JPH06340622A - Production of benzylsuccinic acid derivative and intermediate for its synthesis - Google Patents

Abstract

PURPOSE:To readily produce an optically active benzylsuccinic acid derivative having a blood sugar-reducing effect and useful as an antidiabetic agent in a high yield only by using a new benzylsuccinic acid derivative and hydrolyzing it. CONSTITUTION:The objective benzylsuccinic acid derivative of formula II can be readily produced only by hydrolyzing a new benzylsuccinic acid derivative represented by formula I [A is ethylene, trimethylene, o-phenylene or bicyclo[2,2,1]hept-5-en-2,3-diyl; The configuration of a carbon atom marked with (s) is (s) configuration]. In addition, an N-hydroxyimide derivative of formula III formed as a by-product in this reaction is readily soluble in water and, therefore, can be readily removed according to a simple operation by water- washing of the reaction solution. The compound of formula I can be synthesized, e.g. by reacting a benzylsuccinic acid of formula IV with a reactive derivative of an N-hydroxyimide derivative of formula III to obtain a benzylsuccinic acid derivative of formula V and further reacting the resultant benzylsuccinic acid derivative of formula V with a cyclic amine of formula VI.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a benzylsuccinic acid derivative useful as a medicine and an intermediate for producing the same.

More specifically, the present invention has a hypoglycemic effect and is useful as a therapeutic drug for diabetes.

[0003]

[Chemical 4]

The present invention relates to a method for producing a benzyl succinic acid derivative represented by the formula (the arrangement of carbon atoms marked with (S) shows the S arrangement) conveniently and in high yield, and an intermediate for producing the same. .

[0005]

2. Description of the Related Art As a method for synthesizing a benzylsuccinic acid derivative represented by the above formula (I), for example, JP-A-4-356 is known.
In No. 459, the general formula

[0006]

[Chemical 5]

(Wherein R is an alkyl group having 1 to 6 carbon atoms,
It is a protecting group for an aralkyl group having 7 to 10 carbon atoms or other carboxyl group, and the arrangement of carbon atoms marked with * is R
Configuration, S-configuration or a mixed configuration thereof), a phenylbutyric acid derivative or a reactive functional derivative thereof, and a formula

[0008]

[Chemical 6]

A method which can be prepared by reacting with a cyclic amine represented by and then removing a protecting group such as a lower alkyl group and an aralkyl group is shown, but only one carboxyl group is protected. The production of an intermediate represented by the general formula (II) in which a group is introduced is a method which itself has a long number of steps and a low yield, and further, an expensive catalyst is used when removing the protecting group of the carboxyl group. The contact hydrogenation has to be carried out, which is not a suitable method for industrial production.

Therefore, it is strongly desired to find a method which can produce the optically active benzylsuccinic acid derivative represented by the above formula (1) of the present invention simply and in high yield, and can be applied to industrial production. Was wanted.

[0011]

The object of the present invention is to provide a simple and high-yield production method of an optically active benzylsuccinic acid derivative having a hypoglycemic action and useful as a therapeutic agent for diabetes, and an intermediate thereof. It is to be.

[0012]

[Means for Solving the Problems] As a result of intensive studies conducted by the present inventors to solve the above problems, the general formula

[0013]

[Chemical 7]

(A in the formula is an ethylene group, a trimethylene group, an o-phenylene group or a bicyclo [2,2,1] hept-5-ene-2,3-diyl group, and a carbon having (S) attached thereto. The atom has the same meaning as above), the N-carbonyloxyimide group of the benzyl succinic acid derivative represented by the formula is hydrolyzed under extremely mild conditions to be converted into a carboxyl group, and the above formula ( It was found that the benzyl succinic acid derivative of I) can be produced.
Furthermore, a general formula that is eliminated during the hydrolysis reaction

[0015]

[Chemical 8]

Since the N-hydroxyimide derivative represented by (A in the formula has the same meaning as described above) has a property of being easily dissolved in water, a simple operation of treating the reaction solution with water is performed. The compound of formula (I) of interest can be obtained as a pure product without any special isolation procedure, and can be easily removed as it is or after it is converted into a salt to give a simple product. The present invention has been completed based on the finding that a highly pure product that can be used as a drug can be obtained only by the recrystallization step.

That is, in the production method of the present invention, the benzyl succinic acid derivative represented by the above formula (I) is obtained by hydrolyzing the benzyl succinic acid derivative represented by the above general formula (IV). Is the way.

The benzyl succinic acid derivative represented by the general formula (IV) used as a starting material in the present production method is a novel compound which has not been described in any literature, and can be produced, for example, by the following method. That is, the formula

[0019]

[Chemical 9]

Benzylsuccinic acid represented by the formula (wherein the carbon atom with (S) has the same meaning as described above) and N,
By reacting with a reactive derivative of the N-hydroxyimide derivative represented by the general formula (V) such as N′-disuccinimidyl carbonate, the general formula

[0021]

[Chemical 10]

A benzyl succinic acid derivative represented by the formula (wherein the carbon atoms with A and (S) have the same meanings as described above), and then the cyclic amine represented by the formula (III) is added thereto. It can be produced by reacting. Since the N-carbonyloxyimide group of the benzylsuccinic acid derivative represented by the general formula (VII) has high reactivity and high selectivity, the desired benzyl represented by the general formula (IV) can be obtained. A succinic acid derivative is produced. Therefore, the benzyl succinic acid derivative represented by the general formula (IV) as the starting material thus produced is
In the actual production, there is no particular need for isolation and purification, and the reaction mixture may be subjected to the next step as it is.

The present production method will be described in more detail, including the production of the starting benzylsuccinic acid derivative of the formula (IV) from the benzylsuccinic acid of the formula (VI). When the benzyl succinic acid represented by the formula (VI) is used, the benzyl succinic acid represented by the formula (VI) and the general formula (V) such as N, N′-disuccinimidyl carbonate can be used. The reactive derivative of the represented N-hydroxyimide derivative is reacted in an inert solvent, if necessary, in the presence of a basic substance, or the benzyl succinic acid represented by the above formula (VI) and the above general formula (V) Or an benzyl succinic acid represented by the above formula (VI) in the presence of a condensing agent in an inert solvent in the presence of a basic substance, if necessary. And the N-hydroxyimide derivative represented by the general formula (V) are reacted in an inert solvent in the presence of a basic substance, if necessary, to obtain the general formula (VII). A benzyl succinic acid derivative of formula (VII) is prepared, and then the benzyl succinic acid derivative of formula (VII) and an approximately equimolar amount of the cyclic amine of formula (III) are mixed with each other in an inert solvent at −30. The benzyl succinic acid derivative represented by the general formula (IV) is obtained by reacting at -40 to 40 ° C., preferably room temperature for 3 to 20 hours, preferably several hours. In the production method, the above formula (VI
The production intermediate represented by I) may be isolated and purified to be used as a production raw material in the next step, but it can be used in the next step without isolation and purification without any problem, and rather, in an actual industrial process. In production, it is preferable that the product is directly subjected to the next step because the operation is simple.

The above-mentioned general formula (I
The benzyl succinic acid derivative represented by V) is stirred with a 0.5 to 2N, preferably 1N aqueous sodium hydroxide solution without solvent or in a solvent at -30 to 40 ° C, preferably at room temperature for several hours. After that, after distilling off the solvent if necessary,
The residue is dissolved in an organic solvent and the aqueous layer is separated. By acidifying the separated aqueous layer and extracting with an organic solvent, the benzyl succinic acid derivative represented by the above formula (I) with high yield and high optical purity can be easily produced. Furthermore, if desired, the benzyl succinic acid derivative represented by the above formula (I) can be treated with an inorganic base or an organic amine to form a pharmacologically acceptable salt such as a calcium salt.

The above-mentioned general formula (I
The benzyl succinic acid derivative represented by V) may be isolated and purified to be used as a starting material for the next step, but it can be used in the next step without isolation and purification without causing any problem, and in fact In industrial production, it is preferable that the product is directly subjected to the next step because the operation is simple.

The benzyl succinic acid represented by the above formula (VI) used as the starting material in the present production method is a known compound described in the literature and can be easily obtained by a known method. [Journal of the Chemical Society Perkin Transaction I (J.
Chem. Soc. PERKIN TRANS. I) 1
989, page 1571]

As the condensing agent which can be used in the production of the benzylsuccinic acid derivative represented by the above general formula (VII) of the present production method, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, oxychloride can be used. Phosphorus, dichloromethyl methyl ether, phosgene, thionyl bromide,
Examples include halogenating agents such as oxalyl bromide, N, N′-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and other coupling reagents used in ordinary peptide synthesis. be able to.

The basic substance may be an organic tertiary base such as triethylamine, pyridine or N-methylmorpholine, and the inert solvent may be ethyl acetate, methylene chloride, acetonitrile, toluene, 1,2.
An inert organic solvent such as dichloroethane or tetrahydrofuran can be used.

In order to suitably carry out the present production method, a mixture of 4 times mol of N-hydroxysuccinimide and 4 times mol of triethylamine to benzylsuccinic acid represented by the above formula (VI) is added to -30 ° C. Then, a 2-fold molar amount of thionyl chloride is added dropwise and stirred, and then benzyl succinic acid represented by the above formula (VI) is added, and the mixture is gradually returned to room temperature and reacted at room temperature. ) A cyclic amine represented by the formula (1) is added dropwise and the reaction is carried out at room temperature. A 1N aqueous sodium hydroxide solution is added to the reaction mixture, the mixture is stirred at room temperature for several hours, an organic solvent is added, and the aqueous layer is separated. The aqueous layer is acidified with dilute hydrochloric acid to obtain the succinic acid derivative represented by the above formula (I), and if necessary, converted to a salt and recrystallized. This production method has a high yield in each step and is extremely easy to operate, and does not particularly require isolation or purification in each step.
Moreover, it is possible to obtain the target product with high optical purity.
This is a very suitable method as an industrial manufacturing method.

[0030]

EFFECTS OF THE INVENTION The production method of the present invention is capable of easily producing a benzyl succinic acid derivative represented by the above-mentioned general formula (I), which has a blood glucose lowering action and is useful as a therapeutic drug for diabetes, and has a high optical purity. The product can be produced in high yield and is extremely useful as an industrial production method.

[0031]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 Disuccinimidyl (S) -benzylsuccinate 2.1 g (10 mmol) of (S) -benzylsuccinate and 5.7 g of N, N'-disuccinimidyl carbonate
(22 mmol) was suspended in 30 ml of dry acetonitrile, 1.8 ml (22 mmol) of pyridine was added dropwise,
Stir overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in methylene chloride and washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-diethyl ether to give 3.9 g (97%) of (S) -disuccinimidyl benzylsuccinate as white crystals. Got as.

Melting point: 159 ° C. H-NMR (CDCl ₃ ) δ: 2.8 to 2.9 (9H, m), 3.04 (1H, d
d, J = 7.6, 17.4 Hz), 3.07 (1H, d
d, J = 7.4, 14.1 Hz), 3.30 (1H, d
d, J = 6.3, 14.1 Hz), 3.53 (1H,
m), 7.2-7.4 (5H, m) IR (KBr): 1812, 1791, 1738 cm ¹ MS (m / e): 403 (M + H) ⁺ , 288 Elemental analysis value (C ₁₉ H ₁₈ N _2). O ₈₎ calculated value C; 56.72 H; 4.51 N;
6.96% analytical value C; 56.40 H; 4.34 N;
6.90% [α] _D ²⁵ -1.6 ° (c = 1.0, chloroform)

Reference Example 2 (S) -Benzylsuccinic acid Bis (5-norbornene-)
2,3-dicarboxyimidyl) N-hydroxy-5
-Norbornene-2,3-dicarboximide 8.0 g
(44 mmol) was dissolved in 30 ml of dry methylene chloride, 0.2 ml (44 mmol) of triethylamine was added, and 1.62 ml (22 m of thionyl chloride was stirred under ice cooling.
(10 mol) of a dry methylene chloride solution was added dropwise. After stirring with ice cooling for 1 hour, 2.1 g (10 mmol) of (S) -benzylsuccinic acid was added, and the mixture was gradually warmed to room temperature and stirred overnight. It was washed with water and saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the obtained crystals were recrystallized from ethyl acetate-hexane,
(S) -Benzyl succinic acid bis (5-norbornene-
2,3-Dicarboxyimidyl) 4.74 g (88%)
Was obtained as white crystals.

Melting point: 220 ° C. H-NMR (CDCl ₃ ) δ: 1.55 (2H, d, J = 9.0 Hz), 1.80
(2H, dd, J = 1.3, 8.9Hz), 2.74
(1H, dd, J = 6.9, 17.4Hz), 2.96
(1H, dd, J = 7.0, 17.4Hz), 3.07
(1H, dd, J = 7.0, 14.0 Hz), 3.24
(1H, dd, J = 6.4, 14.1 Hz), 3.34
(4H, s), 3.4 to 3.5 (5H, m), 6.22
(2H, s), 6.23 (2H, s), 7.2 to 7.4
(5H, m) IR (KBr): 1828, 1817, 1780, 1
733 cm ⁻¹ MS (m / e): 531 (M + H) ⁺ elemental analysis value (as C ₂₉ H ₂₆ N ₂₈ O) calculated value C; 65.65 H; 4.94 N;
5.28% analytical value C; 65.42 H; 5.03 N;
5.21% [α] _D ²⁵ + 1.5 ° (c = 1.0, chloroform)

Example 1 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) succinimidyl (S) -benzyl disuccinimidyl succinate 402m
g (1 mmol) was dissolved in 6 ml of dry methylene chloride,
Cis-hexahydroisoindoline 125 under ice-cooled stirring
A solution of mg (1 mmol) dissolved in 1 ml of dry methylene chloride was added dropwise. After stirring overnight at room temperature, it was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 371 mg (90%) of succinimidyl (S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionate as a colorless oil.

H-NMR (CDCl ₃ ) δ: 1.3 to 1.6 (8H, m), 2.1 to 2.3 (2)
H, m), 2.42 (1H, dd, J = 6.4, 16.
3 Hz), 2.6 to 3.9 (12 H, m), 7.1 to
7.4 (5H, m) IR (neat): 1812,1783,1740,1
638,1450 cm ^-1 MS (m / e): 413 (M + H) ⁺ [α] _D ²⁵ + 4.2 ° (c = 0.65, chloroform)

Example 2 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid 5-norbornene-2,3-dicarboxyimidyl (S) -benzyl succinic acid bis (5-norbornene-
5,3-Dicarboxyimidyl 531 mg (1 mmo
l) was dissolved in 6 ml of dry methylene chloride, and 125 mg of cis-hexahydroisoindoline (1
a solution of 1 mmol of dry methylene chloride in 1 ml) was added dropwise.
After stirring overnight at room temperature, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and (S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid 5-norbornene-2,3-dicarboxyimidyl 447 mg (94%). Was obtained as a colorless oil.

H-NMR (CDCl ₃ ) δ: 1.3-1.6 (9H, m), 1.77 (1H,
d, J = 9.0 Hz), 2.1 to 2.7 (2H, m),
2.3-2.4 (1H, m), 2.5-2.7 (1H,
m), 2.9 to 3.0 (1H, m), 3.09 (1H,
dd, J = 6.3, 98 Hz), 3.1-3.5 (8
H, m), 3.60 (1H, m), 6.19 (2H,
s), 7.2-7.3 (5H, m) IR (neat): 1808, 1777, 1738, 1
642,1450 cm ⁻¹ MS (m / e) = 476 (M ⁺ ), 206 [α] _D ^{25 +} 1.1 ° (c = 1.0, chloroform)

Example 3 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) succinimidyl propionate 133 mg (0.32 mmol) was dissolved in methanol 5 ml, and 1N sodium hydroxide aqueous solution 0.5
ml was added and stirred for 3 hours. The solvent was distilled off under reduced pressure,
Ethyl acetate was added. It was extracted twice with a saturated aqueous sodium hydrogen carbonate solution and washed once with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. It was washed once with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and oily (S) -2-benzyl-3- (cis-
Hexahydro-2-isoindolinylcarbonyl) propionic acid 50 mg (49%) was obtained.

H-NMR (CDCl ₃ ) δ: 1.15 to 17 (8H, m), 2.05 to 2.3
(2H, m), 2.35 to 2.55 (2H, m), 2.
65-3.5 (7H, m), 7.1-7.4 (5H,
m) IR (neat): 1735, 1605 cm ^-1 [α] _D ²⁵ -15.4 ° (c = 5.76, chloroform).

Example 4 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid N-hydroxysuccinimide 461 mg (4.0 mm)
ol), 560 μl of triethylamine (4.0 mmo
l) is suspended in 10 ml of dry acetonitrile and -30 ° C.
Cooled to. With stirring, 146 μl of thionyl chloride (2.0 μl
mmol) was added dropwise. After 30 minutes, 208 mg (1.0 mmol) of (S) -benzylsuccinic acid was added, and the mixture was stirred overnight while gradually returning to room temperature. 140 μl (1. gmmol) of triethylamine and 162 mg (1.0 mmo) of cis-hexahydro-2-isoindoline hydrochloride under ice cooling.
1) was added, and the mixture was further stirred overnight while gradually returning to room temperature. After adding 1N aqueous sodium hydroxide solution and stirring for 4 hours, the solvent was distilled off under reduced pressure. Add ethyl acetate,
After washing once with 0.5N hydrochloric acid, the mixture was extracted twice with a 1N aqueous sodium hydroxide solution and washed once with ethyl acetate.
The aqueous layer was acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. It was washed once with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 235 mg (75%) of oily (S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid. The physical property values were in agreement with those of the sample obtained in Example 3.

Example 5 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid 5-norbornene-2,3-dicarboximidyl 50 mg
(0.1 mmol) was dissolved in 1 ml of methanol, 0.5 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added.
The mixture was extracted twice with 0.5N aqueous sodium hydroxide solution, the aqueous layer was acidified with concentrated hydrochloric acid, and then extracted twice with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 30 mg (91%) of oily (S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid. . The physical property values were in agreement with those of the sample obtained in Example 3.

Example 6 (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) calcium propionate dihydrate (S) -2-benzyl-3- (cis-hexahydro-2
-Isoindolinylcarbonyl) propionic acid 4.04
g was dissolved in 15 ml of ethanol, 6.4 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was concentrated to dryness. The residue is water 3
It was dissolved in 0 ml, and a 10 ml aqueous solution of 2.84 g of calcium chloride was added dropwise with vigorous stirring. After stirring for 1 hour, the mixture was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 50 ml of 5% hydrous ethanol and left overnight. The precipitated crystals were collected by filtration and dried to obtain 4.1 g of (S) -2-benzyl-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionate calcium dihydrate.

Melting point: 179 to 185 ° C. H-NMR (CDCl ₃ ) δ: 1.15 to 1.5 (16 H, m), 1.9 to 2.4
(6H, m), 2.55-3.1 (14H, m), 3.
2 to 3.5 (6H, m), 7.1 to 7.3 (10H,
m) IR (KBr): νCO 1660, 1625 cm ⁻¹ [α] _D ^17.5 + 5.7 ° (c = 1.0, methanol)

Claims (2)

[Claims] 1. A general formula: (A in the formula is an ethylene group, a trimethylene group, an o-phenylene group or a bicyclo [2,2,1] hept-5-ene-2,3-diyl group, and the arrangement of the carbon atom with (S) Represents the S configuration) and hydrolyzes a benzyl succinic acid derivative represented by the formula: A method for producing a benzyl succinic acid derivative represented by (the arrangement of carbon atoms with (S) in the formula indicates the S arrangement). 2. A general formula: (A in the formula is an ethylene group, a trimethylene group, an o-phenylene group or a bicyclo [2,2,1] hept-5-ene-2,3-diyl group, and the arrangement of the carbon atom with (S) Represents the S configuration), and is a benzyl succinic acid derivative.