JPH03258778A - 4-hydroxyteterahydropyran-2-one derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is -CH2-CH2- or -CH=CH-; n is 1 or 2; R1 is H, lower alkyl, lower alkenyl, aralkyl, acyl, alloyl or substituted sulfonyl; R2 is H or 2-tetrahydropyranyl). EXAMPLE:trans-(+ or -)-6-(5-Benzyloxy-2,3-dihydro-2,2,4,6-tetramethylbenzo[b]furan-7- yl)ethyl-4-hydroxytetrahydropyran-2-one. USE:A cholesterol lowering agent, hypolipemic agent and peroxylipid formation inhibitor. PREPARATION:An aldehyde expressed by formula II is reacted with a dianion of an acetoacetic acid ester to provide a condensate expressed by formula III, which is then reduced. The resultant ester expressed by formula IV is subsequently hydrolyzed with a base to afford a lactone expressed by formula V. The obtained compound expressed by formula V in which group R3 is benzyl is then catalytically reduced to provide the compound expressed by formula I (R1 is H).

Description

Detailed Description of the Invention [Technical Field of the Invention] 4-hydroxytetrahydropyran-2- represented by
on derivatives (wherein A is -Cl(, -CI(, - or -
CH=CH-, n is 1 or 2, R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group, an acyl group, an aroyl group, or a substituted sulfonyl group, and R2 is a hydrogen atom or a 2- It is a tetrahydropyranyl group (hereinafter abbreviated as THP). 〉Regarding.

[Industrial application field]

The present invention relates to compounds useful as cholesterol-lowering agents, lipid-lowering agents, and lipid peroxide production inhibitors.More specifically, the present invention relates to compounds useful as cholesterol-lowering agents, lipid-lowering agents, and lipid peroxide production inhibitors. The present invention relates to the 4-hydroxytetrahydrobilan-2-one derivative represented by the above formula (1), which is a strong inhibitor of lipid peroxidation (abbreviated as ) and has the ability to prevent lipid peroxidation.

[Conventional technology]

It is known that high levels of blood cholesterol, blood lipids, and lipid peroxides are involved as major factors in the development of arteriosclerosis. Lowering blood cholesterol levels by inhibiting cholesterol biosynthesis is an effective method for treating arteriosclerosis. Does it inhibit cholesterol biosynthesis by competing with its rate-limiting enzyme, HMG-CoA reductase, and exhibit blood cholesterol lowering effects at the individual animal level? 1L-23
6B has been discovered (see JP-A-50-155690). ML-236B is a compound having a 6-substituted tetrahydro-4-hydroxypyran-2-one skeleton. M
After L-236B, various 4s with blood lipid-lowering effects
Compounds with a -hydroxybilan-2-one skeleton have been reported (T, -J, Lee+ Trends in
Pharmacol.

5cie, 8 (1), 4420 (1987)
and Drugs of the Future 12
(5), (1987)).

On the other hand, suppressing the production of lipid peroxides is also thought to be useful for treating arteriosclerosis, and vitamin E and probucol have been reported to have this effect.

[Problems to be Solved by the Present Invention] The present invention inhibits IMG-Co heliductase, in fact strongly lowers blood cholesterol levels in animals, while inhibiting the production of vitamin E-like lipid peroxides. The object of the present invention is to provide a 4-hydroxytetrahydrobilan-2-one derivative having the following.

[Means for solving problems]

According to the present invention, the above object can be achieved by providing a 4-hydroxytetrahydropyran-2-one derivative represented by the above formula (1).

Among the 4-hydroxytetrahydropyran-2-one derivatives represented by formula (1), A is -CFI, -
The derivative in which CH,- and n=1 can be produced, for example, by the following method (Formula-1).

(Formula-1) (V) (I[) (I) (VI) (IV) (V) (1) (R1=H) (1) (R1=R4) (In the formula, R+ and THP are the same as above. are the same; R3 is a lower alkyl group, lower alkenyl group or aralkyl group; R4 is an acyl group, aroyl group or substituted sulfonyl group; Bn is a benzyl group; ^ is a lower alkyl group. , ) [First step] This step is to react the aldehyde represented by the formula (II) with the dianion of acetoacetate to produce a condensate represented by the formula (I [I)] . In the aldehyde represented by formula (II) used in this step, R3 is a lower alkyl group, a lower alkenyl group, or an aralkyl group. The lower alkyl group refers to a straight chain, branched chain or cyclic alkyl group having 1 to 6 carbon atoms, and specifically includes a methyl group, ethyl group, n-propyl group, 2-propyl group, n- These include butyl group, 5ec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, cyclopentyl group, cyclohexyl group, and the like.

The lower alkenyl group is a linear or branched alkenyl group having 1 to 6 carbon atoms, and specifically includes an allyl group, methallyl group, prenyl group, and 4-methyl-3-penten-1-yl group. These are the basics.

Examples of the aralkyl group include a benzyl group, a pyridylmethyl group, a naphthylmethyl group, a thiophenylmethyl group, a furylmethyl group, an imidazolylmethyl group, and aromatic nucleus-substituted products thereof.

The acetoacetate used in this step is methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate,
Butyl acetoacetate and the like can be used.

The amount of acetoacetate used in this step is as follows:
At least an equivalent amount, preferably 1 to 1.5 moles, can be used per mole of aldehyde represented by formula (II).

In carrying out this step, the dianion of acetoacetate is derived using a strong base such as sodium hydride, butyllithium, etc., and then used. This step is preferably carried out under an atmosphere of an inert gas such as nitrogen, argon, or the like.

The reaction can usually be carried out in a suitable inert solvent, and ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc. can be used alone or in combination. The reaction is usually carried out at -78°C
- Can be carried out at room temperature.

[Second Step] This step reduces the keto alcohol represented by the formula (II[) above, and converts the keto alcohol represented by the formula (IV) into 3,
5-dihydroxypentanoic acid ester derivatives are produced. For the reduction in this step, a reducing agent used for reducing carbonyl groups can be used, and for example, sodium borohydride can be suitably used.

In carrying out this step, the amount of reducing agent used is
The amount used is 1 to 6 equivalents, preferably 2 to 4 equivalents, per mole of the keto alcohol represented by formula (III).

The reaction is usually carried out in an inert solvent, such as water; alcohols such as methanol, ethanol, and butanol; ethers such as tetrahydrofuran and dioxane; dichloromethane,
Halogenated hydrocarbons such as dichloroethane; benzene,
Aromatic hydrocarbons such as toluene can be used alone or in combination. The reaction temperature can be from -78°C to room temperature.

In addition, in order to carry out the reduction reaction in this step more stereoselectively, known methods (for example, Tetrahedron+ 40+
2233 (1983)) may also be applied.

[Third Step] In this step, the ester represented by the above-mentioned formula (IV) is hydrolyzed using a base, and the corresponding hydroxyheptanoic acid derivative produced is heated and ring-closed to form the desired above-mentioned formula (IV). This method produces a lactone represented by V). As the base used in the hydrolysis in this step, hydroxides of alkali metals and alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc. can be used.

In this step, the amount of the base to be used is as shown in the formula (IV) above.
It is used in an amount of 0.5 to 3 equivalents, preferably 0.8 to 1.2 equivalents, per mole of the ester represented by the formula.

The reaction can usually be carried out in water or in a mixed solvent of water and a water-miscible solvent.

The reaction can usually be carried out at 0 to 80°C.

Furthermore, the lactone represented by formula (V) can be produced without isolation from the hydroxyheptanoic acid derivative obtained by hydrolysis. The reaction is carried out under neutral or near-neutral conditions in an inert solvent such as toluene,
This can be carried out in an aromatic hydrocarbon such as xylene.

The reaction can normally be carried out at 40-150'C.

In addition, in this step, the above-mentioned formula (IV
) can be carried out without isolating the ester.

[Fourth Step] In this step, among the lactone derivatives represented by the formula (V), those in which R5 is a benzyl group are subjected to catalytic reduction to form a compound in which R1 is hydrogen in the formula (1). It manufactures.

The catalytic reduction in this step can be carried out in a hydrogen atmosphere using a catalyst such as a so-called Lindlar catalyst or platinum black in addition to a palladium carbon catalyst.

The reaction can usually be carried out in an inert solvent, and alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethyl acetate and tetrahydrofuran can be used alone or in combination.

[Fifth Step] In this step, among the lactone derivatives represented by the above-mentioned formula (V), R3 is a benzyl group.
This method produces a lactone derivative represented by Vl).

In this step, first, the hydroxyl group of the lactone ring of the derivative represented by formula (V) above, in which R3 is a benzyl group, is protected using dihydropyran according to a conventional method. The reaction can be carried out in an inert solvent such as halogenated hydrocarbons such as dichloromethane and dichloroethane; ethers such as tetrahydrofuran and dioxane.

To carry out this reaction, it is preferable to add an acid catalyst such as p-toluenesulfonic acid, pyridinium P-)toluenesulfonate, hydrochloric acid, or the like. The reaction is usually O'C~100
℃, preferably room temperature to 8°C.

Furthermore, it is a reaction to deprotect the benzyl group of the dihydrobenzofuran ring. This reaction can be carried out according to the fourth step.

Next, the generated hydroxyl group can be reacted with an acid halide or the like according to a conventional method to produce a lactone represented by the above-mentioned formula (VI). The acid halides used here include acetyl chloride, propionic acid chloride,
Straight-chain and branched butanoyl chloride, pivalic acid chloride, benzoyl chloride, naphthalenecarboxylic acid chloride, nicotinic acid chloride, isonicotinic acid chloride, thiophenecarboxylic acid chloride, furanic acid chloride, toluenesulfonyl chloride, methanesulfonyl chloride
Lido etc. can be exemplified.

The amount of acid halide to be used can be 0.5 to 2 moles per mole of the lactone represented by formula (Vl) above.

The reaction can be carried out usually without a solvent or in an inert solvent, such as halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene and toluene.

When carrying out this reaction, it is preferable to add a base, such as triethylamine, pyridine, etc.

The reaction can usually be carried out at 0 to 80°C.

[Step 6] In this step, the hydroxyl group of the compound represented by formula (Vl) is deprotected using an acid to produce a derivative represented by formula (1).

In this step, the acids used are generally mineral acids such as sulfuric acid and hydrochloric acid; P-) organic acids such as luenesulfonic acid, camphorsulfonic acid, and citric acid; p-) pyridinium luenesulfonate, pyridinium chloride, etc. It is preferable to use salt or the like.

The amount of acid used in this step is a so-called catalytic amount.

The reaction can be carried out in a usual solvent, for example, water; acetone; alcohols such as methanol, ethanol, propatool, etc., and mixtures thereof.

The reaction can usually be carried out at a temperature ranging from room temperature to 80°C.

The aldehyde represented by the formula (I[) used in the first step can be produced from a commercially available phenol derivative (■), for example, according to the following formula (Formula-2) (
For details, see Reference Examples 1 to 16, 18 and 19 below).

01 ((X) (XI) (X It ) (Formula-2) (■) (■) (IX) (n) Among the 4-hydroxytetrahydropyran-2-one derivatives represented by the above-mentioned formula (1) A is -CHz-C)
lx- and n=2, in the above-mentioned formula (1), A is -cuz-cut- and n=
1 (Formula-1) is the above formula (n
It can be produced by applying a compound represented by the general formula (in the formula, R8 is the same as above) instead of the aldehyde represented by.

The aldehyde represented by formula (XIV) can be produced by, for example, producing compound (XVI) from compound (■) according to the following formula (Formula-3), and following the reaction process applied to compound (XI). (See Reference Examples 21 to 26 below for details).

(Formula-3) Among the 4-citroxytetrahydropyran-2-one derivatives represented by formula (I), A is -CH=CH-
For example, in the production method of (Formula-1), the derivative is
It can be produced by applying a compound represented by the general formula (wherein R5 is the same as above and n is 1 or 2) instead of the aldehyde represented by formula (II).

Further, representative examples of the compound represented by formula (1) provided by the present invention are as follows.

trans-(±)-6-(2,3-dihydro-5(vI
ll] H-hydroxy-2,2,4,6-titramethylbenzo[
b] chroman-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(5-benzyloxy-2,3
-dihydro-2,2,4,6-titramethylbenzo [b
] chroman-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(5-acetoxy-2°3-dihydro-2,2,4,6-titramethylbenzo(b )furan-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5-(pyridine-3-carboxy')-2,2,4 ,6-titramethylbenzo[b)furan-7-yl]ethyl-4-
Hydroxytetrahydropyran-2-one; trans-(±')-6-(5-benzoyloxy-2
,3-dihydro-2,2,4,6-titramethylben'
/”[b)furan-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6
-[2,3-dihydro-2゜2.4.6-titramethyl-5-(p-)luenesulfonyloxy)benzo(b]
chroman-7-yl]ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5-isopropoxy-2,2,4,6-titramethylbenzo(b
) Furan-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5-methallyloxy-2,2,4,6-titramethylbenzo[ b
] chroman-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5-methoxy-2,2,4,6-titramethylbenzo[b ] chroman-7-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-hydroxy-2,2,
5,7-tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydrobilan-2-one; trans-(±)-6-((6-benzyloxy-2,
2,5,7-tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydrobilan-2-one; trans-[±)-6-((6-itubropoxy2.
2.5.7-tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydrobilan-2-one; trans-(±)-6-((6-methallyloxy-2,
2,5,7-tetramethyl)chroman-8-yl)ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-acetoxy-2,2,
5,7-tetramethyl)chroman-8-yl)ethyl-
4-Hydroxytetrahydropyran-2-one; trans-(±)-6-((6-(pyridine-3-carboxy)-2,2,5,7-tetramethyl]chroman-8-yl]ethyl-4- Hydroxytetrahydropyran-2-one; trans-(±)-6-((6-penzoyloxy-2
．． 2.5.7-tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-[[6-(p-)luenesulfonyloxy)-2,2 ,5,7-tetramethyl]chroman-8-yl]ethyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5-hydroxy-2,2,4, 6-Titramethylbenzo[b]chroman-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(5-benzyloxy-2,3
-dihydro-2,2,4,6-titramethylbenzo [b
] chroman-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(5
-acetoxy-2゜3-dihydro-2,2,4,6-titramethylbenzo(b)furan-7-yl)ethynyl-
4-Hydroxytetrahydropyran-2-one; trans-(±)-6-1:2.3-dihydro-5-(
pyridine-3-carboxy”) -2,2,4,6-titramethylbenzo[b]furan-7-yl]ethynyl-
4-Hydroxytetrahydropyran-2-one: trans-(±')-6-(5-benzoyloxy-2
,3-dihydro-2,2,4,6-titramethylben/
'(b)furan-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6
-[2,3-dihydro-2゜2.4.6-titramethyl-5-(p-toluenesulfonyloxy)benzo[b]
Furan-7-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,3-dihydro-5isopropoxy-2,2,4,6-titramethylbenzo(b )
Furan-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-(2,
3-dihydro-5methallyloxy-2,2,4,6-titramethylben/”(b)furan-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans=(±)-6=( 2,3-dihydro-5-methoxy-2,2,4,6-titramethylbenzo(b)furan-
7-yl)ethynyl-4-hydroxytetrahydropyran-2-one; trans=(±)-6-((6-hydroxy2.2,5
．． 7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-benzyloxy-2,
2,5,7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-C(6-itubropoxy2.
2,5.7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-methallyloxy-2,
2,5,7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-acetoxy-2,2,
5,7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydrobilan-2-one; trans-(±)-6-((6-(pyridine-3-carboxy)-2,2,5, 7-tetramethyl]chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-penzoyloxy-2
．． 2.5.7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one; trans-(±)-6-((6-(p-t-ruenesulfonyloxy-2,2 , 5.7-tetramethyl)chroman-8-yl)ethynyl-4-hydroxytetrahydropyran-2-one, and the like.

(Function) The 4-hydroxytetrahydropyran-2-one derivative represented by the general formula (1) of the present invention exhibits a cholesterol biosynthesis inhibitory effect based on an HMG-Co A reductase inhibitory effect, as shown in the following test examples. have.

It also has a vitamin E-like inhibitory effect on lipid peroxide production, making it an effective drug for treating arteriosclerosis.

These derivatives can be administered intravenously, subcutaneously or intramuscularly in addition to orally. For this purpose, these compounds can be used in various dosage forms, such as tablets, capsules, liquids or herbal medicines.

Furthermore, the 3,5-dihydroheptanoic acid derivative with the lactone ring opened in the 4-hydroxytetrahydropyran-2-one derivative represented by the general formula (1) of the present invention is
It is a compound that is produced in vivo after administration, and has the formula (I)
It has the same HMG-CoA reductase inhibitory effect as
It is included in the present invention.

〔Example〕

A more detailed explanation will be given below using reference examples, working examples, and test examples.

3.5-dimethylphenol 1 46.73 g (3
83 mole) was dissolved in 100 mf of methyl ethyl ketone, and 55.6 g (460 mmol) of allylpromide was dissolved in 100 mf of methyl ethyl ketone.
, anhydrous potassium carbonate 79.3 g (575a+mo
1) was added, and the mixture was heated to reflux under an argon atmosphere overnight. The reaction product was extracted with hexane, washed with water, then washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. As a result, 65.0 g of a crudely purified ether was obtained as a colorless oil.

'HNMR (CDCf3.300 2) 62.28 (s
, 61(), 4.50(ddd, J=5.4.1.5
and 1.5) 1z, 2H), 5.27(ddd
, J=10.5.1.5 and 1.5) 1z, 18
).

5.40(ddd, J=17.4.1.5 and 1
．． 5Hz, IH).

6.05 (dat, J=17.4. 10.5 and
5.4Hz, IH).

6.55 (s, 2H), 6.60 (s, IH)
ppmIR (liquid film) 308B, 3026. 1617. 1597
265.0 g of the crude compound was dissolved in 200 ml of N,N dimethylaniline, and the mixture was heated for 200 mL under an argon atmosphere.
Stirred at ℃ for 2 days. After the reaction was completed, the reaction mixture was poured into IN aqueous hydrochloric acid and extracted with ethyl acetate. The extracted layer was back-extracted with an IN aqueous sodium hydroxide solution, and the aqueous layer was made acidic with 6N hydrochloric acid, and then extracted with hexane. Furthermore, the extracted layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated. 43.0 g of the main phenol was obtained with a yield of 66.0%.

Melting point: 16.0-47.5°C (yellow needle-like crystals, recrystallized from ethyl acetate)'HNMR (C
DC13,300MHz) δ2.24 (s, 6H),
3.38 (d, J=6.0Hz, 2H).

4.77 (s, 1B), 5.02 (d with f
ine coupling, J=17.1Hz, LH
), 5.05 (d 1yith fine coup
ling, J=10.2Hz, IH), 5.95
(dat, J=17.1. 10.2.and 4.2
Hz, 1B), 6.50 (s, 11), 6.6
0(s, 1B) ppmIR, (Br) 3348.29B4, 2932, 1736.1625
cm-' Noble 1 ■ Crude 1 Phenol 3 synthesized in Reference Example 1 22.56 g (13
9,2n+mol) was dissolved in a mixed solvent of 25mf of N,N-dimethylformamide (hereinafter abbreviated as DMF) and 75ml of ethylene glycol dimethyl ether (hereinafter abbreviated as DME), and 57.6g (41
7.6 mmol), methallyl chloride 15.13 g (1
67,1w + mol) and heated in an oil bath at 105°C for 10
The mixture was heated to reflux for an hour. After the reaction was completed, the reaction mixture was poured into water and extracted with hexane. The extracted layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to yield 25.28 g of crude metall ether 4.
g was obtained in a yield of 84.0% as a pale yellow oil. 4
was used in the next reaction without further purification.

'HNMR (CDCj2+, 300 MHz) δ1.
82 (s, 3H), 2.25 (s, 3H), 2.2
8(s, 38) 3.42(d, J=6.6Hz, 2Fl
), 4.39 (s, 2H) 4.90-4.98 (#l
, 3H), 5°10 (s, IH), 5.84-5.
96 (m, IH), 6.54 (s, 1B), 6.6
1(s, 1) 1) ppmIR(liquid fi
lm) 2928, 1652 cm-' Reference Example 3 41.465 g of methallyl ether synthesized in Reference Example 2 was dissolved in 5 mf of N,N-diethylaniline, and 210
The mixture was heated and stirred in an argon atmosphere for 15 hours in an oil bath at °C.

After the reaction was completed, the reaction solution was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to silica gel column chromatography and flushed out with a 1:10 mixed solvent of ethyl acetate and hexane to obtain 1.02 g of phenol as a pale yellow oil with a yield of 69.7%. .

'HNMR (CDCj!+, 300 MHz)61.
77 (s, 3H), 2.22 (s, 31 (), 2.
24 (s, 3H).

3.35 (s, 2H), 3.39 (d 5m1th
fine coupling, J=4.5Hz, 2H
), 4.66 (s, 18), 4.84 (s, IH)
.

4.98 (d wfth fine coupling
, J=17.1Hz+IH)+5.03(d wtt
h fine coupling + J=10.2Hz
, IH).

5.12 (s, LH), 5.95 (ddt, J=17
．． 1.10.2. and 4.5Hz, LH), 6.
30(s, IH) PpmIR(liquid, f
il@) 3550, 2984.2932.1639 clfi
-'5.432g of phenol synthesized in Reference Example 3 (2,
00 mmol), sarcomine 65 wg (0.2 m
mol) to ethanol 10m/! The mixture was stirred at room temperature for 3 days under an oxygen atmosphere. After the reaction was completed, the reaction mixture was concentrated, a mixed solvent of hexane and ethyl acetate was added, and the mixture was filtered through Celite. The filtrate was concentrated and subjected to silica gel column chromatography.
When washed out with a mixed solvent of 10%, Kino Y6 was 326%
(2) Obtained as a yellow oil with a yield of 70.9%.

'HNMR (CDCj2s, 300 MHz)61.
76 (s, 3H), 2.02 (s, 3H), 2.0
5 (s, 3H) 3.21 (s, 2H), 3.26 (d
, J=5.4Hz, 2H), 4.53(s, IH).

4.76 (s with fine coupling
, IH).

5.03(d with ffne coupling
, J=17.7Hz, IH).

5.03(d with fine coupling
+ J=9.9)1z+IH)+5.76(ddt,J
=17.7.9.9 and 5.4Hz, IH)
ppmIR (liquid, film) 29B4.2932.1648 cm-'nobleffi Quinone 6.310cm (1,35mm) synthesized in Reference Example 4
ol) in 2 mf of methylene chloride, and dissolved 56 kg of sodium borohydride (1,48
ms+ol) was added. Furthermore, several drops of methanol were added until the color of the solution changed from red to yellowish white.

The reaction solution was cooled to 0° C. and stirred for 130 minutes, and then 22 μm (0.58 mmol) of sodium borohydride and several drops of methanol were added and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate.

The extracted layer was washed with water and then with saturated brine, dried with anhydrous magnesium sulfate, concentrated, subjected to silica gel column chromatography, and flushed out with a 1=6 mixed solvent of ethyl acetate and hexane. Hydroquinone 7 240■
, with a yield of 76.6%.

Melting point 791.0-99.0°C (colorless fine granular crystals, recrystallized from diethyl ether and hexane) 'HNMR (CDCf 3.300 MHz) δ1.
79 (s, 3) 1), 2.17 (s, 3H), 2.
18 (s, 3H).

3.37 (s, 2) 1), 3.43 (d, J=5.7
tlz, 1) 1), 4.28 (s, IH).

4.6Hs with fine coupling,
IH), 4.68 (s, IH).

4.83(s with fine coupling
, IH).

4.95 (d with fine coupling
, J=17.1Hz, IH).

5.03(d with fine coupling
+ J=10.5Hz, IH) 5.95(dat, J=
17. L 10.5 and 5.7Hz, 1) 1)
ppmIR (KBr) 34'7B, 1641 CI-' Mass (m/z+%) 232 (M", 100), 176 (29),
16H12), 9H16).

Hydroquinone 7 165 mg (0,
711 mmol) was dissolved in 2 ml of methylene chloride, and 0
°C, boron trifluoride etherate 1 under argon flow
211 g (0,853 mmol) was added and stirred for 25 minutes. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracted layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was subjected to silica gel column chromatography and flushed with a 1:6 mixed solvent of ethyl acetate and hexane to obtain 152 mg of phenol 8 in a yield of 92.1%.

Melting point: 93.0-94.8°C (colorless columnar crystals, recrystallized from diethyl ether and hexane) 'HNMR (CDC 1,3,300MHz) 61.43
(s, 6H), 2.11(s, 3H), 2.13(
s, 3Fl) 2.91 (s, 2H), 3.3Hd+
with fine coupling, J=6, (E
z, 211), 4.13(s, IH).

4.94 (d with fine coupling
, J=17.1Hz, IH).

4.95 (d with fine coupling
, J=10.3Hz, IH) 5.88(dat, J=1
7.1.10.3 and 6.0Hz, 1B) p
pmJR (KBr) 3530, 297B, 1640 cllI-'
Mass (m/z, %) 232 (M”, 100), 176 (21)
, 161(7), 9H10).

43 (2B), 4H16) Phenol synthesized in Reference Example 6 8,182■ (0,78
4 mmol), DMFO, 5 ml and DMEl,
Benzyl bromide 161■ (
0,941 mmol), anhydrous potassium carbonate 325 ■ (
2.35 mn+ol) was added, and the mixture was heated under an argon atmosphere.
The mixture was heated under reflux for 30 minutes.

After the reaction was completed, the reaction solution was returned to room temperature, poured into water, and extracted with hexane. The extracted layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

The concentrate was subjected to silica gel column chromatography,
When washed out with a mixed solvent of ethyl acetate and hexane (1=9), 9,228 cm of benzyl ether was obtained in a yield of 90.5%.

Melting point: 35.5-36.2°C (colorless fine granular crystals, recrystallized from ethanol and water) 'HNMR (CDC 13,300MHz) 61.45 (
s, 6H), 2.16(s, 3H'), 2.20(
s, 3H) 2.91 (s, 2H), 3.31 (d, J
=6.9Hz, IH), 4.71(s, 2H)4.9
5 (de emith fine coupling, J
=16.2Hz, IH).

4.96 (devith ffne couple
g, J = 10.2 Hz, LH) 5.90 (dat, J =
16.2.10.2 and 6.9Hz, IH)7.
30-7.54 (+a, 5Fl) ppmIR (KB
r) 2980, 1642 cm-' Mass (m/z, %) 322 (M'', 6), 231 (100), 1
75(5), 9N21) 35 mj2 of anhydrous tetrahydrofuran (hereinafter abbreviated as THF) was added to a flask filled with argon, followed by 4.65 g of 9-borabicyclo(3,3,1)nonane (hereinafter abbreviated as 9-BBN). (38
, 1 gmol) was added at room temperature. Further to this solution, 5
9 synthesized in Reference Example 7 dissolved in ml of anhydrous THF,
9.68 g (30.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour under an argon stream. 3.65 ml (60.1 mmol) of ethanol was added to the reaction solution, and after stirring for 20 minutes, 30.1 ml of 2N aqueous sodium hydroxide solution was added.
1 (60.2 mmol) was added. 0°
Cool to C and add 13.6 m of 30% hydrogen peroxide solution!
(120.2 mmol) was gradually added. The solution was returned to room temperature and heated under reflux for an additional hour.

The reaction solution was returned to room temperature and extracted with ethyl acetate.

The extracted layer was washed successively with water, an aqueous sodium thiosulfate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. When the concentrate was subjected to silica gel column chromatography and flushed out with a 1:3 mixed solvent of ethyl acetate and hexane, 9.19 g of alcohol was obtained, yield 89.9.
Obtained in %.

Melting point: 42.5-43.5°C (colorless needle crystals, recrystallized from hexane) 'HNMR (CDCj!s, 300 MHz) δ1.
49 (s, 6H), 1.70-1.80 (+w, 2
H).

2.16 (s, 3H), 2.22 (s, 3H), 2
．． 70 (t, J=6.3Hz, 2Fl).

2.94 (s, 2H), 3.51 (t, J=5.4H
z, 18), 4.72 (s, 2tl).

7.30-7.55 (m, 5H) ppmIR (KB
r) 3468, 2944 CI-' Mass (n/z, %) 34() (1'l'', 7), 249(100)
, 205(19), 9H32) 4.0 ml (55,6 mm) of dimethyl sulfide at 0°C under a stream of argon.
ol) was added to 100 ml of toluene, 5.33 g (39.9 mmol) of N-chlorosuccinimide was added, and the mixture was stirred for 30 minutes.

The reaction solution was cooled to -25°C, 7.0 g (21,!5++■ol) of the alcoholic acid synthesized in Reference Example 8 was added, and the mixture was stirred for 2 hours while maintaining the temperature at -20 to -35°C.

4.04 g of triethylamine (39,
After gradually dropping 9 mmol), the temperature was raised to room temperature.

The reaction solution was washed successively with water, IN hydrochloric acid, saturated aqueous sodium osulfate solution, aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The concentrate was subjected to silica gel column chromatography,
When poured out with a 2:9 mixed solvent of ethyl acetate and hexane and crystallized from hexane, the aldehyde ■ was 6.19
g, with a yield of 88.9%.

Melting point: 100.0-101.5°C (colorless fine granular crystals)'
HNMR (CDCl s = 300 MHz > 61.4
5 (s, 6H), 2.16 (s, 3H), 2.22
(s, 38).

2.63(t with fine coupling
, J=7.8Hz+2H)+2.89(t, J=7.8
Hz, 2H), 2.90(s, 2H)', 4.71
(s, 2H).

7.30-7.55 (m, 5H), 9.82 (s w
ith fine coupling.

IFI) ppm IR (KBr) 2904, 2864. 2740. 1718c
m-'Mass (ll/z, %) 338 (M'', 6), 247 (100
), 205(21), 203(29).

9H37), 41(9) Reference Example 10 550 ml (13,8111 mol) of 60% sodium hydride was suspended in 100 ml of anhydrous THF in an eggplant flask at 0°C under an argon stream. 1.75 ml (13.8 mmol) of ethyl acetoacetate was added to this solution and stirred for 30 minutes. Next, butyllithium 15
% hexane solution 8.81 m 12 (13,8 mmo
1) was added and stirred for 1 hour.

The reaction solution was cooled to -78°C, and 3.10 g (9,17+u+ol) of aldehyde LL synthesized in Reference Example 9 was added.
10m! Anhydrous THF solution was added and stirred for 30 minutes.

After the reaction was completed, saturated ammonium chloride water was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with ethyl acetate.

The extract layer was washed successively with saturated ammonium chloride solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

The concentrate was subjected to silica gel column chromatography,
Elution with a 1:2 mixed solvent of ethyl acetate and hexane gave 3.03 g of ketoester 12 as a yellow oil in a yield of 70.6%.

'HNMR (CDC423, 300MHz) 61.26
(t, J=7.2Hz, 3H), 1.47(s, 3H
).

1.48 (s, 3H), 1.54-1.75 (m, 2
H), 2.16 (s, 3H).

2.21 (s, 3H), 2.52-2.81 (m, 4
H), 2.93 (s, 2H).

3.50 (s, 2) 1), 3.64 (d, J=3.3
) 1z, 1) 1) 3.85-3.98 (m, 11),
4.17 (q, J=7.2Hz, 2H).

4.72 (s, 2H), 7.31-7.57 (m, 5
H) ppmIR(film) 3528, 29B0.2940.1748.1716
C11-'Mass (re/z, %) 46B (?'l", 4), 377 (6
1), 33H14), 247(66)205(
52), 203 (100), 91 (85),
43 (82L 3H72) pivalic acid 801g (
0.7B+u+ol) at room temperature under an argon atmosphere.16.
5 ml <16.5yatao1") was added and stirred for 1 hour. To this solution, a solution of 12.6.22 g (13.3 mmol) of the ketoester synthesized in Reference Example 10 in 50 ml of anhydrous THF was added dropwise for 1 hour. After, -7
After cooling to 8°C and adding 18 ml of methanol, 43011 g of sodium borohydride (11,4+++ m
ol) was added.

After 40 minutes, 18 m2 of 5N aqueous sodium hydroxide solution, followed by 28 mf of 30% hydrogen peroxide solution were added, and the temperature was raised to 0°C. After the temperature was further raised to room temperature, the mixture was stirred for 1 hour.

The reaction mixture was made acidic with IN aqueous hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed successively with water, saturated aqueous sodium thiosulfate, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

The concentrate was dissolved in 50 m2 of toluene and heated under reflux for 4 hours. After the reaction was completed, the solvent was distilled off and subjected to silica gel column chromatography, which was flushed out with a 2:1 mixed solvent of ethyl acetate and hexane.
±)-6-(5-hensyloxy-2,3-dihydro-
2,2,4,6-ketramethylbenzo(b)furan-7
-yl)ethyl-4-hydroxytetrahydrobilane-
4.74 g of 2-one 13 was obtained with a yield of 84.1%.

Melting point: 121.0-122. OoC (colorless columnar crystals, recrystallized from ethyl acetate and hexane) 'HNMR (CDCf 3.300 ?Itlz) δ1
．． 45 (s, 3FIL 1.46 (s, 3H), 1.
75-2.04 (m, 4H) 2.16 (s, 38),
2.24 (s, 3) 1), 2.45-2.82 (m,
4t()2.90(s, 2H), 4.35~4.4
5 (a+, LH), 4.66-4.77 (g, 01
), 4.71 (s, 2H), 7.32-7.5
3(w+,5)1) ppmIR(KBr) 3520, 2974. 2934. 1734. 1
594 C11-'Mass (m/z, %) 424 (M", 6), 333 (71)
, 315(11), 229(11).

205 (27), 203 (100), 6H91) 13
14 Dissolve 50 mg of Lacto713 synthesized in Example 1 in 1 ml of methanol,
10% Pd/C10+g was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere.

The reaction mixture was diluted with ethyl acetate and methylene chloride, filtered through Celite, and concentrated. The concentrate was subjected to silica gel column chromatography and flushed with a 1:1 mixed solvent of ethyl acetate and hexane, followed by ethyl acetate. Hydroxy-2,2,4,6-ketramethylbenzo(b)furan-7-yl)ethyl-4-hydroxytetrahydropyran-2-one was obtained in a yield of 33 μm, 83.7%.

Melting point: 131.0-133.0''C (colorless columnar crystals, recrystallized from ethyl acetate and hexane) 'HNMR (CDC 13,300MHz) 61.42 (
s, 3tl), 1.44 (s, 3H), 1.70~
1.96 (m, 4) 1) 1.97-2.06 (m, IN
), 2.10(s, 3H), 2.18(s, 3)1
)2.61(ddd, J=17.4.3.9 and
1.5.1(Z,I)l).

2.76 (dd, J=17.4 and 4.8Hz,
IH), 2.65-2.81 (+n, 28), 2.
90 (s, 2H), 4.18 (s, 1) 1), 4.
35-4.43 (m, IH), 4.64-4.75 (
m, IN) ppIllR(KBr) 3546, 2972.2930.1684 am-'
Mass (+/z, %) 334 (?I”, 100), 205 (60),
204(44), 189(26).

43 (45) Reference Example 11 11.2.27 g of benzyl ether synthesized in Reference Example 9
(6.72 mmol) in ethyl acetate 7.5 m!
! After adding 10% Pd/C227m, the system was placed under a hydrogen atmosphere. 2.5 ml of methanol was added to the solution and stirred for 20 minutes at room temperature. Furthermore lO%Pd
100 μ of /C was added and stirred for 2 days.

The reaction mixture was diluted with ethyl acetate and filtered through Celite.

The filtrate was concentrated and crystallized from hexane to obtain 475 g of phenol in a yield of 88.5%.

Melting point: too, s ~ 102.5°C (colorless fine granular crystals) H
NMR (CDC1,3,300MHz) 61.43(s
, 6H), 2.10 (s, 3H), 2.16 (s,
3H).

2.6Htd with fine coupling
, J=7.7 and 1.8Hz, 2H), 2
゜89(t, J=7.7Hz, 2)1) 2.90(
s 2H) 9.80 (t, J = 1.8 days z, 11 ()
ppH4,15 (s, 2FI) IR (KBr) 3380.2976.1703 cm-'Mass
(m/z, %) 248 (M”, 90) 77 (39L 55 (26).

205(93), 189(55), 9H49)
.

43 (100), 39 (82), 29 (86)
Phenol f5 synthesized in Reference Example 11.1.00g (4
, 03 mmol), DMF 1 mf and DME
Dissolved in a mixed solvent of 3 mI2, methyl iodide 2.63
ml-(4.23 mmol), anhydrous potassium carbonate 1
．． 67g.

(12,1+uwol) and 4
The mixture was heated to reflux for an hour.

After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was subjected to silica gel column chromatography and flushed with a 1=10 mixed solvent of ethyl acetate and hexane, followed by ethyl acetate.
Obtained with a yield of 9%.

Melting point: 52. O~54°0°C (colorless columnar crystals, recrystallized from ethyl acetate and hexane) J NMR (CDCl 3I300 MFlz) 61.
44 (s, 6) (L 2.13 (s, 3H), 2.2
0(s, 3H).

2.62 (td, J= 7.8 and 1.8 Fl
z, 2H).

2.87 (t, J=7.8Hz, 2H), 2.89 (
s, 2H), 3.64(s, 3f(L9.81(t,
J=1.8Hz, 1fl) ppmIR (KBr) 2978, 2950.2818.1723 cm-'
Mass (m/z, %) 262 (do, 100), 247 (33), 21
9(27), 203(44).

191(10), 9H17), 53(16), 4
3 (22), 4N28) 39 (20), 29 (20
) 1521 g (3.82 gmol) of 60% sodium hydride was added to anhydrous THF at 0°C and under an argon stream.
7m! To this solution, add 484 u 42 (3,8o+a+ol) of ethyl acetoacetate,
Stir for 5 minutes. Subsequently, 2.43 m i (3.80 mmol) of a 15% hexane solution of butyllithium was added, and the mixture was stirred for 35 minutes.

The reaction solution was cooled to -78°C, and 3 m
1 anhydrous THF solution was added and stirred for 2 hours.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was brought to room temperature and extracted with ethyl acetate. The extracted layer was washed successively with saturated ammonium chloride aqueous solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to silica gel column chromatography and flushed out with a 1:2 mixed solvent of ethyl acetate and hexane, yielding 469 cm of ketoester H as a pale yellow oil with a yield of 52.5%. .

'HNMR (CDC1s, 300 MHz) δ 1.
26 (t, J=7.2Hz, 3H), 1.46 (s,
3H).

1.47 (s, 3H), 2.13 (s, 3H), 2
．． 19(s, 3H).

2.52-2.80 (+m, 41), 2.92 (s,
2H), 3.49(s, 2H).

3.60-3.65 (s+, IB), 3.64 (s,
3H), 3.85-3.95 (m, 1) 1), 4.
17(q, J=7.2Hz, 21() ppmIR(
liquid, filWf) 3528, 2980.2940.1750.1718
am-'Mass (s+/z,%) 392 (M", 51), 346 (17), 2
62(25), 219(64).

203(53), 189(9), 115(13),
9H17), 53 (13) 43 (100), 4N
25), 31(25), 29(84) 111 7 8 To pivalic acid 6 (0,063 mmol) was added triethylborane (1,0M T H
Solution E) 1.26 ml (1.26 mmol) was added and stirred for 1 hour. In this solution, 17,449 μ (1,145 mmol) of the ketoester synthesized in Reference Example 13 was added.
was dissolved in 3mf of anhydrous THF and added dropwise. 1 hour later
The reaction solution was cooled to -78°C, and 1.79 mf of methanol was added.
was added, followed by 48μ of sodium borohydride (1,2
6 mmol) was added. After 55 minutes, add 4.66 ml of 5N aqueous sodium hydroxide solution, then 4.4 ml of 30% hydrogen peroxide solution.
．． Added 66mf. The reaction mixture was heated to 0° C. and then to room temperature, and then stirred overnight.

The reaction mixture was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed successively with water, saturated aqueous sodium thiosulfate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The 20m condensate was dissolved in 3 ml of motoluene and heated under reflux for 5 hours. After the completion of the reaction, the solvent was distilled off, and the mixture was subjected to silica gel column chromatography and flushed with a 2:1 mixed solvent of ethyl acetate and hexane. When I took it out, the transformer-(±
)-6-(2,3-dihydro-5-methoxy-2,2,
4,6-ketramethylbenzoCb)furan-7-yl)
Ethyl-4-hydroxytetrahydrobyran-2-off 1B was obtained in a yield of 260 μm and 62.7%.

Melting point: 112. O~113.5°C (colorless columnar crystals, recrystallized from diethyl ether and hexane)'HNMR (CD
Cj2s, 300 MHz) 61.43(s, 3H),
1.44 (s, 3) 1), 1.72-2.08 (m
, 5H).

2, 13 (s, 3B), 2.21 (s, 3H
).

2.6Hddd, J=17.4.3.9 and 1.
5Hz, IH).

2.76 (dd, J=17.4 and 5.1Hz,
18).

2.60-2.80 (m, 2H), 2.89 (s, 2
H), 3.64 (s, 38) 4.35-4.44 (m
, 1B), 4.65-4.78 (m, 1B) IR (
KBr) 3502.2978, 2940. l708,1704
cm-'Mass (a+/z, %) 348 (M", 100), 219 (30
L 203 (58) Reference Example 14 11m 1:1 mixed solvent of methanol and ethyl acetate 30ml
106.618 g of alcohol synthesized in Reference Example 8
(19,5 mmol) and 10% Pd/C310■
was added, and the mixture was stirred at room temperature for 21 hours under a hydrogen atmosphere of 1 atm. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the mixture was passed through Celite. When the 0 solution was concentrated and the concentrate was crystallized from a mixed solvent of ethyl acetate and hexane, phenol
was obtained in a yield of 2.866 g and 58.9%. The mother liquor was concentrated, applied to a silica gel column, and flushed out with a 1=2 mixed solvent of ethyl acetate and hexane to obtain an additional 1.568 g (32.2%) of ■.

Melting point: 122. O~123.0"C (colorless granular crystals, recrystallized from ethyl acetate and hexane) YiHNMR (CDC123, 300111z) δ1.4
7 (s, 6H), 1.67-1.79 (m, 2H).

2.11 (s, 3H), 2.16 (s, 3H), 2
．． 67-2.75 (m, 2H).

2.95 (s, 28), 2.98 (t, J=7.0H
z, 18).

3.44-3.53 (m, 28), 4.23 (s, I
H) ppmIR (KBr) 3460, 3336.2976, 2944 cl'M
ass (m/z, %) 250 (M”, 60L 205 (61), 18
9(24), 9H27).

53(27), 43(7B), 4H57), 3H
100) Phenol 19.5 synthesized in Reference Example 14 in a mixed solvent of DMF 2mj2 and DME 3mf
00■ (2,OOwmol), potassium carbonate 500■
(3,621111no1) and methallyl chloride 0.4
0 ml (4.05 mmol) was added thereto, and the mixture was heated under reflux for 3 hours under an argon atmosphere.

After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed out with a 4:1 mixed solvent of hexane and ethyl acetate, the amount of methallyl ether was 603 cm and 99.2 cm.
% yield.

Melting point: 59.0-59.5°C (colorless needle crystals, recrystallized from hexane) 'HNMR (CDCfa, 300 MHz) δ1.4
B (s, 6B), 1.69-1.79 (m, 2H).

1.88 (s, 3H), 2.13 (s, 3H), 2
．． 19(s, 3H).

2.64-2.73 (m, 2H), 2.84-2.9
6 (a+, LH) 2.92 (s, 2N), 3.44~
3.54Lm, 2H), 4.08(s, 2J()4.
97(s With fine coupling, 1
B).

5.17(s With fine coupling
, IH) I) I) fflIR (KBr) 3488, 29B0. 2936. 2868. 1
802. 1660 cln-'Mass (m/
z, %) 304 (M”, 7L 249 (70), 205
(28), 55(100).

29 (75) Reference Example 16 Dimethyl sulfoxide 25m! and dry THF15m
Reference Example 15 in a mixed solvent of f at room temperature under an argon atmosphere.
20.2.25g of ether synthesized in (7,40a+m
ol), triethylamine 4.5 ml (32,
3 mmol'l) and sulfur pyridine trioxide complex 3.5
g (22.0 mmol) were added one after another, and the mixture was stirred for 50 minutes.

The reaction mixture was poured into IN hydrochloric acid and extracted with hexane. The extracted layer was washed three times with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a 10:1 mixed solvent of hexane and ethyl acetate.
1.80 g of aldehyde was obtained with a yield of 80.5%.

Melting point: 55.5-56.0°C (colorless columnar crystals, recrystallized from hexane) 'HNMR (CDCl 3.300 MHz) 61.
44 (s, 6H), 1.88 (s, 3H), 2.1
2(s, 3f()2.19(s, 3H), 2.6Ht
d, J=7.8 and 1.8Hz, 21().

2.87(t, J=7.8Hz, 2H), 2.88(
s, 2H), 4.06 (s, 2H).

4.97 (broad s, 18), 5.17 (br
oad s, IH) 9.81 (t, J=1.8Hz, I
H) ppmIR(toBr) 2984, 2924.2864.2816.2716.
1?24.1662CalKiMass (a+/z+ %) 302 (M”, 9), 247 (100), 2
05(47), 203(61).

9N24), 55 (100), 41 (59), 3
9(57), 29(94).

27 (94) Reference Example 17 60% oily sodium hydride 258cm (6,45mmo
l) in a solution of 10mj2 of dry THF,
Ethyl acetoacetate 0.83 at 0°C under argon stream
m j! (6.51 mmol) was added and stirred for 25 minutes.

Add 15% hexane solution of butyl lithium to this solution.
．． 1 m 12. (6.41 mmol) and added 25
Stir for a minute. Cool the solution to -78°C and dilute with dry THF.
1,423 g (4,71 mmol) of the aldehyde nail synthesized in Reference Example 16 dissolved in 10 ml was added, and the mixture was stirred for 1 hour and 20 minutes. After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed three times with saturated brine, dried over magnesium sulfate, and concentrated.

The concentrate was applied to a silica gel column and flushed out with a 4:1 mixed solvent of hexane and ethyl acetate to obtain 1.605 g of ketoester 22 in a yield of 78.8%.

Melting point: 53.5-55.0°C (colorless columnar crystals, recrystallized from ethyl acetate and hexane) 'HNMR (CDCI23.300 MHz) 61.2
6(t, J=7.1Hz, 3B), 1.46(s, 3
H) 1.47 (s, 3H), 1.50-1.75 (m
, 2H), 1.89 (s, 3H) 2.12 (s, 3H
), 2.18(s, 3t(), 2.50-2.81
(m, 4H).

2.92 (s, 2H), 3.49 (s, 2H), 3
．． 64 (d with fine coupling, J
=3.6Hz, IH)+3.84~3.96(m,L
H).

4.08 (s, 2H), 4.17 (q, J=7.1)
1z, 2H) 4.97 (broad s, IH), 5
．． 17 (broad s, LH) ppmIR (KB
r) 3572, 29B4.2932.1744.1704.
1660 cmMass (m/z+%) 432 (M”, 2), 377 (1B), 24
7(35), 205(2B).

203 (54), 55 (59), 43 (85),
29 (100), 27 (45) 1 volume triethylborane (LM THF solution) 5.0 ml
To (5,00 mmol) was added 22 µ (0,22 mmol) of thehybalic acid at room temperature under an argon atmosphere, and the mixture was stirred for 1 hour. To the solution was added 22 µ (0,22 mmol) of the ketoester synthesized in Reference Example 17, dissolved in 15 ml of dry THF, 1.435 g □ (
3.32 mw+ol) was added and stirred for 1 hour and 20 minutes.

The solution was cooled to -78°C and added with 5 ml of methanol followed by 140 μl of sodium borohydride (3.70 mmol).
l) was added and stirred for 20 minutes. Add 5N to this solution.
Sodium hydroxide aqueous solution 5.5 m 12 and 30%
After adding 9.0 g (79.4 mmol) of an aqueous hydrogen peroxide solution, the mixture was cooled with water, and 5.5 ml of a 5N aqueous sodium hydroxide solution was added, followed by stirring for 1 hour. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate.

The extracted layer was washed successively with IN hydrochloric acid, aqueous sodium periosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in 15 ml of dry toluene and heated under reflux for 6 hours. The reaction mixture was applied to a silica gel column and flushed with a 2:1 mixture of hexane and ethyl acetate, followed by a 1:1 mixture, resulting in trans-(±)-6-(2,3-
Dihydro-5methallyloxy-2,2,4,6-ketramethylbenzo(b)furan-7-yl)ethyl-4-hydroxytetrahydropyran-2-one η is 1.043
g, with a yield of 81.3%.

Melting point near S, O~79.5°C (colorless columnar crystals, recrystallized from diethyl ether and hexane) 'HNMR (CDCl 3,300 MHz) 61.4
3 (s, 3H), 1.44 (s, 3H), 1.73
~2.08 (m, 4H), 1.88 (s, 3H),
2.12 (s, 3H), 2.20 (s, 3H) 2.6
Hddd, J=17.5 4.0 and 1.5Hz
, IH) 2.60-2.81 (m, 2Fl), 2.7
6 (dd, J=17.5 and 5.0HzIH),
2.88(s, 21(), 4.07(s, 2H).

4.35-4.44 (m, 1B), 4.64-4.74
(m, IH).

4.97(broad s, It(), 5.17(
broad s, IH) ppmIR (KBr) 3464.2984, 2932, 1698.1660
Cl0-'Mass (m/z, %) 388 (M", 5), 333 (36),
205 (27), 203 (100) 55 (53
), 43(45) 19.1.104 g of phenol synthesized in Reference Example 14 in a mixed solvent of DMF 3mf and DME 6mf
(4.42 mmol), potassium carbonate 1.50 g
(10,9 mmol) and isopropyl bromide 0.83
ml (8.84 mmol) was added, and the mixture was heated under reflux for 10 hours and 30 minutes under an argon atmosphere. Add 0.4 ml of isopropyl bromide to the reaction mixture.

(4°26 mmol) was added, and the mixture was further heated under reflux for 3 hours.

The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate.

The extracted layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a 5=1 mixed solvent of hexane and ethyl acetate.
Isopropyl ether 24 1.039g, 80.6%
was obtained in a yield of .

Melting point: 29.0-32.0°C (colorless needle crystals, recrystallized from hexane) 'HNMR (CDCl 3.300 MHz) 61.2
6 (d, J=6.1Hz, 6H), 1.47 (s, 6
H).

1.67-1.79 (m, 2B), 2.10 (s, 3
H), 2.17 (s, 3H) 2.64-2.72 (m
, 2H), 2.92 (s, 2H).

2.99 (t, J=7.0)lz, IH), 3.44
~3.53(m, 2t().

4.00 (hept, J=6.1Hz, IH) pp
mIR(KBr) 34B0.2980.2936 C'm-'Mass
(ta/z, %) 292 (M”, 74), 250 (100),
249 (53), 205 (59) 43 (82), 4
H64) Meeting ILL! - 12.5mf dimethyl sulfoxide and dry THF
7.5mj! Isopropyl ether synthesized in Reference Example 18 in a mixed solvent under an argon atmosphere at room temperature,
1.00 g (3.42 mmol),) ethylamine 2.0 m 1. (14,3+wmol) and sulfur pyridine trioxide complex 1.70 g (10,7+n
mol) were added sequentially and stirred for 20 minutes. The reaction mixture was poured into IN hydrochloric acid and extracted with hexane. The extracted layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a 10:1 mixed solvent of hexane and ethyl acetate to obtain 789 mg of aldehyde as a colorless oil with a yield of 79.4%.

'HNMR (CDC423, 300MHz) 61.26
(d, J=6.2Hz, 6H), 1.44(s, 6
FI).

2.10 (s, 3H), 2.17 (s, 3H).

2.61 (td with fine couple
g, J=7.7Hz andl, 9th z, 2H),
2.87 (t, J=7.7Hz, 28), 2.88
(s, 2H).

3.98 (hept, J=6.2Hz, LH), 9
．． 80 (t, J=1.9Hz, IH) 99m IR (liquid film) 2980, 2936. 2728. 1728c
m-Mass (m/z, %) 290 (M”, 100), 248 (65)
, 247(53), 205(52).

203 (27) 60% oily sodium hydride 137■ (3,43 mmo
0.43 ethyl acetoacetate was added to a solution of 1) suspended in 6 ml of dry THF at 0°C under an argon atmosphere.
M! 2 (3.37 m+wol) was added and stirred for 15 minutes. To this solution, 2.2 m 12 (3.44 mmol) of a 15% hexane solution of butyllithium was added, and 1
Stir for 5 minutes. This solution was cooled to -78°C, and 25,691 mmol (2.38 mmol) of the aldehyde synthesized in Reference Example 19 dissolved in 5 ml of dry THF was added and stirred for 30 minutes. After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed three times with saturated brine, dried over magnesium sulfate, and concentrated.

The concentrate was applied to a silica gel column and flushed with a 5:1 mixed solvent of hexane and ethyl acetate to give 792 ml of ketoester 26 in a yield of 79.1% as a colorless oil.

'HNMR(CDCfs, 300M)Iz)61
．． 26 (t, J=7.1Hz, 3H), 1.27 (d
, J=6.2Flz, 3H).

1.27 (d, J=6.2Hz, 3H), 1.46 (
s, 38), 1.47 (s, 3H).

1.50-1.75 (+n, 28), 2.10 (s,
3H), 2.16(s, 31(L2.50-2.81
(m 48) 2.9Hs, 2H), 3.49(
s, 28).

3.67 (d with fine coupling
, J=3.7Hz+IH) 3.85-3.96(m, I
H), 3.99 (hept, J=6.2Hz, LH
)4.17(q, J=7.1t(z,2)1) pp
mIR (liquid film) 3528, 2980.2936. 1748. 172
0. 1652 cm-'Mass (m/z,
%) 420 (M”, 8), 378 (10),
248 (18), 205 (42) 203 (26
), 43(100), 41(51L 29(
80L 27 (56) Next 11 Crude 1 OEt Box 7 Triethylborane (IM THF solution) 2.7m! !
, (2.7 tmol) was added with 22 μm (0.22 mmol) of pivalic acid at room temperature under an argon atmosphere, and the mixture was heated for 1 hour.
The same ketoester synthesized in Reference Example 20 was dissolved in 10 mff1 of dry THF in a solution stirred for 5 minutes.

Add 900 mg (2.14 mmol) and incubate for 1 hour.
- Stirred for o minutes. This solution was cooled to -78°C, and methanol 3rr+1! Then, 87 μm (2°30 mmol) of sodium borohydride was added and stirred for 40 minutes. To this solution, 3 ml of 5N aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide solution 5-Og (44.1 m
mol), the mixture was cooled with ice-cold water, and 3 ml of a 5N aqueous sodium hydroxide solution was added, followed by stirring for 1 hour. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate.

The extracted layer was washed successively with IN hydrochloric acid, aqueous sodium periosulfate solution, and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in 10 mj2 of dry toluene and heated under reflux for 3 hours and 30 minutes. After the reaction was completed, the reaction mixture was concentrated, applied to a silica gel column, and flushed out with a 3:1 and then 3:2 mixed solvent of hexane and ethyl acetate. 5-isopropoxy-2,2,4,6-ketramethylbenzo(b)furan-7-yl)ethyl-4-hydroxytetrahydrobilan-2-one nail was 625 μm, colorless viscous with a yield of 78.0%. Obtained as a thing.

'HNMR (CDC13+ 300 MHz) 61
．． 26 (d J = 6.1Hz, 6H), 1.43 (
s, 3H) 1.44 (s, 3H), 1.75-2.
15 (m, 4B), 2.09 (s, 3H).

2.18 (s, 3H), 2.60 (dd with
fine coupling.

J=17.5 and 4.0Hz, IH), 2.
59-2.79(m, 2f(): 2.75(dd, J=
17.5 and 5.1Hz, IH), 2.87
(s, 2H) 3.98 (hept, J=6.1) 1z,
LH), 4.32-4.42 (m, LH).

4.62-4.75 (m, IH) ppmIR (KB
r) 3464.2980, 2936, 1716.1705
cmMass (m/z, %) 376 (M”, 13), 334 (46), 20
5 (34), 203 (41) 43 (100), 4H73
), 27(44) Lactone 13,1 synthesized in Example 1
66■(0,379n+a+ol) in dichloroethane 2
ml of dihydrobirane (38 ul (0,
454 mmol) and 101 g (0.04 mmol) of pyridinium p-toluenesulfonate were added, and the mixture was stirred overnight at room temperature under an argon stream.

Furthermore, dihydropyran 38 μN (0,454 mmo
l) and p-) pyridinium luenesulfonate 10■ (0
, 0411IIIlol) was added and stirred for 6 hours.

The reaction mixture was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The concentrate was subjected to silica gel column chromatography,
When the mixture was flushed out with a 1=1 mixed solvent of ethyl acetate and hexane, THP ether was obtained as a colorless oil with a yield of 94.4% and a yield of 89 cm.

'HNMR (CDC/!s, 300 MHz)61.
45 (s, 6H), 1.46-1.60 (m, 4H)
.

1.60-1.98 (01,5H), 2.05-2.
14 (m, 18).

2.16(s, 3t(), 2.24(s, 3H),
2.62-2.80 (m, 4H).

2.90 (s, 2H), 3.44-3.57 (m, I
H).

3.76-3.88 (m, IH), 4.20-4.
35 (m, IH).

4.55-4.75 (ni 2H), 4.71 (s, 2
H) 7.30-7.52 (*, 5H) 1) I) II
IIR (liquid film) 2940.2876.1744.1598 cm”M
ass (m/z, %) 508 (M”, 3), 417 (36), 315
(13), 205(22).

203(47), 9H33), 85(100)
8 9 THP ether 28,123IIg synthesized in Example 6
(0,242 mmol) was dissolved in 3 ml of methanol, 10% Pd/C35 was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours.

After the reaction was completed, the reaction mixture was diluted with ethyl acetate and methylene chloride, filtered through Celite, and the filtrate was concentrated. The concentrate was subjected to silica gel column chromatography and flushed out with a 1=1 mixed solvent of ethyl acetate and hexane to obtain phenol as a colorless amorphous solid in a yield of 93.91.9%.

'HNMR (CDCl:l, 300 MHz)61.
43 (s, 6tl), 1.45-1.61 (m, 4H
).

1.60-2.00 (++, 5H), 2.03-2.
09 (m, 1) 1).

2.10 (s, 3B), 2.17 (s, 3H), 2
．． 60-2.85 (+n, 4H).

2.90 (s, 2H), 3.45-3.60 (m, I
H) + 3.77-3.90 (m, 1tl), 4.1
8 (d, J=2.4Hz, IH), 4.20-4.3
0 (m.

IH), 4.55-4.77 (m, 2 days) p
pmIR (KBr) 3488, 2944.2874.1725 cm Tatami?
jass (ta/z,%) 41B (M”, 71), 334(47), 2
05(76), 204(39L189(15), 8
5(100), 4H51) 29.1.276 g of the phenol synthesized in Example 7 (
3.05 mmol) was dissolved in 20 ml of dichloroethane, and 1.0 mmol of triethylamine was dissolved under water cooling and an argon stream.
16 m i! , (8.32 mmol) was added. To this solution, add 712 μm of hydrochloric acid nicotinic acid chloride (3.99 m
m. 1) was added and stirred for 15 minutes.

The reaction solution was heated to room temperature, extracted with ethyl acetate, and washed successively with dilute hydrochloric acid, water, saturated hydrogen carbonate solution, and saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated, subjected to silica gel column chromatography, and flushed out with a 2:1 mixed solvent of ethyl acetate and hexane, yielding 1.64 g of nicotinic acid ester 30 (
Quantitative.

Melting point: 149.0-150.5°C (colorless columnar crystals, recrystallized from diethyl ether) 'HNMR (CDCl: l, 300 MHz) δ1.
47 (s, 6H), 1.45-1.60 (m, 2) 1
).

1.60-1.95 (m, 6H), 2.01 (s, 3
B), 2.09 (s, 3H) 1.95-2.18 (face, 2FI), 2.64-2.88 (Rin, 4B).

2.95 (s, 2H), 3.44-3.58 (+++
, IH).

3.75-3.88 (m, 1B), 4.22-4.3
1 (m, 18).

4.57-4.80 (i+, 21(), 7.5Hd
d, J=4.6 and 7-8Hz+IB).

8.50<d 5m1th fine couple
g+J=7.8Hz+IH)+8.88(d with
fine coupling+J=4.6Hz, IH
)+9.43(s with fine couple
ng, IH) pPMIR (KBr) 2974, 2948.2876, 1744.1592
Cl11-'Mass (1,/Z,%) 523 (M'', 20L 310(13), 20
5(13), 203(33).

106 (48), 85 (100), 78 (27),
41 (43) S] 1 y Ester low synthesized in Example 8, 14 (0,0268
1.3 mg of ethyl acetate. Dissolve in 1
A catalytic amount of 2N hydrochloric acid was added, and the mixture was stirred at room temperature for one day under an argon stream.

The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The concentrate was subjected to silica gel column chromatography,
When flushed with ethyl acetate, trans-(±)-6
-(2,3-dihydro-5-(pyridine-3-carboxy) -2,2,4,6-ketramethylben'/'(b
) Furan-7-yl]ethyl-4-hydroxytetrahydropyran-2-off 31 was obtained in a yield of 21 μm, 93.5%.

Melting point: 182.5-184.0''C (colorless granular crystals, recrystallized from diethyl ether and hexane)'HNMR (CD
C1,3+ 300 Mn2) 61.47 (s, 6H)
, 1.70~2.00(m, 4FIL2.01(s,
3t(), 2.09(s, 3H), 2.10-2.
21 (m, IH).

2.61(ddd, J=17.7.3.9 and 1
．． 5 Flz, IFI).

2.76 (dd, J=17.7 and 5.0Hz,
IH) 2.65-2.88 (+a, 2H), 2.95
(s, 2H).

4.32-4.41 (*, IH), 4.65-4.7
7 (m, IN) 7.49 (dd, J=8.1 and
4.8Hz, IH).

8.48(ddd, J=8.1.1.8 and 1.
5Hz, IH).

8.87 (dd, J=4.8 and 1.8Hz, I
FI).

9.43 (d, J=1.5Hz, IH) I) Ilm
IR(KBr) 3550, 2970.2936.1737.1593
am-'Mass (adzs%) 439 (total, 78), 42H13), 333 (2
0), 310 (12) 205 (26), 203 (1
00), 191(15), 106(78), 78
(44) The phenol compound synthesized in Example 7, 59■, was added to pyridine 0
．． 5 m 1. Dissolved in acetic anhydride, 0.5 mE
(5.30 mm+ol) was added and stirred overnight at room temperature under an argon stream. The reaction mixture was extracted with ethyl acetate,
After sequentially washing with dilute hydrochloric acid, water, 1 saturated aqueous sodium bicarbonate solution, and saturated saline, drying with anhydrous magnesium sulfate,
Concentrated. The concentrate was subjected to silica gel column chromatography and flushed out with a 1:1 mixed solvent of ethyl acetate and hexane.
% yield.

Melting point: 116.0-117.5°C (colorless fine granular crystals, recrystallized from diethyl ether) IHNMR (CDCl 51300 MHz>61.4
4 (s, 6H), 1.48-1.62 (m, 4Fl)
1.64-1.98 (m, 5H), 1.95-2.10
(+a, IH).

1.97 (s, 3H), 2.04 (s, 3H), 2.3
2(s, 2H).

2.62-2.87 (m, 4H), 2.91 (s, 2H
).

3.45-3.58 (Kaku, LH), 3.78-3.90
(a+, IH) 4.22-4.32 (m, IH),
4.55-4.77 (n, 2t() ppmIR(K
Br) 2942.2862, 1762, 174L 1597
cm bi1 ester 32.824■ (1,79 mmo
l) in 10 ml of diethyl ether, add 0
°C, 0.3 m 60% perchloric acid under argon atmosphere
1 was added and stirred for 15 minutes. After the reaction was completed, the reaction mixture was poured into saturated brine and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated.

When the concentrate was applied to a silica gel column and flushed out with a 3-1 mixed solvent of dichloromethane and ethyl acetate, trans-(±)-6-(5-acetoxy-2,3-dihydro-2,2,4,6- Ketramethylbenzo(b)furan-
7-yl)ethyl-4hydroxytetrahydrobilane-
305++ g of 2-on well was obtained with a yield of 45.3%.

Melting point: 126.5-128. OoC (colorless fine granular crystals,
Recrystallized from diethyl ether and hexane)'HNMR (
CDC1,3,300MFlz)61.44(s,6H
), 1.65-1.98 (m, 4H).

1.97(s, 3H), 2.05(s, 3t(),
2.32 (s, 38).

2.60(ddd, J=17.7.3.9 and 1
．． 5FIz, 1) 1).

2.75 (dd, J=17.7 and 5.1Hz
IH).

2.65-2.80 (m, 2F, 2.91 (s, 2
H).

4.30-4.40 (a+, IH), 4.60-4.
72 (n+, IH) ppmIR (KBr) 3542, 2980.293B, 1733.1594
CIl+-'Mass (m/z, %) 376 (M'', 11), 334 (100),
205(23), 204(1B).

43 (36) Fruit f Phenol 29,203 (0,4
9 mmol) in 2 mj2 of 1,2-dichloroethane was added 0.20 m 12 (1,43 mmof) of triethylamine and 0.10 ml (0,86 mmol) of benzoyl chloride at room temperature under an argon atmosphere.
was added and stirred for 1 hour and 30 minutes. After the reaction is complete, add saturated aqueous sodium hydrogen carbonate solution and dichloromethane,
Stir overnight at room temperature. Transfer the reaction mixture to a separatory funnel;
The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated.

When the concentrate was applied to a silica gel column and flushed with dichloromethane, 241 ml of ester was obtained in a yield of 95.0%.

Melting point: 139.0-140.5°C (colorless columnar crystals, recrystallized from diethyl ether and hexane)'HNMR (CD
CII s, 300 MFlz)61.47(s, 6
H), 1.40-2.20 (m, 10H).

2.0Hs, 3)1), 2.09(s, 3tl),
2.61-2.86 (m, 4H) 2.94 (s, 2H)
, 3.44-3.57 (m, IH).

3.75-3.89 (m, IH), 4.20-4.3
2 (m, 1B).

4.56-4.78 (m, 2H), 7.53 (t, J
=7.61(z,2)1).

7.65 (t with fine coupling
, J=7.6Hz, IH).

8.24 (d lll1th fine couple
ng, J=7.6Hz, 2H) ppmIR(KBr
) 2976, 2950.2874.1743.1735.
1601 cm4 5 Ester synthesized in Example 12 34.141■ (0,2
7 mmol) to 2 mi! of ethyl acetate! One drop of concentrated hydrochloric acid was added to the solution dissolved in , and the mixture was stirred at room temperature for 7 hours.

(During the course of the reaction, 3 hours and 20 minutes after the start of the reaction, 2 ml of ethyl acetate was added.) After the reaction was completed, the reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and 10% of dichloromethane and ethyl acetate was added.
:1 mixed solvent revealed trans-(±)-
6-(5-benzoyloxy-2,3-dihydro-2,
2,4,6-ketramethylbenzo(b)furan-7-yl)ethyl-4-hydroxytetrahydrobilane-2-
A yield of 77 μm, 65.1%, was obtained.

Melting point: 188.0-190.0°C (colorless columnar crystals, recrystallized from diethyl ether and hexane)'HNMR (CD
Cf 31300 MFlz) 61.47 (s, 6H)
, 1.40-2.20 (n, 4H) 2.01 (s, 3
H), 2.08 (s, 38).

2.60 (dd with fine couple
g, J=17.4 and 3.6Hz, IH),
2.65-2.87 (m, 3) 1), 2.94 (s
, 2H).

4.29-4.40 (m, LH), 4.63-4.
76 (m, IH) 7.52 (t, J=7.5Hz, 2H
), 7.65 (t, J=7.5Hz, IH).

8.23 (d with fine coupling
, J=7.5Hz, 2H) ppIIIR (KBr
) 3536.2976.2936, 1744.1717,
1599 Robi IMass (*/z, %) 438 (M”, 23), 203 (22
), 105 (100) 1,2-
Triethylamine (0.18 ml) was dissolved in 2 ml of dichloroethane at room temperature under an argon atmosphere.
1.29 mmol) and 126 μm (0.66 mmol) of p-toluenesulfonyl chloride were added and stirred for 45 minutes. After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed with dichloromethane followed by a 4:1 mixed solvent of dichloromethane and ethyl acetate.
6 was obtained as a colorless amorphous solid with a yield of 90.2%.

'HNMR (CDC13,300MHz) 61.45 (
s, 6H), 1.40-2.20 (s+, 10Fl)
.

1.90 (s, 3Fl), 2.06 (s, 3H),
2.48 (s, 3H).

2.54-2.86 (m, 4H), 2.89 (s, 2
)1).

3.43-3.57 (m, LH), 3.76-3.8
8 (m, IH).

4.20-4.30 (++, LH), 4.48-4.
74 (m, 2H).

7.36 (d, J=8.1Hz, 2H), 7.83
(d, J=8.1Hz, 2H) 29M IR (KBr) 2944, 2876, 1743.159B, 1371
．． 1178 CI-' real [Tosylate synthesized in Example 14 36.202■ (0,
35 mmol) dissolved in 2 ml of ethyl acetate,
One drop of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 7 hours.

(During the reaction, 2 ml of ethyl acetate was added 3 hours after the start of the reaction.) After the reaction was completed, the reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and 10% of dichloromethane and ethyl acetate was added.
:1 mixed solvent revealed trans-(±)-
6-(2,3-dihydro-2,2,4,6-ketramethyl-5-(p-toluenesulfonyloxy)benzo[b
[Furan=7-yl]ethyl-4-hydroxytetrahydrobilan-2-one 37 was obtained as a colorless amorphous solid in a yield of 103 cm, 59.6%.

'HNMR (CDC13,300MHz) 61.44 (
s, 6H), 1.40-2.20 (m, 4H).

1.91 (s, 3H), 2.04 (s, 3H), 2
．． 48 (s, 3H).

2.53-2.80 (s+, 4H), 2.88 (s,
28).

4.31-4.42 (cocoon, IH), 4.58-4.7
0 (Tsuyoshi, IH).

7.36 (d, J=8.1Hz, 2H), 7.83
(d, J=8.1Hz, 2H) ppm IR (KBr) 34B2.2978.2932.1736.1?17.
1599.1370°1178 ctn-Heavy Mass (m/z, %) 488 (M”, 3), 333 (61), 31
5(32), 205(27).

203 (100), 9H30) Phenol 3, 8.02 g (49,
5 mmol) was dissolved in 250 mf of ethanol, 1.61 g (4.95 mmol) of sarcomine was added, and the mixture was stirred at room temperature under an oxygen stream for 5 days. After the reaction was completed, the solvent was distilled off, and the solution diluted with ethyl acetate was filtered through Celite. After concentrating the filtrate, it was diluted again with hexane and filtered through Celite. The filtrate was concentrated, subjected to silica gel column chromatography, and flushed out with a 1=6 mixed solvent of ethyl acetate and hexane, resulting in 5.478 g and 62.9 g of quinone.
% yield as a yellow oil.

'HNMR (CDC1,8,300M) (z)62.0
5 (s, 61), 3.24 (d, J=6.3Hz, 2
H).

5.04 (d with fine coupling
, J=17.4Hz, IH)5.04(d with
fine coupling, J=9.6Hz, IH)
+5.76 (dat, J=17.4.9.6 and
6.3Hz, IH).

6.57 (s with fine coupling
, 11 () ppm IR (liquid film) 2930, 1652.1618 c+n-'Qin''' 38,226■ (1,28
mmol) in 2 mJ2 of methylene chloride and heated to 0°C.
, Sodium borohydride 53.3■ under argon flow
(1.41 mmol) was added. Subsequently, methanol was gradually added dropwise until the color of the solution changed from red to white. After 90 minutes, a saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and the mixture was extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous ammonium chloride solution, then water, and saturated brine, dried with anhydrous magnesium sulfate, and then concentrated. Hydroquinone dish is 217■
, with a yield of 95.2%.

Melting point: 113.6-115.5°C (colorless fine granular crystals.

Recrystallized from ethyl acetate and hexane)'l (NMR (CDCl 5I300 MHz) 62.
18 (s, 3F, 2.20 (s, 3H).

3.4Hddd, J=5.7. 1.8 and 1
．． 5Hz, 2)1).

4.25 (s, IH), 4.39 (s, IH)4.
99 (ddd, J=17.1. 1.8 and 1
．． 5Hz, IH).

5.06 (ddd, J=10.2. 1.8 and
1.5Hz, IH).

5.95 (dat, J=17.1. 10.2 and
5.7Hz, IH) 6.50(s, IH)
ppm IR (KBr) 3276, 1641 c+n-' Mass (m/z, %) 178 (M", 100), 163 (2
9), 15H13), 135(22).

91(13), 77(13) 39.6.00 g of hydroquinone synthesized in Reference Example 22
(33.7 mmol) in 1,2-dichloroethane 150
Boron trifluoride etherate was dissolved in 5.98 m 12 (48,54
mmol) was added. Furthermore, 3-methyl-2-butene-
1 ol 4.11 ml (40,46+u+ol)
100mj! A solution of 1,2-dichloroethane was added dropwise over 1 hour while maintaining the temperature at 0°C.

A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, stirred for a while, returned to room temperature, and extracted with methylene chloride. The extract layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 9.75 g of crudely purified phenol 40 as a yellow oil.

'HNMR (CDC41!s, 300 MHz)6
1.27 (s, 68), 1.79 (t, J=6.9H
z, 2H).

2.11 (s, 3H), 2.17 (s, 3H), 2
．． 62 (t, J=6.9Hz, 2H).

3.38(ddd, J=6.3.1.5 and 1.
5Hz, 2H).

4.18 (s, IH), 4.92 (ddd, J=10
．． 2.1.5 and 1.5Hz.

LH), 4.96 (ddd, J=17.1.1.5
and 1.5Hz, 18).

5.86 (dat, J=17.1.10.2 and
6.3Hz, IFI) ppmIR (liquid
film) 3498, 29B2.2936.1640 cm-'
Mass (m/z, %) 246 (M″, 100), 191 (51
), 175(45), 147(10).

91 (16) Crude purified product similar to phenol synthesized in Reference Example 23 5, 24
g was dissolved in 20 mf of methyl ethyl ketone, 2.52 ml (21.2 mmol) of benzyl bromide and 9.33 g (67.6 mmol) of anhydrous potassium carbonate were added, and the mixture was heated under reflux for 6 hours under an argon atmosphere.

After cooling the reaction solution to room temperature, it was poured into water and extracted with ethyl acetate. The extracted layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

The concentrate was subjected to silica gel column chromatography,
When flushed out with hexane and a 6=1 mixed solvent of hexane and ethyl acetate, ether ■ was obtained.

4.43 g was obtained with a yield of 74.5%. Additionally, 606 μ of phenol was recovered (13.9%).

Melting point: 46.8-48.0°C (colorless needle crystals, recrystallized from ethanol and water) 'HNMR (CDCl z, 300 MHz) δ1.2
9(s, 6H), 1.81(t, J=6.8Flz,
2H).

2.18 (s, 3H), 2.24 (s, 3H), 2
．． 61 (t, J=6.8Hz, 2H).

3.38 (d, J=6.2Hz, 2H), 4.70 (
s, 2H).

4.93(de emith fine couple
g, J=10.1Hz, LH)+4.96(d wit
h fine coupling, J=17.1Filz
, IFI).

5.89 (dat, J=17.1.10.1 and
6.2Hz, IH).

7.30-7.54 (m, 5H) ppmIR(K
Br) 2982, 2946.1637 cm-'Mass
(Dec/z+%) 336 (M”, 8), 245 (100), 2
04(9), 189(9L91(33) Reference Example 25 Ether 4L750■(2,23) synthesized in Reference Example 24
m5+ol) in 2mfTHF under an argon stream.
9-BBN 409■ (3.35 mmol) at room temperature
The mixture was added to a 10 mf THF solution of and stirred for 20 minutes.

1.34 mjl of ethanol to the reaction mixture! and then 2.23 m of 2N aqueous sodium hydroxide solution 41!
(4,46IIIlol), followed by 0.591ml of 30% hydrogen peroxide solution (5,69111RIOI) were carefully added and stirred for 10 minutes.

The mixture was further heated under reflux for 1 hour, and the reaction solution was extracted with ethyl acetate and washed successively with a saturated aqueous sodium thiosulfate solution, water, and saturated brine. The extracted layer was dried with anhydrous magnesium sulfate,
After concentration, it was subjected to silica gel column chromatography and flushed out with a 1:6 mixed solvent of ethyl acetate and hexane, followed by ethyl acetate, to obtain 706■, a crude alcohol product, as a yellow oil. Ta.

'HNMR (CDCl s, 300 MHz) 61.3
4(s, 6H), 1.76(t, J=6.9Hz, 2
H).

1.83(t, J=6.8Hz, 2H), 2.18(
s, 3H), 2.25(s, 3H).

2.63 (t, J=6.9Hz, 2H), 2.60-
2.75 (m, LH).

2.76 (t, J=6.9Hz, 2H), 3.46
~3.56 (a+, 2B).

4.71 (s, 2H), 7.30-7.53 (m,
5H) pps+IR (liquid film) 3456.2934 CI-' Mass (m/z+%) 354 (?l", 8), 263 (100
), 245(11), 219(6).

163(6), 10B(10), 91(54) Reference Example 2
42.2.448 g of alcohol synthesized in step 5 (6.9
mmol) dissolved in 25 mf of dimethyl sulfoxide, add 5.0 m j! of triethylamine! (35,
9mmol), THF 15mA! Subsequently, 3.5 g (22, On+mol) of sulfur pyridine trioxide complex
was added, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed out with a 9-1 mixed solvent of hexane and ethyl acetate, 1.723 g of the aldehyde was obtained as a pale yellow oil with a yield of 70.8%.

'HNMR (CDCl s, 300 MHz) 61.3
0 (s, 6H), L, 80 (t, J=7.0Hz, 2
H).

2.18 (s, 3H), 2.24 (s, 38), 2
．． 58 (td, J=7.2 andl, 8Hz, 2H)
, 2.61 (t, J=7.0Hz, 2)1).

2.94 (t, J=7.2Hz, 2H), 4.70 (
s, 2H).

7.31-7.55 (+n, 5H), 9.82 (t,
J=1.8Hz, 1) 1) ppmIR (liquid
film) 2980, 1728 cm-' Mass Cta/z, %) 352 (M'', 8), 261 (100
), 217(16), 163(5).

91 (51) 53011 g (13.3 gunol) of 60% sodium hydride was dissolved in anhydrous THF at 0°C under an argon stream.
Suspend in 40 mj2 and add 1,69 m f! of ethyl acetoacetate to this solution. (13.3 mmol) was added,
Stir for 30 minutes. Subsequently, 8.48 ml (13.3 mmol) of a 15% hexane solution of butyllithium was added, and the mixture was stirred for 30 minutes.

The reaction solution was cooled to -78°C, and the aldehyde 43. synthesized in Reference Example 26 was added. 3.11 g (8.83 mmol)
10 ml of anhydrous THF solution was added and stirred for 20 minutes.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was brought to room temperature and extracted with ethyl acetate. The extracted layer was washed successively with saturated ammonium chloride aqueous solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The concentrate was subjected to silica gel column chromatography,
When washed out with a 1:3 mixed solvent of ethyl acetate and hexane, 2.98 g of ketoester 44 was obtained as a yellow oil with a yield of 70.0%.

'HNMR (CDCl s, 300 MHz)61.
27 (t, J=7.2Hz, 3H), 1.30 (s
, 3H) 1.36 (s, 3H), 1.55-1.7
0(a+, 2H).

1.83 (t, J=7.1Hz, 2H), 2.18
(s, 3H), 2.24 (s, 3H).

2.55-2.95 (m, 6H), 3.45 (d,
J=2.4Hz, IH).

3.50 (s, 2H), 3.9 (1-4.00 (m
IH) 4.18 (q, J=7.2Hz, 28) 4
．． 70s 2H) 7.30-7.52 (m, 5H)
ppmIR (liquid film) 3524, 2982. 2936. 1744 17
17 cm-'FIass (a/z, %) 482 (M'', 3), 39H33), 345
(16), 26H84).

217 (30), 205 (12), 130 (13
), 105(10), 91(74).

6.82 ml (6.82 mmol) of triethylborane (1.0 M hexane solution) was added to 43 (100) pivalic acid, 35 ml (0,341 mmol) at room temperature under an argon atmosphere, and the mixture was stirred for 1 hour. To this solution was added 2.9 g (6.04 mmol) of the ketoester 44 synthesized in Reference Example 27.
15 ml of anhydrous THE solution of ) was added and stirred for 1 hour and 20 minutes.

The reaction solution was cooled to -78°C, and 5.58 m of methanol was added.
j2 followed by sodium borohydride 234 w
a: (6,20o+mol) was added. 20 minutes later, 5
Add 24.8 m of N aqueous sodium hydroxide solution, followed by 24.8 m of 30% hydrogen peroxide solution, and heat to 0°C.
The temperature rose to .

After the temperature was further raised to room temperature, the mixture was stirred for 2 hours.

The reaction mixture was made acidic with IN hydrochloric acid, extracted with ethyl acetate, washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

Add this concentrate to 20ml of toluene! , and heated under reflux for 3 hours. After the reaction was completed, the solvent was distilled off and subjected to silica gel column chromatography and flushed out with a 1=1 mixed solvent of ethyl acetate and hexane, trans-(±)-6-((6-benzyloxy -2,2,5,
7-tetramethyl)chroman-8-yl]ethyl-4-
Hydroxytetrahydropyran-2-one average is 1.7
Obtained as a colorless amorphous solid in a yield of 5 g and 66.3%.

'HNMR (CDCl 3-300 MHz) δ1.3
0(s, 3H), 1.3Hs, 38), 1.80(
t, J=6.9 Flz.

2H), 1.52-1.94 (m, 4H), 1.9
6-2.06 (m, 1) 1).

2.18 (s, 3) 1), 2.26 (s, 3H),
2.61 (t, J=6.9Hz, 2Fl).

2.60-2.67 (m 1) IL 2.70-2.8
2 (m, 3)1).

4.37-4.45 (in, IH), 4.70 (s,
2FI), 4.70-4.79 (ag, IH), 7
．． 31-7.55 (m, 5H) ppmIR (KBr
) 3466, 2978.293B, 1717.1707
cx-'Mass (m/z, %) 43B (M", 6), 347 (100), 3
29(19), 217(1B).

91 (56) Lactone 45,592+ag(1
, 32 mmol) was dissolved in methanol 5 mf, and 5%
Pd/C59■ was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Next, add 10% Pd/C30 and incubate at room temperature for 3
The mixture was stirred for several days.

The reaction solution was diluted with ethyl acetate, filtered through Celite, and concentrated. The concentrate was subjected to silica gel column chromatography and flushed out with a 2=1 mixed solvent of ethyl acetate and hexane, trans-(±)-6-((6-hydroxy-2,2,5,7- Tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydropyran-2-
On46 is 309mg.

Obtained with a yield of 65.5%.

Melting point: 136.0-137.0°C (colorless fine granular crystals recrystallized from ethyl acetate and hexane) 'HNMR (CDCj!s, 300 MHz) 61.
28 (s, 3H), 1.28 (s, 3H), 1.7
0-1.95 (m, 4) ().

1.78 (t, J=6.9Flz, 28), 1.96
~2.08 (m, IH).

2.12 (s, 3H), 2.20 (s, 3H), 2
．． 62 (t, J=6.9Hz, 2H) 2.59-2.6
9 (+w, IH), 2.70-2.84 (m, 3F).

4.22 (s, IH), 4.37-4.46 (m, L
H), 4.67-4.80 (m, IH) ppm IR (KBr) 33B0.2980.2930. 1708 cm-
'Mass (m/z, %) 348 (M'', 100), 330 (10),
293(25), 219(15).

203(19), 163(41) Lactone 45,101■(0,2
31 mmol) was dissolved in 2 ml of 1,2-dichloroethane, and dihydrobilane 80 tli, (0,877 m
mol), Pyridinium P-toluenesulfonate 10■
(0,040 mmol) was added thereto, and the mixture was stirred at room temperature under an argon stream for 3 hours.

After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extracted layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

The concentrate was subjected to silica gel column chromatography,
When the mixture was flushed out with a 1:1 mixed solvent of ethyl acetate and hexane, 122 μm of THP ether U was quantitatively obtained.

Melting point: 95.0-95.5°C (colorless amorphous crystals, recrystallized from diethyl ether and hexane)'I (NMR (C
DCls, 300 Mt(z)61.31(s, 6H
), 1.48-1.59 (m, 4H).

1.65-1.96 (m, 5H), 1.81 (t, J
=6.9Hz, 2H).

2.05-2.15 (m, IH), 2.18 (s, 3
H), 2.26 (s, 3H).

2.61 (t, J=6.!llz, 2H), 2.6
5-2.70 (++, IFI).

2.70-2.80 (m, 3H), 3.45-3.
57 (+++, 18) 3.79~3°88 (m, L
H), 4.22-4.34 (m, LH).

4.58-4.80 (s+, 2H), 4.70 (s
, 2H), 7.30-7.53 (+*, 5H)
ppm IR (KBr) 2944.2856.1?24 1606 cv-'
Example 19 THP ether synthesized on day 1 of Example 47.209 mg
(0,400 mmol) was dissolved in 3 rnl of methanol, 10% Pd/C40 was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes under a hydrogen stream. The reaction mixture was diluted with ethyl acetate and methylene chloride, and filtered through Celite.

The filtrate was concentrated, subjected to silica gel column chromatography, and flushed out with a 1:1 mixed solvent of ethyl acetate and hexane, resulting in 161 cm of phenol, a colorless amorphous solid with a yield of 93.1%. obtained as.

'HNMR (CDC1,z, 300 MHz)61.
28 (s, 6H), 1.45-1.66 (m, 4H)
.

1.66+~1.90 (m, 5H), ,! , 7B(t
, J=6.9Hz, 2H).

2.02-2.19 (m, IH), 2.11 (s, 3
H), 2.20 (s, 3H).

2.62 (t, J=6.9Hz, 2H), 2.64~
2.69 (a, LH).

2.71-2.82 (o, 3H), 3.45-3.5
7 (n, IH) 3.76-3.87 (w, IH),
4.20-4.33 (m, 2H).

4.57-4.80 (+n, 2H) ppmIR(K
Br) 3477, 2944.2876, 1738 cm - phenol 48, 1.15 g (2
, 67 mn+ol) to 12 ml of 1,2-dichloroethane
1.2 ml of pyridine (14,
8 mmol) and acetic anhydride 0.6 ml (6,3
6 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours under an argon atmosphere. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate.

The extracted layer was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and concentrated.

When the concentrate was applied to a silica gel column and flushed out with a 2:1 mixed solvent of hexane and ethyl acetate, acetate 49
was obtained in a yield of 1.20 g and 94.7%.

Melting point: 117.5-119.5°C (colorless fine granular crystals recrystallized from diethyl ether and hexane)'HNMR (CD
Cj2s, 300 MHz) 61.30(s, 6H)
, 1.46-1.62 (+n, 4H).

1.64-1.94 (m, 5H), 1.79 (t, J
=6.9Hz, 2H).

1.96-2.17 (o+, IH), 1.98 (s,
3FI), 2.06 (s, 3H) 2.33 (s, 3H
), 2.61 (t, J=6.9Hz, 2H) 2.65
~2.70(n, 1f(), 2.71~2.87(m
, 3H).

8 9 3.45~3.57 (+++, IH), 3.78~
3.88 (m, 18).

4.21-4.33 (m, IH), 4.56-4.
79 (I++, 2H) ppn+IR (KBr) 2960.2852.2746.1757.1747
cm-' Same as acetate synthesized in Example 20 40■
(0,0844 mmol) was dissolved in 1 ml of ethyl acetate, a catalytic amount of 12N hydrochloric acid was added, and the mixture was stirred at room temperature under an argon atmosphere for 7 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated.

When the concentrate was subjected to silica gel column chromatography and flushed out with a 2=1 mixed solvent of ethyl acetate and hexane, and then with ethyl acetate, trans(±”)-6-((
6-acetoxy-2,2,5,7tetramethyl)chroman-8-yl]ethyl-4-hydroxytetrahydrobilan-2-one was obtained in a yield of 23 μm, 69.9%.

Melting point: 143. O~143.5°C (colorless columnar crystals, recrystallized from diethyl ether and hexane)'HNMR (CD
Cl s, 300 MHz) δ1.30 (s, 6H)
, 1.79 (t, J=6.9Hz, 2H).

1.65-1.90 (+o, 3H), 1.98 (s,
3H), 2.06 (s, 3Fl).

1.90-2.10 (m, 2B), 2.33 (s, 3
H) 2.54-2.65 (+++, IH), 2.6H
t, J=6.9Flz, 2B).

2.70-2.85 (s, 3H), 4.30-4.4
0 (m, IH).

4.65-4.76 (n, IH) ppmIR (KB
r) 3492, 2978.293B, 1753.1710
cm-'Mass (m/z+%) 390 (M", 12), 348 (100),
330(23), 163(17).

43 (50) m%I2λ Phenol synthesized in Example 19 48,511■ (1,
18 mmol) was dissolved in 5 m2 of 1,2 dichloromethane at room temperature under an argon stream, and 295 μm (1,66 mmol) of hydrochloric acid nicotinic acid chloride and 694 tt 12 (4,98 mmol) of triethylamine were added.
- Stirred overnight. Furthermore, 84■ of hydrochloric acid nicotinic acid chloride.

(0,472 wvol) and triethylamine 195
μ! (1,40+mol) was added and stirred at room temperature for 3 hours.

The reaction mixture was poured into saturated ammonium chloride water and extracted with ethyl acetate. The extracted layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. When the concentrate was subjected to silica gel column chromatography and flushed out with a mixed solvent of ethyl acetate and hexane (2:2), nicotinic acid ester (2) was obtained in a yield of 577 cm and 91.1%.

Melting point: 15.0-77.0°C (colorless fine granular crystals, recrystallized from diethyl ether) 'HNMR (CDCl 3+ 300 MHz) 61.
31 (s, 3H), 1.34 (s, 3FIL 1.4
6-1.62 (m, 4H).

1.65-1.95(m, 5t(), 1.82(t,
J=6.9Hz, 2)1).

1.96-2.19(m, IFIL 2.02(s, 3
N), 2.10 (s, 38).

2.60-2.70 (m, 3) 1), 2.70-2.
88 (m, 3)]).

3.45-3.58 (m, 1B), 3.77-3.9
0(m, IH).

4.23-4.35 (m, IH), 4.60-4.8
0 (m, 2H).

7.49 (dd with fine couple
g, J=8.1 and 4.8HzIH), 8.4
8 (ddd, J=8.1. L, S and 1.8H
z, 1) Ri.

8.87 (dd, J=4.8 and 1.8Hz, I
H).

9.44 (d tnith fine couple
g, J = 1.8) 1z, IH) ppmIR (Br
) 2952, 287B, 1735.1728.1633
．． Ester synthesized in Example 22 51.26 cm (0,05
0go+5ol) in 1ml of ethyl acetate,
A catalytic amount of N-hydrochloric acid was added, and the mixture was stirred overnight at room temperature under an argon stream. The reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to silica gel column chromatography and extracted with ethyl acetate, resulting in trans-(±)-6-((6-(pyridine-
3-carboxy)-2,2,5,7-tetramethyl]
Chroman-8-yl]ethyl-4-hydroxytetrahydropyran-2-one was obtained in a yield of 17 cm, 77.5%.

Melting point: 124. OC ~ 125. OoC (colorless fine granular crystals recrystallized from diethyl ether and hexane)'HNMR
(CDCl 3+ 300 MHz) 61.32 (br
oad s, 6H), 1.82(t, J=6.9Hz
, 2H).

1.73-2.10 (m, 5) 1), 2.02 (s,
38), 2.10 (s, 3H) 2.64 (t, J=6
．． 9Hz, 2H), 2.55-2.70 (+w, IH
) 2.70-2.90 (m, 3H), 4.34-4.
44 (m, IH).

4.76-4.89 (s+, 18).

7.49 (dd, J=7.8 and 4.8Hz, I
FI).

8.48(ddd, J=7.8.1.8 and 1.
8t(z, 18).

8.87 (dd, J=4.8 and 1.8Hz, I
H).

9.44 (d, J=1.8Hz, LH) ppmIR
(KBr) 3472, 2980.2936.1736.1596
cm-'Mass (m/z, %) 453 (M", 69), 435 (16), 3
47(29), 217(19).

106 (100), 7B (4B) Examination J! LL House ■ Aldehyde 53. 25.29 g (81.6 mm
l) and diethyl cyanomethylphosphonate 15.0
m 1 (92,711 IIol) to 70 m ethyl acetate
! 2, 30 mf of water, tetrabutylammonium hydrogen sulfate, 612 ml (1,80 ml Iol)
and potassium carbonate 45.0 g (0,326 mol
) and heated under reflux for 2 hours and 30 minutes under an argon atmosphere. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was diluted with IN hydrochloric acid and then with saturated saline.
After washing twice and drying magnesium sulfate, it was concentrated. When the concentrate was crystallized from a mixed solvent of hexane and ethyl acetate,
21.254 g of starch was obtained with a yield of 78.2%.

The 0 solution was concentrated, applied to a silica gel column, and flushed out with a mixed solvent of hexane and dichloromethane in a ratio of 1:2 and then 1:1.
Obtained with a yield of 2.8%.

Melting point: 118.0-119.5°C (colorless fine granular crystals, recrystallized from hexane and ethyl acetate) 'HNMR (CDCI! s, 300 MFlz) δ
1.51 (s, 6H), 2.19 (s, 3H), 2
．． 32 (s, 3H).

2.91 (s, 2H), 4.70 (s, 2H), 6
．． 45 (d, J=16.5Hz, IH).

7.32-7.50 (m, 5H), ? , 49(d,
J=16.5Hz, 1) 1) ppmIR (KBr) 2940, 2884.2220.1606.1586
cm-'Mass (kaku/z+%) 333 (?I", 8), 242 (100),
91 (34) Nitrile power,, 3.00 g (9,
01 mmol) in 30 ml of dry toluene was added diisobutylaluminum hydride (25 g/100 mj2 hexane solution, 5.
After the completion of the reaction, the reaction mixture was poured into IN hydrochloric acid and extracted sequentially with ethyl acetate and dichloromethane. Each extracted layer was washed twice with saturated brine, dried over magnesium sulfate, and then combined and concentrated. When the concentrate was applied to a silica gel column and flushed out with a mixed solvent of hexane and dichloromethane in a ratio of 1:1 and then 2:3, 2.983% of the aldehyde
g, with a yield of 98.5%.

Melting point: 7108.0-109.0°C (colorless columnar crystals, recrystallized from ethyl acetate) 'HNMR (CDCfs, 300 MHz) 61.
51 (s, 6H), 2.20 (s, 31), 2.4
0(s, 3H).

2.92 (s, 2H), 4.72 (s, 2H), 7
．． 19 (dd, J=15.8 and8.0Hz, IH
), 7.32-7.52 (m, 5H), 7.60 (
d, J=15.8Hz, IH), 9.66(d, J=
8.0Hz, IH) p111+11R (KBr) 2984, 28B4.2860.1684.1618.
1604.1584CM-' Mass (m/z+%) 336 (M'', 9), 245 (100)
, 9H33) 60% oily sodium hydride 450■
(11,3 songs-of) was dried with THF10m! 1.45 m Il (11.4 m*ol) of ethyl acetoacetate was added to the solution suspended in 2.
Stir for a minute. To this solution was added 7,2 m j! of a 15% hexane solution of butyllithium. (11.3m+1ol)
was added and stirred for 30 minutes.

This solution was added to 2.867 g (8.58 mmol) of an aldehyde dish dissolved in 20 mf of dry THF at -78°C under an argon stream and stirred for 50 minutes. After the reaction was completed, the reaction mixture was dissolved in a saturated aqueous ammonium chloride solution. and extracted with ethyl acetate. The extracted layer was washed with saturated saline solution.
After washing twice and drying magnesium sulfate, it was concentrated. The concentrate was applied to a silica gel column using 4:1 hexane and ethyl acetate.
When flushed out with a mixed solvent, the keto ester was found to be 3.
Obtained 206 g, 80.5% yield.

Melting point: 96.0-96.5 °C (colorless fine granular crystals,
Recrystallized from hexane and ethyl acetate) ”HNMR (CDC1251300MHz) 61.28
(t, J=7.2Hz, 3H), 1.48(s, 6H
).

2.16 (s, 3H), 2.29 (s, 3H), 2
．． 69 (d, J=3.7Hz, IH).

2.80-2.94 (m, 2H), 2.89 (s, 2
1), 3.53 (s, 2H).

4.21 (q, J=7.2FIz, 2H), 4.69
(s, 2H).

4.70-4.84 (a, 1B), 6.56 (dd,
J=15.9 and 6.1Hz.

IH), 6.68 (d, J=15.9Hz, 11),
7.30-7.52 (m, 5H) pp+* IR (KBr) 3528, 2988.174B, 1718.1648
ell-'Mass (II/21%) 466 (M", trace), 245 (100
), 9H51), 43(57).

31 (26) 1m triethylborane (IM THF solution), 2.0mf
(2,00 mi+of) was added with 12 μm of pivalic acid (0,12 vsol) at room temperature under an argon atmosphere and stirred for 1 hour and 40 minutes. To the solution was added 6 mf of dry THF! 56.710 μm (1.52 mmol) of ketoester dissolved in was added and stirred for 1 hour and 20 minutes. Heat this solution to 78°C.
2 ml of methanol and then 60 μm (1,59 mmol) of sodium borohydride were added, and the mixture was stirred for 30 minutes. Add 2 m of 5N sodium hydroxide aqueous solution to this solution.
1. and 3.5 g of 30% hydrogen peroxide aqueous solution (30,9
mmol), cooled on ice, and then added 2 m of 5N aqueous sodium hydroxide solution! The reaction mixture was stirred for 1 hour, poured into IN hydrochloric acid, and extracted with ethyl acetate. The extracted layer was washed successively with IN hydrochloric acid, aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated.

Dry the concentrate with 15ml of toluene! , and heated under reflux for 5 hours.

After the reaction was completed, the reaction mixture was concentrated, applied to a silica gel column, and flushed out with a 2:1 and then 1:1 mixed solvent of hexane and ethyl acetate, resulting in trans-(±)-6-
(5-benzyloxy-2,3-dihydro-2,2,4
,6-ketramethylbenzo(b)furan-7-yl)ethynyl-4-hydroxytetrahydropyran-2-one H is 379■.

Obtained with a yield of 58.9%.

Melting point: 144.0-145.5°C (colorless fine granular crystals, recrystallized from hexane and ethyl acetate) 'HNMR (CDCI! 3,300 MHz) 61.
49 (s, 3B), 1.49 (s, 3H), 1.9
6-2.20 (m, 2H).

2.17 (s, 3H), 2.30 (s, 3H).

2.66 (ddd, 17.7.4.1 and 1.
6Hz, IH).

2.83 (dd, J=17.7 and 5.1Hz,
18), 2.89 (s, 21).

4.40-4.50 (m, IH), 4.69 (s,
2H), 5.28-5.39(+*, 11(),
6.61 (dd, J=16.0 and 6.3Hz,
IH) 6.72 (dd, J=16.0 and 0.7
Hz, IH), 7.30-7.53 (■, 5H)
3504.29B0.2932.2872.1704.
1654 C11-”Mass (m/z, %
) 422 (M”, 6), 331 (58), 269
(88), 243(100).

225 (27), 91 (87), 65 (21), 44 (
25), 43(36) 60% oily sodium hydride 41
7■ (10,4-■ol) suspended in 15 mf of dry THF was added with 1.78 m i of diethylcyanomethylphosphonate at 0°C under an argon atmosphere. , (11,
0w+wol) was added and stirred for 20 minutes. To this solution was added aldehyde 5B dissolved in 10 ml of THF; 2.
541 g C'7.84 mmol) was added and stirred for 30 minutes. After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid,
Extracted with ethyl acetate. The extracted layer was washed three times with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was crystallized from a mixed solvent of hexane and ethyl acetate, 1.350 g of nitrile was obtained in a yield of 49.6%. The 0 solution was concentrated, applied to a silica gel column, and flushed out with a 10:1 mixed solvent of hexane and ethyl acetate.
Further plates were obtained with a yield of 960 cm and 35.3%.

Melting point 7107.5-108.0°C (colorless columnar crystals, recrystallized from hexane and ethyl acetate) 'HNMR (CDCj2s, 300 MHz) 61.
36(!1,6H), 1.85(t, J=6.9Fl
z, 2H).

2.21 (s, 3H), 2.34 (s, 3H), 2
．． 64 (t, J=6.9Hz, 2H).

4.68 (s, 2B), 6.38 (d, J=16.7
Hz, IH).

7.32-7.52 (m, 5H), 7.53 (d,
J=16.7) lz, 11) ppmIR (KBr) 29B4.2940.2880.2212.1608.
1586 cm-'Mass (■/z+%) 347 (M", 10), 256 (100),
91 (4B) Emperor' (Li Nitrile 59. 1.885 g (5,43+u+o
l) in 20 ml of dry toluene was added diisobutylaluminum hydride (
25g/100ml hexane solution, 3.3ml (
5.8 mol) was added and stirred for 30 minutes. After the reaction was completed, the reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed twice with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed out with a 5:1 mixed solvent of hexane and ethyl acetate, 1.727 g of an aldehyde-like substance was obtained in a yield of 90.8%.

Melting point: 98.0-99.5°C (colorless columnar crystals, recrystallized from hexane and ethyl acetate) 'HNMR (CDCj!s, 300 MHz)6
1.37 (s, 6H), 1.86 (t, J=6.9H
z, 2H).

2.23 (s, 3H), 2.40 (s, 3H),
2.65 (t, J=6.9Hz, 2H).

4.71 (s, 2H), 7.02 (dd, J=16
．． 0 and 7.9Hz, 11).

7.32-7.52 (m, 5H), 7.69 (d,
J=16.0Hz, IH).

9.65 (d, J=7.9Hz, IH) ppmIR
(KBr) 2984.2936.1678.1616.1582
CI-'Mass (s/z, %) 350 II'''', 11), 259 (100), 9
H51) 60% oily sodium hydride 229■ (5,7
2+uiol) suspended in 12.5 mf of dry THF was added 0.7 ethyl acetoacetate at 0°C under an argon stream.
3 m j! (5.73 m5 ol) was added and stirred for 10 minutes. To this solution was added 3,65 mA! of a 15% hexane solution of ptyrrhium. (5.70 mmol) was added and stirred for 15 minutes. Cool the solution to -78°C and dry T
HF 10m! Same as aldehyde dissolved in 1.50
6 g (4.30s+mol) was added and stirred for 1 hour. After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed three times with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a mixed solvent of hexane and ethyl acetate in a ratio of 4:1 and then 3:1 to obtain 1.607 g of ketoester (II) in a yield of 77.8%.

Melting point: 83.0-83.5°C (colorless fine granular crystals, recrystallized from hexane and ethyl acetate) 'HNMR (CDC 1,8,300MHz) 61.28
(t, J=7.2Hz, 3H), 1.32(s, 6H
).

1.81(t, J=6.8Hz, 2H), 2.18(
s, 38), 2.30 (s, 3H).

2.55-2.68 axis, 3H), 2.83-2.93
(m, 2H).

3.53 (s, 28), 4.21 (q, J=7.2H
z, 2H), 4.69 (s, 2H).

4.70-4.85 (s+, IH), 6.25 (dd
, J=16.0 and 6.6)1z.

LH), 6.66 (d, J=16.0Hz, IH),
7.30-7.54 (m, 5H) ppm IR (KBr) 3556, 29B4. 2936. 1730. 1
718 cm-True Mass (m/z+%) 480 (M”, trace), 259 (10
0), 9H65), 43(62).

31 (39) Triethylborane (LM THF solution), 4.9m
20 μ (0.20 mmol) of pivalic acid was added to 1 C4, 90 mmol) at room temperature under an argon atmosphere and stirred for 1 hour and 10 minutes. To the solution was added 1.502 g of ketoester, Ωl, dissolved in 15 mf of dry THF.
13-101) was added and stirred for 1 hour. This solution was cooled to -78°C, 5 ml of methanol was added, followed by 135 μm (3,57-01) of sodium borohydride, and 3.
Stirred for 0 minutes. Add 5ml of 5N sodium hydroxide aqueous solution to this solution! and 8.5 g of 30% hydrogen peroxide aqueous solution (
After adding 75.05 eal), the mixture was cooled with water, and 5 mf of a 5N aqueous sodium hydroxide solution was added, followed by stirring for 30 minutes. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed successively with IN hydrochloric acid, aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in 12.5 ml of dry toluene and heated under reflux for 3 hours and 30 minutes. After the reaction was completed, the reaction mixture was condensed, applied to a silica gel column, and flushed with a 2:1 mixed solvent of hexane and ethyl acetate. When extracted, trans-(±)-6-((6-benzyloxy-2゜2
．． 544 ml of 5,7-tetramethyl)chroman-8-yl]ethynyl-4-hydroxytetrahydropyran-2-one were obtained in a yield of 39.9%.

Melting point: 122.0-124.5°C (colorless fine granular crystals, recrystallized from hexane and ethyl acetate) Supervised HNMR (CDC 13,300MHz) δ 1.32
(s, 6H), 1.82 (t, J=6.8Hz, 2
tl).

1.87 (d, J=3.3Hz, IH), 1.94
~2.20 (m, 2H).

2.19 (s, 3H), 2.30 (s, 3H),
2.62 (t, J=6.8Hz, 2H).

2.56-2.72 (m, IH), 2.84 (dd
, J=17.7 and 5.1Hz.

1B), 4.40-4.50 (Zeng, IH), 4
．． 70 (s, 2H).

5.27-5.40 (m, IH), 6.25 (dd
, J-16,0and 6.7Hz.

1B), 6.70 (d, J=16.0Hz, IH)
, 7.30-7.54 (m, 5H) pm IR (KBr) 3476.2980.2936.1714.1594
am-"Mass (m/z+ %) 436 (M+, 5), 374 (21),
345(47), 283(82).

257 (52), 91 (100), 65 (20), 44
(46) LLLLHMG Journal about the compounds synthesized in Examples for measuring Co-A reductase inhibitory activity.

of Biological Chemistry (J, Biol
.

Cheap, ) vol. 234, p. 2835 (1959)
The HMG Co-A reductase inhibitory effect was measured according to the method described, and the inhibitory activity was determined. The results are shown in Table 1.

l-Uppercentage of inhibition of cholesterol synthesis (1) (a) 0.
Using a 1HM sample (b) Relative value when compactin is set as 100 Note that compactin had an inhibition rate of 82 to 86% at 0.1HM.

fi Measurement of cholesterol level lowering effect Endo et al.'s method (Endo, A., Thujita+, + Kur
odaM,, and Tanzawa+, Bio
che11+, Biophys, Acta.

HL266 (1979))
The serum total cholesterol level lowering effect was investigated in ton-induced hyperlipidemia model rats. Compactin value (ML-23
Table 2 shows the effects based on 6B).

The antioxidant capacity was as shown in Table 3.

Claims (1)

[Claims] (1) 4-hydroxytetrahydropyran-2- represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼
on derivatives (wherein A is -CH_2-CH_2- or -CH=CH
-, n is 1 or 2, R_1 is a hydrogen atom, lower alkyl group, lower alkenyl group, aralkyl group, acyl group, aroyl group, or substituted sulfonyl group, R_2
is a hydrogen atom or a 2-tetrahydropyranyl group. )
.