JP3426640B2 - Bicycloheptane derivative and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL APPLICABILITY The present invention is useful as an intermediate of a drug having a thromboxane A2 receptor antagonistic action (1
S, 2R, 3S, 4R) or (1R, 2S, 3R, 4
S) 3-Aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid and salts thereof, and a process for producing them.

[0002]

2. Description of the Related Art (1S, 2R,
3S, 4R) or (1R, 2S, 3R, 4S) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-
En-2-carboxylic acid and its salts are novel compounds.

[0003]

The (1S, 2R, 3S, 4R) 3-aminocarbonyl-prepared by the present invention.
Bicyclo [2,2,1] hept-5-ene-2-carboxylic acid and its salts are intermediates of the thromboxane A2 receptor antagonist S-1452 (1R, 2S, 3S,
4S) 3-phenylsulfonylamino-bicyclo [2,2
It is a novel compound useful as a raw material for producing 2,1] heptane-2-carboxylic acid.

Conventionally known (1R, 2S, 3S, 4
S) 3-Phenylsulfonylamino-bicyclo [2,2
As a method for producing 2,1] heptane-2-carboxylic acid, norbornene dicarboxylic acid anhydride is subjected to asymmetric esterification using a lithium alcoholate of (R) benzyl mandelate, followed by hydrogenation, isomerization, The following method is known in which amidation, hydrolysis, and Hoffmann decomposition are performed, and then sulfonamide is formed with phenylsulfonyl chloride.

(J. Org. Chem. 56, 212
2, 1991)

[0006]

[Chemical 1] However, this method uses the expensive lithium alcoholate of benzyl (R) mandelate in the first step,
There is a problem that the basic unit becomes large.

[0007]

Means for Solving the Problems As a result of repeated research to solve such problems, the present inventors have found that (1R, 2S, 3
(1S, 2R, 3S, 4R) 3-Aminocarbonyl-bicyclo [2,2,2,2S, 4S) 3-phenylsulfonylamino-bicyclo [2,2,1] heptane-2-carboxylic acid 1] hept-5-ene-2
It has been found that -carboxylic acids are obtained by optical resolution of the corresponding racemate with (-) ethylbenzylamine as the resolving agent.

Produced according to the invention (1S, 2R, 3
S, 4R) 3-Aminocarbonyl-bicyclo [2,2,2
1] Hept-5-ene-2-carboxylic acid is, for example, as shown below, subjected to Hofmann decomposition, phenylsulfonylation, esterification, isomerization, hydrogenation, and then ester hydrolysis to give a high yield ( 1R, 2S, 3S, 4S) 3
-Phenylsulfonylamino-bicyclo [2,2,1]
It can lead to heptane-2-carboxylic acid.

[0009]

[Chemical 2] Next, embodiments of the present invention will be described in detail.

The compound of the present invention (1S, 2R, 3
S, 4R) 3-Aminocarbonyl-bicyclo [2,2,2
1] Hept-5-ene-2-carboxylic acid and its salts are the corresponding racemic (endo, endo) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-.
It can be produced by allowing an optically active ethylbenzylamine to act on a carboxylic acid or a salt thereof and performing optical resolution. Racemic (endo, endo) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-
2-Carboxylic acid or a salt thereof can be produced by reacting norbornene dicarboxylic acid anhydride, which is a known substance, with aqueous ammonia and, if desired, acidifying it or, if desired, making it basic with an alkali metal hydroxide. it can.

Ethylbenzylamine, which is an optical resolving agent, is a 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid or its salt when the (-) form is used. (1S, 2R, 3S, 4R) body is obtained, and when (+) body is used, (1R, 2S, 3R,
4S) body is obtained.

Optically active ethylbenzylamine and (endo, endo) 3-aminocarbonyl-bicyclo [2,2]
The molar ratio of 2,1] hept-5-ene-2-carboxylic acid or its salt is not particularly limited, but it is preferable to use 0.4 to 1 equivalent for efficient and high-purity resolution.

Examples of the solvent used for the purpose of the present invention include lower alcohols such as methanol and ethanol, lower ketones such as acetone and methyl ethyl ketone, and water, but a particularly preferable solvent is water. is there. The amount of the solvent used varies depending on the type of the solvent, the melting temperature and the crystallization temperature and cannot be unambiguously specified, but it is usually in the range of 300 to 3000 ml with respect to 1 mol of the optically active ethylbenzylamine used. Used in. The crystallization temperature also depends on the type of solvent used, the amount of solvent used, and the dissolution temperature, but from an economical standpoint, it is usually -2.
It is selected from the range of 0 to 50 ° C.

The present invention is implemented by the following method, for example.

When a racemic (endo, endo) ammonium salt of 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid is used as a raw material, it is added to water. Dissolve, 0.4 to 1 equivalent
Add optically active ethylbenzylamine and its equivalent amount of mineral acid. (The optically active ethylbenzylamine mineral acid salt may be prepared and used in advance.) After raising the temperature to a suitable temperature to dissolve the whole amount, cooling is performed to achieve supersaturation, preferably seed crystals. Inoculate a small amount of
(, R, 2S, 4R) 3-Aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid (-) ethylbenzylamine salt, or (1R, 2S,
3R, 4S) 3-aminocarbonyl-bicyclo [2,2
The (+) ethylbenzylamine salt of 2,1] hept-5-ene-2-carboxylic acid is precipitated and separated. The corresponding carboxylic acid is obtained by acidifying the obtained ethylbenzylamine salt with hydrochloric acid, sulfuric acid or the like. Further, by alkalizing with sodium hydroxide, potassium hydroxide or the like, the corresponding alkali metal salt of carboxylic acid can be obtained.

[0016]

EXAMPLES The present invention will be specifically described below with reference to examples. Example 1 7.92 g (40 mmol) of (amino, endo) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylate ammonium was dissolved in water and diluted to a total volume of 100 ml. did.

This is heated to 45 ° C. and 20 ml of 2M hydrochloric acid is added to it.
And (-) ethylbenzylamine (5.40 g, 40 mmol) were mixed and added as a salt. It is cooled to 25 ° C. and filtered to give (1S, 2R, 3S, 4R) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-
White crystals of (-) ethylbenzylamine salt of carboxylic acid
4.46 g was obtained.

[Α] _D = -9.3 °, [α] ₄₃₅ = -2
1.6 ° (c 0.5, methanol) IR spectrum: 34
^{22cm -1, 1654cm -1, 1534cm -1} , 702cm -1 with 1M sodium hydroxide 32ml was added to the salt 3.36 g (10.6 mmol), was dissolved with stirring. The released (−) ethylbenzylamine was extracted and removed with ether, and (1S, 2R, 3
S, 4R) 3-Aminocarbonyl-bicyclo [2,2,2
1] An aqueous solution of sodium hept-5-ene-2-carboxylate was obtained. Reference Example (1S, 2R, 3S, 4R) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-obtained in Example 1
The aqueous solution of sodium ene-2-carboxylate was cooled to 0 ° C., 7.5 ml of 1.5 M sodium hypochlorite was added, and
The mixture was stirred at 8 ° C for 8 minutes, then heated to 80 to 85 ° C and stirred for 8 minutes.

Next, this solution was cooled to 0 ° C., 1.87 g (10.6 mmol) of benzenesulfonyl chloride and 1.3 ml of dioxane were added, and the mixture was stirred for 2 hours. After the reaction was completed, the solution was acidified with Congo red with concentrated hydrochloric acid and extracted with dichloromethane,
After drying over anhydrous sodium sulfate, the solvent was distilled off to give (1S, 2R, 3S, 4R) 3-phenylsulfonylamino-bicyclo [2,2,1] hept-5-ene-2.
-2.25 g (8.7 mmol) of carboxylic acid was obtained.

[Α] _D = + 9.2 ° (c 0.5, methanol) The obtained (1S, 2R, 3S, 4S) 3-phenylsulfonylamino-bicyclo [2,2,1] hept-5-ene- 2.19 g (7.5 mmol) of 2-carboxylic acid in dry methanol
15 ml and 0.38 g of phosphorus oxychloride were added, and the mixture was heated under reflux for 3 hours.

After completion of the reaction, methanol was distilled off under reduced pressure, 15 ml of water was added, and the mixture was filtered (1S, 2R, 3S, 4).
R) 3-phenylsulfonylamino-bicyclo [2,2
Methyl 2,1] hept-5-ene-2-carboxylate 2.0
8 g (6.8 mmol) was obtained.

[Α] _D = -18.3 ° (c 0.5, methanol), e. e. 88% (HPLC) melting point 112-11
6 ° C. This was recrystallized with 11 ml of methanol to give optically nearly pure (1S, 2R, 3S, 4R) 3-phenylsulfonylamino-bicyclo [2,2,1] hept-5-ene-2-
1.36 g (4.4 mmol) of methyl carboxylate was obtained.

[Α] _D = -20.5 ° (c 0.5, methanol), e. e. > 99% (HPLC) melting point 121-1
22 ° C. The obtained (1S, 2R, 3S, 4R) 3-phenylsulfonylamino-bicyclo [2,2,1] hept-5-ene-2-carboxylate methyl ester 614 mg was dried with methanol 100 m.
1 and 460 mg of metallic sodium were added to the sodium methylate solution, and the mixture was stirred at room temperature for 24 hours.

After methanol was distilled off under reduced pressure, Congo red was acidified with 3M hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off (1
There was obtained 580 mg (1.9 mmol) of methyl S, 2S, 3S, 4R) 3-phenylsulfonylamino-bicyclo [2,2,1] hept-5-ene-2-carboxylate.

2S / 2R ratio by HPLC analysis is 90/10
Met.

Next, this was dissolved in 6 ml of methanol and Pd
/ C 50 mg was added, and hydrogen was reduced at room temperature and atmospheric pressure. After completion of the reaction, the mixture was filtered to remove methanol from the mother liquor, and then 2
Recrystallized with propanol (1R, 2S, 3
Obtained methyl S, 4S) 3-phenylsulfonylamino-bicyclo [2,2,1] heptane-2-carboxylate.

[Α] _D = + 16.4 °, [α] ₄₃₅ = +
27.1 ° (c 0.5, methanol) 2S / 2R = 100/0, e. e. 100% Obtained (1R, 2S, 3S, 4S) 3-phenylsulfonylamino-bicyclo [2,2,1] heptane-2-
Methyl carboxylate was hydrolyzed with an aqueous solution of sodium hydroxide to obtain a known compound (J. Org. Chem. 56, 21.
22, 1991) (1R, 2S, 3S, 4S) 3-phenylsulfonylamino-bicyclo [2,2,1] heptane-2-carboxylic acid.

[Α] _D = + 7.7 ° (c 0.2, methanol)

[0029]

INDUSTRIAL APPLICABILITY The present invention is useful as an intermediate of a drug having a thromboxane A2 receptor antagonistic action (1S, 2
R, 3S, 4R) or (1R, 2S, 3R, 4S) 3
-Aminocarbonyl-bicyclo [2,2,1] hept-
Provided are 5-ene-2-carboxylic acid and salts thereof, and a method for producing them.

Claims (2)

(57) [Claims] 1. (1S, 2R, 3S, 4R) or (1
R, 2S, 3R, 4S) 3-Aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid and salts thereof. 2. The reaction of racemic (endo, endo) 3-aminocarbonyl-bicyclo [2,2,1] hept-5-ene-2-carboxylic acid or a salt thereof with an optically active ethylbenzylamine. (1S, 2
R, 3S, 4R) or (1R, 2S, 3R, 4S) 3
-Aminocarbonyl-bicyclo [2,2,1] hept-
A method for producing 5-ene-2-carboxylic acid or a salt thereof.