JP3249847B2 - Method for producing Z-cyclohexylideneacetic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing a novel Z-cyclohexylideneacetic acid derivative. The Z-cyclohexylideneacetic acid derivative produced according to the present invention is effective for treating calcium metabolic deficiencies such as chronic renal failure, hypoparathyroidism, osteomalacia and osteoporosis.
- hydroxyvitamin D _3, 1α, 25- dihydroxyvitamin D _3, 1.alpha.-hydroxy vitamin D _2, 24- epi 1 alpha, 25-dihydroxyvitamin D _2, 2.beta.
1-α-hydroxyvitamin D derivatives such as (3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D ₃ , and are effective in treating skin diseases such as psoriasis and diseases in which the cell differentiation function is abnormal such as myeloid leukemia. Expected 1α, 24-dihydroxyvitamin D ₃ , 22
-Oxa-1α, 25-dihydroxyvitamin D ₃ , 2
It is useful as an intermediate for synthesizing 1α-hydroxyvitamin D derivatives such as 2-dehydro26,27-cyclo-1α, 24-dihydroxyvitamin D ₃ .

[0002]

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

[0003] In a method for synthesizing a convergent 1α-hydroxyvitamin D derivative in which a compound corresponding to the A ring of a 1α-hydroxyvitamin D derivative is synthesized and bonded to a compound corresponding to a CD ring, Z-cyclohexylide is used as the compound corresponding to the A ring. A method using Z-cyclohexylideneethyldiphenylphosphine oxide obtained from a denacetic acid derivative is known. For example, Journal of Organic Chemistry
ry), Vol. 51, p. 3098 (1986)
(S)-(+)-Carvone was used as a raw material, and Z- (2-methylene-) was added via E- and ethyl Z- (2-methylene-3,5-dihydroxycyclohexylidene) acetate.
A method for synthesizing 3,5-di (tert-butyldimethylsilyloxy) cyclohexylidene) ethyldiphenylphosphine oxide (hereinafter referred to as conventional method (1))
Has been reported and Tetrahedron Letters (Te
trahedron Letters), vol. 31, p. 1577 (19
1990), using cyclohexene dicarboxylic acid ester as a raw material, and using 6,8-di (tert-butyldimethylsilyloxy) -3,4,4a, 5,6,7,8,8a
A method for synthesizing methyl Z- (2-methylene-3,5-di (tert-butyldimethylsilyloxy) cyclohexylidene) acetate via -octahydrobenzo-2-pyran-1H-3-one (hereinafter referred to as Is referred to as conventional method (2).)
Have been reported.

[0004]

The above conventional method (2)
Has disadvantages such as a long reaction step leading to methyl Z- (2-methylene-3,5-di (tert-butyldimethylsilyloxy) cyclohexylidene) acetate and an expensive reactant. I have. In the conventional method (1), since the configuration of the cyclohexylidene moiety cannot be controlled, Z-
In order to selectively synthesize (2-methylene-3,5-dihydroxycyclohexylidene) ethyl acetate, E-
It is necessary to isomerize ethyl (2-methylene-3,5-dihydroxycyclohexylidene) acetate into a Z-isomer by a photoreaction, and mass synthesis is difficult.
It is difficult to employ when producing a cyclohexylideneacetic acid derivative.

Further, 1α-hydroxyvitamin D having a substituent at the 2β-position such as 2β- (3-hydroxypropoxy) -1α, 25-dihydroxyvitamin D ₃
A method for producing an intermediate applicable to a derivative has not been conventionally known.

Accordingly, an object of the present invention is to provide a highly selective Z-cyclohexylideneacetic acid derivative which is useful as an intermediate for synthesizing 1α-hydroxyvitamin D derivatives in a relatively short process using easily available and inexpensive raw materials. To provide a manufacturing method.

[0007]

According to the present invention, the above objects have been achieved by the general formula (I)

[0008]

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( Wherein R ¹ , R ² and R ³ each represent a hydrogen atom or a hydroxyl-protecting group, and A represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group). This is abbreviated as cyclohexanone derivative (I)) and a compound represented by general formula (II)

[0010]

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Wherein R ⁴ represents a lower alkyl group;
R ⁵ , R ⁶ and R ⁷ each represent a lower alkyl group or an aryl group. Wherein the silyl acetate derivative (hereinafter abbreviated as silyl acetate derivative (II)) is reacted in the presence of a base.

[0012]

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Wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above (hereinafter referred to as Z-cyclohexylidene acetic acid). Derivative (III)).

In the above general formulas (I) to (III), R
^As the protecting group for the hydroxyl group represented by ¹ , R ² and R ³ , and the protecting group for the hydroxyl group when A represents a protected hydroxyl group, any substituent can be used as long as it is a substituent that protects the hydroxyl group. For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-
Trisubstituted silyl groups such as butyldimethylsilyl group and tert-butyldiphenylsilyl group; 1-alkoxyalkyl groups such as methoxymethyl group, methoxyethoxymethyl group, 1-ethoxyethyl group and 1-methoxy-1-methylethyl group; 2-oxacycloalkyl groups such as tetrahydrofuranyl group and tetrahydropyranyl group; benzyl group, p
And arylmethyl groups such as -methoxybenzyl group and diphenylmethyl group. As the hydroxyl-protecting group, a trisubstituted silyl group such as a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group is preferable. Also, if it represents a hydroxyl group A is protected, ethylidene group and the protecting group of the hydroxyl group and R ¹ together, isopropylidene group, a cyclic acetal by an optionally substituted methylene group such as benzylidene group formed May be. Further, when A represents a protected hydroxyl group, examples of the protecting group for the hydroxyl group include an acyl group such as an acetyl group, a propanoyl group, a butyryl group, a benzoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, and an allyloxy group. Examples thereof include an alkoxycarbonyl group such as a carbonyl group.

The lower alkyl group represented by R ⁴ , R ⁵ , R ⁶ and R ⁷ includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-
Butyl, pentyl, hexyl and the like ;
Examples of the aryl group represented by ⁵ , R ⁶ and R ⁷ include, for example,
Examples include a phenyl group, a tolyl group and a pentafluorophenyl group.

The base used in the present invention includes:
Strong bases such as lithium diisopropylamide, lithium hexamethyldisilazide, and lithium dicyclohexylamide can be exemplified. Among them, lithium hexamethyldisilazide and lithium dicyclohexylamide are particularly preferable. The amount of the base used is preferably in the range of 0.8 to 2.0 equivalents, more preferably in the range of 0.9 to 1.2 equivalents, based on the starting material silyl acetate derivative (II). preferable.

The above base is prepared by reacting the corresponding amine with an organolithium compound such as butyllithium, methyllithium or tert-butyllithium in an inert solvent such as tetrahydrofuran or diethylether according to a conventional method. can do. The organolithium compound is preferably used in a range of 0.5 to 1.2 equivalents to the amine, and more preferably in a range of 0.8 to 1.0 equivalents. The preparation temperature is 0 to -1
Preferably, a temperature in the range of 00 ° C. is used,
More preferably, a temperature in the range of -78 ° C is employed.

The silyl acetate derivative (II) is used in an amount of 0.5 to 0.5% based on the cyclohexanone derivative (I) as a raw material.
Preferably used in the range of 2.0 equivalents,
More preferably, it is used in the range of 1.2 equivalents.

The reaction can be carried out at a temperature in the range of 30 to -100 ° C, but more preferably at a temperature in the range of 0 to -78 ° C. Further, the temperature may be raised to room temperature in order to complete the reaction.

Isolation of the Z-cyclohexylideneacetic acid derivative (III) thus obtained from the reaction mixture.
Purification is generally performed by the same method as that used for isolating and purifying an organic compound from a reaction mixture. For example, the reaction mixture is treated with dilute hydrochloric acid, an aqueous solution of ammonium chloride, etc., extracted with an organic solvent such as diethyl ether, ethyl acetate, etc., and the extract is washed sequentially with an aqueous solution of sodium bicarbonate, brine, etc., and anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. And then concentrated to obtain a crude product. The crude product is purified by recrystallization, chromatography or the like, if necessary, to give a Z-cyclohexylideneacetic acid derivative (III).
Get.

Cyclohexanone derivative (I) as raw material
Uses inexpensive mannitol or tartaric acid as a raw material, “Preliminary Proceedings of the 61st Annual Meeting of the Chemical Society of Japan, 1D227 (199
0, published by The Chemical Society of Japan) and "Journal of American Chemical Society (J. Am. C.)
hem. Soc.), 113, 2789 (1991).
Year)), a 1,2-epoxy-5-hexene-3,4-diol derivative or a 1,2-epoxy- compound represented by the following general formula (VIII).
It can be produced according to the following reaction step A using a 5-hexen-4-ol derivative.

[0022]

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In the above formula, R ¹ , R ² , R ³ and A are as defined above.

A 1,2-epoxy-5-hexene-3,4-diol derivative or a 1,2-epoxy-5-hexen-4-ol derivative represented by the general formula (VIII) is converted into methanol, ethanol, tetrahydrofuran, By reacting with a cyanating agent such as potassium cyanide, sodium cyanide or magnesium cyanide in an inert solvent such as dimethylformamide, a corresponding nitrile derivative represented by the general formula (VII) is obtained.

The nitrile derivative represented by the general formula (VII) is protected with a hydroxyl group as required, and then reduced with diisopropylaluminum hydride, diisobutylaluminum hydride or the like according to a conventional method to obtain a compound represented by the general formula (VI) The aldehyde derivative represented by the formula (1) is obtained.

The aldehyde derivative represented by the general formula (VI) is protected with a hydroxyl group, if necessary, and then reacted with hydroxylamine according to a conventional method to obtain the oxime derivative represented by the general formula (V). .

The oxime derivative represented by the general formula (V) is treated with an oxime derivative in an inert solvent such as methylene chloride, chloroform, dichloroethane, toluene and dioxane in the presence or absence of a catalyst such as triethylamine or pyridine. The nitrile oxide formed by reacting the derivative with an oxidizing agent such as an aqueous solution of sodium hypochlorite in an amount of 1 to 20 equivalents and tert-butyl hypochlorite at -20 to 30 ° C. is converted to a 1,3-dipole. The addition-cyclized isoxazole derivative represented by the general formula (IV) is obtained.

The isoxazole derivative represented by the general formula (IV) is converted into an inert solvent such as methanol, ethanol or tetrahydrofuran or a mixed solvent of the inert solvent and water, if necessary, such as boric acid or acetic acid. Hydrogenolysis using a catalyst such as Raney nickel, palladium-carbon, or platinum oxide in the presence of an acid and, if necessary, protecting or deprotecting a hydroxyl group, the cyclohexanone derivative (I) can be obtained. .

The cyclohexylideneacetic acid derivative (III) obtained according to the present invention is useful as a synthetic intermediate for a 1α-hydroxyvitamin D derivative. For example, the 2-hydroxymethyl-3,5-di (tert.
-Butyldimethylsilyloxy) cyclohexylideneacetate is described in Tetrahedron Letters, Vol. 31,
Pp. 1577 (1990) "to 2-methylene-3,5-di (tert-butyldimethylsilyloxy) cyclohexylideneethanol.

[0030]

The present invention will be described below in detail with reference to examples. Note that the present invention is not limited by these examples.

Reference Example 1 [Synthesis of 4,5- (dimethylmethylenedioxy) -3-hydroxy-6-heptenenitrile] 50 ml of a saturated aqueous solution of magnesium sulfate was cooled to 10 ° C, and sodium cyanide was added to the aqueous solution. 23 g were added little by little so as not to generate heat. 10 ° C.
After stirring for 45 minutes with 1,2-epoxy-3,4-
(Dimethylmethylenedioxy) -5-hexene 7.61
g was dissolved in 30 ml of methanol, and a solution obtained was added little by little so as not to generate heat. After the reaction solution was stirred at room temperature for 2 hours, it was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the following properties 4,
5- (dimethylmethylenedioxy) -3-hydroxy-
2.11 g of 6-heptenenitrile was obtained. ¹ H- NMR spectrum (90 MHz, CCl ₄ ) δ: 5.94 (ddd, 1H, J = 7.6 Hz, 10.7H)
z and 18.3 Hz), 5.25 to 5.55 (m, 2
H), 4.40 (dd, 1H, J = 7.6 Hz and 8.0 Hz), 4.08 (m, 1H), 3.76 (d
d, 1H, J = 5.8 Hz and 7.7 Hz), 2.6
4 (d, 1H, J = 5.9 Hz), 2.63 (d, 1
H, 6.4 Hz), 2.46 (brs, 1H), 1.4.
2 (s, 6H) IR spectrum (neat, cm ^-1 ) 3446, 3086, 2886, 2934, 2892,
2250, 1645, 1456, 1411, 1372,
1215,1168,1121,1066,991,9
33,873,810,511

Reference Example 2 [Synthesis of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenenitrile] 4,5- (dimethylmethylenedioxy) -3 obtained in Reference Example 1 -Hydroxy-6-heptenenitrile 2.11
To the resulting solution, 9 ml of diisopropylethylamine was added, and 2 ml of methoxymethoxy chloride was added little by little to the obtained solution at 0 ° C. The reaction solution was stirred at 0 ° C. for 16 hours, diluted with 300 ml of diethyl ether, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography,
2.28 g of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenenitrile having the following physical properties was obtained (88% yield). ¹ H- NMR spectrum (90 MHz, CCl ₄ ) δ: 5.93 (ddd, 1 H, J = 6.3 Hz, 10.2 H)
z and 17.3 Hz), 5.16 to 5.52 (m, 2
H), 4.74 (s, 2H), 4.35 (dd, 1H,
J = 6.6 Hz and 7.3 Hz), 3.78-4.0.
0 (m, 2H), 3.45 (s, 3H), 2.60-
2.80 (m, 2H), 1.42 (s, 6H) IR spectrum (neat, cm ^-1 ) 2986, 2934, 2896, 2826, 2248,
1644, 1455, 1414, 1380, 1372,
1245, 1216, 1154, 1106, 1062
1039,992,920,875,809,512

Reference Example 3 [Synthesis of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal oxime] 4,5- (dimethylmethylenedioxy)-obtained in Reference Example 2 3-methoxymethoxy-6-heptenenitrile 1
59.8 mg was dissolved in 20 ml of dry toluene, and 1.6 ml of a 0.5 N solution of diisopropylaluminum hydride in toluene was added to the obtained solution at -78 ° C.
The reaction was stirred at -78 ° C for 2 hours, then at -40 ° C for 3 hours.
After stirring for 0 minutes, 5% diluted sulfuric acid was added little by little to the reaction solution at 0 ° C. Dilute the reaction with diethyl ether,
The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 91.9 mg of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal. The 4,5- obtained above
91.9 mg of (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal was dissolved in 1 ml of pyridine, and 45 mg of hydroxylamine hydrochloride was added to the resulting solution at room temperature. The reaction solution was stirred at room temperature for 8 hours, diluted with diethyl ether, washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 89.5 mg of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal oxime having the following physical properties. Rate 52
%). ¹ H- NMR spectrum (90 MHz, CCl ₄ ) δ: 8.02 (br.s, 1H), 7.62 (br.s, 1)
H), 7.49 (t, 1H, J = 6.4 Hz), 6.9
3 (t, 1H, J = 5.4 Hz), 5.64 to 6.10.
(M, 2H), 5.16-5.00 (m, 4H), 4.
56 to 4.90 (m, 4H), 4.24 to 4.48
(M, 2H), 3.72-4.10 (m, 4H), 3.
39 (s, 6H), 2.67 (t, 2H, J = 5.7H)
z), 2.50 (t, 2H, J = 5.9 Hz), 1.4
2 (s, 12H) IR spectrum (neat, cm ^-1 ) 3379, 3088, 2894, 2892, 2826,
1727, 1647, 1453, 1427, 1380,
1371, 1244, 1214, 1152, 1100,
1032, 991, 920, 876, 813, 705,
665, 512, 453

Reference Example 4 [Synthesis of 4,5- (dimethylmethylenedioxy) -6- (methoxymethoxy) -3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole] 89.5 mg of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal oxime obtained in Example 3 was dissolved in 4 ml of methylene chloride, and the resulting solution was added with 0.1 ml of triethylamine at 0 ° C. 035 ml was added. 2.6 ml of 10% aqueous sodium hypochlorite solution was added to the obtained solution at 0 ° C., and the mixture was stirred at 0 ° C. for 57 hours. The reaction solution was diluted with diethyl ether, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4,5- (dimethylmethylenedioxy) -6- (methoxymethoxy) -3,3a, 4 having the following physical properties.
50.5 mg of 5,6,7-hexahydro-2,1-benzoisoxazole was obtained (56% yield). ¹ H- NMR spectrum (90 MHz, CCl ₄ , TM
S) 4.76 (d, 1H, J = 4.1 Hz), 4.66
(D, 1H, J = 4.1 Hz), 4.63 (ABX, 1
H, J = 8.5 Hz and 10.0 Hz), 4.41
(Ddd, 1H, J = 2.3 Hz, 2.4 Hz and 3.3 Hz), 4.13 (ABX, 1H, J = 8.5 H)
z and 10.0 Hz), 3.98 (dd, 1H, J =
9.5 Hz and 10.0 Hz), 3.63 (dd, 1
H, J = 2.3 Hz and 9.5 Hz), 3.56 (d
9. dd, 1H, J = 1.3 Hz, 8.5 Hz and 10.
0Hz), 3.39 (s, 3H), 3.05 (ABX,
1H, J = 2.4 Hz and 15.7 Hz), 2.41
(ABXY, 1H, J = 1.3 Hz, 3.3 Hz and 15.7 Hz), 1.45 (s, 3H), 1.44
(S, 3H) ¹³ C- NMR spectrum (22.5 MHz, CCl ₄ ) 154.7, 111.4, 96.1, 80.6, 76.
2,68.8,55.6,53.5,29.6,27.
0,26.6 IR spectrum (neat, cm ^-1 ) 3522, 2982, 2932, 2892, 2824,
1720, 1632, 1455, 1381, 1371,
1333, 1306, 1266, 1231, 1151,
1089, 1038, 988, 918, 870, 83
2,794,780,672,590,518

Reference Example 5 [Synthesis of 2-hydroxymethyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone] Raney nickel W-2 (NDHF, manufactured by Kawaken Fine Chemical Co., Ltd.) was placed in a reaction vessel. -90) Add 550mg,
Washed once with water and methanol. Then boric acid 48
mg was added, and the inside of the reaction vessel was replaced with argon, and then replaced with hydrogen. 1.5 ml of methanol and 0.3 of water
After dissolving the boric acid by adding ml, the 4,5- (dimethylmethylenedioxy) -6- (methoxymethoxy) -3,3a, 4,5,6,7-hexahydro obtained in Reference Example 4 was obtained. A solution obtained by dissolving 80 mg of -2,1-benzoisoxazole in 3.5 ml of methanol was added at room temperature, and then stirred for 5 hours. The reaction was diluted with diethyl ether and filtered through florisil. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 49 mg of 2-hydroxymethyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone having the following physical properties (yield). 61%). ¹ H- NMR spectrum (90 MHz, CCl ₄ , TM
S) 4.52-4.88 (m, 2H), 4.38-4.50.
( M , 1H), 3.80-4.30 (m, 4H), 3.
36 (s, 3H), 2.32 to 2.88 (m, 4H),
1.50 (s, 3H), 1.46 (s, 3H) 13 C- NMR spectrum (22.5MHz, CCl ₄₎ 207.8,112.3,96.2,80.4,72.
8, 68.7, 59.5, 56.6, 55.6, 46.
0, 27.2, 26.6, 14.7 IR spectrum (neat, cm ^-1 ) 3494, 2982, 2930, 2892, 1713,
1644, 1455, 1383, 1371, 1325
1228, 1169, 1150, 1100, 1038,
999,918,851,803,787,693,5
27,506,439 Specific rotation [α] _D = −7.35 ° (c = 0.14, CHCl ₃ )

Reference Example 6 [2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy)
Synthesis of Cyclohexanone] 2-Hydroxymethyl-3,4- obtained in Reference Example 5
1.353 g of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone were dissolved in 20 ml of dry methylene chloride, and a catalytic amount of pyridinium p-toluenesulfonate was added to the resulting solution at 0 ° C., followed by ethyl vinyl ether 0.55 ml was added in small portions. The reaction solution was stirred at 0 ° C. for 8 hours, neutralized with ice-cooled aqueous sodium hydrogen carbonate, and extracted with 200 ml of diethyl ether.
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 2- (1-ethoxyethoxy) having the following physical properties.
Methyl-3,4- (dimethylmethylenedioxy) -5
1.468 g of (methoxymethoxy) cyclohexanone
Obtained. ¹ H- NMR spectrum (90 MHz, CCl ₄ , TM
S) 4.5-4.9 (m, 3 Hz), 4.3-4.5 (m, 3 Hz)
1H), 4.1 to 4.3 (m, 1H), 3.2 to 4.1.
(M, 5H), 3.36 (s, 3H), 2.3-2.9.
(M, 3H), 1.50 (s, 3H), 1.45 (s,
3H), 1.31 (d, J = 5.3 Hz, 3H), 1.
30 (d, J = 5.3 Hz, 3H), 1.21 (t, J
= 7.1 Hz, 3H) IR spectrum (neat, cm ^-1 ) 2980, 2930, 2892, 1720, 1453,
1381, 1340, 1226, 1149, 1098,
1038,992,952,919,852,803,
788,680,525, 423

Reference Example 7 [4,5- (dimethylmethylenedioxy) -3- (tert
Synthesis of -butyldiphenylsilyloxy) -6-heptenenitrile] 4,5- (dimethylmethylenedioxy) -3-hydroxy-6-heptenenitrile 2.11 obtained in Reference Example 1
g and imidazole 2.0 g in methylene chloride 30 ml
Was added at 0 ° C little by little to a solution obtained by dissolving 3.65 g of tert-butyldiphenylsilyl chloride. The reaction solution was stirred at room temperature for 16 hours, and diethyl ether (300 ml) was added.
, Then washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine in that order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4,5- (dimethylmethylenedioxy) -3- (tert-
4.0 g of (butyldiphenylsilyloxy) -6-heptenenitrile was obtained (86% yield). FD mass spectrum [M] ⁺ 435

Reference Example 8 [4,5- (dimethylmethylenedioxy) -3- (tert
Synthesis of -butyldiphenylsilyloxy) -6-heptenal oxime] In Reference Example 3, 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenenitrile 1
4,5- (dimethylmethylenedioxy) -3- (tert-butyldiphenylsilyloxy) -6-heptenenitrile 288.4 obtained in Reference Example 7 instead of 59.8 mg.
The reaction and separation and purification were carried out in the same manner except that mg was used to give 4,5- (dimethylmethylenedioxy) -3- (tert-butyldiphenylsilyloxy) -6-heptenal oxime having the following physical properties. Was obtained (yield 75%). FD mass spectrum [M] ⁺ 453

Reference Example 9 [4,5- (dimethylmethylenedioxy) -6- (tert
-Butyldiphenylsilyloxy) -3,3a, 4,
Synthesis of 5,6,7-hexahydro-2,1-benzoisoxazole] In Reference Example 4, 89.5 mg of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenaloxime was used. The 4,5- obtained in Reference Example 8
(Dimethylmethylenedioxy) -3- (tert-butyldiphenylsilyloxy) -6-heptenal oxime 1
The same reaction and separation and purification were carried out except that 57 mg was used to obtain 4,5- (dimethylmethylenedioxy) -6- (tert-butyldiphenylsilyloxy) -3,3a, 4,4 having the following physical properties. 91.5 mg of 5,6,7-hexahydro-2,1-benzoisoxazole was obtained (yield 59%). FD mass spectrum [M] ⁺ 451

REFERENCE EXAMPLE 10 [Synthesis of 2-hydroxymethyl-3,4- (dimethylmethylenedioxy) -5- (tert-butyldiphenylsilyloxy) cyclohexanone] Oxy) -6- (methoxymethoxy) -3,3a, 4,5
Instead of 80 mg of 6,7-hexahydro-2,1-benzoisoxazole, 4,5- (dimethylmethylenedioxy) -6- (tert-butyldiphenylsilyloxy) -3,3a, obtained in Reference Example 9. The same reaction and separation and purification were conducted except that 141 mg of 4,5,6,7-hexahydrobenzisoxazole was used to obtain 2-hydroxymethyl-3,4- (dimethylmethylenedioxy) having the following physical properties. 103 mg of -5- (tert-butyldiphenylsilyloxy) cyclohexanone was obtained (yield 73%). FD mass spectrum [M] ⁺ 454

Reference Example 11 [Synthesis of 2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (tert-butyldiphenylsilyloxy) cyclohexanone] Methyl-3,4-
Reference Example 10 instead of 1.353 g of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone
The same reaction and separation and purification were carried out except that 2.36 g of 2-hydroxymethyl-3,4- (dimethylmethylenedioxy) -5- (tert-butyldiphenylsilyloxy) cyclohexanone obtained in the above was used. 2- (1-ethoxyethoxy) methyl having the following physical properties
3,4- (dimethylmethylenedioxy) -5- (tert-
2.63 g of (butyldiphenylsilyloxy) cyclohexanone was obtained. FD mass spectrum [M] ⁺ 526

Reference Example 12 [Synthesis of 4,5-dihydroxy-6- (tert-butyldiphenylsilyloxy) -3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole] Reference Example 4,5- (dimethylmethylenedioxy) -6- (tert-butyldiphenylsilyloxy)-obtained in 9
451 mg of 3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole was added to tetrahydrofuran 1
The resulting solution was dissolved in 0 ml, 1N-hydrochloric acid (1 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with diethyl ether, neutralized with aqueous sodium bicarbonate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue is purified by silica gel column chromatography to give 4,5-dihydroxy-6- (tert-butyldiphenylsilyloxy) -3,3a, 4,5,6,7-hexahydro having the following physical properties. −2,
341 mg of 1-benzoisoxazole was obtained (yield 8
3%). FD mass spectrum [M] ⁺ 411

Reference Example 13 [Synthesis of 4,6-bis (tert-butyldiphenylsilyloxy) -5-hydroxy-3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole] The 4,5-dihydroxy-6- (te obtained in Example 12
rt-butyldiphenylsilyloxy) -3,3a, 4,
411 mg of 5,6,7-hexahydro-2,1-benzisoxazole was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole was added to the resulting solution under ice-cooling.
357 mg of tert-butyldiphenylsilyl chloride were added. The reaction solution was stirred overnight at room temperature, diluted with diethyl ether, and then washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate, and brine,
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4,6-
Bis (tert-butyldiphenylsilyloxy) -5-hydroxy-3,3a, 4,5,6,7-hexahydro-
422 mg of 2,1-benzoisoxazole was obtained (65% yield). FD mass spectrum [M] ⁺ 649

Reference Example 14 Synthesis of 5-acetoxy-4,6-bis (tert-butyldiphenylsilyloxy) -3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole 4,6-bis (tert-butyldiphenylsilyloxy) -5-hydroxy-3,3a obtained in Example 13
649 mg of 4,5,6,7-hexahydro-2,1-benzoisoxazole was dissolved in 20 ml of methylene chloride, and 5 ml of triethylamine and 4-ml of 4-ethylamine were added to the resulting solution.
0.5 g of dimethylaminopyridine was added, followed by 100 mg of acetyl chloride. The reaction solution was stirred at room temperature overnight, diluted with diethyl ether, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-acetoxy-4,6-bis (tert-
Butyldiphenylsilyloxy) -3,3a, 4,5
671 mg of 6,7-hexahydro-2,1-benzoisoxazole was obtained (97% yield). FD mass spectrum [M] ⁺ 691

Reference Example 15 Synthesis of 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone In Reference Example 5, 4,5- (dimethylmethylenedioxy) -6 -(Methoxymethoxy) -3,3a, 4,5
Instead of 80 mg of 6,7-hexahydro-2,1-benzoisoxazole, 5-acetoxy-4,6-bis (tert-butyldiphenylsilyloxy) -3,3a, 4,5 obtained in Reference Example 14. 6,7-hexahydro-2,
The same reaction and separation and purification were carried out except that 215 mg of 1-benzoisoxazole was used to obtain 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone having the following physical properties. Was obtained (yield 72%). FD mass spectrum [M] ⁺ 694

REFERENCE EXAMPLE 16 [Synthesis of 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2- (1-ethoxyethoxy) methyl-cyclohexanone] , 4-
Reference Example 15 instead of 1.353 g of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone
The following physical properties were obtained by carrying out the same reaction and separation and purification except that 3.61 mg of 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone obtained in the above was used. 3.74 g of 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2- (1-ethoxyethoxy) methyl-cyclohexanone was obtained. FD mass spectrum [M] ⁺ 766

Reference Example 17 [Synthesis of 3-hydroxy-5- (tert-butyldiphenylsilyloxy) -6-heptenenitrile] In Reference Example 1, 1,2-epoxy-3,4- (dimethylmethylenedioxy The same reaction and separation and purification were conducted except that 15.8 g of 5,6-epoxy-3- (tert-butyldiphenylsilyloxy) -1-hexene was used instead of 7.61 g of -5-hexene. 3-hydroxy-5- (tert-butyldiphenylsilyloxy) -6-heptenenitrile 14.6 having the following physical properties.
g was obtained. FD mass spectrum [M] ⁺ 379

REFERENCE EXAMPLE 18 [Synthesis of 3,5-bis (tert-butyldiphenylsilyloxy) -6-heptenenitrile] In Reference Example 7, 4,5- (dimethylmethylenedioxy) -3-hydroxy-6 -Heptenenitrile 2.11
In place of g, the 3-hydroxy-5 obtained in Reference Example 17 was used.
The reaction and separation and purification were carried out in the same manner except that 4.06 g of (tert-butyldiphenylsilyloxy) -6-heptenenitrile was used to obtain 3,5 having the following physical properties.
-Bis (tert-butyldiphenylsilyloxy) -6
5.95 g of heptenenitrile were obtained. FD mass spectrum [M] ⁺ 617

Reference Example 19 [Synthesis of 3,5-bis (tert-butyldiphenylsilyloxy) -6-heptene-1-aloxime] In Reference Example 3, 4,5- (dimethylmethylenedioxy) -3- Methoxymethoxy-6-heptenenitrile 1
The same reaction and separation and purification were performed except that 405 mg of 3,5-bis (tert-butyldiphenylsilyloxy) -6-heptenenitrile obtained in Reference Example 18 was used instead of 59.8 mg. 3, which has the physical properties of
5-bis (tert-butyldiphenylsilyloxy) -6
-Heptene-1-al oxime 320 mg was obtained. FD mass spectrum [M] ⁺ 635

Reference Example 20 [4,6-bis (tert-butyldiphenylsilyloxy) -3,3a, 4,5,6,7-hexahydro-2,
Synthesis of 1-Benzoisoxazole] In Reference Example 4, 39.5 obtained in Reference Example 19 was used instead of 89.5 mg of 4,5- (dimethylmethylenedioxy) -3-methoxymethoxy-6-heptenal oxime. 5-
The same reaction and separation and purification were conducted except that 219 mg of bis (tert-butyldiphenylsilyloxy) -6-heptene-1-aloxime was used to obtain 4,6-bis (tert-butyldiphenyl) having the following physical properties. 168 mg of (silyloxy) -3,3a, 4,5,6,7-hexahydro-2,1-benzoisoxazole was obtained. FD mass spectrum [M] ⁺ 633

Reference Example 21 [Synthesis of 3,5-bis (tert-butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone] In Reference Example 5, 4,5- (dimethylmethylenedioxy) -6- (methoxymethoxy) ) -3,3a, 4,5
4,6-bis (tert-butyldiphenylsilyloxy) -3,3a, obtained in Reference Example 20, instead of 80 mg of 6,7-hexahydro-2,1-benzoisoxazole.
The same reaction and separation and purification were conducted except that 197 mg of 4,5,6,7-hexahydro-2,1-benzoisoxazole was used to obtain 3,5 having the following physical properties.
-Bis (tert-butyldiphenylsilyloxy) -2-
180 mg of hydroxymethylcyclohexanone were obtained. FD mass spectrum [M] ⁺ 636

Reference Example 22 [3,5-bis (tert-butyldiphenylsilyloxy) -2- (1-ethoxyethoxy) methylcyclohexyl
Synthesis of Sanone ] In Reference Example 6, 2-hydroxymethyl-3,4-
Reference Example 21 instead of 1.353 g of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone
The reaction and separation and purification were carried out in the same manner except that 3.31 g of 3,5-bis (tert-butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone obtained in the above was used to obtain 3,5 having the following physical properties. -Screw (te
rt-butyldiphenylsilyloxy) -2- (1-ethy
3.50 g of (xyethoxy) methylcyclohexanone were obtained. FD mass spectrum [M] ⁺ 708

Reference Example 23 [Synthesis of 3,5-bis (tert-butyldiphenylsilyloxy) -2- (tert-butyldiphenylsilyloxy) methylcyclohexanone] In Reference Example 7, 4,5- (dimethylmethylenedioxy ) -3-Hydroxy-6-heptenenitrile 2.11
In place of g, the 3,5-bis (tert-
Butyldiphenylsilyloxy) -2-hydroxymethylcyclohexanone was reacted and separated and purified in the same manner except for using 5.16 g to give 3,5-bis (tert-butyldiphenylsilyloxy) -2 having the following physical properties. 6.10 g of-(tert-butyldiphenylsilyloxy) methylcyclohexanone was obtained. FD mass spectrum [M] ⁺ 874

Reference Example 24 [2-tert-butyldimethylsilyloxymethyl-3,
Synthesis of 4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone] 2-hydroxymethyl-3,4- obtained in Reference Example 5
659 mg of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone and 1.13 ml of triethylamine were dissolved in 15 ml of methylene chloride, and 566 mg of tert-butyldimethylsilyl chloride was added to the resulting solution at 0 ° C., followed by stirring for 5 hours. . The resulting solution was diluted with diethyl ether and washed with ice-cooled 1N hydrochloric acid. The organic phase was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 2-tert having the following physical properties.
714 mg of -butyldimethylsilyloxymethyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone was obtained (yield: 75%). ¹ H- NMR spectrum (90 MHz) 4.76 (AB, 1H, J = 6.81 Hz), 4.63
(AB, 1H, J = 6.81 Hz), 4.40 (dd,
3H, J = 9.77 Hz and 11.57 Hz);
37 (ddd, 1H, J = 2.06 Hz, 2.83 Hz
And 4.63 Hz), 4.10 (dd, 1H, J =
2.57 Hz and 10.18 Hz), 3.89 (d
d, 1H, J = 2.06 Hz and 11.57 Hz),
3.79 (dd, 1H, J = 4.11 Hz and 10.
18Hz), 3.33 (s, 3H), 2.67 (dd,
1H, J = 2.83 Hz and 16.97 Hz), 2.
52 (dd, 1H, J = 4.63 Hz and 16.97
Hz), 2.50 (ddd, 1H, J = 2.57 Hz,
4.11 Hz and 9.77 Hz), 1.48 (s, 3
H), 1.44 (s, 3H), 0.85 (s, 9H),
^{0.05 (s, 6H) 13 C-} NMR spectrum (22.5MHz) 205.0,111.7,96.3,80.4,71.
7, 68.7, 58.1, 56.8, 55.4, 46.
0, 27.3, 26.6, 25.9 (3), 18.3,
−5.5 (2) IR spectrum (neat, cm ⁻¹ ) 3424, 2982, 2928, 2888, 2854,
1722, 1462, 1382, 1370, 1224,
1150, 1100, 1040, 952, 919, 83
9,779,732,680 Specific rotation [α] _D ²⁵ = −7.60 ° (c = 0.929, CHC
l ₃ )

Example 1 Under a nitrogen atmosphere, 0.46 ml of dicyclohexylamine was dissolved in 7 ml of tetrahydrofuran.
1.35 ml of butyllithium hexane solution at 20 ° C
(1.70 N, 2.30 mmol) was added dropwise and then 3
Stirred for 0 minutes. After cooling the obtained solution to −78 ° C., 0.43 ml of ethyl trimethylsilyl acetate was added to the solution.
(2.35 mmol) was added, followed by stirring at −78 ° C. for 1 hour. The obtained reaction solution was treated with 2-
A solution obtained by dissolving 736 mg (2.21 mmol) of (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone in 12 ml of tetrahydrofuran is -78 ° C.
For 10 minutes. The reaction solution was stirred at the same temperature for 2 hours, then at 0 ° C. for 5 minutes, and then stirred for 1 hour with ice.
Poured into N hydrochloric acid and extracted with diethyl ether. The extract was washed successively with an aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography.
(Z) -2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy)-having the following physical properties
492 mg (yield 50%) of ethyl 5- (methoxymethoxy) cyclohexylideneacetate was obtained. In addition, 2-
418 mg of (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone were recovered. ¹ H- NMR spectrum (90 MHz, CCl ₄ , TM
S) δ: 5.75 (br.s, 1H), 4.82 (d, J = 6.
8Hz, 1H), 4.69 (m, 1H), 4.65
(D, J = 6.8 Hz, 1H), 3.37-4.45
(M, 9H), 3.37 (s, 3H), 2.72 (b
d, J = 7.0 Hz, 2H), 1.70 (br.s, 1
H), 1.43 (s, 6H), 1.08-1.43.
(M, 9H) IR spectrum (neat, cm ^-1 ) 2980, 2930, 2892, 1713, 1644,
1444, 1377, 1271, 1209, 1150,
1098, 1045, 959, 920, 857, 78
2,686,508

Example 2 In Example 1, 736 mg of 2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone (2.2 mg)
2- (1-) obtained in Reference Example 11 instead of 1 mmol).
1.16 g (2.21 mmol) of ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (tert-butyldiphenylsilyloxy) cyclohexanone
The same reaction and separation and purification were carried out except for using l) to give (Z) -2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- having the following physical properties. 803 mg of ethyl (tert-butyldiphenylsilyloxy) cyclohexylideneacetate was obtained (61% yield). FD mass spectrum [M] ⁺ 596

Example 3 In Example 1, 736 mg of 2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone (2.2 mg)
1.69 g (2.21 mmol) of 4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2- (1-ethoxyethoxy) methyl-cyclohexanone obtained in Reference Example 16 in place of 1 mmol). The same reaction and separation and purification were carried out except for using, thereby obtaining the following physical properties of (Z) -4-acetoxy-3,5-bis (tert-butyldiphenylsilyloxy) -2- (1-
1.07 g of ethyl (ethoxyethoxy) methylcyclohexylideneacetate was obtained (58% yield). FD mass spectrum [M] ⁺ 836

Example 4 In Example 1, 736 mg of 2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone (2.2 mg)
1 mmol) instead of 3,5-bis (tert-butyldiphenylsilyloxy) -2- (1
-Ethoxyethoxy) methylcyclohexanone 1.56
g (2.21 mmol) except that the same reaction and separation and purification were carried out to give (Z) -3,5-bis (tert-butyldiphenylsilyloxy) -2- (1- 1.22 g of ethyl (ethoxyethoxy) methylcyclohexylideneacetate was obtained (yield: 71).
%). FD mass spectrum [M] ⁺ 778

Example 5 In Example 1, 736 mg of 2- (1-ethoxyethoxy) methyl-3,4- (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone (2.2 mg)
1 mmol) instead of 3,5-bis (tert-butyldiphenylsilyloxy) -2- (te) obtained in Reference Example 23.
The same reaction and separation and purification were carried out except that 1.93 g (2.21 mmol) of rt-butyldiphenylsilyloxy) methylcyclohexanone was used to obtain (Z) -3,5-bis (tert- 1.42 g of ethyl butyldiphenylsilyloxy) -2- (tert-butyldiphenylsilyloxy) methylcyclohexylideneacetate was obtained (68% yield). FD mass spectrum [M] ⁺ 944

Example 6 In an argon atmosphere, a solution obtained by dissolving 0.77 ml of N, N-dicyclohexylamine in 4 ml of tetrahydrofuran was added at −20 ° C. to 2.27 ml of a hexane solution of n-butyllithium (1.70 N, 1.70 N). (3.86 mmol) was added dropwise and then stirred for 30 minutes. The resulting solution was -78
After cooling to 0 ° C, 0.71 ml (3.88 mmol) of ethyl trimethylsilyl acetate was added to the solution, and the mixture was stirred for 1.5 hours. The obtained reaction solution was mixed with 2 obtained in Reference Example 24.
-Tert-butyldimethylsilyloxymethyl-3,4-
364 mg (0.97 mmol) of (dimethylmethylenedioxy) -5- (methoxymethoxy) cyclohexanone
Was dissolved in 6 ml of tetrahydrofuran, a solution obtained was slowly added, and the mixture was left at -78 ° C for 4 hours. The reaction solution was poured into ice-cooled saturated aqueous ammonium chloride and extracted with diethyl ether. The extract was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give (Z)-(2-tert-butyldimethylsilyloxymethyl-3,4- (dimethylmethylenedioxy) -5- (methoxy) having the following physical properties. Methoxy) cyclohexylidene) ethyl acetate
65 mg was obtained (85% yield). ¹ H- NMR spectrum (300 MHz) 5.74 (bs, 1H), 4.79 (AB, 1H, J =
6.86 Hz), 4.65 (AB, 1H, J = 6.86)
Hz), 4.54 (dd, 1H, J = 9.15 Hz and 10.68 Hz), 4.20 (ddd, 1H, J =
4.58 Hz, 6.10 Hz and 7.63 Hz),
4.14 (q, 2H, J = 6.10 Hz), 3.97
(Dddd, 1H, J = 3.05 Hz, 9.15 Hz and 19.83 Hz), 3.60 (dddd, 1H, J =
1.53 Hz, 1.53 Hz, 4.58 Hz and 9.
15 Hz), 3.44 (1H, J = 4.58 Hz and 10.68 Hz), 3.36 (s, 3H), 2.75
(Ddd, 1H, J = 1.52 Hz, 6.10 Hz and 13.73 Hz), 2.71 (dd, 1H, J = 7.
63 Hz and 13.73 Hz), 1.44 (s, 3
H), 1.43 (s, 3H), 0.88 (s, 9H),
0.05 (s, 3H), 0.00 (s, 3H) ¹³ C- NMR spectrum (75 MHz) 165.48, 158.84, 117.97, 112.
07, 96.60, 79.50, 71.90, 69.1
3,64.12,59.95,55.54,46.4
4,42.44,27.61,26.78,26.03
(3), 18.45, 14.42, -5.35, -5.
40 IR spectrum (neat, cm ^-1 ) 2924, 2856, 1715, 1639, 1465,
1442, 1378, 1350, 1249, 1207,
1149,1096,1045,961,920,83
6,778,679,650,507 Specific rotation [α] _D ²⁵ = -100.5 ° (c = 0.38, CHC
l ₃ )

[0061]

As described above, a Z-cyclohexylideneacetic acid derivative useful as a synthetic intermediate for a 1α-hydroxyvitamin D derivative can be produced from inexpensive starting materials in a relatively short process with high selectivity.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 67/343 C07C 69/732 CA (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) ( Wherein R ¹ , R ² and R ³ each represent a hydrogen atom or a hydroxyl-protecting group, and A represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group) and a general formula (II) ) ( Wherein , R ⁴ represents a lower alkyl group; R ⁵ , R ⁶ and
R ⁷ represents a lower alkyl group or an aryl group, respectively. Wherein the silyl acetic acid ester derivative of the formula (III) is reacted in the presence of a base. (In the formula, R ¹ , R ² , R ³ , R ⁴ and A are as defined above.) A method for producing a Z-cyclohexylideneacetic acid derivative represented by the formula: