JP2002069067A - Method for producing isocoumarin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an efficient method for producing an isocoumarin-3-yl-acetic acid derivative, particularly a derivative having a substituent at the 2-position of an acetic acid chain. SOLUTION: The formula: Reacting an isocoumarin-3-yl-acetic acid derivative represented by the formula with an organic halide or disulfide. A method for producing an isocoumarin-3-ylacetic acid derivative represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to isocoumarin-3
The present invention relates to a method for producing an -yl-acetic acid derivative, particularly a derivative having a substituent at the 2-position of the acetic acid chain.

[0002]

BACKGROUND OF THE INVENTION Isocoumarin-3-yl-acetic acid derivatives,
For example, the expression

Embedded image Is known to be effective in preventing and treating diseases associated with abnormal immunoregulatory effects or angiogenesis (WO 97/48693). According to this international publication pamphlet, 8-hydroxy-3-
It is produced from methyl-6-methoxy-isocoumarin in several steps. Each step in this production method is an excellent method in that all proceed at a good yield,
There will still be a need for providing better manufacturing methods.

As a method for introducing a substituent at the 2-position of the acetic acid chain in an isocoumarin-3-yl-acetic acid derivative,
Japanese Patent Application Laid-Open No. 10-287667 discloses a method via a cyano derivative. According to this method, a di-substituted product having two substituents is easily produced, and the target substituted product is mono-substituted. -When it was a substituted product, it was sometimes difficult to control the reaction conditions.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to efficiently convert a mono-substituted derivative at the 2-position of the acetic acid chain, which can greatly affect the physiological activity of the isocoumarin-3-yl-acetic acid derivative. It is to provide a manufacturing method.

[0005]

SUMMARY OF THE INVENTION The present inventors have developed certain isocoumarin-3-yl-protected carboxyl groups.
By subjecting the acetic acid derivative to a nucleophilic substitution reaction in an inert organic solvent, one substituent can be efficiently added without generating a di-substitute at the 2-position of the acetic acid chain in the isocoumarin-3-yl-acetic acid derivative. Found that only can be introduced. The present invention is based on such findings.

That is, the present invention provides a compound represented by the formula (I)

[0007]

Embedded image (In the above formula, R represents an unsubstituted or substituted lower alkyl group, an unsubstituted or substituted lower alkenyl group, an unsubstituted or substituted lower alkynyl group, or a substituted sulfide substituted with the substituent, and Ra represents _a carboxyl group. A protecting group or a hydrogen atom, R _b represents a hydroxyl protecting group or a hydrogen atom, and R _c represents an unsubstituted or substituted lower alkyl group). Having the formula (II)

[0008]

Embedded image (Wherein, R _c has the same meaning as defined for formula (I), R ₁ represents a hydroxyl-protecting group or a hydrogen atom, and R ₂ represents a carboxyl-protecting group, respectively) -3-yl-acetic acid derivative is converted to a compound of formula (III) in an inert organic solvent containing a base.

[0009]

Embedded image (Wherein, R has the same meaning as defined for formula (I) and X represents a halogen atom), or an organic halide represented by formula (IV)

Embedded image (In the above formula, R ′ represents an unsubstituted or substituted lower alkyl group, an unsubstituted or substituted lower alkenyl group, an unsubstituted or substituted lower alkynyl group). A production method characterized by subjecting the obtained compound to an elimination reaction of a protecting group.

According to the method of the present invention, isocoumarin-3
One substituent can be introduced selectively and at a high yield into the 2-position of the acetic acid chain in the -yl-acetic acid derivative.

Hereinafter, the present invention will be described specifically.

The specific contents of the definition of each group that specifies the compound represented by each formula related to the present invention are as follows.

"Lower alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl. , Sec-butyl, tert-butyl, n-pentyl, isoamyl, n-hexyl and the like. Preferred alkyl groups are groups with up to 4 carbon atoms. Hereinafter, in the present specification, the above examples can be applied including the case where a lower alkyl occupies a part of the group. When these alkyl groups are substituted, the substituent is halo, cycloalkyl having 3 to 7 carbon atoms, optionally substituted with one or more lower alkyl, halo, or nitro (eg, Phenyl, naphthyl), lower alkoxy, lower alkylthio, mono- or di-lower alkyl-substituted amino, and the like, and one or more of these substituents may be present. Halo means fluorine, chlorine, bromine or iodine, and halo in the above substituent is preferably fluorine or chlorine. The lower alkyl in the lower alkoxy, the lower alkylthio and the lower alkyl-substituted amino follows the definition of the above-mentioned "lower alkyl" (hereinafter common throughout the present specification). Specific examples of the substituted alkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, cyclopropylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, benzyl, benzhydryl, methoxymethyl, i-propoxymethyl , Methylthiomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl and the like.

"Lower alkenyl" means a straight-chain or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and containing a carbon-carbon double bond, such as ethenyl, propenyl, n -Butenyl, i-butenyl, 3-methylbut-2-enyl, n-heptenyl and the like. When these lower alkenyl are substituted, the substituent is
It may have the same meaning as the substituent for the above "lower alkyl". In addition, the manner of substitution of the substituents is the same as in the case of the lower alkyl.

"Lower alkynyl" means a straight-chain or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and containing a carbon-carbon triple bond, for example, ethynyl, propynyl, n- Butynyl, i-butynyl, 3-methylbut-2-ynyl, n-pentynyl and the like can be mentioned. When these lower alkynyls are substituted, the substituent may be the same as the substituent for the above “lower alkyl”. In addition, the manner of substitution of the substituents is the same as in the case of the lower alkyl.

The "protecting group for hydroxyl group" and "protecting group for carboxyl group" function to suppress the reactivity of the corresponding functional group in order to avoid or reduce undesirable side reactions in the reaction according to the present invention. Means a group having In the present invention, a group that makes the corresponding compound usable as a prodrug while these protecting groups are still present may be included in the protecting groups. These protecting groups are commonly used by those skilled in the art, for example, “Protective
Groups in Organic Chemistry ”, John Wiley a
nd Sons, 1991.

Among the above-mentioned preferred protecting groups in "hydroxyl protecting group", lower alkyl, lower alkanol (eg, acetyl, propionyl, etc.), arylcarbonyl (eg,
Benzoyl, etc.), silyl (eg, tert-butyldimethylsilyl, t-butyldiphenylsilyl, etc.), aryl- or lower alkyl-oxycarbonyl (eg, benzyloxycarbonyl, tert-butoxycarbonyl, etc.), lower alkylsulfonyl or arylsulfonyl (Eg, mesyl, tosyl, etc.).

Examples of the "protecting group for carboxyl group" include lower alkyl groups and optionally substituted phenyl-substituted lower alkyl (eg, benzyl, benzhydryl, trityl, p-nitrobenzyl, etc.).

In the formula (I), when R _b is a hydroxyl-protecting group, the compound which can be a prodrug is -OR _b is an acetate, a propionate, a succinate or a fumarate. In some cases, R _b is selected from residues in which a hydroxyl group or the remaining carboxyl group is protected such that an acid ester, a maleate ester, a lactate ester, a tartrate ester, a malonate ester and the like can be finally formed. Can be mentioned.

As described above, for example, the isocoumarin-3-yl-acetic acid derivative of the formula (I) which is effective for the prevention and treatment of a disease associated with abnormal immunomodulatory action or angiogenesis is obtained by isocoumarin-formula of the formula (II) A 3-yl-acetic acid derivative and an organic halide of formula (III) or a compound of formula (I
The disulfide of V) can be produced by subjecting it to a nucleophilic substitution reaction in an inert organic solvent containing a base.

A typical example of the production method of the present invention will be described with reference to the following synthesis scheme.

[0022]

Embedded image In the above scheme, R, R ′, R _c , R ₁ , R ₂ and X are as described above.

The reaction of the compound of the formula (II) with the compound of the formula (III) is carried out in an inert solvent (for example, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane, dioxane, etc.). In the presence of a base (for example, an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or potassium t-butoxide, or an organic base such as diisopropylethylamine, triethylamine, pyridine, lutidine, or lithium diisopropylamide), ,
It can be completed by stirring at -30 to 60C, preferably -5 to 0C for 1 to 5 hours, preferably 2 to 3 hours.

The proportion of each raw material to be used can be appropriately selected in consideration of the economics of the compound to be used, etc., but usually, the compound of the formula (III) is used in an equimolar amount with respect to the compound of the formula (II). It is preferable to use three times the molar amount. As for the usage ratio of other raw materials, a preferable one for each case can be selected with reference to the production examples described later.

The reaction of the compound of the formula (II) with the compound of the formula (IV) is carried out in an inert solvent (for example, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane, dioxane, etc.). In the presence of a base (for example, an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or potassium t-butoxide, or an organic base such as diisopropylethylamine, triethylamine, pyridine, lutidine, or lithium diisopropylamide). Usually, at -30 to 60 ° C, preferably at -5 to 0 ° C, 1 to 5
It can be completed by stirring for a time, preferably 2-3 hours.

The proportion of each raw material to be used can be appropriately selected in consideration of the economics of the compound to be used, etc., but usually the compound of the formula (IV) is equimolar to the compound of the formula (II) in an equimolar amount. It is preferable to use three times the molar amount. In addition, those skilled in the art can also appropriately determine the preferred ratio of each reactant used in the above reaction.

In order to separate the thus-formed compound of the formula (I-1) from the reaction mixture, an extraction method using an organic solvent such as ethyl acetate and, if necessary, a chromatography using silica gel can be used. . The thus obtained product can be converted to the desired physiologically active substance (I-2) by removing each protecting group by a known elimination reaction, if necessary.

The isocoumarin-3-yl-acetic acid derivative represented by the formula (II) can be obtained by subjecting a derivative whose corresponding substituent is unprotected to a known protecting group introduction reaction described in the aforementioned literature. Although it can be produced, more preferably, it can be produced by subjecting a newly discovered homophthalic acid derivative and a malonic acid derivative to a cyclocondensation reaction in an inert solvent. 11-3
No. 34471 and Japanese Patent Application No. 11-336555).

Therefore, according to the process of the present invention, the desired isocoumarin-3-yl-acetic acid derivative compound in which the 2-position of the acetic acid chain is mono-substituted can be obtained from the readily available starting materials in a small number of steps and in high yield. Can be manufactured.

The process of the present invention also uses a compound of formula (III) or (IV) labeled with a radioactive element such as ³ H or ¹⁴ C to form a substituent R in formula (I).
Can efficiently produce a labeled compound in which a part of hydrogen atoms or carbon atoms constituting is labeled. Such a labeled compound can be a very effective tool in performing basic research on the biological activity of the isocoumarin-3-yl-acetic acid derivative represented by the formula (I).

[0031]

Now, the present invention will be described in further detail with reference to specific examples.

Production Example 1 : Production of methyl 2- (8-hydroxy-6-methoxy-1H-2-benzopyran-1-one-3-yl) propionate

[0033]

Embedded image

2- (8-hydroxy-6-methoxy-1
H-2-benzopyran-1-one-3-yl) methyl acetate (200 mg, 0.76 mmol) was dissolved in N, N-dimethylformamide (2 ml), cooled to 0 ° C., and potassium carbonate (310 mg, 2.27 mmol) and iodine were added. Methyl chloride 2
40 μl (3.79 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. The obtained reaction solution was diluted with 30 ml of ethyl acetate, and washed with water and saturated saline. After dehydration and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (toluene / ethyl acetate = 10 / 1-5 / 1) to give the title compound 56
mg (yield 27%).

[0035] FAB MS (m / z) 279 (M + H) + 1 H-NMR (400MHz.CDCl 3): δ11.0
2 (1H, s), 6.49 (1H, d, J = 2.2H
z), 6.38 (1H, d, J = 2.2 Hz), 6.3
4 (1H, s), 3.87 (3H, s), 3.75 (3
H, s), 3.60 (1H, q, J = 7.3 Hz),
1.55 (3H, d, J = 7.3 Hz)

Production Example 2 : Production of 2- (8-hydroxy-6-methoxy-1H-2-benzopyran-1-one-3-yl) propionic acid

[0037]

Embedded image

2- (8-hydroxy-6-methoxy-1)
Dissolve 25 mg (0.09 mmol) of methyl H-2-benzopyran-1-one-3-yl) propionate in 1 ml of acetonitrile, cool to 0 ° C., add 0.2 ml of 1 M sodium hydroxide, and leave for 2 hours Stirred. After adding 0.5 ml of 1M hydrochloric acid to the obtained reaction solution, 10 ml of ethyl acetate was added for dilution, and the mixture was washed with water and saturated saline. After dehydration and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 19 mg of the title compound (yield: 7).
8%).

[0039] FAB MS (m / z) 265 (M + H) + 1 H-NMR (400MHz.DMSO-d 6): δ1
0.90 (1H, s), 6.68 (1H, s), 6.6
7 (1H, J = 2.2 Hz), 6.56 (1H, d, J
= 2.2 Hz), 3.86 (3H, s), 3.70 (1
H, q, J = 7.3 Hz), 1.39 (3H, d, J =
7.3 Hz)

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Tomio Takeuchi 5-1F Higashi Gotanda Shinagawa-ku, Tokyo 5-111 New Fuji Mansion 701 F term (reference) 4C062 GG08 4H039 CA42 CD10

Claims (1)

[Claims] 1. A compound of the formula (I) (Wherein R is an unsubstituted or substituted lower alkyl group,
Represents an unsubstituted or substituted lower alkenyl group, an unsubstituted or substituted lower alkynyl group, or a substituted sulfide group substituted with the substituent, Ra represents _a carboxyl-protecting group or a hydrogen atom, and R _b represents a hydroxyl-protected group. Wherein R _c represents an unsubstituted or substituted lower alkyl group, wherein R _c represents an unsubstituted or substituted lower alkyl group, wherein R _c represents an unsubstituted or substituted lower alkyl group; (Wherein, R _c has the same meaning as defined for formula (I), R ₁ represents a hydroxyl-protecting group or a hydrogen atom, and R ₂ represents a carboxyl-protecting group, respectively) The -3-yl-acetic acid derivative is converted to a compound of the formula (III) in an inert organic solvent containing a base. (Wherein, R has the same meaning as defined for the formula (I), and X represents a halogen atom), or an organic halide represented by the formula (IV): (In the above formula, R ′ represents an unsubstituted or substituted lower alkyl group, an unsubstituted or substituted lower alkenyl group, an unsubstituted or substituted lower alkynyl group). A production method comprising subjecting the compound obtained to an elimination reaction of a protecting group.