JP2003327589A - Intermediate for producing (+)-calanolide a, method for producing the same, and method for producing (+)- calanolide a using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide intermediates for producing (+)-calanolide A, to provide method(s) for producing the intermediate(s), and to provide a method for producing the (+)-calanolide A using the intermediates. <P>SOLUTION: First, (±)-chromanone (II) is subjected to optical resolution using an optically active amine to obtain (+)-chromanone (I), which is then reacted with 3-methyl-2-butenal to obtain (+)-12-oxocalanolide A (III), which is then reduced to obtain the objective (+)-calanolide A (IV). <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing (+)-calanolide A, a method for producing the same, a method for producing (+)-calanolide A using the intermediate, and the production of other intermediates. Regarding the method. (+)-Calanolide A produced by the present invention is useful as an HIV-1 reverse transcriptase inhibitor.

[0002]

2. Description of the Related Art The following method is known as a method for producing (+)-calanolide A. (1) A method in which an intermediate β-keto alcohol is subjected to kinetic optical resolution using an enzyme, and then a chromanone ring is constructed by a Mitsunobu reaction, followed by reduction (see Patent Document 1). (2) A method of subjecting calanolide A obtained as a racemate to kinetic optical resolution using an enzyme (see Patent Document 1). (3) A method of optically resolving calanolide A obtained as a racemate by high performance liquid chromatography (see Patent Document 1). (4) A method in which an addition reaction of an optically active boron compound is a key step (see Patent Document 2). (5) A method in which an asymmetric allylation reaction using a palladium catalyst modified with an optically active phosphorus ligand is a key step (see Patent Document 3 and Non-Patent Document 1). (6) A method in which intramolecular asymmetric Michael addition reaction with cinchona alkaloid and isomerization with magnesium iodide are key steps (see Non-Patent Document 2). (7) A method of constructing a chromanone ring after introducing an optically active alcohol unit by Mitsunobu reaction (see Patent Document 4).

[0003]

[Patent Document 1] US Pat. No. 5,892,060 (page 33, page 42, page 48, page 49)

[Patent Document 2] International Publication No. 96/26934 (page 8)

[Patent Document 3] International Publication No. 00/64902 (page 3)

[Patent Document 4] International Publication No. 00/64903 (page 13)

[Non-Patent Document 1] Journal of American Chemical Society [Journal of Ameri
can Chemical Society], 199
8th year, No. 120, p. 9074

[Non-Patent Document 2] Tetrahedron Letters [Tetr
ahedron Letters], 2000, 4th
No. 1, p. 10229

[0004]

[Problems to be Solved by the Invention] However,
In the methods of (1), (2) and (3), it is difficult to recycle unnecessary enantiomers by racemization, and considering that optical resolution is performed at the final compound or at a stage close to it, loss is large and efficient. It is difficult to say that it is a simple process.

Further, (1), (4), (5) and (7)
In the method of using the Mitsunobu reaction industrially difficult to implement,
In addition, since the method (4) uses an expensive optically active boron reactant, and the method (5) uses an expensive phosphorus ligand and a palladium catalyst, these methods are industrially inexpensive. It is not a process that can be implemented.

Further, in the methods (4), (5), (6) and (7), it takes a very long process of 10 steps or more to obtain (+)-calanolide A from the raw material compound. It is difficult to say that the method can be industrially advantageous.

An object of the present invention is to provide a method for synthesizing (+)-calanolide A from an easily available starting material, which can be carried out industrially more conveniently and inexpensively.
Another object of the present invention is to provide an intermediate for producing (+)-calanolide A simply and inexpensively by a method which can be industrially carried out. A further object of the present invention is to provide a method for producing such an intermediate, and a method for producing an intermediate for producing (+)-calanolide A using such an intermediate.

[0008]

The inventors of the present invention have shown that the formula (I
I)

[0009]

[Chemical 11]

The compound of formula (I) obtained by optically resolving the compound of formula

[0011]

[Chemical 12]

By using the intermediate represented by
The present invention has been completed by finding that (+)-calanolide A can be produced from a readily available starting material by a method that can be industrially implemented easily and inexpensively.

The present invention provides (1) formula (I)

[0014]

[Chemical 13]

(+)-2 (R), 3 (R)-
Trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b:
3,4-b ′] dipyran-1,9-dione [hereinafter, this may be referred to as (+)-chromanone (I)],
(2) Formula (II)

[0016]

[Chemical 14]

(±) -2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-
b ′] dipyran-1,9-dione [hereinafter, this (±)
-Sometimes referred to as chromanon (II)], and a compound of formula (I)

[0018]

[Chemical 15]

A method for producing (+)-chromanone (I) represented by: (3) Formula (I)

[0020]

[Chemical 16]

The (+)-chromanone (I) represented by
Reacting with -methyl-2-butenal to give formula (III)

[0022]

[Chemical 17]

(+)-12-oxocalanolide A [hereinafter referred to as (+)-12-oxocalanolide A
Sometimes referred to as (III)] and reduction of (+)-12-oxocalanolide A to give a compound of formula (I
V)

[0024]

[Chemical 18]

(+)-Calanolide A [hereinafter referred to as
This may be referred to as (+)-calanolide A (IV)], and (+)-calanolide A (IV)
Manufacturing method of (4) formula (I)

[0026]

[Chemical 19]

The (+)-chromanone (I) represented by
A compound of formula (III) comprising the step of reacting with -methyl-2-butenal

[0028]

[Chemical 20]

A method for producing (+)-12-oxocalanolide A (III) represented by: (5) Formula (V)

[0030]

[Chemical 21]

2,3-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H- represented by
Benzo [1,2-b: 3,4-b '] dipyran-1,9
A compound of formula (II) comprising the step of isomerizing a dione [hereinafter, this may be referred to as chromanone (V)]

[0032]

[Chemical formula 22]

A method for producing (±) -chromanone (II) represented by:

In the present specification, with respect to the configuration of the structural formula of the compound having an asymmetric carbon atom, those having (±) in the structural formula represent a racemic compound, and (+) in the structural formula. The attached one represents an optically active substance having an optical rotation of (+).

[0035]

DETAILED DESCRIPTION OF THE INVENTION A preferred method for preparing (+)-calanolide A according to the method of the present invention is Scheme 1
Shown in.

[0036]

[Chemical formula 23]

Step (a): (±) -2,3-trans-
Dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-
b ′] dipyran-1,9-dione [(±) -chromanone (II)] is optically resolved. (+)-chromanone (I) is optically resolved by racemic (±) -chromanone (II). Is not particularly limited, for example, a method of forming a salt with an optically active amine to perform optical resolution, or (±) -chromanone in a column packed with a support on which an optically active compound is immobilized. Examples include liquid chromatography in which a liquid containing (II) is circulated and separated.

A method of performing optical resolution using an optically active amine will be described. Racemic (±) -chromanone (II) reacts with an optically active amine to form a salt,
At this time, (±) -chromanone (II) contains (+)
The (+) form of -chromanone (I) and a salt of an optically active amine are combined with each other, and the enantiomer of (+)-chromanone (I) and a salt of an optically active amine are combined with each other. In the stereomeric relationship, such a mixture of diastereomeric salts can be obtained by an appropriate method in the (+) form or the (−) form.
It can be separated into salts containing predominantly the enantiomers of each body. Here, "predominantly includes (+) form" means that the (+) form is contained more than the (-) form,
The phrase "predominantly contains the (-) form" means that the (-) form is contained more than the (+) form.

The amine used in such a method is not particularly limited as long as it is an optically active amine. For example, (+)-α-methylbenzylamine, (-)-α-methylbenzylamine, (+)-1 -(1-naphthyl) ethylamine, (-)-1- (1-naphthyl) ethylamine, (+)-phenylalaninol, (+)-phenylglycinol, (-)-phenylglycinol, (+)
-Prolinol, (+)-alaninol, (-)-ephedrine, (-)-sparteine, (-)-brucine,
(−)-Strychnine, (+)-Cinchonine, (−)
Industrially easily available optically active amines such as -cinchonidine, (+)-quinidine, and (-)-quinine.

Among the above optically active amines, (+)-
Cinchonine, (−)-cinchonidine, (+)-quinidine and (−)-quinine are preferred, and (+)-quinidine is particularly preferred.

The amount of the optically active amine used is preferably in the range of 0.2 to 3.0 equivalents, and particularly preferably in the range of 0.8 to 1.5 equivalents, relative to (±) -chromanone (II).

A mixture of diastereomeric salts of (±) -chromanone (II) and an optically active amine predominantly contains the enantiomers of each of (+)-chromanone (I) or its antipodal (-) isomer. The method for separating the salt is not particularly limited, but it is preferably separated by recrystallization.

When separating by recrystallization, (±)
Among the enantiomers contained in -chromanone (II), the one mainly contained in the crystal to be precipitated may be the (+) form or the (-) form.

When crystals of a salt mainly containing the (+) form are precipitated, recrystallization is repeated to obtain a crystal of a salt containing the (+) form predominantly and having high optical purity. You can

Further, when crystals of a salt containing predominantly the (-) form are precipitated, a liquid containing predominantly the (+) form can be obtained by removing the crystals. Such a filtrate is reacted with an acid or a base to remove the optically active amine, and then is reacted with a different optically active amine to form a salt, and thereafter, the optically active amine salt containing the (+) form is more predominant. Crystals can be precipitated by recrystallization.

Such recrystallization is performed using a solvent.
The type of solvent is not particularly limited, for example, hexane, heptane, octane and other aliphatic hydrocarbons; benzene, toluene, xylene, ethylbenzene, mesitylene, chlorobenzene, trifluoromethylbenzene, dichlorobenzene and other aromatic hydrocarbons; tetrahydrofuran,
Ethers such as diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diglyme; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol. Alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1-octanol; nitriles such as acetonitrile and benzonitrile; esters such as ethyl acetate and butyl acetate; dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane; dimethylformamide, dimethylsulfoxide, water and the like. These may be used alone or in combination of two or more.

Of these solvents, methanol, ethanol, 1-propanol, 2-propanol and 1-butanol are preferably used alone or in combination with water, and methanol, ethanol, 1-propanol, 2-propanol or 1 is used. It is especially preferred to use each butanol in combination with water.

The amount of the solvent used is a salt of (±) -chromanone (II) and an optically active amine or predominantly (+).
0.3-100 based on the salt of the optically active amine containing the body
Weight times are preferable, and 1 to 20 times are particularly preferable.

The temperature at which the salt of (±) -chromanone (II) and the optically active amine or the salt of the optically active amine containing predominantly the (+) form is dissolved in a solvent is preferably 0 ° C to 150 ° C, and 20 ° C. -80 degreeC is especially preferable.

The temperature for crystal precipitation is -7.
0 degreeC-70 degreeC is preferable, and -20 degreeC-50 degreeC is especially preferable.

Separation of (+)-chromanone (I) from the resulting (+)-chromanone (I) and the optically active amine salt is carried out by treating with an acid or a base.

Examples of the acid used for such treatment include sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
Examples include trifluoromethanesulfonic acid and the like. on the other hand,
Examples of the base include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, trioctylamine, triethanolamine, N-methylmorpholine, and 1,8-diazabicyclo [5.4.0] -7-undecene; Inorganic bases such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide can be mentioned.

The amount of the acid or base used in such treatment is preferably in the range of 0.2 to 3.0 equivalents relative to the salt of (+)-chromanone (I) and the optically active amine,
A range of 0.8 to 1.5 equivalents is particularly preferred.

Such a treatment is usually carried out by extraction with water and an organic solvent which separates from water.

The organic solvent used for such extraction is not particularly limited as long as it dissolves (+)-chromanone (I) or the optically active amine, but for example, aliphatic hydrocarbons such as hexane, heptane, octane; Benzene, toluene, xylene, ethylbenzene, mesitylene, chlorobenzene, trifluoromethylbenzene,
Aromatic hydrocarbons such as dichlorobenzene; tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-
Ethers such as dioxane and diglyme; alcohols such as 1-butanol, 2-butanol, tert-butanol and 1-octanol; nitriles such as acetonitrile and benzonitrile; esters such as ethyl acetate and butyl acetate; dichloromethane, chloroform, carbon tetrachloride. And halogenated hydrocarbons such as 1,2-dichloroethane. These may be used alone or in combination of two or more.

When treated with an acid, (+)-chromanone (I) can be extracted on the organic layer side. Such an organic layer can be concentrated, or (+)-chromanone (I) can be obtained by recrystallizing the concentrate as necessary.

On the other hand, when the treatment is carried out using a base,
(+)-Chromanone (I) can be extracted on the aqueous layer side. The aqueous layer is neutralized with an acid and then extracted again with an organic solvent to give (+) on the organic layer side.
It is possible to extract chromanone (I). As the acid used for neutralization, the same acids as those listed above can be used. Such an organic layer can be concentrated, or (+)-chromanone (I) can be obtained by recrystallizing the concentrate as necessary.

Next, a method of optical resolution using liquid chromatography will be described. The kind of the optically active compound used as the stationary phase of liquid chromatography is not particularly limited, and examples thereof include ester derivatives of cellulose, carbamate derivatives of cellulose,
Examples include carbamate derivatives of amylose.

The type of solvent used as the eluent is not particularly limited, but for example, hexane, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, 2-propanol, ethanol,
Methanol, water and the like can be used alone or in combination. In addition, salts may be added to the solvent and used according to the purpose of adjusting pH, for example.

Isolation of (+)-chromanone (I) from the separated liquid containing (+)-chromanone (I) is required in the same manner as in the case of the optical resolution using the above-mentioned optically active amine. Depending on the case, it can be carried out by an operation of handling an ordinary organic compound such as extraction or concentration.

Step (b): (+)-2 (R), 3 (R)
-Trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-
b: 3,4-b '] dipyran-1,9-dione [(+)
-Chromanone (I)] was reacted with 3-methyl-2-butenal to give (+)-12-oxocalanolide A (II
Step of obtaining I) The amount of 3-methyl-2-butenal used is preferably in the range of 0.5 to 10 equivalents, more preferably 1.0 to 5. It is within the range of 0 equivalents.

This reaction can be carried out in the presence of an acid catalyst. Examples of the acid catalyst include sulfuric acid, hydrochloric acid, nitric acid, acetic acid, boric acid, phenylboric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and the like.
Preferred are p-toluenesulfonic acid and sulfuric acid. These can be used alone or in combination of two or more.
The amount of the acid catalyst used is preferably within the range of 0.001 to 10 equivalents, and more preferably within the range of 0.01 to 0.1 equivalents relative to (+)-chromanone (I).

This reaction can also be carried out in the presence of a base catalyst. Examples of the base catalyst include pyridine,
Picoline, lutidine, 4-dimethylaminopyridine,
N, N-dimethylaniline, N, N-diethylaniline, trimethylamine, triethylamine, diisopropylethylamine, trioctylamine, triethanolamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene And the like; inorganic bases such as lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium carbonate, sodium carbonate, potassium carbonate and the like, and the like, and tertiary amines are preferable. These can be used alone or in combination of two or more. The amount of the base catalyst used is preferably 0.01 to 100 with respect to (+)-chromanone (I).
It is within the equivalent range, more preferably within the range of 0.1 to 10 equivalents.

In this reaction, a suitable organic solvent can be used as long as it does not inhibit the reaction. Examples of the organic solvent include aliphatic hydrocarbons such as hexane, heptane, and octane; benzene, toluene, xylene,
Aromatic hydrocarbons such as ethylbenzene, mesitylene, chlorobenzene, trifluoromethylbenzene and dichlorobenzene; ethers such as tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane and diglyme; methanol , Ethanol, 1-propanol, 2
-Propanol, 1-butanol, 2-butanol, t
ert-butanol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1-octanol and other alcohols; acetonitrile, benzonitrile and other nitriles; ethyl acetate, butyl acetate and other esters; dichloromethane, chloroform, carbon tetrachloride, 1 , 2-dichloroethane and other halogenated hydrocarbons; dimethylformamide, dimethyl sulfoxide and the like.

The amount of the solvent used is preferably 1 to 100 times by weight with respect to (+)-chromanone (I),
2 to 30 times by weight is particularly preferable.

The reaction is preferably carried out in the range of 50 ° C to 150 ° C, particularly 70 ° C to 120 ° C. Although the reaction time depends on the reaction temperature and the like, it is usually completed in 3 hours to 8 hours.

For the isolation of the product, the method used for isolation of usual organic compounds can be used. For example, after pouring the reaction mixture into water, extraction with a suitable organic solvent such as ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, the solvent was distilled off, and the product was recrystallized,
It can be isolated by a method such as silica gel chromatography.

Step (c): (+)-12-oxocalanolide A (III) is reduced to (+)-calanolide A (I).
Examples of the reducing agent used in the step of obtaining V) include lithium aluminum hydride, lithium bis (2-methoxyethoxy) aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium borohydride, lithium borohydride, and the like. And preferably hydrogenated ter.
This is lithium t-butoxyaluminum. These can be used alone or in combination of two or more. The amount of the reducing agent used is (+)-12-oxocalanolide A (II
For I), preferably 0.5-10 on a hydride basis.
It is within the equivalent range, more preferably within the range of 1.0 to 3.0 equivalents.

For the reaction, a suitable organic solvent can be used as long as it does not inhibit the reaction. Examples of the organic solvent include benzene, toluene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, diisopropyl ether, tert-butyl methyl ether and the like. These can be used alone or in combination of two or more.

The amount of the solvent used is 1 to 10 times the weight of (+)-12-oxocalanolide A (III).
0 times by weight is preferable, and 2 times by weight to 30 times by weight is particularly preferable.

The reaction is preferably carried out within the range of -50 ° C to 80 ° C, particularly within the range of -30 ° C to 40 ° C. Although the reaction time depends on the reaction temperature and the like, it is usually completed in 3 hours to 8 hours.

For the isolation of the product, the method used for isolation of usual organic compounds can be used. For example, after pouring the reaction mixture into water, extraction with a suitable organic solvent such as ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, the solvent was distilled off, and the product was recrystallized,
It can be isolated by a method such as silica gel chromatography.

The starting material (±) -chromanone (II) in the present invention is 2,3-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2- b: 3,4-b '] dipyran-1,9-
It can be produced by isomerizing dione [chromanone (V)]. Chromanon (V) here is 2
A single stereoisomer in which the methyl groups at the 3- and 3-positions have an arbitrary configuration or a mixture thereof in an arbitrary quantitative ratio is shown.

Chromanone (V) was recovered from the mother liquor of recrystallization in the optical resolution using the optically active amine in step (a), or separated in the optical resolution using high performance liquid chromatography ( +)
The (-) isomer, which is the antipode of -chromanone (I), or the stereoisomer in which the methyl groups at the 2- and 3-positions have a cis configuration, and the like can be preferably used. In addition, from 5,7-dihydroxy-8-[(2-methyl) -2-butenoyl] -4-propylcoumarin (XI) described later (±)
-Stereoisomers in which the methyl groups at the 2- and 3-positions, which are by-produced in the step of producing chromanone (II), have a cis configuration are also suitably used. By introducing these into (±) -chromanone (II) by isomerization, they can be reused in the optical resolution step.

A base catalyst can be used as the reaction condition without limitation for such isomerization. As a base catalyst,
For example, pyridine, picoline, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N, N-diethylaniline, trimethylamine, triethylamine, diisopropylethylamine, trioctylamine, triethanolamine, N-methylmorpholine,
Tertiary amines such as 1,8-diazabicyclo [5.4.0] -7-undecene; inorganic bases such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, etc. Can be mentioned. These can be used alone or in combination of two or more. The amount of the base catalyst used is preferably in the range of 0.01 to 100 equivalents, more preferably in the range of 0.1 to 10 equivalents with respect to the chromanone (V).

A suitable organic solvent can be used as long as it does not inhibit such isomerization. Such organic solvents include, for example, hexane, heptane, aliphatic hydrocarbons such as octane; aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, mesitylene, chlorobenzene, trifluoromethylbenzene, and dichlorobenzene; tetrahydrofuran, diisopropyl ether, t
ethers such as ert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diglyme;
Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert
-Alcohols such as butanol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 1-octanol; nitriles such as acetonitrile and benzonitrile; esters such as ethyl acetate and butyl acetate; dichloromethane, chloroform, carbon tetrachloride, 1, Halogenated hydrocarbons such as 2-dichloroethane; dimethylformamide, dimethylsulfoxide and the like.

The amount of solvent used is Chromanone (V).
On the other hand, 1 to 100 times by weight is preferable, and 2 to 30 times by weight is particularly preferable.

The isomerization reaction is carried out within the range of 0 ° C to 150 ° C,
It is particularly preferable to carry out the treatment within the range of 70 to 120 ° C.
The reaction time depends on the reaction temperature and the like, but is usually 3 hours to
It will be completed in 12 hours.

For the isolation of the product, the method used for isolation of usual organic compounds can be used. For example, after pouring the reaction mixture into water, extraction with a suitable organic solvent such as ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, the solvent was distilled off, and the product was recrystallized,
It can be isolated by a method such as silica gel chromatography.

The (±) -chromanone (II), which is the starting material in the present invention, can be produced from phloroglucinol, which is an industrially easily available starting material, by the following method, for example (Japanese Patent Application Laid-Open No. 2000-242242). 2002-19
3971).

[0081]

[Chemical formula 24]

Phloroglucinol (VI) or a hydrate thereof and ethyl butyryl acetate (VII) are reacted in the presence of an acid catalyst (eg concentrated sulfuric acid) to give 5,7-dihydroxy-4-propylcoumarin (VIII). ) Is obtained (step (d)).

5,7-Dihydroxy-4-propylcoumarin (VIII) was reacted with tigloyl chloride (IX) to give 5-hydroxy-7-[(2-methyl) -2-
Butenoyloxy] -4-propylcoumarin (X) is obtained (step (e)).

5-hydroxy-7-[(2-methyl)-
2-butenoyloxy] -4-propylcoumarin (X)
Is subjected to an intramolecular rearrangement reaction to give 5,7-dihydroxy-8
-[(2-Methyl) -2-butenoyl] -4-propylcoumarin (XI) is obtained (step (f)).

5,7-Dihydroxy-8-[(2-methyl) -2-butenoyl] -4-propylcoumarin (X
I) is subjected to an intramolecular ring closure reaction to obtain (±) -chromanone (II) (step (g)).

[0086]

EXAMPLES The present invention will be described in more detail below with reference to production examples and examples, but it goes without saying that the present invention is not limited to the following examples.

Production Example 1: 5,7-Dihydroxy-4-propylcoumarin (VIII) Phloroglucinol dihydrate (VI) (3.0 g, 1)
8.5 mmol) and ethyl butyryl acetate (VII)
Concentrated sulfuric acid (2.15 g, 21.9 mmol) was added in a suspension of (3.23 g, 20.4 mmol). The reaction mixture exothermed to a uniform yellow solution and then solidified. After standing at room temperature for 2 hours, the resulting solid was well ground. It was washed with water and the product was filtered off. The washing and filtering operations were repeated until the washing liquid reached pH 3. After thoroughly drying the product, the title compound was obtained as a pale yellow powder (3.92 g, yield 96%).

Mp; 227-229 ° C. ¹ H-NMR (DMSO); δ 0.95 (t, 3H, J = 7.3 Hz), δ 1.58 (se
xtet, 2H, J = 7.4Hz), δ 2.85 (t, 2H, J = 7.5Hz), δ 5.8
3 (s, 1H), δ 6.19 (d, 1H, J = 2.3Hz), δ 6.27 (d, 1H, J
= 2.3Hz), δ 10.30 (s, 1H), δ 10.59 (s, 1H) ¹³ C-NMR (DMSO); δ 13.82, δ 22.53, δ 37.24, δ 9
4.74, δ 99.17, δ 99.26, δ 101.37, δ 108.28, δ
108.32, δ 156.84, δ 157.42, δ 158.51, δ 160.18,
δ 160.91 MS (EI); 221 (13.8, M + 1), 220 (100, M +), 205 (37.0),
192 (73.4), 177 (30.0) IR (KBr); 3204, 1649, 1622, 1591, 1561 cm ^-1

Production Example 2: 5-hydroxy-7-{(2-
Methyl) -2-butenoyloxy} -4-propylcoumarin (X) 5,7-dihydroxy-4-propylcoumarin after nitrogen substitution in a three-necked flask equipped with an efficient mechanical stirrer, thermometer and dropping funnel (VIII) (20
0 mg, 0.91 mmol) and 1,2-dichloroethane (1 ml) were charged, and the mixture was stirred at room temperature. Tigloyl chloride (IX) (350 mg, 2.92 mmo)
l) and aluminum chloride (360 mg, 2.72 m)
1,2-dichloroethane (1 ml) solution of (mol) was added dropwise at room temperature. The reaction mixture became a yellow solution with vigorous bubbling. After completion of dropping, the mixture was stirred at room temperature for 30 minutes. After adding water (3 ml), the mixture was extracted with ethyl acetate. The organic layers were collected, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and the solvent was distilled off to obtain a light brown solid. This is ethyl acetate: hexane = 1: 1
After washing with ethyl acetate: hexane = 1: 4, the title compound was obtained as a white solid (241 m
g, yield 88%).

Mp; 153-154 ° C. ¹ H-NMR (CDCl ₃ ); δ 0.94 (t, 3H, J = 7.3 Hz), δ 1.49 (s
extet, 2H, J = 7.4Hz), δ 1.93 (d, 3H, J = 7.1Hz), δ 1.
97 (s, 3H), δ 2.74 (t, 2H, J = 7.6Hz), δ 6.03 (s, 1H),
δ 6.39 (d, 1H, J = 2.3Hz), δ 6.64 (d, 1H, J = 2.3Hz),
δ 7.21 (q, 1H, J = 7.0Hz), δ 7.36 (s, 1H) ¹³ C-NMR (CDCl ₃ ); δ 12.12, δ 13.89, δ 14.91, δ
22.42, δ 37.84, δ 102.82, δ 105.99, δ 107.15,
δ 112.56, δ 127.52, δ 142.04, δ 152.88, δ 155.
61, δ 156.35, δ 158.10, δ 160.85, δ 167.13 MS (EI); 303 (2.6, M + 1), 302 (13.3, M +), 220 (2.8), 8
3 (100), 55 (31.6) IR (KBr); 3107, 2969, 1730, 1680, 1609 cm ^-1

Production Example 3: 5,7-Dihydroxy-8-
{(2-Methyl) -2-butenoyl} -4-propylcoumarin (XI) Efficient mechanical stirrer, thermometer, three-neck reaction vessel equipped with reflux cooling tower and dropping funnel, and aeration possible from reaction vessel The sodium hydroxide aqueous solution tank thus prepared was prepared, and the whole was replaced with argon. 5,7 in this reaction vessel
-Dihydroxy-4-propylcoumarin (VIII)
(10.0 g, 45.4 mmol) and 1,2-dichloroethane (30 ml) were charged and stirred at room temperature. To this was added tigloyl chloride (IX) (8.94 g, 75.
4 mmol) and aluminum chloride (18.2 g, 1
36.2 mmol) of 1,2-dichloroethane (20 m
l) The solution was added dropwise at room temperature over 20 minutes. The reaction mixture became a tan solution with vigorous bubbling. After completion of dropping, the mixture was stirred at room temperature for 30 minutes. TLC analysis was performed and the disappearance of the starting materials and 5-hydroxy-7-{(2-methyl) -2-
Formation of butenoyloxy} -4-propylcoumarin (X) was confirmed. The internal temperature was raised to 50 ° C. and the mixture was stirred for 30 minutes, and further stirred at an internal temperature of 70 ° C. for 3.5 hours. Hydrogen chloride generated during this was aerated through a sodium hydroxide aqueous solution tank for neutralization. Then, the reaction mixture was poured into water (200 ml) at a liquid temperature of 50 ° C. or higher. The light brown solid that precipitated was filtered off and washed with water (100 ml), followed by ethyl acetate: hexane = 1: 3 (40 ml). The solid product is then treated with ethyl acetate (200 ml) and ethanol (100 ml).
ml) and the insoluble matter was filtered off using Celite. The filtrate was concentrated to give the title compound as a light brown solid (10.8 g, yield 79%).

Mp; 213-215 ° C. ¹ H-NMR (CDCl ₃ / DMSO = 10/1); δ 1.00 (t, 3H, J = 7.3 Hz),
δ 1.66 (sextet, 2H, J = 7.4Hz), δ 1.83 (d, 3H, J = 6.9
Hz), δ 1.94 (s, 3H), δ 2.92 (t, 2H, J = 7.5Hz), δ 5.
87 (s, 1H), δ 6.32 (q, 1H, J = 6.9Hz), δ 6.41 (s, 1H),
δ 10.41 (brs, 1H), δ 10.78 (brs, 1H) ¹³ C-NMR (CDCl ₃ / DMSO = 10/1); δ 11.94, δ 14.00, δ
14.60, δ 22.77, δ 38.19, δ 99.70, δ 102.47, δ
106.01, δ 109.28, δ 136.94, δ 137.86, δ 139.4
0, δ 155.39, δ 159.10, δ 159.90, δ 160.34, δ
161.69 MS (EI); 303 (4.9, M + 1), 302 (24.3, M +), 288 (20.8),
287 (100), 259 (47.8), 100 (14.9), 55 (10.1) IR (KBr); 3299, 1694, 1622, 1588 cm ^-1

Production Example 4: (±) -2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-
b ′] dipyran-1,9-dione [(±) -chromanone (II)] 5,7-dihydroxy-8-{(2-methyl) -2-butenoyl} -4-propylcoumarin (XI) (1. 0
g, 3.3 mmol) and triethylamine (0.2
ml, 1.4 mmol) was dissolved in methanol (10 ml) and heated at 60 ° C. for 4.5 hours. The reaction solution is concentrated,
After dissolving in ethyl acetate, it was passed through a silica gel layer.
The solvent was evaporated to give a brown solid (927 mg, yield 93)
%). When ¹ H-NMR was measured for this, it was a diastereomeric mixture of the title compound and the corresponding cis isomer, and the production ratio thereof was 1.00: 0.65. Therefore, the yield of the title compound was calculated to be 56%. The crude product was purified by silica gel chromatography to give pure (±) -2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2]. -B: 3,4-b '] dipyran-1,9-dione [(±) -chromanone (II)] was obtained as a white solid.

Mp; 238-240 ° C. ¹ H-NMR (CDCl ₃ ); δ 0.98 (t, 3H, J = 7.3 Hz), δ 1.19
(d, 3H, J = 6.9Hz), δ 1.48 (d, 3H, J = 6.3Hz), δ 1.60
(sextet, 2H, J = 7.4Hz), δ 2.51 (dq, 1H, J = 6.9Hz, 11.
1Hz), δ 2.88 (tABq, 2H, J = 7.5Hz, 13.9Hz), δ 4.22 (d
q, 1H, J = 6.3Hz, 11.1Hz), δ 6.01 (s, 1H), δ 6.17
(s, 1H) ¹³ C-NMR (CDCl ₃ ); δ 10.60, δ 13.91, δ 19.66, δ
22.71, δ 38.33, δ 47.36, δ 79.28, δ 99.24, δ 1
03.12, δ 104.35, δ 110.75, δ 156.42, δ 158.80,
δ 160.85, δ 161.69, δ 164.39, δ 190.56 MS (EI); 303 (10.4, M + 1), 302 (52.9, M +), 247 (16.4),
246 (100), 217 (34.0), 203 (17.3), 190 (21.1) IR (KBr); 3086, 2961, 1721, 1609, 1209 cm ^-1

Example 1: (±) -2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-
b ′] dipyran-1,9-dione [(±) -chromanone (II)] optical resolution using (+)-quinidine (first recrystallization) (±) -2,3-trans-dihydro- 6-hydroxy-2,3-dimethyl-7-propyl-
1H, 9H-benzo [1,2-b: 3,4-b ′] dipyran-1,9-dione [(±) -chromanone (II)]
(18.0 g, purity 75%, gross 59.5 mmo
1) and (+)-quinidine (19.3 g, 59.5 m)
mol) to a mixture of 2-propanol (145 ml)
When water and water (15 ml) were added and the mixture was heated with stirring at 50 ° C. for 20 minutes, the reaction solution became a pale yellow solution. Water (81 ml) was further added to this and mixed well with stirring, and then the liquid temperature was adjusted to 32.
After cooling to ℃ and inoculating seed crystals, crystals were precipitated at the same temperature. The liquid temperature was cooled to 10 ° C., the crystals were separated by filtration, washed with 2-propanol / water = 1/2 (25 ml × 2 times), and then vacuum dried to obtain 1 of the title compound and (+)-quinidine. : 1 salt was obtained as pale yellow crystals (19.7 g, yield 6).
4% [(±) -chromanone (II) standard], purity 91
%). The obtained crystal is analyzed by HPLC [column: CHIRALCEL OJ- manufactured by Daicel Chemical Industries, Ltd.]
R (4.6 × 150 mm), mobile phase: 0.5 MH ₃ P
O ₄ (Na) buffer (pH 2.0) / CH ₃ CN
= 7/3, flow rate: 0.5 ml / min], the optical purity of (+)-chromanone (I) contained in the crystal was 1
1% e. e. Met.

¹ H-NMR (CDCl ₃ ) (Racemic); δ 0.98 (t, 3
H, J = 7.3Hz), δ 1.07 (d, 1.5H, J = 7.0Hz), δ 1.10 (d,
1.5H, J = 7.0Hz), δ 1.20-1.26 (m, 1H, quinidine moiet
y), δ 1.39 (d, 1.5H, J = 6.2Hz), δ 1.39 (d, 1.5H, J =
6.2Hz), δ 1.64 (sextet, 2H, J = 7.4Hz), δ 1.69-1.81
(m, 2H, quinidine moiety), δ 1.94 (brs, 1H, quinidi
ne moiety), δ 2.25-2.30 (m, 1H, quinidine moiety),
δ 2.32-2.40 (m, 1H), δ 2.45-2.50 (m, 1H, quinidine
moiety), δ 3.02-3.14 (m, 2H), δ 3.16-3.22 (m, 1H, q
uinidine moiety), δ 3.27-3.41 (m, 3H, quinidine moi
ety), δ 3.88 (s, 3H, quinidine moiety), δ 3.98-4.0
8 (m, 1H), δ 5.16 (d, 1H, J = 4.4Hz, quinidine moiet
y), δ 5.18 (s, 1H, quinidine moiety), δ 5.78 (s, 0.
5H), δ 5.79 (s, 0.5H), δ 6.02-6.09 (m, 2H, quinidin
e moiety), δ 6.14 (s, 1H), δ 7.28 (d, 1H, J = 2.6Hz,
quinidine moiety), δ 7.36 (dd, 1H, J = 2.6Hz, 9.2Hz,
quinidine moiety), δ 7.66 (d, 1H, J = 4.5Hz, quinidin
e moiety), δ 8.02 (d, 1H, J = 9.2Hz, quinidine moiet
y), δ 8.76 (d, 1H, J = 4.5Hz, quinidine moiety) ¹³ C-NMR (CDCl ₃ ); δ 10.81, δ 14.05, δ 19.78, δ
19.84, δ 22.83, δ 24.96, δ 25.38, δ 27.86, δ 3
8.47, δ 38.68, δ 47.06, δ 47.12, δ 49.31, δ 5
0.09, δ 55.76, δ 60.48, δ 64.44, δ 78.17, δ 9
9.61, δ 100.81, δ 101.38, δ 106.73, δ 107.38,
δ 116.24, δ 118.84, δ 121.49, δ 126.27, δ 131.
74, δ 138.34, δ 144.23, δ 145.80, δ 147.59, δ
157.62, δ 158.09, δ 162.66, δ 162.83, δ 164.9
0, δ 190.47 IR (KBr); 2965, 1680, 1591, 1313, 1228 cm ^-1

(Second recrystallization) 2-Propanol (92 ml) was added to the crystal (19.4 g) obtained in the first recrystallization.
When water and water (10 ml) were added and the mixture was heated with stirring at 50 ° C. for 30 minutes, the reaction solution became a pale yellow solution. Water (51 ml) was added to this, and the mixture was stirred and mixed well, and then the liquid temperature was adjusted to 38
The mixture was cooled to ℃, and crystals were precipitated at the same temperature. Liquid temperature 10 ℃
The mixture was cooled to 1, the crystals were filtered off, and 2-propanol / water = 1 /
After washing with 2 (90 ml) and vacuum drying, the title compound and a 1: 1 salt of (+)-quinidine were obtained as pale yellow crystals (15.1 g, yield 49% [(±) -chromanone ( I
I) Standard], purity 97%). As a result of HPLC analysis of the obtained crystals under the above conditions, (+)-contained in the crystals.
The optical purity of chromanone (I) is 24% e. e. Met.

(Third recrystallization) 2-propanol (55 ml) was added to the crystal (14.0 g) obtained by the second recrystallization.
When water and water (5 ml) were added and the mixture was heated with stirring at 50 ° C. for 50 minutes, the reaction solution became a pale yellow solution. Water (32 ml) was further added to this, and the mixture was stirred and mixed well, and then the liquid temperature was adjusted to 38
The mixture was cooled to ℃, and crystals were precipitated at the same temperature. Liquid temperature 10 ℃
The mixture was cooled to 1, the crystals were filtered off, and 2-propanol / water = 1 /
After washing with 2 (50 ml) and vacuum drying, a 1: 1 salt of the title compound and (+)-quinidine was obtained as pale yellow crystals (10.9 g, yield 39% [(±) -chromanone ( I
I) Standard], purity 99%). As a result of HPLC analysis of the obtained crystals under the above conditions, (+)-contained in the crystals.
The optical purity of chromanone (I) is 40% e. e. Met.

(Fourth recrystallization) The crystal (10.9 g) obtained by the third recrystallization was mixed with 2-propanol (43 ml).
The crystals were recrystallized from water and water (29 ml) under the same conditions as the third time, to obtain the title compound and a 1: 1 salt of (+)-quinidine as pale yellow crystals (9.4 g, yield 34%).
[(±) -chromanone (II) standard]. As a result of HPLC analysis of the obtained crystals under the above conditions, the optical purity of (+)-chromanone (I) contained in the crystals was 52% e.
e. Met.

(Fifth recrystallization) The crystal (9.4 g) obtained in the fourth recrystallization was recrystallized from 2-propanol (43 ml) and water (29 ml) under the same conditions as in the third recrystallization, A 1: 1 salt of the title compound and (+)-quinidine was obtained as pale yellow crystals (8.0 g, yield 29% [(±)].
Chromanon (II) criteria]). As a result of HPLC analysis of the obtained crystal under the above conditions, the optical purity of (+)-chromanone (I) contained in the crystal was 65% e. e.
Met.

(6th recrystallization) The crystal (8.0 g) obtained in the 5th recrystallization was recrystallized from 2-propanol (50 ml) and water (33 ml) under the same conditions as in the 3rd recrystallization, A 1: 1 salt of the title compound and (+)-quinidine was obtained as pale yellow crystals (6.5 g, yield 23% [(±)).
Chromanon (II) criteria]). As a result of HPLC analysis of the obtained crystals under the above conditions, the optical purity of (+)-chromanone (I) contained in the crystals was 73% e. e.
Met.

(7th recrystallization) The crystal (6.5 g) obtained in the 6th recrystallization was recrystallized from 2-propanol (40 ml) and water (27 ml) under the same conditions as in the 3rd recrystallization, A 1: 1 salt of the title compound and (+)-quinidine was obtained as pale yellow crystals (5.4 g, yield 19% [(±)).
Chromanon (II) criteria]). As a result of HPLC analysis of the obtained crystals under the above conditions, the optical purity of (+)-chromanone (I) contained in the crystals was 80% e. e.
Met.

(8th recrystallization) The crystal (5.4 g) obtained in the 7th recrystallization was recrystallized from 2-propanol (38 ml) and water (19 ml) under the same conditions as in the 3rd recrystallization, A 1: 1 salt of the title compound and (+)-quinidine was obtained as pale yellow crystals (4.0 g, yield 14% [(±)].
Chromanon (II) criteria]).

Crystal obtained by the 8th recrystallization (500 m
g) in dichloromethane (10 ml) and water (10 m)
1) was added and the pH was adjusted to 3 with dilute hydrochloric acid. The organic layer was separated, dried over sodium sulfate, and concentrated to give a white powder (221 mg, yield 92%). As a result of HPLC analysis under the above conditions, (+)-chromanone (I)
Has an optical purity of 89% e. e. Met. [α] _D ²⁰ = + 68.8 ° (c = 0.5, EtOH) ¹ H-NMR (CDCl ₃ ); δ 0.98 (t, 3H, J = 7.3Hz), δ 1.19
(d, 3H, J = 6.9Hz), δ 1.48 (d, 3H, J = 6.3Hz), δ 1.60
(sextet, 2H, J = 7.4Hz), δ 2.51 (dq, 1H, J = 6.9Hz, 11.
1Hz), δ 2.88 (tABq, 2H, J = 7.5Hz, 13.9Hz), δ 4.22 (d
q, 1H, J = 6.3Hz, 11.1Hz), δ 6.01 (s, 1H), δ 6.17
(s, 1H) ¹³ C-NMR (CDCl ₃ ); δ 10.60, δ 13.91, δ 19.66, δ
22.71, δ 38.33, δ 47.36, δ 79.28, δ 99.24, δ 1
03.12, δ 104.35, δ 110.75, δ 156.42, δ 158.80,
δ 160.85, δ 161.69, δ 164.39, δ 190.56 MS (EI); 303 (10.4, M + 1), 302 (52.9, M +), 247 (16.4),
246 (100), 217 (34.0), 203 (17.3), 190 (21.1) IR (KBr); 3086, 2961, 1721, 1609, 1209 cm ^-1

Example 2: (±) -2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-
Optical resolution (±) -2,3-trans-dihydro-6-hydroxy-2,3- carried out using liquid chromatography of b ′] dipyran-1,9-dione [(±) -chromanone (II)]. Dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4-b ′] dipyran-1,9-dione [(±) -chromanone (II)] (26 mg) in methanol and dichloromethane. It is dissolved and subjected to optical resolution by liquid chromatography under the following conditions to contain a liquid containing (+)-chromanone (I) and a (-)-form which is an antipode of the (+)-chromanone (I). Separated into liquid.

Column: CHIRALCEL OD-RH
(4.6 × 150 mm) Mobile phase: 0.5MH ₃ PO
₄ (Na) buffer (pH 2.0) / CH ₃ CN =
6/4 Flow rate: 1.0 ml / min

Water (1 ml) was added to the obtained liquid containing (+)-chromanone (I), and the mixture was neutralized with NaHCO ₃ .
It was extracted with ethyl acetate and concentrated to give a white solid (9.4 m
g). When analyzed under the same conditions, the optical purity of (+)-chromanone (I) was 97% e. e. Met. Further, the same operation is performed on a liquid containing a (-) body which is an antipode of (+)-chromanone (I), and a (-) body which is an antipod of (+)-chromanone (I) (10.5 mg, 0.0
35 mmol, 82% e. e. ) Got.

Example 3: (+)-12-oxocalanolide A (III) (+)-2 (R), 3 (R) -trans-dihydro-6
-Hydroxy-2,3-dimethyl-7-propyl-1
H, 9H-benzo [1,2-b: 3,4-b ′] dipyran-1,9-dione [(+)-chromanone (I)] (1
88 mg, 0.62 mmol), 3-methyl-2-butenal (520 mg, 6.18 mmol) were dissolved in pyridine (1.00 g) and toluene (2.0 ml), and heated at 100 ° C for 4 hours. After heating, the reaction solution was concentrated and purified by silica gel chromatography,
(+)-12-Oxocalanolide A (III) was obtained as a white solid (101 mg, 44% yield). This is HP
Analysis by LC [Column: Daicel Chemical Industries, Ltd.
CHIRALCEL AD (4.6 × 250 mm), mobile phase: ethanol / hexane = 1/9, flow rate: 1.0 m
1 / min], the optical purity was 84% e.p.m. e. Met.

[Α] _D ²⁰ = + 30.7 ° (c = 0.7, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ); δ 1.03 (t, 3H, J = 7.3 Hz), δ 1.21
(d, 3H, J = 6.9Hz), δ 1.52 (s, 3H), δ 1.53 (d, 3H, J =
6.4Hz), δ 1.55 (s, 3H), δ 1.64 (sextet, 2H, J = 7.5H
z), δ 2.55 (dq, 1H, J = 6.3Hz, 11.1Hz), δ 2.86-2.89
(m, 2H), δ 4.29 (dq, 1H, J = 6.3Hz, 11.1Hz), δ 5.60
(d, 1H, J = 10.1Hz), δ 6.03 (s, 1H), δ 6.65 (d, 1H,
J = 10.1Hz) ¹³ C-NMR (CDCl ₃ ); δ 10.47, δ 13.88, δ 19.59, δ
23.13, δ 27.97, δ 28.28, δ 38.72, δ 47.27, δ 7
9.21, δ 79.57, δ 103.51, δ 104.42, δ 105.46, δ
112.04, δ 115.82, δ 126.97, δ 155.51, δ 155.9
1, δ 157.04, δ 159.04, δ 159.69, δ 189.89 MS (EI); 369 (9.4, M + 1), 368 (38.6, M +), 354 (21.4),
353 (100), 325 (6.7), 312 (6.7), 297 (34.3), 269 (12.3) IR (KBr); 2967, 2934, 1740, 1684, 1557, 1200 cm ^-1

Example 4: (+)-Calanolide A (IV) (+)-12-Oxocalanolide A (III) (88 mg, 0.24 mmo) cooled to -5 ° C. under nitrogen atmosphere.
1, 80% optical purity e. e. To a solution of () in tetrahydrofuran (3.0 ml) was added lithium tri-tert-butoxyaluminum hydride (92 mg, 0.36 mmol). After stirring at the same temperature for 3.5 hours, the hydrogenated trit
ert-Butoxyaluminum lithium (90 mg) was added, and the mixture was further stirred for 1 hr. The reaction solution was adjusted to pH 3 with diluted hydrochloric acid and extracted with ethyl acetate. The organic layers are collected and dried over sodium sulfate, then the solvent is distilled off,
(+)-Calanolide A (IV) was obtained as a white solid (87 mg, yield 98%). This is analyzed by HPLC [column: CHIRAL manufactured by Daicel Chemical Industries, Ltd.
CELAS (4.6 × 250 mm), mobile phase: ethanol / hexane = 1/9, flow rate: 1.0 ml / min], and as a result, optical purity was 79% e. e. Met.

The optical rotation of the obtained (+)-calanolide A (IV) was measured and compared with the optical rotation of (+)-calanolide A reported in US Pat. No. 5,892,060 to obtain (+).
I confirmed that it was a body. From the reported absolute configuration of (+)-calanolide A, the absolute configuration of (+)-chromanone (I) is the absolute configuration represented by the above formula (I), and (+)
It was confirmed that the absolute configuration of -12-oxocalanolide A (III) was the absolute configuration represented by the above formula (III).

[Α] _D ²⁰ = + 54.0 ° (c = 0.5, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ); δ 1.03 (t, 3H, J = 7.3 Hz), δ 1.15
(d, 3H, J = 6.8Hz), δ 1.46-1.47 (m, 6H), δ 1.51 (s, 3
H), δ 1.55 (s, 3H), δ 1.66 (sextet, 2H, J = 7.4Hz),
δ 1.89-1.97 (m, 1H), δ 2.83-2.96 (m, 2H), δ 3.80-
3.89 (br, 1H), δ 3.93 (dq, 1H, J = 6.4Hz, 8.9Hz), δ
4.71 (d, 1H, J = 7.7Hz), δ 5.54 (d, 1H, J = 10.0Hz), δ
5.95 (s, 1H), δ 6.62 (d, 1H, J = 10.0Hz) ¹³ C-NMR (CDCl ₃ ); δ 14.00, δ 16.16, δ 18.97, δ
23.29, δ 27.42, δ 28.05, δ 38.69, δ 40.53, δ 6
7.10, δ 77.29, δ 77.72, δ 104.11, δ 106.42, δ
106.51, δ 110.10, δ 116.56, δ 127.00, δ 151.1
8, δ 153.21, δ 154.52, δ 159.09, δ 160.77 MS (EI); 371 (8.1, M + 1), 370 (28.2, M +), 356 (26.1),
355 (100), 337 (21.9), 299 (29.5) IR (KBr); 3484, 3260, 2971, 1698, 1584 cm ^-1

Example 5: Isomerization of chromanone (V) (+)-chromanone (I) obtained in Example 2.
(-) Form (10.5 mg, 0.035 m), which is the antipode of
mol, 82% e. e. ) To triethylamine (7.0
mg, 0.07 mmol) and ethanol (0.2 m
1) was added and heated at 80 ° C. for 10 hours. The reaction solution was concentrated and then subjected to ¹ H-NMR measurement to find that it was a mixture of (±) -chromanone (II) and a corresponding diastereomer, and the production ratio was 1.00: 0.70. It was When (±) -chromanone (II) (5.5 mg) obtained by purification by silica gel chromatography was analyzed by liquid chromatography under the same conditions as in Example 2, (+)-chromanone was obtained. The enantiomeric excess of (I) is 5% e. e. Met.

[0114]

INDUSTRIAL APPLICABILITY According to the present invention, (+)-calanolide A can be produced from a readily available starting material by a method that can be carried out industrially easily and inexpensively. In the method of the present invention, optically active intermediate (+)-chromanone (I) is obtained by optically resolving (±) -chromanone (II), which can be synthesized from readily available starting materials. By using this optically active intermediate (+)-chromanone (I), (+)-calanolide A can be efficiently produced. According to the method of the present invention, (+)-calanolide A is obtained by performing optical resolution in the intermediate step.
Can be manufactured efficiently. Further, (+)-calanolide A can be produced by a reaction that can be carried out on an industrial scale without using an expensive reagent. Therefore, it is an industrially extremely useful manufacturing method.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Keiro Terashima             2-27-4 Kyodo, Setagaya-ku, Tokyo F term (reference) 4C071 AA01 AA08 BB01 BB05 CC12                       EE07 FF17 GG01 HH09 KK08                       KK14 KK16 LL07                 4D017 AA03 BA04 CA05 CB01 DA03                       EA05

Claims (8)

[Claims] 1. Formula (I): (+)-2 (R), 3 (R) -trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4 −
b '] dipyran-1,9-dione. 2. Formula (II): (±) -2,3-trans-dihydro-6-
Hydroxy-2,3-dimethyl-7-propyl-1H,
9H-benzo [1,2-b: 3,4-b '] dipyran-
Comprising the step of optically resolving a 1,9-dione of formula (I) (+)-2 (R), 3 (R) -trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4 −
b ′] A method for producing dipyran-1,9-dione. 3. The production method according to claim 2, wherein the optical resolution is performed by using an optically active amine. 4. The production method according to claim 3, wherein the optically active amine is quinidine. 5. The production method according to claim 2, wherein the optical resolution is performed by using liquid chromatography. 6. Formula (I): (+)-2 (R), 3 (R) -trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4 −
b ′] dipyran-1,9-dione is reacted with 3-methyl-2-butenal to give a compound of formula (III) To obtain (+)-12-oxocalanolide A, and reducing (+)-12-oxocalanolide A to give a compound of formula (IV) A step of obtaining (+)-calanolide A represented by
(+)-Method for producing calanolide A. 7. Formula (I): (+)-2 (R), 3 (R) -trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H, 9H-benzo [1,2-b: 3,4 −
b ′] dipyran-1,9-dione comprising the step of reacting with 3-methyl-2-butenal of formula (III): The manufacturing method of (+)-12-oxo calanolide A shown by these. 8. Formula (V): 2,3-dihydro-6-hydroxy-2,3 represented by
-Dimethyl-7-propyl-1H, 9H-benzo [1,
2-b: 3,4-b '] dipyran-1,9-dione, comprising the step of isomerizing formula (II): (±) -2,3-trans-dihydro-6-
Hydroxy-2,3-dimethyl-7-propyl-1H,
9H-benzo [1,2-b: 3,4-b '] dipyran-
A method for producing 1,9-dione.