, 1H), 4.675 (AB, J = 6.7)
8 Hz, 1 H), 4.402 (dd, J = 7.49,
8.15Hz, 1H), 4.184 (dd, J = 3.0)
0, 5.7 Hz, 2H), 4.010 (ddd, J =
3.02, 4.13, 8.09 Hz, 1H), 3.87
0 (dd, J = 3.02, 8.15 Hz, 1H), 3.
366 (s, 3H), 2.794 (dd, J = 8.0)
9, 14.39Hz, 1H), 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, 109.35, 1
04.94, 96.93, 81.98, 78.47, 7
4.69, 67.25, 56.00, 47.12, 2
6.96 (2) IR spectrum (neat, cm ↑ -1) 3424, 3080, 2980, 2930, 1712,
1644, 1450, 1378, 1240, 1216,
1151, 1098, 1032, 920, 876, 81
1,732,511 Specific rotation +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, 7S) -3-iodo- was added thereto.
A solution of 60 mg of 5-methoxymethoxy-6,7-O-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, the residue was purified by silica gel column chromatography and has the following physical properties (5R, 3S, 4R) -2-((5-methoxymethoxy)-(3,4-O-isopropylidene-2). 23.4 mg of -methylene-cyclohexylidene) -ethanol was obtained (yield 58%).

↑ 1H-NMR spectrum (300MH
z, CCl ↓ 4, TMS) δ: 5.691 (ddd, J
= 2.29, 5.35, 7.8 Hz, 1H), 5.27
7 (t, J = 1.86 Hz, 1H), 4.829 (t,
J = 1.86 Hz, 1H), 4.827 (AB, J =
6.77 Hz, 1H), 4.704 (AB, J = 6.7)
7 Hz, 1 H), 4.410 (dd, J = 7.8, 1
2.35 Hz, 1 H), 4.407 (ddd, J = 1.
86, 1.86, 9.89Hz, 1H), 4.329
(Ddd, J = 2.03, 2.41, 2.74 Hz, 1
H), 4.183 (bd, J = 12.35 Hz, 1
H), 3.583 (dd, J = 2.41, 9.89H
z, 1H), 3.399 (s, 3H), 2.547 (d
d, J = 2.74, 15.28 Hz, 1H), 2.48
4 (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 (neat, cm ↑ -1) 3436, 2982, 2924, 1730, 1695,
1649, 1453, 1370, 1229, 1151,
1089, 1063, 1040, 965, 916, 86
7,837,808,773 Specific rotation -109.2 (c = 0.0293, CHCl ↓ 3)

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, a novel synthetic intermediate useful for synthesizing a 1α-hydroxyvitamin D derivative is provided by using an inexpensive raw material that is available as a starting material, in a relatively short step, and Methods of making the compounds are provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 59/42 8930-4H 67/343 69/732 Z 9279-4H C07F 7/08 F 8018-4H

Claims (2)

[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, and R ↑ 4 represents a hydrogen atom, a trisubstituted silyl group, —CO ↓ 2 R ↑ 5 or —CH ↓. 2 OR
↑ 6 is represented, R ↑ 5 represents a hydrogen atom or a lower alkyl group, and R ↑ 6 represents a hydrogen atom or a hydroxyl-protecting group. ) 7-octyne-1-ene derivative represented by 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): (In the formula, R ↑ 4 is as defined above.) The acetylene derivative represented by the formula is reacted in the presence of a basic substance or a Grignard reagent, and the hydroxyl group is protected or deprotected as necessary. 7- according to claim 1
Method for producing octyne-1-ene derivative.