JPH06293733A - N-cinnamoylproline derivative as new optically resolving agent and its alkali salt - Google Patents

Abstract

PURPOSE:To obtain a new optically resolving agent useful for resolving a raw material for producing a medicine, containing N-cinnamoylproline derivatives and their salt most of which are new compounds. CONSTITUTION:A new optically active resolving agent selected from N- cinnamoylproline derivatives of formula I (R<1> H or lower alkyl; R<2> is H, halogen, hydroxy, nitro, lower alkoxy, lower alkyl or phenyl which may be substituted; R<3> is hydroxy or reactive residue) or its alkali salt. Among compounds of formula I, compounds except a compound wherein R<1> and R<2> are H at the same time are all new compound. The optically resolving agent of formula I is effective for optical resolution of a racemic modification having a structure capable of possessing pi-pi mutual action on a cinnamoyl part, such as an N-substituted-3-hydroxymethyl-5-nitro-2,3-dihydroindole. The compound of formula I is obtained by reacting an (S)- or (R)-proline derivative of formula II with a cinnamoyl derivative of formula III in the presence of a base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel N-cinnamoylproline derivatives and their use for optical resolution.

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

[0003]

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

Known conventional methods for synthesizing an optically active substance include a method utilizing an optically active substance obtained from nature, an asymmetric synthesis method, an optical resolution method and the like. Among them, the optical resolution method has the advantage that the racemate can be divided evenly and both enantiomers can be obtained at one time. The optical resolution method, after forming a bond such as ester or amide between the resolving agent and the racemate or forming a salt to form a diastereomer, a recrystallization method,
There is a method of separating each diastereomer by a column chromatography method, a high performance liquid chromatography method and the like, and then removing a resolving agent to obtain an optically pure compound.

In this method, the difficulty of separation varies greatly depending on the nature of the racemic compound, and when separating diastereomers, it may be necessary to use a high performance liquid chromatography method, but in that case, much labor and time are required. Because it requires, 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, Journal of Organic Chemistry, Vol. 53, p. 695 (1988), reported separation of optically active indoline-3-methanol derivative.
Several optical resolving agents are mentioned, but in each case the separation of diastereomers is not easy.

[0008]

DISCLOSURE OF THE INVENTION The present invention is to provide a novel optical resolving agent which provides diastereomers or diastereomeric salts which can be easily separated upon optical resolution of a racemic compound.

[0009]

DISCLOSURE OF THE INVENTION The present inventors have faced a racemic compound which cannot be resolved by a conventional optical resolving agent in the optical resolution of a raw material for producing pharmaceutical products, and provide a diastereomer or a diastereomer salt which can be easily separated. As a result of earnest research on the development of a novel optical resolving agent, the general formula (1)

[0010]

[Chemical 3]

(Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a halogen atom, a hydroxy group,
The N-cinnamoylproline derivative represented by a nitro group, a lower alkoxy group, a lower alkyl group or an optionally substituted phenyl group, R ³ represents a hydroxy group or a reactive residue, and an alkali salt thereof. The present invention has been completed by finding a solution to the above.

The lower alkyl group or lower alkoxy group is a linear or branched alkyl group or alkoxy group having 1 to 4 carbon atoms, and the optionally substituted phenyl group is 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 or barium salt. .

The compound of the present invention is a useful optical resolving agent which gives a diastereomer or a diastereomer salt which can be easily separated by binding to or addition to various racemic compounds.

Among the compounds of the present invention, compounds 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 Perkintrans I pp. 759 (1986).
However, its usefulness as an optical resolving agent is not mentioned.

The usefulness of the compound of the present invention as an optical resolving agent is mainly exerted by the function of the cinnamoyl moiety. That is, a pi-pi (π-π) interaction with one enantiomer of a racemic compound, in which a cinnamoyl moiety having a fixed conformation is divided by a proline nucleus, causes a pi-pi (π-π) interaction. The shape and solubility of the whole molecule are greatly different from the other enantiomer that does not act, and the properties of the diastereomer or diastereomeric salt are completely different, resulting in easy separation. By having such a special function, the compound of the present invention exerts its ability as an efficient optical resolving agent.

From the 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 heterocycle, 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 can be mentioned.

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

[0018]

[Chemical 4]

(Wherein X represents a reactive residue, R ¹ ,
R ² and R ³ are the same as above. That is, the (S) or (R) -proline derivative and the cinnamoyl derivative are combined with an appropriate base (for example, an alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide). Salt, alkaline earth metal carbonates such as sodium hydrogen carbonate and potassium carbonate, or tertiary amines such as triethylamine, diisopropylethylamine and pyridine) in the presence of water or water and a suitable organic solvent at -20 ° C to 50 ° C.
It can be synthesized by reacting with.

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). The diastereomeric salt 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. Any can be used as long as it does not participate in the reaction. The diastereomers and diastereomeric salts thus obtained can be purified and separated by usual organic chemistry techniques (eg extraction, recrystallization, distillation, column chromatography, high performance liquid column chromatography, etc.). You can According to this method, the physical properties of the diastereomers differ so that the obtained diastereomers can be easily separated by column chromatography even if they are oily substances.

Further, the compound of the present invention has one asymmetric carbon atom, but naturally, in the present invention, it includes both the R configuration and the S configuration.

[0022]

EXAMPLES The usefulness of the compounds of the present invention is shown below, but the present invention is not limited to these examples.

Example 1 5-Benzyloxy-3- (t-butoxycarbonyl)
-1-hydroxymethyl-7,8-dioxo-1,2,
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) are dissolved in tetrahydrofuran (6 ml), dimethylaminopyridine (7.6 mg, 0.062 mmol) is added under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Stirred for an additional 1.5 hours. The solvent was evaporated, ethyl acetate was added to the obtained residue, the insoluble material was filtered off, and then ethyl acetate was evaporated. The obtained 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,
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 to 4.12 (2H, m), 4.30 to
4.42 (1H, m), 4.45-4.52 (2H,
m), 4.99 to 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) body 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 to 4.13 (1H, m), 4.46 to
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 attached and separation by thin layer chromatography was tried using various developing solvents, but gave separable diastereomers in all cases. There wasn't.

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,
(-)-Camphoric chloride In addition, all amino acid-based resolving agents used (L) -amino acid.

Claims (2)

[Claims] 1. A compound represented by the general formula (1): (In the formula, 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 an optionally substituted phenyl group, R ³ Is a hydroxy group or a reactive residue) and is an optical resolving agent consisting of an N-cinnamoylproline derivative or an alkali salt thereof. 2. A general formula (2): (In the formula, 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 an optionally substituted phenyl group, R ³ Represents a hydroxy group or a reactive residue, but R ¹ and R ² are not hydrogen atoms at the same time), and an alkali salt thereof.