JPH04305548A - Halogeno allyl alcohol derivative - Google Patents

Abstract

PURPOSE:To provide a novel halogeno allyl alcohol derivative useful as an intermediate enabling to produce an A ring part synthon useful for the synthesis of 1alpha-hydroxyvitamin D derivatives from readily available inexpensive raw materials in a relatively short process. CONSTITUTION:A compound of formula I (R<1> is CO2R<3>, CHO, CH=CHCO2R<4>; R2 is H, the protecting group of OH; one of Y, Z is H, and the other is OH, or Y and Z together are O; X is halogen; R<3>, R<4> are lower alkyl), e.g. 6-bromo-5- hydroxy-3-oxo-6-heptenoic acid methyl eater. A compound of formula II in the compound is obtained by reacting acetoacetic acid diester dianion with a 2-halogenoacrolein in an inert solvent at a temperature of -100 to 0$0C and, if necessary, protecting the OH group. The above-mentioned vitamin D derivative derived from the compound is expected to be effective for the treatment of calcium metabolism-defective diseases such as chronic renal failures and also for the treatment of cell differentiation function-abnormalized diseases such as psoriasis.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to halogenoallylic alcohol derivatives. The halogenoallylic alcohol derivative of the present invention contains 1α-hydroxyvitamin D3, 1α,
25-dihydroxyvitamin D3, 1α-hydroxyvitamin D2, 24-epi-1α,25-dihydroxyvitamin D2, 2β-hydroxypropoxy-1α
, 25-dihydroxyvitamin D3 and other 1α-hydroxyvitamin D derivatives, and 1α,24-dihydroxy, which is expected to be effective in treating skin diseases such as psoriasis and diseases with abnormalities in cell differentiation function such as myeloid leukemia. It is useful as a synthetic intermediate for 1α-hydroxyvitamin D derivatives such as vitamin D3, 22-oxa-1α,25-dihydroxyvitamin D3, and 22-dehydro-26,27-cyclo-1α,24-dihydroxyvitamin D3.

0002

[Prior Art] In recent years, with the progress of vitamin D research, many 1α-hydroxyvitamin D derivatives, including the above-mentioned 1α-hydroxyvitamin D derivatives, have been developed as pharmaceuticals. Convergent synthetic methods are useful for synthesizing metabolites, decomposition products, or labeled compounds that are essential for developing pharmaceuticals.

[0003] A method for synthesizing a convergent 1α-hydroxyvitamin D derivative in which the A ring portion of the 1α-hydroxyvitamin D derivative is synthesized and bonded to the CD ring is as follows.
For example, a method using (S)-(+)-carvone as a raw material (
Journal of Organic Chemistry (Jo
urnal of Organic Chemistry
y) Vol. 51, p. 3098 (1986)), (R
)-(-)-method using carvone as raw material (Journal/
of Organic Chemistry (Journal)
of Organic Chemistry) No. 54
Vol. 3515 (1989)), method using cyclohexene dicarboxylic acid ester (tetrahedron
Letters (Tetrahedron Letters)
) Vol. 31, p. 1577 (1990)) are known.

0004

[Problems to be Solved by the Invention] However, these methods for synthesizing A-ring synthons have drawbacks such as expensive starting materials and long reaction steps to reach key intermediates, making them difficult to use industrially. Implementation is not always satisfactory.

Therefore, the object of the present invention is to use readily available and inexpensive raw materials as starting materials to produce 1α-
The object of the present invention is to provide a novel synthetic intermediate that can be derived from an A-ring synthon useful for the synthesis of hydroxyvitamin D derivatives.

[0006]

[Means for Solving the Problems] According to the present invention, the above object is achieved by formula (1)

[Formula 2] (In the formula, R1 represents a -CO2 R3 group, -CHO group or -CH=CHCO2 R4 group, R2 represents a hydrogen atom or a hydroxyl group protecting group, and one of Y and Z represents a hydrogen atom. , the other represents a hydroxyl group or a protected hydroxyl group, or Y and Z together represent an oxygen atom,
X represents a halogen atom, and R3 and R4 each represent a lower alkyl group. ) is achieved by providing a halogenoallylic alcohol derivative (I) shown in (I).

The protecting group for the hydroxyl group represented by R2, Y and Z, respectively, may be any substituent as long as it protects the hydroxyl group, such as trimethylsilyl group, triethylsilyl group, triisopropyl group, etc. Silyl group, tert-butyldimethylsilyl group, tert
-Trisubstituted silyl groups such as butyldiphenylsilyl groups; 1-substituted silyl groups such as methoxymethyl groups, methoxyethoxymethyl groups, 1-(ethoxy)ethyl groups, and methoxyisopropyl groups;
(Alkoxy)alkyl group; tetrahydrofuranyl group,
Examples include 2-oxacycloalkyl groups such as tetrahydropyranyl groups.

The lower alkyl groups represented by R3 and R4 may be either linear or branched,
Examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, and hexyl group.

The halogen atom represented by X may include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, with a bromine atom or an iodine atom being preferred.

The halogenoallylic alcohol derivative (I) of the present invention can be produced, for example, by the following method. That is, after preparing the dianion of acetoacetate according to a conventional method, 2-halogenoacrolein is reacted in an inert solvent such as diethyl ether, tetrahydrofuran, or dimethoxyethane at a temperature in the range of -100 to 0°C, and as necessary. By protecting the hydroxyl group accordingly, formula (I-1)

A halogenoallyl alcohol derivative (hereinafter referred to as halogenoallyl alcohol derivative (I-1)) represented by the formula (wherein R2, X and R3 are as defined above) can be obtained. .

[0011] Halogenoallylic alcohol derivative (I-1
) by treating with a reducing agent and protecting the hydroxyl group as necessary, the formula (I-2)

embedded image (wherein, R2, X and R3 are as defined above, and Y and Z represent a hydroxyl group or a protected hydroxyl group) I-2)) can be obtained. Any reducing agent may be used as long as it can stereoselectively reduce the ketone moiety without reducing the ester moiety, but in order to obtain 1,3-anti-diol, tetramethylammonium triacetoxyborohydride is used. Particularly preferred, and for obtaining 1,3-syn-diol, is the triethylborane-sodium borohydride combination. The amount of these reducing agents used is approximately 1.0 to 2.0 equivalents relative to the halogenoallyl alcohol derivative (I-1), and the reaction temperature is -80 to
It is carried out at a temperature in the range of 20°C.

[0012] Next, the ester moiety of the halogenoallylic alcohol derivative (I-2) is reduced directly to an aldehyde, or by reducing it to an alcohol and then oxidizing it to an aldehyde, (Formula I-3)

It is possible to obtain a halogenoallylic alcohol derivative (hereinafter referred to as halogenoallylic alcohol derivative (I-3)) represented by the formula (wherein R2, Y, Z and X are as defined above). can. As the reducing agent, diisobutylaluminum hydride is particularly preferable for direct reduction to an aldehyde, and halogenoallylic alcohol derivatives (
It can be produced by using about 1.0 to 1.5 molar equivalent of diisobutylaluminum hydride to I-2) and reacting at a temperature in the range of -100 to 0°C.

[0013] When reducing the alcohol to an alcohol, preferred reducing agents include lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium bis(methoxyethoxy)aluminum hydride, and diisobutylaluminum hydride. The amount of these reducing agents used is approximately 2.0 to 10 equivalents relative to the halogenoallyl alcohol derivative (I-2), and -8
It can be produced by reacting at a temperature in the range of 0 to 30°C.

Methods for oxidizing the resulting alcohol to aldehyde include dimethyl sulfoxide-oxalyl chloride-triethylamine, pyridinium chlorochromate,
Various known methods commonly known as oxidation methods to aldehydes such as ruthenium chloride-N-methylmorpholine oxide can be applied.

Furthermore, the halogenoallylic alcohol derivative (I-3) was prepared by Wittig-Horner.
-Horner) reaction, by forming an olefin, the formula (I-4)

embedded image (wherein R2, Y, Z, X and R4 are as defined above) (hereinafter referred to as halogenoallylic alcohol derivative (I-4)
). ) can be obtained.

[0016] Wittig-Horner (Wittig
-Horner) reaction, when a reagent prepared from dialkyl alkoxycarbonylmethylphosphonate and a base such as sodium hydride or lithium diisopropylamide is used, the double bond formed will be trans-coordinated, and 18-crown-6 A cis-coordinated double bond can be generated using a reagent prepared from ditrifluoroethyl alkoxycarbonylmethylphosphonate and a base such as potassium hexamethyldisilazide in the presence of a crown ether such as .

Isolation and purification of the halogenoallyl alcohol derivative (I) thus obtained from the reaction mixture is carried out in the same manner as in the conventional isolation and purification of organic compounds. For example, the reaction mixture is poured into ice water, extracted with an organic solvent such as diethyl ether,
Wash sequentially with cold dilute hydrochloric acid, sodium bicarbonate solution, and brine, dry, and concentrate to obtain a crude product, and if necessary, purify by recrystallization, chromatography, etc. to obtain halogenoallyl alcohol derivative (I). be able to.

The halogenoallylic alcohol derivatives (I-1), (I-2) and (I-3) of the present invention are synthetic intermediates of the halogenoallylic alcohol derivative (I-4),
By cyclizing the halogenoallylic alcohol derivative (I-4) using a palladium catalyst, it can be converted into a cyclohexylidene acetic acid derivative useful for the synthesis of 1α-hydroxyvitamin D derivatives.

Here, as the palladium catalyst, for example,
Tetrahedron No. 42
Volume, No. 16, pp. 4361-4401 (1986), Accounts of Chemical Research
of Chemical Research)
Volume 13, No. 11, pp. 385-393, "Organic Synthesis with Palladium Compounds" by Jiro Tsuji (published by Springer-Verlag, 1980)
Palladium Compounds” J.
Tuji, Springer-Verlag (198
0)) and “Palladium Reagents in Organic Synthesis” by Richard F. Heck
(Published by Academic Press, 1985) (“Pa
lladium Reagents in Orga
nic Synthesis” Richard F.
．． Heck, Academic Press (19
Various palladium complexes described in 85)) can be used. Preferably palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II)
Acetate, bis(tri-o-tolylphosphine)palladium(II) Acetate, bis(triphenylphosphine)palladium(II) Chloride, bis(acetonitrile)palladium(II) Chloride, tetrakis(triphenylphosphine)palladium, tris(
dibenzylideneacetone) dipalladium, chloroform, etc., and these palladium compounds and palladium in an amount of 1 to 4 molar equivalents of triphenylphosphine, tritolylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis (diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-1
, 1'-binaphthyl, or combinations with phosphites such as trimethyl phosphite, triethyl phosphite, etc., and the amount of these palladium catalysts used is less than that of the halogenoallylic alcohol. 0.001 for derivative (I-4)
~1 equivalent, preferably about 0.01-0.2 equivalent.

The reaction temperature during cyclization depends on the solvent used, but is usually 0 to 120°C, preferably 20 to 80°C.
It is ℃. Although the reaction time depends on the reaction temperature, it is usually 5
The time period is from minutes to 100 hours, preferably from 1 to 30 hours. The reaction is carried out in an organic solvent, and examples of the solvent include hydrocarbon solvents such as hexane and benzene, ether solvents such as ethyl ether, tetrahydrofuran, and dioxane,
Alcohol solvents such as methanol, ethanol, propyl alcohol, and t-butyl alcohol, acetonitrile, dimethylformamide, dimethyl sulfoxide, and chloroform are used, and acetonitrile is preferred.

[0021]

[Examples] The present invention will be specifically explained below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples in any way.

Example 1

[Chemical formula 7] Under an argon atmosphere, diisopropylamine (2.9 ml
, 21 mmol) of tetrahydrofuran (THF) (8
n-butyllithium (1.0 ml) solution at -78°C.
58M hexane solution 13ml 21mmol
) was added dropwise, the temperature was raised to 0°C, and the mixture was stirred for 10 minutes. Methyl acetoacetate (1.13 ml, 10
mmol) THF solution (10 ml) was added dropwise at 0°C,
The mixture was stirred for an additional 30 minutes. After cooling this solution to -78°C, α-bromoacrolein (1.35 g, 10 m
mol) of THF solution (10 ml) was slowly added dropwise,
Stir for 20 minutes. A saturated aqueous ammonium chloride solution was added to the resulting reaction solution, followed by extraction with ethyl acetate. The resulting extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel C-300, hexane:ethyl acetate = 3:2) to obtain methyl 6-bromo-5-hydroxy-3-oxo-6-heptenoate ( 1.88 g, yield 75%) was obtained. 1 H-NMR spectrum (90 MHz, CDCl3
) δ: 5.95 (brs, 1H), 3.45 (d, 2H)
, 5.58 (d, 1H), 2.95 (m, 2H), 4.
62 (m, 1H), 2.25 (s, 1H)
, 3.71 (s, 3H)

Example 2

[Chemical formula 8] Acetic acid (2 ml) was added to tetramethylammonium borohydride (212 mg, 2.4 mmol) under an argon atmosphere.
was added dropwise at 0°C, and then stirred at room temperature for 15 minutes. Methyl 6-bromo-5-hydroxy-3-oxo-6-heptenoate (300ml) obtained in Example 1 was added to the solution cooled to 0°C again and diluted with acetonitrile (2ml).
g, 1.2 mmol) in acetonitrile (3 ml) was added dropwise. After stirring the obtained reaction solution at 0°C for 2 hours, water was added and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. Distilled away. The obtained residue was purified by column chromatography (silica gel C-300, hexane: ethyl acetate = 3:1) to obtain rel-(3S,5S)-6-bromo-3,5-dihydroxy- having the following physical properties. Methyl 6-heptenoate (225 mg, yield 75
%) was obtained. 1 H-NMR spectrum (90 MHz, CDCl3
) δ: 6.04 (brs, 1H), 3.72 (s, 3H)
, 5.60 (brs, 1H), 2.55 (d li
ke, 2H), 4.40 (m, 4H),
1.88 (t like, 2H)

Example 3

embedded image Methyl rel-(3S,5S)-6-bromo-3,5-dihydroxy-6-heptenoate (3
4 mg, 0.13 mmol) and imidazole (100 m
g, 1.47 mmol) was dissolved in N,N-dimethylformamide (0.3 ml) and t-butyldimethylsilyl chloride (45 mg, 0.3 mmol) was added.
Stirred at room temperature for 1 hour. Water was added to the resulting reaction solution, extracted with ether, and the resulting extract was washed with saturated brine.
After drying over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was subjected to column chromatography (
Silica gel C-300, hexane: ethyl acetate = 8:1
) and has the following physical properties: rel-(3S,5S
)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)-6-heptenoate (65 mg, yield 95%) was obtained. 1 H-NMR spectrum (90 MHz, CDCl3
) δ: 5.82 (brs, 1H), 2.48 (m, 1H)
, 5.50 (brs, 1H), 1.12-2.85
(m, 3H), 4.20 (m, 2H), 0
．． 85 (s x 2, 18H), 3.62 (s, 3H),
0.05 (s×2, 12H)

Example 4

embedded image Under an argon atmosphere, rel-(3S
,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)-6-heptenoate (120m
Diisobutylaluminum hydride (1M toluene solution, 0.3 ml, 0.3 mmol) was added dropwise to a toluene (3 ml) solution of the solution (1M toluene solution, 0.3 ml, 0.3 mmol) at -78°C, and the mixture was stirred for 30 minutes. Isopropanol (0.5 ml) and water (0.5 ml) were added to the resulting reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 20 minutes. Silica gel (200 mg) and anhydrous magnesium sulfate were added to the resulting reaction solution, and the mixture was further stirred for 1 hour and filtered. The solvent was distilled off, and rel-(3S,5S)-6-bromo having the following physical properties was obtained. -3,5-di-(t-butyldimethylsilyloxy)-6-heptenal (101 mg, yield 95%) was obtained. 1 H-NMR spectrum (90 MHz, CDCl3
) δ: 9.74 (s, 1H), 2.55
(m, 1H), 5.80 (brs, 1H),
1.10-2.00 (m, 3H), 5.49 (brs
, 1H), 0.88 (s x 2, 18H), 3.60~4
．． 30 (m, 2H), 0.05 (s x 2, 12H)

0
Example 5

[Chemical formula 11] Under argon atmosphere, 18-crown-6 (304 mg,
Di(2,2,2-trifluoroethyl) methoxycarbonylmethylphosphonate (63 μl, 0.3 mmol) was added to a THF (2 ml) solution of 1.15 mmol) at -78°C.
After stirring for 10 minutes, add potassium hexamethyldisilazide (0.6 ml of 0.5 M toluene solution, 0.6 ml of 0.5 M toluene solution,
3 mmol) was added dropwise, and the mixture was further stirred for 10 minutes. Add rel-(3S,5S)-6 obtained in Example 4 to this solution.
-Bromo-3,5-di-(t-butyldimethylsilyloxy)-6-heptenal (101 mg, 0.22 mm
ol) in THF (3 ml) was added dropwise at the same temperature.
Stir for a minute. Water was added to the obtained reaction solution and extracted with ether. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel C-300, hexane:ethyl acetate = 10:1) to obtain rel-(5R,7S)-(2
Z)-8-bromo-5,7-di-(t-butyldimethylsilyloxy)-2,8-nonadienoate (89m
g, yield 80%). 1H-NMR spectrum (400MHz, CDCl3
) δ: 6.34 (dt, 1H), 3.05 (m, 1H
), 5.85 (d, 1H), 2.65 (m, 1H), 5
．． 81 (s, 1H), 1.75 (m, 1H
), 5.45 (s, 1H), 1.60 (m
, 1H), 4.15 (t, 1H), 0.83 (s×2,
18H), 3.80 (t like, 1H), 0.0
4 (s x 2, 12H), 3.65 (s, 3H)

Example 6 Methyl rel-(3S,5S)-6-bromo-3,5-dihydroxy-6-heptenoate (0
．． 253 mg, 1.0 mmol) in methylene chloride (5 m
l), add a catalytic amount of p-toluenesulfonic acid,
Next, dihydropyran (0.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the resulting reaction solution, and the mixture was extracted with ethyl ether. The obtained extract was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off from it under reduced pressure. By purifying the obtained residue by silica gel column chromatography, re
Methyl l-(3S,5S)-6-bromo-3,5-di(tetrahydropyran-2-yloxy)-6-heptenoate (400 mg, yield 95%) was obtained. FD mass spectrum [M] + 420,422

Example 7 Methyl rel-(3S,5S)-6-bromo-3,5-dihydroxy-6-heptenoate (0
．． 253 mg, 1.0 mmol) was dissolved in ethyl vinyl ether (2 ml), and pyridinium p-
A catalytic amount of toluenesulfonate was added and the mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the resulting reaction solution, and the mixture was extracted with ethyl ether. The obtained extract was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain rel-(3S,5S)-6-bromo-3,5-di Methyl (1-ethoxyethoxy)-6-heptenoate (405 mg, yield 100%) was obtained. FD mass spectrum [M] + 396,398

Example 8 In Example 4, rel-(3S,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)
rel-(3S,5S)-6 obtained in Example 6 instead of methyl-6-heptenoate (0.23 mmol)
rel-(3S,5S )-6-bromo-3,
5-di(tetrahydropyran-2-yloxy)-6-
Heptenal (71 mg, yield 79%) was obtained. FD mass spectrum [M] + 390,392

Example 9 In Example 4, rel-(3S,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)
rel-(3S,5S)-6 obtained in Example 7 instead of methyl-6-heptenoate (0.23 mmol)
-bromo-3,5-di(1-ethoxyethoxy)-6-
Reaction and separation and purification were carried out in the same manner as in Example 4, except that 0.23 mmol of methyl heptenoate was used.
1-(3S,5S)-6-bromo-3,5-di(1-ethoxyethoxy)-6-heptenal (68 mg, yield 81%) was obtained. FD mass spectrum [M] + 366,368

Example 10 In Example 5, rel-(3S,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)
-6-heptenal (0.22 mmol) was replaced with rel-(3S,5S)-6-bromo-3,5-di(tetrahydropyran-2-yloxy)-6-heptenal obtained in Example 8. By reacting and separating and purifying in the same manner as in Example 5 except that .22 mmol was used, rel-(5R,7S)-(2Z)-8-bromo-5
,7-di-(tetrahydropyran-2-yloxy)-
Methyl 2,8-nonadienoate (78 mg, yield 79%)
I got it. FD mass spectrum [M] + 446,448

Example 11 In Example 5, rel-(3S,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)
-6-heptenal (0.22 mmol) was replaced with 0.22 mmol of rel-(3S,5S)-6-bromo-3,5-di(1-ethoxyethoxy)-6-heptenal obtained in Example 9. rel-(5
R,7S)-(2Z)-8-bromo-5,7-di-(1
-ethoxyethoxy)-2,8-methyl nonadienoate (
66 mg, yield 71%) was obtained. FD mass spectrum [M] + 422,424

Example 12 Under an argon atmosphere, 55% sodium hydride (6.5 m
g, 0.15 mmol) in THF (1 ml) was added ethyl diethylphosphonoacetate (33 μl, 0.15 mmol).
rel-(3) was added at 0°C and stirred for 5 minutes.
S,5S)-6-bromo-3,5-di-(t-butyldimethylsilyloxy)-6-heptenal (58 mg,
A solution of 0.13 mmol) in THF (1 ml) was added dropwise at the same temperature, and the mixture was stirred for 30 minutes. After the reaction, water was added and extracted with ether, and the resulting extract was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel C-300,
Purified with hexane: ethyl acetate = 10:1) and rel
Ethyl -(5R,7S)-(2E)-8-bromo-5,7-di-(t-butyldimethylsilyloxy)-2,8-nonadienoate (48 mg, yield 72%) was obtained. 1 H-NMR spectrum (90MHz) δ: 6.95
(m, 1H), 2.35 (m, 2H), 5.7
5 (d, 1H), 1.79 (m, 2H), 5.74
(brs, 1H), 1.19 (t, 3H), 5.45 (
brs, 1H), 0.82(s, 18H), 4.12(
q, 2H), 0.01 (s, 12H) 3.82 (m
,2H),

Reference example 1

embedded image rel-(5R,7S)-(2Z)-8-bromo-5,
7-di-(t-butyldimethylsilyloxy)-2,8
-Methyl nonadienoate (38 mg, 0.075 mmol
), palladium acetate (4 mg, 0.018 mmol),
Triphenylphosphine (9.7mg, 0.037mm
ol), potassium carbonate (25 mg, 0.18 mmol)
A solution of the mixture in acetonitrile (6 ml) was heated under reflux for 24 hours.
Stir for hours. The resulting reaction solution was cooled to room temperature, filtered through Celite, and then the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel C-300, hexane:ethyl ether = 20:1) to obtain rel-(3S,5R)- having the following physical properties.
(2-methylene-3,5-di-(t-butyldimethylsilyloxy)cyclohexylidene)methyl acetate (29m
g, yield 90%) was obtained. 1H-NMR spectrum (400MHz, CDCl3
) δ: 5.60 (s, 1H), 2.37 (dd, 1H
), 5.15 (s, 1H), 2.22 (dd, 1H),
4.96 (s, 1H), 1.92 (m, 1H)
, 4.52 (m, 1H), 1.75 (m, 1H
), 4.22 (m, 1H), 0.87 (s×2, 1
8H), 3.61(s, 3H), 0.05(s
×2,12H)

Reference Examples 2 and 3 In Reference Example 1, rel-(5R,7S)-(2Z)
Methyl -8-bromo-5,7-di-(t-butyldimethylsilyloxy)-2,8-nonadienoate (0.075
mmol) instead of rel-(5R,7S)-(2Z
)-8-bromo-5,7-di-(tetrahydropyran-
Methyl 2-yloxy)-2,8-nonadienoate or rel-(5R,7S)-(2Z)-8-bromo-5,
By reacting and separating and purifying in the same manner as in Example 1 except that 0.075 mmol of methyl 7-di-(1-ethoxyethoxy)-2,8-nonadienoate was used,
rel-(3S,5R)-(2-methylene-3,5-di(tetrahydropyran-2-yloxy)cyclohexylidene)methyl acetate (24 mg, yield 87%) or r
el-(3S,5R)-(2-methylene-3,5-di(
Methyl 1-ethoxyethoxy)cyclohexylidene)acetate (20 mg, yield 78%) was obtained. FD mass spectrum [M] + 366 or [M] + 342

[0036]
Reference example 4 rel-(5R,7S)-(2E)-8-bromo-5,
7-di-(t-butyldimethylsilyloxy)-2,8
-Ethyl nonadienoate (24 mg, 0.046 mmol
), palladium acetate (2 mg, 0.009 mmol),
Triphenylphosphine (4.8mg, 0.018mm
ol), potassium carbonate (13 mg, 0.09 mmol)
A solution of the mixture in acetonitrile (5 ml) was heated under reflux for 24 hours.
Stir for hours. The resulting reaction solution was cooled to room temperature, filtered through Celite, and then the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel C-300, hexane:ethyl ether = 10:1) to obtain rel-(3S,5R)- having the following physical properties.
(2-methylene-3,5-di-(t-butyldimethylsilyloxy)cyclohexylidene)ethyl acetate (17m
g, yield 86%). 1 H-NMR spectrum (900 MHz, CDCl3
) δ: 5.91 (s, 1H), 2.00 (m, 1H)
, 5.18 (s, 1H), 1.62 (m, 1H),
5.13 (s, 1H), 1.28 (t, 3H)
, 4.17 (q, 2H), 0.92 (s, 9H
), 4.07 (m, 2H), 0.90 (s, 9
H), 3.75 (m, 1H), 0.10 (s,
6H), 2.22 (m, 1H), 0.07 (s
,6H)

[0037]

Effects of the Invention The compounds of the present invention can be obtained in a relatively short process using easily available and inexpensive raw materials as starting materials.
A synthetic intermediate for α-hydroxyvitamin D derivatives,
The A-ring synthon can be easily produced by cyclizing the compound of the present invention.

Claims (1)

[Claims] Claim 1: Formula (1) [Formula 1] (wherein, R1 represents a -CO2 R3 group, -CHO group, or -CH=CHCO2 R4 group, R2 represents a hydrogen atom or a hydroxyl group-protecting group, and Y and Z each represents a hydrogen atom and the other represents a hydroxyl group or a protected hydroxyl group, or Y and Z together represent an oxygen atom,
X represents a halogen atom, and R3 and R4 each represent a lower alkyl group. ) Halogenoallylic alcohol derivatives.