JPH11209364A - Gamma-alkoxycarboxylic acid derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an intermediate for synthesizing medicines. SOLUTION: This compound is expressed by formula I (R<1> is acetylamino, p-cyanobenzoylamino or the like; R<2> is a 1-4C alkyl; R<3> is H or a 1-4C alkyl), for example, 6-(benzyloxycarbonyl)amino-4-methoxychromane-3-acetic acid methyl ester. The compound of formula I is obtained by reacting a compound of formula II with an ortho ester derivative of the formula: R<4> C(OR<5> )3 (R<4> is a 1-4C alkyl or the like; R<5> is a 1-4C alkyl) (for example, trimethyl orthoformate) preferably in the presence of 0.01-20 equivalents of an acid catalyst (hydrochloric acid, p-toluenesulfonic acid or the like) usually at 0-150 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel intermediate represented by the following general formula (1):

Embedded image (Wherein R ¹ represents an acetylamino group, a p-cyanobenzoylamino group, a benzyloxycarbonylamino group,
² represents a lower alkyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom and a lower alkyl group having 1 to 4 carbon atoms) and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Since the discovery that platelets play an important role in the development of thrombosis, various drugs that inhibit platelet aggregation have been used for the treatment of thrombosis. In recent years, it has been reported that chroman derivatives having an amino substituent at the 6-position have a strong platelet aggregation inhibitory action (Japanese Patent Application Laid-Open No.
JP-A-231486, JP-A-09-124581) and a number of synthetic methods for 6-aminochroman derivatives that can be used as pharmaceuticals or intermediates of pharmaceuticals have been reported (JP-A-09-059234, JP-A-09-0909).
-227548, JP-A-09-227448).

As described above, the γ-alkoxycarboxylic acid derivative represented by the general formula (1) is useful as an intermediate for the synthesis of pharmaceuticals, but is not known at all, and is represented by the general formula (1) There was no report on a method for producing a γ-alkoxycarboxylic acid derivative.

[0004]

An object of the present invention is to provide a γ-alkoxycarboxylic acid derivative represented by the general formula (1) useful as a pharmaceutical intermediate and a method for producing the same.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on γ-alkoxycarboxylic acid derivatives useful as intermediates for the synthesis of pharmaceuticals, and as a result, have found novel γ-alkoxycarboxylic acid derivatives. Was completed.

That is, the present invention relates to [1] a general formula (1)
[Formula 5]

Embedded image (Wherein R ¹ represents an acetylamino group, a p-cyanobenzoylamino group, a benzyloxycarbonylamino group,
² represents a lower alkyl group having 1 to 4 carbon atoms, R ³ represents a hydrogen atom and a lower alkyl group having 1 to 4 carbon atoms), and a γ-alkoxycarboxylic acid derivative represented by the formula:
[2] General formula (2)

Embedded image (Wherein R ¹ represents an acetylamino group, a p-cyanobenzoylamino group, a benzyloxycarbonylamino group,
³ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms) in the presence of an acid catalyst in the presence of an acid catalyst.
[Formula 7]

R ⁴ C (OR ⁵ ) ₃ (3) (wherein, R ⁴ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms)
This is a method for producing a γ-alkoxycarboxylic acid derivative represented by the general formula (1), which is reacted with an orthoester derivative represented by the following formula:

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
In the present invention, a lower alkyl group having 1 to 4 carbon atoms means a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
-Butyl group, isobutyl group and tert-butyl group.

The compounds included in the general formula (1) are specifically illustrated below, but the invention is not limited thereto. 6
-Acetylamino-4-methoxychroman-3-acetic acid,
Methyl 6-acetylamino-4-methoxychroman-3-acetate, ethyl 6-acetylamino-4-methoxychroman-3-acetate, n-propyl 6-acetylamino-4-methoxychroman-3-acetate, 6-acetyl Amino-4-methoxychroman-3-acetic acid isopropyl, 6-acetylamino-4-methoxychroman-3-
N-butyl acetate, 6-acetylamino-4-methoxychroman-3-isobutyl acetate, 6-acetylamino-4-methoxychroman-3-tert-butyl acetate, 6- (4-cyanobenzoyl) amino-4-methoxy Chroman-3-acetic acid, 6- (4-cyanobenzoyl)
Methyl amino-4-methoxychroman-3-acetate, 6
-(4-cyanobenzoyl) amino-4-methoxychroman-3-acetic acid ethyl, 6- (4-cyanobenzoyl) amino-4-methoxychroman-3-acetic acid n-propyl, 6- (4-cyanobenzoyl) amino -4-methoxychroman-3-isopropyl acetate, 6- (4-
Cyanobenzoyl) amino-4-methoxychroman-3
-N-butyl acetate, 6- (4-cyanobenzoyl) amino-4-methoxychroman-3-isobutyl acetate,
6- (4-cyanobenzoyl) amino-4-methoxychroman-3-acetic acid tert-butyl, 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-acetic acid, 6- (4-cyanobenzoyl) amino Methyl 4-ethoxycycloman-3-acetate, ethyl 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-acetate, 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-acetic acid n -Propyl, 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-
Isopropyl acetate, 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-n-butyl acetate,
6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-acetic acid isobutyl, 6- (4-cyanobenzoyl) amino-4-ethoxycycloman-3-acetic acid t
tert-butyl, 6- (benzyloxycarbonyl) amino-4-methoxychroman-3-acetic acid, 6- (benzyloxycarbonyl) amino-4-methoxychroman-
3-methyl acetate, 6- (benzyloxycarbonyl) amino-4-methoxychroman-3-ethyl acetate, 6-ethyl acetate
(Benzyloxycarbonyl) amino-4-methoxychroman-3-acetic acid n-propyl, 6- (benzyloxycarbonyl) amino-4-methoxychroman-3-isopropyl acetate, 6- (benzyloxycarbonyl) amino-4-methoxy Chroman-3-n-butyl acetate, 6-
(Benzyloxycarbonyl) amino-4-methoxychroman-3-acetic acid isobutyl, 6- (benzyloxycarbonyl) amino-4-methoxychroman-3-acetic acid t
tert-butyl, 6- (benzyloxycarbonyl) amino-4-ethoxycycloman-3-acetic acid, 6- (benzyloxycarbonyl) amino-4-ethoxycycloman-
3-methyl acetate, 6- (benzyloxycarbonyl) amino-4-ethoxycycloman-3-ethyl acetate, 6-ethyl acetate
N-propyl (benzyloxycarbonyl) amino-4-ethoxycycloman-3-acetate, isopropyl 6- (benzyloxycarbonyl) amino-4-ethoxycycloman-3-acetate, 6- (benzyloxycarbonyl) amino-4-ethoxy Chroman-3-n-butyl acetate, 6-
(Benzyloxycarbonyl) amino-4-ethoxycycloman-3-acetic acid isobutyl, 6- (benzyloxycarbonyl) amino-4-ethoxycycloman-3-acetic acid t
tert-butyl, etc., and both R configuration and S configuration with respect to asymmetric carbon are included in the present invention.

Furthermore, these salts can be exemplified as specific compounds of the present invention. Examples include salts with organic bases such as primary amine salts such as ammonia, secondary amines such as dimethylamine, and tertiary amines such as triethylamine.

Next, a method for producing the γ-alkoxycarboxylic acid derivative of the present invention will be described. The compound represented by the general formula (2), which is a starting material, can be produced, for example, by the following method. That is, JP-A-9-2275
General formula (4) described in JP-A-48-48

Embedded image (Wherein R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), and a benzyloxycarbonyl chloride, p-cyanobenzoyl chloride, acetyl By reacting with an acid halide such as chloride in the presence of a base, a γ-hydroxycarboxylic acid derivative represented by the general formula (2) can be obtained.

The base used is triethylamine,
Organic bases such as N-methylmorpholine and pyridine; and inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate.

Examples of the reaction solvent include water, protic solvents such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, esters such as ethyl acetate and butyl acetate, and hydrocarbons such as toluene and xylene. They can be used alone or in combination.

[0013] The reaction temperature is usually in the range of -20 to 80 ° C, preferably -10 to 30 ° C, and the reaction can be carried out for 1 to 24 hours.

The thus obtained γ-hydroxycarboxylic acid represented by the general formula (2) is reacted with the general formula (3) [formula 9] in the presence of an acid catalyst.

R ⁴ C (OR ⁵ ) ₃ (3) (wherein, R ⁴ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms)
And can be converted to a compound represented by the general formula (1).

Specific examples of the orthoester derivative represented by the general formula (3) include trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, trimethyl orthoacetate, triethyl orthoacetate and the like.

The amount of the orthoester derivative to be used is 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to the compound represented by the general formula (2).

Examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid; and cationic resins such as Amberlyst 15 and Dowex 50. And Lewis acids such as titanium tetrachloride, boron trifluoride, aluminum chloride and tin tetrachloride.

The acid catalyst is used in an amount of 0.01 to 20 equivalents, preferably 0.1 equivalent, to the compound represented by the general formula (2).
5 to 2 equivalents.

The reaction temperature is usually in the range of 0 to 150 ° C., preferably 40 to 100 ° C., and the reaction time is 1 to 24 hours. Examples of the reaction solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, esters such as ethyl acetate and butyl acetate, and hydrocarbons such as toluene and xylene, which may be used alone or in combination. I can do it.

The salt of the γ-alkoxycarboxylic acid derivative represented by the general formula (1) of the present invention can be produced by a conventional method by adding a base.

The γ-alkoxycarboxylic acid derivative represented by the general formula (1) of the present invention thus obtained can be separated and purified by usual means such as extraction, concentration, neutralization, filtration, recrystallization,
It can be isolated and produced by using means such as column chromatography.

[0022]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Example 1 Synthesis of methyl 6- (benzyloxycarbonyl) amino-4-methoxychroman-3-acetate (1-1) (6-Nitro-4-oxo-3,4-dihydro-2H-1-benzopyran-3) Methyl (ylidene) acetate (273.7 g) in methanol (2010.6 g)
, And the reaction system was purged with nitrogen. After that, 5% palladium / carbon (54.2 g) was added, and a hydrogen pressure of 7 kg / c was added.
The mixture was stirred at 70 ° C. for 3 hours at m ² . The palladium / carbon was removed by filtration to obtain a methanol solution of methyl 6-amino-4-hydroxychroman-3-acetate (2662.7 g). (1-2) The reaction solution (2662.7) obtained in the step (1-1)
g) was cooled to -10 <0> C. Triethylamine (102.7 g) was added dropwise thereto, then benzyloxycarbonyl chloride (168.4 g) was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 1 hour to give 6- (benzyloxycarbonyl) amino-4. -Hydroxychroman-3
-A methanol solution of methyl acetate (2933.8 g) was obtained. (1-3) The reaction solution (2933.8) obtained in the step (1-2)
g), trimethyl orthoformate (534 g) and Amberlyst 15 (116.8 g) are added, and the mixture is heated under reflux at 60 ° C. for 2 hours. After evaporating the solvent of the obtained reaction solution, xylene (2181 g) and celite (100.3 g) were added, and the mixture was concentrated again to distill off methanol. After concentration, the reaction is stirred at room temperature for 2 hours and the solid is filtered. The obtained filtrate is concentrated under reduced pressure to give 6- (benzyloxycarbonyl)
Methyl amino-4-methoxychroman-3-acetate (2
18.1 g). ¹ H-NMR (90 MHz, CDCl ₃ ): 2.10-
2.71 (3H, m), 3.38 and 3.42
(3H, s), 3.67 and 3.68 (3H,
s), 3.90-4.36 (3H, m), 5.16 (2
H, s), 6.58-6.75 (1H, m), 6.75.
(1H, d, J = 8.80), 7.08 and 7.
21 (1H, d, J = 8.80), 7.34 (5H,
s)

[0023]

According to the present invention, γ represented by the general formula (1)
-The discovery of an alkoxycarboxylic acid derivative makes it possible to efficiently produce a therapeutic agent for thrombosis.

Continued on the front page (72) Inventor Mitsuhiko Miyamoto 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals Co., Ltd.

Claims (2)

[Claims] 1. A compound of the general formula (1) (Wherein R ¹ represents an acetylamino group, a p-cyanobenzoylamino group, a benzyloxycarbonylamino group,
² represents a lower alkyl group having 1 to 4 carbon atoms, and R ³ represents a hydrogen atom and a lower alkyl group having 1 to 4 carbon atoms). 2. A compound of the general formula (2) (Wherein R ¹ represents an acetylamino group, a p-cyanobenzoylamino group, a benzyloxycarbonylamino group,
³ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms) in the presence of an acid catalyst in the presence of an acid catalyst.
R ³ C (OR ⁵ ) ₃ (3) (wherein R ⁴ is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ is a lower alkyl group having 1 to 4 carbon atoms) Indicates a group)
A method for producing a γ-alkoxycarboxylic acid derivative represented by the general formula (1), which is reacted with an orthoester derivative represented by the following formula: