JP3181671B2 - New optical resolution agent N-cinnamoyl proline derivative and alkali salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel N-cinnamoyl proline derivatives and their use for optical resolution.

The compound of the present invention is useful as an optical resolving agent capable of forming an ester, an amide, or a salt with a pharmaceutical, an agricultural chemical or a synthetic intermediate thereof to easily convert them into an optically active substance.

[0003]

2. Description of the Related Art In recent years, many pharmaceuticals and agricultural chemicals have a compound containing an asymmetric carbon in their structure, and each optically active substance may have different effects such as medicinal properties, toxicity and metabolism in a living body. It is required to separate the optically active substance.

As a conventional method for synthesizing an optically active substance, a method utilizing an optically active substance obtained from nature, an asymmetric synthesis method, an optical resolution method and the like are known. Among them, the optical resolution method has the advantage that the racemate can be evenly split and both enantiomers can be obtained at once, so it is an important methodology even in the present age when the asymmetric synthesis method has been developed. The optical resolution method includes forming a bond such as an ester or an amide between the resolving agent and the racemic compound or forming a salt to form a diastereomer, followed by a recrystallization method,
There is a method in which each diastereomer is separated by column chromatography, high performance liquid chromatography, or the like, and then the resolving agent is removed to obtain an optically pure compound.

[0005] In this method, the difficulty of separation varies greatly depending on the nature of the racemic compound, and high-performance liquid chromatography must be used to separate diastereomers. In this case, much labor and time are required. Cost performance is poor. Furthermore, many compounds are difficult to separate even by using high performance liquid chromatography.

For example, 5-benzyloxy-3- (t-butoxycarbonyl) -1-hydroxymethyl-7,8-
In the optical resolution of dioxo-1,2,3,6,7,8-hexahydropyrrolo [3,2-e] indole, N-tosylproline and N- (1 -Or 2-naphthalene) sulfonylproline, N- (substituted benzyloxy) carbonylproline and the like were ineffective.

Further, separation of an optically active form of an indoline-3-methanol derivative was reported in Journal of Organic Chemistry 53, 695 (1988),
Several optical resolving agents are mentioned, but in each case, separation of diastereomers is not easy.

[0008]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel optical resolving agent which gives a diastereomer or a diastereomer salt which can be easily separated upon optical resolution of a racemic compound.

[0009]

Means for Solving the Problems The present inventors have faced a racemate which cannot be resolved with a conventional optical resolving agent in the optical resolution of a raw material for producing a pharmaceutical, and have provided a novel diastereomer or diastereomer salt which can be easily separated. After extensive research into the development of a new optical resolving agent, the general formula (1)

[0010]

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(Wherein, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a halogen atom, a hydroxy group,
A nitro group, a lower alkoxy group, a lower alkyl group or a phenyl group which may be substituted, and R ³ represents a hydroxy group ), and an N-cinnamoylproline derivative represented by the formula: We found a solution and completed the present invention.

The term "lower alkyl group or lower alkoxy group" used herein means a linear or branched alkyl group or alkoxy group having 1 to 4 carbon atoms, and the optionally substituted phenyl group means a halogen atom, a hydroxy group, A phenyl group which may be substituted with a nitro group, an alkyl group, or an alkoxy group; and an alkali salt means an alkali metal or alkaline earth metal salt such as sodium, potassium, magnesium, calcium, barium and the like. .

The compounds of the present invention are useful optical resolving agents which give diastereomers or diastereomeric salts which can be easily separated by bonding or adding various racemic compounds.

Among the compounds of the present invention, those in which R ¹ and R ² are simultaneously a hydrogen atom and R ³ is a hydroxy group are known compounds (Journal of Chemical Society, Parkin Trans I, p. 759 (1986)).
Year)), but its usefulness as an optical resolving agent is not described.

The usefulness of the compound of the present invention as an optical resolving agent is mainly exhibited by the function of the cinnamoyl moiety. That is, a pi-pi (π-π) interaction is caused by a pi-pi (π-π) interaction with one enantiomer of a racemic compound in which the cinnamoyl portion having a fixed conformation is separated by a proline nucleus. Since the shape and solubility of the whole molecule are largely different from those of the other enantiomer that does not act, and the properties as diastereomers or diastereomeric salts are completely different, separation can be easily performed as a result. By having such a special function, the compound of the present invention exhibits the ability as an efficient optical resolving agent.

As described above, the compound of the present invention is particularly effective for optical resolution of a racemic body having a structure capable of pi-pi (π-π) interaction with a cinnamoyl moiety. The interaction with the cinnamoyl moiety may be anything having a pi (π) electron, such as an aromatic ring, a hetero ring, a nitro group,
Examples thereof include ketones, carboxylic acid derivatives, olefins, and acetylene. Specific examples thereof include N-substituted-3-hydroxymethyl-5-nitro-2,3-dihydroindole and N-substituted-5-benzyloxy-1. -Hydroxymethyl-8-methyl-1,2-dihydro-3H-pyrrolo [3,2-e] indole, 2- (1-naphthyl) -1
-Propanol, 2- (1-naphthyl) -1-propylamine, phenylalaninol and the like.

The compound of the present invention can be prepared by a known method (Journal
Of Chemical Society Parkin Trance I
759 (1986)).

[0018]

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(Wherein X represents a reactive residue; R ¹ ,
R ² and R ³ are the same as described above. That is, the (S) or (R) -proline derivative and the cinnamoyl derivative are converted to a suitable base (for example, an alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.). Salts, alkaline earth metal carbonates such as sodium bicarbonate and potassium carbonate, or tertiary amines such as triethylamine, diisopropylethylamine, pyridine and the like) in water or water and a suitable organic solvent at -20 ° C to 50 ° C.
Can be synthesized.

The diastereomer of the compound of the present invention and the racemic compound to be optically resolved can be synthesized according to a known method (for example, Nobuo Izumiya, Peptide Synthesis p117-153, Maruzen). Diastereomeric salts can be synthesized by stirring the compound of the present invention and the racemic compound to be optically resolved in a suitable organic solvent, water or a mixture of an organic solvent and water at −20 ° C. to 50 ° C. Can be used as long as it does not participate in the reaction. The diastereomers and diastereomeric salts thus obtained are purified and separated by ordinary organic chemistry techniques (eg, extraction, recrystallization, distillation, column chromatography, high performance liquid column chromatography, etc.). Can be. According to this method, the physical properties between diastereomers are so different that the obtained diastereomers can be easily separated by column chromatography even if they are oily substances.

Although the compound of the present invention has one asymmetric carbon, the present invention naturally includes both the R configuration and the S configuration.

[0022]

The following examples show the usefulness of the compounds of the present invention, but the present invention is not limited to these examples.

Example 1 5-benzyloxy-3- (t-butoxycarbonyl)
-1-hydroxymethyl-7,8-dioxo-1,2,2
3,6,7,8-hexahydropyrrolo [3,2-e] indole (263.2 mg, 0.62 mmol),
(S) -N-cinnamoylproline (167.3 m,
0.682 mmol) and dicyclohexylcarbodiimide (140.7 mg, 0.682 mmol) were dissolved in tetrahydrofuran (6 ml), dimethylaminopyridine (7.6 mg, 0.062 mmol) was added under ice-cooling, and the mixture was stirred for 30 minutes, and then stirred at room temperature. And further stirred for 1.5 hours. The solvent was distilled off, ethyl acetate was added to the obtained residue, and the insoluble matter was removed by filtration. Then, ethyl acetate was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: benzene: acetonitrile = 3: 1) to give purple crystals of 5-benzyloxy-3- (t-butoxycarbonyl)-(1S)-((2 ′S ) -1′-Cinnamoylprolyloxy) methyl-7,8-dioxo-1,2,2
3,6,7,8-Hexahydropyrrolo [3,2-e] indole (152 mg) and 5-benzyloxy-3-
(T-butoxycarbonyl)-(1R)-((2 ′S)
-1'-cinnamoylprolyloxy) methyl-7,8
-Dioxo-1,2,3,6,7,8-hexahydropyrrolo [3,2-e] indole (119 mg) was obtained.

NMR (δ in CDCl ₃ ) (1S, 2 ′S) form 1.55 (9H, s), 1.94 to 2.28 (4H,
m) 3.52 to 3.72 (1H, m), 3.72 to
3.81 (1H, m), 3.84 to 3.95 (1H,
m), 3.96-4.12 (2H, m), 4.30-
4.42 (1H, m), 4.45 to 4.52 (2H,
m), 4.99-5.12 (2H, m), 6.67 (1
H, d, J = 15.6 Hz), 7.31 to 7.62 (1
1H, m), 7.67 (1H, d, J = 15.6H)
z), 7.97 (1H, s) (1R, 2'S) form 1.56 (9H, s), 1.83 to 2.30 (4H,
m), 3.56 to 3.70 (1H, m), 3.72 to
3.81 (1H, m), 3.83 to 3.94 (1H,
m), 3.98 (1H, dd, J = 4.4, 11.7H)
z) 4.03-4.13 (1H, m), 4.46-
4.52 (3H, m), 5.09 (2H, s), 6.6
7 (1H, d, J = 15.6 Hz), 7.30 to 7.6
2 (11H, m), 7.66 (1H, d, J = 15.6)
Hz), 7.99 (1H, s).

Comparative Example 1 In the same manner as in Example 1, the following optical resolving agent and 5-benzyloxy-3- (t-butoxycarbonyl) -1- were used.
Hydroxymethyl-7, -8-dioxo-1,2,3
6,7,8-Hexahydropyrrolo [3,2-e] indole was coupled, and separation by thin layer chromatography was attempted using various developing solvents, but gave a diastereomer which can be separated in all cases. Did not.

N-tosylproline, N-methanesulfonylproline, N- (2-naphthylsulfonyl) proline, N- (t-butoxycarbonyl) proline, N-benzyloxycarbonylproline, N- (p-methoxybenzyloxycarbonyl) ) Proline, N- (p-nitrobenzyloxycarbonyl) proline, N- (2,
2,2-trichloroethoxycarbonyl) proline, N
-(9-fluorenylmethyloxycarbonylproline, N- (1-naphthylcarbonyl) proline, N-
(2-naphthylcarbonyl) proline, N-tosylphenylalanine, N-methanesulfonylphenylalanine, N- (2-naphthylsulfonyl) phenylalanine, N- (t-butoxycarbonyl) phenylalanine, N-benzyloxycarbonylphenylalanine,
N- (9-fluorenylmethyloxycarbonyl) phenylalanine, S-(+)-O-acetylmandelic acid,
(-)-Camphanic chloride All amino acid-based resolving agents used (L) -amino acid.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 207/16 C07B 57/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) (Wherein, the R ¹ is a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a halogen atom, hydroxy group, a nitro group, a lower alkoxy group, a lower alkyl group or an optionally substituted phenyl group, R ³ N- cinnamoyl proline derivative or an optical resolution agent comprising an alkali salt thereof represented by represents a hydroxy group). 2. A compound of the general formula (2) (Wherein, the R ¹ is a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a halogen atom, hydroxy group, a nitro group, a lower alkoxy group, a lower alkyl group or an optionally substituted phenyl group, R ³ Represents a hydroxy group, but R ¹
And R ² are not hydrogen atoms at the same time) and N-cinnamoyl proline derivatives and alkali salts thereof.