JPH0633265B2 - Method for producing teribarin - Google Patents

Description

TECHNICAL FIELD The present invention relates to pyrrolo-1,4-benzodiazepine compounds having various pharmacological activities such as antitumor and antibacterial properties. Formula (III), which is of particular interest due to its structural features in that it contains an indole ring at the 11-position The present invention relates to a novel method for producing tiliberin.

(Prior art and its problems) Regarding the method for chemically producing tirivaline,
N, Mohr and H. Budzikiewicz's method, (Tetrahedron, 38 ,
147 (1982)) is only known. In this production method, N-benzyloxycarbonyl-L-proline was first converted into acid chloride and then reacted with indole's Gunier reagent in ether to give 3- (N-benzyloxycarbonyl-L).
-Prolyl) indole is catalytically reduced to produce 3-L-prolylindole. This 3-L-prolylindole is condensed with 3-methoxy-2-nitrobenzoic acid in tetrahydrofuran in the presence of a condensing agent (carbonyldiimidazole) to give 3- [N- (3-methoxy-2).
This is a method of producing -nitro) benzoyl] L-prolylindole, and then subjecting the compound to catalytic reduction condensation in ethanol in the presence of a palladium carbon catalyst to give tirivaline.

However, this method requires the use of Indole's Grignard reagent to introduce the indole ring,
Moreover, the condensation yield of N-benzyloxycarbonyl-L-proline with the acid chloride is as low as 53%. Moreover, the condensation reaction between the acid chloride of N-benzyloxycarbonyl-L-proline and the Grignard reagent of indole has a drawback that the racemization reaction of the proline nucleus is accompanied to a large extent. Furthermore, in the final step, the step of producing tirivaline from 3- [N- (3-methoxy-2-nitro) benzoyl] -L-prolineindole is poor in stereoselectivity and the following two types of stereotypes (A) and (B) are used. The isomers are produced at the same rate (the production ratio is (A) :( B) = 48: 5).
2) Therefore, the separation of the two must be complicated.

(Means for Solving Problems) The present inventors have diligently studied a method for chemically producing tirivaline, which is capable of stereoselectively introducing an indole ring without racemization in the production process. . As a result, by using N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal as a raw material, N- (2 -Amino-3-hydroxybenzoyl) -L-prolinal can be directly reacted with indole to produce tirivaline in a single step and in a good yield, and the reaction proceeds extremely stereoselectively and has the structure (A). Have been found to produce almost selectively, and have completed the present invention.

That is, the present invention has the formula (I) (In the formula, R ₁ and R ₂ each independently represent a lower alkyl group or an aralkyl group), and N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal in an organic solvent, Formula (II) (Wherein R ₃ , R ₄ and R ₅ are each independently an alkyl group or an aralkyl group, and X is a halogen atom), and then treated in the presence of a Lewis acid. Formula (III) characterized by reacting with indole It is a method for producing tiliberin represented by.

The present invention uses, as a raw material, N- (2-amino-3-) of the formula (I).
Hydroxybenzoyl) -L-prolinal acetal is used. This raw material is a compound that can be produced relatively easily by the method shown below. One method is to obtain L-prolinal acetal or its hydrochloride obtained by acetalizing N-benzyloxycarbonyl-L-prolinal or N-tertiary butoxycarbonyl-L-prolinal and then catalytically reducing or acid-contacting them. Formula (IV) below Is a method of reacting with 2-amino-3-hydroxybenzoic acid represented by and in the presence of a condensing agent.

Alternatively, the formula (V) 2-nitro-3-hydroxybenzoic acid represented by
After condensing with proline methyl ester to give N- (2-nitro-3-hydroxybenzoyl) -L-proline methyl ester, the ester group is further converted into an acetal form via a methylol group and then an aldehyde group, It can be produced by reducing the nitro group.

The method of the present invention is carried out in an organic solvent. The organic solvent used is not particularly limited as long as it is inert to the reaction of the present invention. Specifically, the following solvents can be used. Hydrocarbon or halogenated hydrocarbon solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, chlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane or tetrachloroethane, ester solvents such as ethyl acetate or butyl acetate. , An ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, or a glycol solvent such as ethylene glycol dimethyl ether, nitromethane, nitropropane, acetonitrile, formamide, acetamide, N, N-dimethylformamide,
N, N-dimethylacetamide, pyridine, picoline,
Nitrogen-containing solvent such as quinoline, N-methylpyrrolidone or N, N-dimethylimidazolidinone, or ion-containing or phosphorus-containing solvent such as carbon disulfide, dimethyl sulfoxide, phosphoric acid triester or hexamethylphosphoramide Is mentioned. Of course, the solvents that can be used are not limited to those listed here. These solvents may be used alone or in combination of two or more kinds.

The silylating agent represented by the formula (II) has an alkyl group having a carbon number of 8 or less, or an aralkyl group represented by a benzyl group or a combination thereof, and a chlorine atom or a bromine atom as a halogen atom. Are commonly used. Of these, trimethylsilyl chloride, which is easily available and relatively inexpensive, is often used. The amount of these silylating agents to be used is 0.8 equivalent or more, preferably 1 equivalent or more based on N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal. The upper limit is not particularly limited, but it is industrially preferable to use 10 equivalents or less.

Specific embodiments of treating N- (2-amino-3-vitroxybenzoyl) -L-prolinal acetal of formula (I) with a silylating agent of formula (II) include, for example, N- (2-amino- A silylating agent is added to a solution of 3-hydroxybenzoyl) -L-prolinal acetal dissolved in an organic solvent, and -70 ° C to 100 ° C, preferably -50 to 80 ° C.
It is achieved by treating at a temperature of. At this time, triethylamine, pyridine, as a hydrogen halide scavenger,
The reaction is promoted if the reaction is carried out in the presence of a tertiary amine represented by picoline or N, N-dimethylaniline. It is also possible to further accelerate the reaction by adding an alkali metal or alkaline earth metal such as sodium bromide, potassium bromide, sodium iodide, or potassium iodide.

Although the treatment time with the silylating agent is not limited, it is usually completed in a short time, and it is sufficient to perform the treatment within a range of 10 minutes to 5 hours.

In the process of the present invention, tirivaline is produced by treating N- (2-amino-3-hydroxyquinobenzoyl) -L-prolinal acetal with a silylating agent and then reacting with indole in the presence of Lewis acid. . Specifically, indole and Lewis acid are added to the reaction solution obtained by treating N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal with a silylating agent for reaction, or indole and Lewis acid are added. For example, a silylating agent treatment solution may be added to a solution that is dissolved or suspended to react, or a silylating agent treatment solution may be added to a solution in which indole is dissolved, and a Lewis acid may be added to react. Various methods can be adopted.

In this reaction, the amount of indole used is more than the theoretical amount with respect to N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal. Of course, even if the amount used is less than the theoretical amount, tirivaline is produced, but naturally the yield is lowered, so industrially it is better to use more than the theoretical amount. The upper limit of the amount used is not particularly limited, but in the method of adding the indole to the silylation treatment liquid at 5 equivalents or less, the indole may remain solid.
It may be dissolved in an organic solvent and added as a solution.

Various Lewis acids can be used. For example, zinc chloride, aluminum chloride, aluminum bromide, stannic chloride, titanium tetrachloride or boron trifluoride. Of course, it is not limited to these. The Lewis acid is usually used alone, but there is no problem even if two or more kinds are used in combination.

When the Lewis acid is used in a small amount, its effect is small, and it is difficult to obtain the desired tiliberin in a high yield. Also, if it is used in an excessive amount, not only the post-treatment after the reaction becomes complicated but also the cost is disadvantageous. I have no choice but to. Therefore, the amount used is 0.1 to 1 relative to N- (2-amino-3-hydroxybenzoyl) -L-prolinal acetal.
The range is 0 mol, preferably 0.2 to 5 mol.

The reaction temperature is −20 in terms of reaction rate and suppression of side reactions.
-100 ° C, preferably 0-80 ° C. The reaction time is arbitrarily selected according to the reaction temperature.

Tilivaline can be obtained in good yield as described above.

Tilivaline obtained by the method of the present invention can be isolated using a means such as column chromatography after removing inorganic substances by an appropriate method.

(Action and Effect) The method of the present invention is a novel production method which has not been known at all in the past. (1) Indole can be directly used as a reaction raw material without being chemically modified. The structure of the above-mentioned structure (A) is selectively produced in a good yield. (3) Production process of-(2-amino-3-hydroxybenzoyl) -L-prolinal acetal as a raw material and the present invention Tilibarin can be produced without racemization of proline nucleus through the production process of (4) It is a production method having various characteristics such as no need for using a special reagent and simple reaction operation.

(Examples) Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples.

Reference Example N- (2-amino-3-hydroxybenzoyl) -L-
Synthesis of prolinal dimethyl acetal 270 mg (1.1 mM) of N-tertiary butoxycarbonyl-L-prolinal dimethyl acetal was added with 2 m of 10% hydrogen chloride-methanol, reacted at room temperature for 30 minutes with stirring, and subsequently obtained by concentration under reduced pressure. L-prolinal dimethyl acetal hydrochloride was added to tetrahydrofuran 8 m.
Dissolve in. Triethylamine 0.17m
Add (1.2 mM) Molecular Sieves 4A and slowly stir for 15 minutes. To this, 153 mg (1 mM) of 2-amino-3-hydroxybenzoic acid was added, and then diethylphosphate cyanide 179 was added at -22 ° C under cooling in an ice-methanol bath.
A tetrahydrofuran (2m) solution containing mg (1.1mM) was added, and the mixture was reacted with stirring at -22 ° C to 19 ° C for 1 hour at room temperature for 1 hour. Subsequently, 1 m of a tetrahydrofuran solution containing 82 mg of diethyl cyanide cyanide was added, and after reacting for 1 hour, 0.08 m (0.6 mM) of triethylamine was added and the reaction was carried out with stirring overnight. Benzene-ethyl acetate (1: 2) 150m
And filter the molecular sieves. The filtrate is washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure to give 349 mg of a crude product. This was purified by silica gel column chromatography using a mixed solution of chloroform-methanol-benzene (15: 1: 3) to give 138 mg of N- (2-amino-3-hydroxybenzoyl) -L-prolinal dimethyl acetal (yield 49 %) Obtained as a pale yellow viscous oil.

Infrared absorption spectrum (cm ^-1 ): 3450, 3360, 3180, 2950, 1620 NMR spectrum (solvent CDCl ₃ δ) 1.52-2.32 (4H, multiplet) 3.12-3.80 (multiplet) (Total 8H) 3.52 (Single line) (Total 8H) 4.24-4.60 (1H, multiple line) 4.60-5.04 (1H, multiple line) 4.60-4.68 (3H, singlet) (disappeared in heavy water) 6.40-6.88 (3H, multiplet) Example 1 N- (2-amino-3-hydroxybenzoyl) -L-prolinal dimethyl acetal 31 mg under argon stream.
(0.47mM) dissolved in 5m anhydrous acetonitrile,
285 mg (1.9 mM) of sodium iodide and 0.19 m (2.4 mM) of pyridine were added and stirred. Under cooling (-15 °) in an ice-methanol bath, 0.24 m (1.9 mM) of chlorotrimethylsilane was added dropwise, and -15 ° C to -13.
The mixture was stirred at 0 ° C for 20 minutes. 110 mg of indole (0.
94 mM) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, 259 mg (1.9 mM) of zinc chloride was added, and the mixture was stirred at room temperature for 18 hours and then reacted at 50 to 53 ° C for 2 hours with stirring. After cooling, 5 m of a saturated sodium hydrogen carbonate aqueous solution was added, followed by extraction with 150 m of ethyl acetate. After extraction, the extract was washed with 50 m of saturated saline and dried over anhydrous sodium sulfate, and the aqueous solution was distilled off. The residue was purified by silica gel column chromatography (solvent chloroform-methanol-benzene = 15: 1: 3) to obtain 130 mg (yield 83%) of tirivaline.

Tirivaline Yellow crystal mp 242 to 245 ° C. (recrystallized from water-containing methanol) IR ν ^KBr cm ⁻¹ : 3380 3200 2900 1610 IH-NMR δ (d ₅ -in pyridine) 1.38 to 2.05 (4H, m) 3. 58-4.20 (2H, m) 4.20-4.60 (1H, m) 4.94 (1H, d, j = 9Hz) 6.68-8.44 (10H, m) 12.19 ( 1H, s) Mass (m / l) 333 (M ⁺ ), 264, 247,
235, 216, 130, 117, 90, 89, 70 High-Mass (m / l) Found: 333, 14815 Calcd: 333, 14773 (C ₂₀ H ₁₉ N ₃ O ₂ ) UV _max (nm): 220 (ε 33200). ) 240 (shoulder) (ε14000) 257 (shoulder) (ε8200) 281 (shoulder) (ε5600) 289 (shoulder) (ε4700) 334 (ε3400) ▲ [α] ²⁷ _D ▼ + 234 ° (C-0.57, MeOH) )

Claims (1)

[Claims] 1. A formula (I) (In the formula, R ₁ and R ₂ each independently represent a lower alkyl group or a lower aralkyl group).
(2-amino-3-hydroxybenzoyl) -L-prolinal acetal in an organic solvent was added to give the compound of formula (II) (Wherein R ₃ , R ₄ and R ₅ are each independently an alkyl group or an aralkyl group, and X is a halogen atom), and then treated with a silylating agent, and then in the presence of a Lewis acid. (III) characterized by reacting with indole The manufacturing method of tilibarin represented by.