JPH0848678A - Production of tricyclic lactone compound - Google Patents

Abstract

PURPOSE:To readily obtain a derivative to be an intermediate for important medicines having antihyperlipemic actions such as dihydrocompactin or dihydromevinolin in good yield an octahydronaphthalene derivative as a starting substance. CONSTITUTION:This method for producing a tricyclic lactone compound of formula VI [R<1> is a (aryl)lower alkyl; R<2> is a lower alkyl] is to hydroborate an octahydronaphthalene derivative of formula I, then oxidize the resultant compound, provide a cis-decalin derivative of formula II, convert the prepared derivative into an enol silyl ether, then dehydrosilylate the enol silyl ether, afford an enone compound of formula III, subsequently carry out the conjugated addition reaction of the enone compound of formula III, provide a compound of formula IV (R<6> is a lower alkyl), then epimerize the prepared compound of formula IV with a base, afford a trans-decalin derivative, convert the trans- decalin derivative into a hydrazone derivative of formula V (Ts is p- toluenesulfonyl), further convert the resultant derivative into a tetrahydronaphthalene derivative by the actions of a strong base and subsequently carry out the deacetalization and oxidation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The production method and the production intermediate according to the present invention are dihydrocompactin having an antihyperlipidemic effect,
It is important as a production method and an intermediate for producing key intermediates such as dihydromevinolin and is useful in the field of medicine.

[0002]

2. Description of the Related Art In the general formula [X] of claim 1, R ²
And compounds in which R ⁶ is a methyl group are useful as intermediates for the production of dihydrocompactin, dihydromevinorin and the like having antihyperlipidemic activity, and several synthetic methods have been reported in the past [Stephan-Hanesian (Steph
an Hannesian) et al., Journal of the Organic Chemistry (J. Org. Che
m. ,) 55, 5766 (1990), etc.].

[0003]

However, since these synthetic methods require multiple steps than starting materials and the total yield is low, it is strongly desired to create a practical manufacturing method.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have the general formula [X] which is an important pharmaceutical intermediate.

[0005]

[Chemical 13] As a result of diligent search for a method for producing (wherein R ² and R ⁶ are the same or different and each represents a lower alkyl group), a readily available general formula [I]

[0006]

Embedded image (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² represents a lower alkyl group) is used as a starting material to produce a compound represented by the general formula [X] in a short step. The manufacturing method was developed and the present invention was completed.

Next, the definitions of terms used in this specification will be explained.

The "lower alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec. -Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group,
Examples thereof include a hexyl group and an isohexyl group.

The "aryl lower alkyl group" has 6 carbon atoms.
To 12 means the above lower alkyl group substituted with an aryl group, and examples thereof include a benzyl group, a phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 1-naphthylethyl group and a 2-naphthylethyl group. To be

The "leaving group" means a group usually used in synthetic organic chemistry, specifically, a halogen atom such as fluorine, chlorine, bromine, iodine or a trifluoromethanesulfonyl group, methanesulfonyl group or p-toluene. Examples thereof include a sulfonyl group.

Next, the abbreviations used in this specification will be described. 9-BBN 9-borabicyclo [3.3.1] nonane DBU 1,5-diazabicyclo [4.3.0] non-5-ene DBN 1,8-diazabicyclo [5.4.0] undec-7- Ene DME 1,2-dimethoxyethane DMSO dimethyl sulfoxide LDA lithium diisopropylamide LCIA lithium cyclohexylisopropylamide LHMDS lithium hexamethyldisilazane KHMDS potassium hexamethyldisilazane PCC pyridinium chlorochromate PDC pyridinium dichromate THF tetrahydrofuran Ts p-toluenesulfonyl group Next, the manufacturing method according to the present invention will be specifically described.

From the compound of general formula [I] to general formula [II]
For the conversion of the compound into a compound, any reagent can be used as long as it is an agent that introduces a hydroxyl group into the asymmetrically substituted carbon-carbon double bond in an anti-Marconnikov manner. A hydroboration reaction using a peroxide such as hydrogen oxide is preferable, and specifically, at a temperature of −78 ° C. to room temperature, with respect to [I] in an inert solvent such as THF or 1,4-dioxane. 0.4 to 2 equivalents of borane / THF complex, borane / pyridine complex or borane / dimethyl sulfide complex or 1 to 3 equivalents of substituted borane such as disiamylborane, thexylborane or 9-BBN is added, and after reaction for 1 to 48 hours, 1 It can be performed by treating with ˜2 equivalents of sodium hydroxide aqueous solution and 1 to 2 equivalents of hydrogen peroxide aqueous solution.

For conversion from [II] to [III], 2
Any oxidizing agent having the ability to oxidize a primary alcohol into a ketone can be used, but especially PCC, P
Oxidation by chromic acids such as DC or Swern (Swer
n) Oxidation reaction using DMSO as an oxidant such as an oxidation step and a Moffat oxidation step is preferable.

The conversion from [III] to [IV] is [II]
[I] in an ether solvent such as diethyl ether or THF at a temperature of −100 to −50 ° C. to 1 [III].
~ 2 equivalents of a strong base such as LDA, LCIA, LHMD
After reacting with lithium amides such as S or KHMDS for 5 minutes to 2 hours, 1 to 2 equivalents of R ³ R ⁴ R ⁵ SiX (in the formula, R ³ , R
⁴ and R ⁵ are the same or different and each represents a lower alkyl group, or R ³ and R ⁴ represent a phenyl group, R ⁵ represents a lower alkyl group, and X represents a leaving group).

The conversion from [IV] to [V] is carried out, for example, by the method of Saegusa et al. [Journal of the Organic Chemistry (J. Org. Chem.) 43 Vol. 101.
1 page (1978)], etc. [V] at 0 ° C to 50 ° C.
[I], preferably at room temperature in a solvent such as acetonitrile, [I
V] is 0.2 to 2 equivalents, preferably 0.4 to 1 equivalents of a divalent palladium compound such as palladium chloride or palladium acetate, and 0.2 to 2 equivalents, preferably 0.4 to
In the presence of 1 equivalent of quinones such as p-benzoquinone
It can be performed by reacting for 30 hours.

The conversion from [V] to [VI] is -100
1 to 5 equivalents of [V] with respect to [V] in an ether solvent such as diethyl ether or THF at preferably room temperature to room temperature, preferably 1
˜2 equivalents of di-lower alkyl copper lithium complex or higher lower alkyl copper lithium complex [B. Lipshutz Synthesis (Synt
hesis) p. 325 (1987), etc.] or 1 to 3 equivalents of a lower alkyl Grineer's reagent and 0.1 to 1 equivalent of copper iodide.

The conversion of [VI] into [VII] is [VI]
In a solvent such as water-containing lower alcohol such as water-containing methanol or water-containing ethanol or water-containing THF or water-containing 1,4-dioxane at a temperature from 0 ° C. to the boiling point of the solvent, 1 to 10 equivalents, preferably 4 to 10 equivalents with respect to [VI]. 6 equivalents of alkali metal carbonate such as sodium carbonate, potassium carbonate or DB
It can be carried out by reacting an organic base such as U or DBN.

The conversion of [VII] into [VIII] is
[VII] in a lower alcohol solvent such as methanol or ethanol at a temperature from 0 ° C. to the boiling point of the solvent for 1 to 1.5.
Equivalent amount of p-toluenesulfonylhydrazine and 10 minutes to 4
It can be carried out by reacting for a while.

The conversion of [VIII] into [IX] is performed by a general Banford-Stevens (Bamford-
Stevens) reaction [W.R. Bamford et al. Journal of the Chemical Society (J. Chem. So
c. ,) 4735 (1952) and Robert H. Shapiro Organic Reactions (Organic Rea).
23) 405 John Wiley
& Sons et al.], [VIII] in an ether solvent such as diethyl ether or THF at −100 ° C.
To room temperature from 5 to 15 equivalents of [VIII] n-butyllithium, sec-butyllithium, te
It can be performed by treating with a strong base such as rt-butyllithium.

The conversion of [IX] into [X] is performed at 0 ° C., for example.
To 1 for [IX] in anhydrous or hydrous acetone at room temperature
It can be carried out by using ~ 5 equivalents of Jones reagent or the like. These are shown.

[0021]

[Chemical 15]

[0022]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

The abbreviations used in NMR measurement are shown below.

S Singlet d Doublet t Triplet q Quartet m Multiplet br Broad J Coupling constant Hz Hertz Reference example 1 (2aR, 7S, 8aS, 8bS) -2-methoxy-7
-Methyl-2a, 3,4,6,7,8,8a, 8b-o
The combination of Kutahydro-2H-naphtho [1.8-bc] furan
Formed Kanematsu et al's method [Tetrahedron: Asymmetry (Te
trahedron: Asymmetry) 1 volume 10
No. 743 (1990)], etc. (1S, 5S)
-5-methyl-1-propargyloxy-3-vinyl-
2.76 g (10.0 mmol) of 2-cyclohexene is dissolved in 30 ml of t-butanol, 6.16 g (55.0 mmol) of t-butoxy potassium is added, and the mixture is refluxed for 1 hour. After cooling to room temperature and adding 50 ml of diethyl ether, the organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated saline solution, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in 60 ml of methanol. ,
Add 3.0 g of (±) -10-camphorsulfonic acid and add 1
Stir for hours. After adding diethyl ether to the reaction solution,
The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: Separation and purification in 1) yields 2.06 g (yield 99%) of the title compound as a colorless oily substance.

[Α] ²³ _D −52.0 ° (c = 2.5 chloroform) ¹ H-NMR (CDCl ₃ , δ, ppm) 0.97 (3 H, d, J = 6.9 Hz), 1. 49-
1.93 (6H, m), 1.97-2.13 (2H,
m), 2.25-2.30 (1H, m), 2.36-
2.43 (1H, m), 2.51 (1H, m), 3.3
8 (3H, s), 4.25 (1H, q, J = 5.2H
z), 4.74 (1H, d, J = 3.6Hz), 5.5
4 (1H, m) ¹³ C-NMR (CDCl ₃ , δ, ppm) 20.931 (q), 21.580 (t), 21.60
5 (t), 27.419 (d), 34.310 (t),
39.990 (t), 41.079 (d), 44.66.
6 (d), 55.523 (q), 77.617 (d),
107.864 (d), 123.336 (d), 13
2.737 (s) IR (KBr, cm ^-1 ) 2920, 1100 High-resolution mass spectrum m / z C ₁₃ H ₂₀ O ₂ Calculated value 208.1464 Measured value 208.1462 Example 1 (2aR, 3S, 5aR) , 7S, 8aS, 8bS) -2
-Oxo-3,7-dimethyl-2a, 3,5a, 6
7,8,8a, 8b-Octahydro-2H-naphtho-
Production of [1.8-bc] furan (2aR, 3s, 5aR, 7S, 8aS, 8bS)
-2a, 3,4,5,5a, 6,7,8,8a, 8b-
Synthesis of decahydro-5-hydroxy-7-methyl-2H-naphtho- [1.8-bc] -furan (2aR, 7S, 8aS, 8bS) -2 obtained in Reference Example 1.
-Methoxy-7-methyl-2a, 3,4,6,7,8,
8a, 8b-Octahydro-2H-naphtho [1.8-b
c] 4.19 g (20.1 mmol) of furan was added to anhydrous T
Dissolve in 20 ml of HF, add 20.1 ml (20.1 mmol) of 1.0 M borane THF complex THF solution at 0 ° C., and stir at 0 ° C. for 20 hours. 20 ml of 10% sodium hydroxide aqueous solution and 10 ml of 30% hydrogen peroxide aqueous solution at room temperature
And the mixture is stirred at 25 ° C. for 2 hours. The reaction solution is extracted with ethyl acetate, the organic layer is washed successively with 5% aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to give the title compound as a colorless oily substance. This product can be used in the next step without further purification.

2. (2aR, 5aR, 7S, 8aS, 8
bS) -5-oxo-2a, 3,4,5,5a, 6
7,8,8a, 8b-decahydro-2-methoxy-7-
Production of Methyl-2H-naphtho- [1.8-bc] furan Obtained in (2aR, 3s, 5aR, 7S, 8a
S, 8bS) -2a, 3,4,5,5a, 6,7,8,
The crude product of 8a, 8b-decahydro-5-hydroxy-7-methyl-2H-naphtho- [1.8-bc] -furan was dissolved in 150 ml of anhydrous methylene chloride to a solution of Celite 20.
PCC 6.47g (30.0mmo
l) is added and the mixture is stirred for 2 hours. 100m of diethyl ether
1 was added and stirred for 20 minutes, passed through a Florisil column, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3.565 g of the title compound (total yield). 79%) as colorless crystals.

Melting point 71.0-71.5 ° C. (recrystallized from hexane) [α] ²⁴ _D- 129.1 ° (c = 1.2 chloroform) ¹ H-NMR (CDCl ₃ , δ, ppm) 0. 87-1.01 (1H, m), 1.03 (3H,
d, J = 6.6 Hz), 1.43-1.64 (2H,
m), 1.77-2.10 (3H, m), 2.31-
2.38 (2H, m), 2.50 (1H, dt, J =
2.9 Hz, 7.7 Hz), 2.57-2.65 (1
H, m), 2.80 (1H, dt, J = 9.2 Hz,
7.8 Hz), 3.34 (3 H, s), 4.25 (1
H, dt, J = 10.2 Hz, 7.3 Hz), 4.79
(1H, s) ¹³ C-NMR (CDCl ₃ , δ, ppm) 22.698 (q), 23.283 (t), 24.57
0 (d), 27.964 (t), 34.165 (t),
35.978 (t), 38.085 (d), 42.88
2 (d), 43.291 (d), 54.407 (q),
77.574 (d), 109.399 (d), 213.
299 (s) IR (KBr, cm ^-1 ) 2950, 2860, 171
0.1100 Mass spectrum m / z 224 (M ⁺ , 5.4), 1
92 (68.4), 164 (81.0), 122 (10)
0) Elemental analysis value C ₁₃ H ₂₀ O ₃ calculated value C, 69.61; H, 8.99 measured value C, 69.75; H, 8.91 3. (2aR, 5aR, 7S, 8aS, 8bS) -5-
Oxo-2-methoxy-7-methyl-2a, 5,5a,
Preparation of 6,7,8,8a, 8b-octahydro-2H-naphtho- [1.8-bc] furan (2aR, 5aR, 7S, 8aS, 8b
S) -5-oxo-2a, 3,4,5,5a, 6,7,
8,8a, 8b-Decahydro-2-methoxy-7-methyl-2H-naphtho- [1.8-bc] furan 2.09
8 g (9.4 mmol) was dissolved in 15 mL of anhydrous THF, and LDA 18.8 mmol of anhydrous THF1 was dissolved at -78 ° C.
Add dropwise to 5 ml solution. After stirring for 30 minutes at the same temperature, 3.58 ml of chlorotrimethylsilane (28.2 mmo
l) was rapidly added and the mixture was stirred at 25 ° C. for 2 hours, the reaction solution was extracted with diethyl ether, the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was depressurized. Evaporation yields the enol silyl ether as a colorless oil. Then, the method of Saegusa et al. [Journal of the Organic Chemistry (J. Org. Chem.) 43: 1011 (19
1978)]], etc.
While maintaining a solution of (10.3 mmol) in 40 ml of acetonitrile at 35 ° C., a solution of 20 ml of acetonitrile in total of the crude product of the enol silyl ether was added dropwise.
Stir at 35 ° C. for 4 hours. The reaction mixture was diluted with methylene chloride, passed through a column of Celite, the solvent was evaporated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound 1.
853 g (total yield 89%) is obtained as colorless crystals.

Melting point 47.0-47.5 ° C. (petroleum ether
Re-crystallized from le) [α]^{twenty five} _D-137.6 ° (c = 1.2, chloroform
)¹ H-NMR (CDCl₃, Δ, ppm) 0.91 (1H, q, J = 11.8 Hz), 1.06
(3H, d, J = 6.7 Hz), 1.58-1.72
(2H, m), 1.82 (1H, dt, J = 13.4H
z, 5.0 Hz), 2.19 (1H, dt, J = 12.
8 Hz, 4.1 hz), 2.56 (1 H, ddd, J =
3.4 Hz, 5.2 Hz, 8.5 Hz), 3.00 (1
H, q, J = 8.3 Hz), 3.14 (1H, dt, J
= 8.1 Hz, 2.9 Hz), 3.36 (3H, s),
4.21 (1H, ddd, J = 4.7Hz, 9.0H
z, 11.4 Hz), 4.88 (1H, s), 6.06
(1H, dd, J = 2.1Hz, 10.1Hz), 6.
72 (1H, dd, J = 3.4Hz, 10.1Hz)¹³ C-NMR (CDCl₃, Δ, ppm) 23.541 (q), 24.552 (d), 28.51
9 (t), 34.819 (t), 37.233 (d),
40.471 (d), 45.813 (d), 54.48
7 (q), 77.758 (d), 107.235
(D), 129.979 (d), 145.7736
(D), 199.792 (s) IR (KBr, cm^-1) 2930, 1685, 108
5,980 High-resolution mass spectrum m / z (C₁₃H₁₈O₃+ H )⁺Calculated value 223.1333 Measured value 223.1325 Elemental analysis value C₁₃H₁₈O₃Calculated value C, 70.24; H, 8.16 Measured value C, 70.29; H, 8.14 4. (2aR, 3S, 5aR, 7S, 8aS, 8bS)
-5-oxo-2a, 3,4,5,5a, 6,7,8,
8a, 8b-decahydro-3,7-dimethyl-2-me
Synthesis of Toxy-2H-naphtho- [1.8-bc] furan 2.533 g (13.3 mmol) diethyl iodide copper
To a suspension of 20 ml of ether at 0 ° C, 1.0M methyllithium
26.6 ml (26.6 mmo) of diethyl ether solution
l) was added dropwise, and the above 3. Obtained (2aR, 5
aR, 7S, 8aS, 8bS) -5-oxo-2-meth
Xy-7-methyl-2a, 5,5a, 6,7,8,8
a, 8b-Octahydro-2H-naphtho- [1.8-b
c] 1.473 g (6.6 mmol) of furan diethyl
Add 10 ml of ether dropwise and stir for 2 hours at 0 ° C.
After that, the reaction solution is poured into water and extracted with diethyl ether.
The organic layer was saturated aqueous ammonium chloride and saturated sodium chloride.
After washing with an aqueous solution of sodium, dry it with anhydrous sodium sulfate and dissolve.
The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography.
Separation by chromatography (hexane: ethyl acetate = 2: 1)
Purified and colorless compound (1.523 g, yield 96%) was obtained.
Obtain as crystals.

Melting point 60.5-61.0 ° C. (recrystallized from petroleum ether) [α] ²⁵ _D -40.1 ° (c = 1.0, chloroform) ¹ H-NMR (CDCl ₃ , δ, ppm) 0.95-1.09 (1H, m), 1.06 (3H,
d, J = 6.3 Hz), 1.08 (3H, d, J = 5.
9Hz), 1.56-2.12 (7H, m), 2.37
-2.44 (1H, m) 2.49-2.57 (1H,
m), 2.93 (1H, q, J = 8.7 Hz), 3.3
7 (3H, s), 4.20 (1H, ddd, J = 4.8)
Hz, 8.7 Hz, 9.9 Hz), 4.84 (s, 1
H) ¹³ C-NMR (CDCl ₃ , δ, ppm) 21.409 (q), 23.298 (q), 25.47.
0 (d), 30.272 (t), 31.527 (d),
35.250 (t), 38.461 (d), 44.80
1 (d), 45.786 (t), 51.628 (d),
54.703 (q), 77.232 (d), 107.4.
91 (d), 212.918 (s) IR (KBr, cm ^-1 ) 2920, 1700, 108
5,1060 Mass spectrum m / z 238 (M ⁺ , 2.2), 2
06 (50.7), 178 (47.3), 136 (10
0) Calculated value as elemental analysis value C ₁₄ H ₂₂ O ₃ C, 70.55; H, 9.30 Measured value C, 70.55; H, 9.34 5. (2aR, 3S, 5aS, 7S, 8aS, 8bS)
-5-oxo-2a, 3,4,5,5a, 6,7,8,
Synthesis of 8a, 8b-decahydro-3,7-dimethyl-2-methoxy-2H-naphtho- [1.8-bc] furan 4. (2aR, 3S, 5aR, 7S, 8a
S, 8bS) -5-oxo-2a, 3,4,5,5a,
6,7,8,8a, 8b-decahydro-3,7-dimethyl-2-methoxy-2H-naphtho- [1.8-bc] furan 228 mg (0.96 mmol) and anhydrous potassium carbonate 663 mg (4.8 mmol). 10m of methanol
The solution is heated to reflux for 2 hours. After cooling to room temperature, the reaction solution was diluted with 50 ml of ethyl acetate, the organic layer was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Graphography (hexane:
Separated and purified with ethyl acetate = 2: 1) to give 209 m of the title compound.
g (92% yield) is obtained as colorless crystals.

Melting point 71.0-72.0 ° C. (recrystallized from petroleum ether) [α] ²⁶ _D + 141.7 ° (c = 1.0, chloroform) ¹ H-NMR (CDCl ₃ , δ, ppm) 1 0.03 (3H, d, J = 6.6Hz), 1.10 (3
H, d, J = 5.3 Hz), 0.94-1.14 (1
H, m), 1.42-1.55 (2H, m), 1.62
-1.76 (2H, m), 1.83-2. 11 (4H,
m) 2.30-2.57 (2H, m), 3.39 (3
H, s), 4.35 (1H, q, J = 5.9 Hz),
4.81 (s, 1H) ¹³ C-NMR (CDCl ₃ , δ, ppm) 20.525 (q), 21.560 (q), 24.72
1 (d), 28.783 (t), 29.778 (d),
33.423 (t), 39.718 (d), 40.01
4 (d), 45.501 (t), 53.087 (d),
54.862 (q), 76.396 (d), 109.9.
53 (d), 213.773 (s) IR (KBr, cm ^-1 ) 2950, 1710, 110
0,1060 mass spectrum m / z 238 (M ⁺ , 2.1), 2
06 (96.0), 178 (47.0), 136 (10)
0) Elemental analysis value C ₁₄ H ₂₂ O ₃ calculated value C, 70.55; H, 9.30 measured value C, 70.46; H, 9.27 6. (2aR, 3S, 5aR, 7S, 8aS, 8bS)
-5-oxo-2a, 3,4,5,5a, 6,7,8,
8a, 8b-decahydro-3,7-dimethyl-2-methoxy-2H-naphtho- [1.8-bc] furan p-
Synthesis of toluenesulfonylhydrazone 5. Obtained in (2aR, 3S, 5aS, 7S, 8a
S, 8bS) -5-oxo-2a, 3,4,5,5a,
6,7,8,8a, 8b-Decahydro-3,7-dimethyl-2-methoxy-2H-naphtho- [1.8-bc] furan 96 mg (0.40 mmol) and p-toluenesulfonylhydrazine 89 mg (0. A methanol solution of 48 mmol) is heated under reflux for 2 hours. After cooling to room temperature, the solvent is evaporated under reduced pressure to give the title compound as a colorless powder. This product can be used in the next step without purification.

7. (2aR, 3S, 5aR, 7S, 8a
S, 8bS) -3,7-Dimethyl-2-methoxy-2
Synthesis of a, 3,5a, 6,7,8,8a, 8b-octahydro-2H-naphtho- [1.8-bc] furan 6. (2aR, 3S, 5aR, 7S, 8a
S, 8bS) -5-oxo-2a, 3,4,5,5a,
The total amount of the crude product of 6,7,8,8a, 8b-decahydro-3,7-dimethyl-2-methoxy-2H-naphtho- [1.8-bc] furan p-toluenesulfonylhydrazone was dissolved in 5 ml of anhydrous THF. , 1.56M n at 0 ° C
-Butyl lithium hexane solution 2.6 ml (4.0 mm
ol) is added dropwise and the mixture is stirred at 0 ° C. for 2 hours, then the reaction solution is poured into water and extracted with diethyl ether. The organic layer is washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to give the title compound as a colorless oily substance. This product can be used in the next step without purification.

8. (2aR, 3S, 5aR, 7S, 8a
S, 8bS) -2-Oxo-3,7-dimethyl-2a,
3,5a, 6,7,8,8a, 8b-octahydro-2
Synthesis of H-naphtho- [1.8-bc] furan (2aR, 3S, 5aR, 7S, 8a
S, 8bS) -3,7-Dimethyl-2-methoxy-2
The total amount of the crude product of a, 3,5a, 6,7,8,8a, 8b-octahydro-2H-naphtho- [1.8-bc] furan was dissolved in 6 ml of acetone, and 2.67M Jones reagent was added at 0 ° C. After adding 2 ml and stirring for 2 hours, diethyl ether was added to the reaction solution and the organic layer was washed successively with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Separation and purification with ethyl acetate = 2: 1) gave the title compound 44 mg.
(53% total yield from 6.) is obtained as colorless crystals.

Melting point 77.0-78.0 ° C. (petroleum ether) [α] ²⁵ _D + 121.6 ° (c = 2.0, chloroform) ¹ H-NMR (CDCl ₃ , δ, ppm) 1.03 ( 3H, d, J = 6.7 Hz), 1.24 (3
H, d, J = 7.3 Hz), 1.48-1.69 (3
H, m), 1.78-1.96 (3H, m), 2.01
(1H, ddd, J = 4.1Hz, 7.2Hz, 13.
7Hz), 2.45 (1H, dd, J = 3.7Hz,
7.3 Hz), 2.52-2.56 (1 H, m), 4.
66 (1H, dt, J = 4.3Hz, 6.9Hz),
5.56 (1H, dt, J = 9.5Hz, 2.4H
z), 5.64 (1H, dt, J = 9.5Hz, 2.3)
Hz) ¹³ C-NMR (CDCl ₃ , δ, ppm) 21.825 (q), 23.024 (q), 24.66
5 (d), 26.868 (d), 29.304 (d),
33.674 (t), 34.837 (t), 39.46
4 (d), 47.493 (d), 78.291 (d),
131.243 (d), 133.055 (d), 17
9.459 (s) IR (KBr, cm ^-1 ) 2960, 1760, 118
0,1150 Mass spectrum m / z 206 (M ⁺ , 6.6), 161 (58.9), 105
(100) Elemental analysis value Calculated value as C ₁₃ H ₁₈ O ₂ C, 75.69; H, 8.79 Measured value C, 75.60; H, 8.78

[0034]

The manufacturing method and manufacturing intermediate according to the present invention are
It is useful as a method for producing an intermediate such as a medicine or an intermediate for production.

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² represents a lower alkyl group), the octahydronaphthalene derivative represented by the general formula [II] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² represents a lower alkyl group)
After being formed into an is-decalin derivative, it is oxidized to give a compound represented by the general formula [III]: (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² represents a lower alkyl group)
An is-decalin derivative, which is represented by the general formula [IV] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, R ² represents a lower alkyl group, R ³ , R ⁴ and R ⁵ are the same or different and represent a lower alkyl group, or R ³ , R 4 ⁴ is a phenyl group and R ⁵ is a lower alkyl group)
It is converted to an enol silyl ether represented by the formula, and this is dehydrosilylated to give a compound of the general formula [V] (In the formula, R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² represents a lower alkyl group.) As an enone compound, the enone compound was subjected to a conjugate addition reaction to give a compound of the general formula [VI] ] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² and R ⁶ are the same or different and represent a lower alkyl group) and then epi-ized with a base to give a compound of the general formula [ VII] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² and R ⁶ are the same or different and represent a lower alkyl group), and the trans-decalin derivative is represented by the general formula [VIII] [Chemical 8] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, R ² and R ⁶ are the same or different and represent a lower alkyl group, and Ts represents a p-toluenesulfonyl group). Conversion and then by the action of a strong base, a compound of the general formula [IX] (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² and R ⁶ are the same or different and represent a lower alkyl group), and then deacetalized and oxidized. General formula [X] characterized in that (Wherein R ² and R ⁶ are the same or different and each represents a lower alkyl group). 2. The general formula [IX]: (Wherein R ¹ represents a lower alkyl group or an aryl lower alkyl group, and R ² and R ⁶ are the same or different and represent a lower alkyl group) [X] (In the formula, R ² and R ⁶ are the same or different and each represents a lower alkyl group.) A production intermediate of a tricyclic lactone derivative.