JPS6366161A - N-(2-amino-3-hydroxybenzoyl)-l-prolinal acetal and production thereof - Google Patents

Abstract

NEW MATERIAL:N-(2-amino-3-hydroxybenzoyl)-L-prolinal acetal of formula I (R1 and R2 are alkyl). EXAMPLE:N-(2-amino-3-hydroxybenzoyl)-L-prolinal dimethyl acetal. USE:A production intermediate for pyrrolo-1,4-benzodiazepine compound having antitumor or antibacterial activity, etc. PREPARATION:The objective compound of formula I can be produced by acetalizing an N-protected-L-prolinal, removing protective group from the resultant N-protected-L-prolinal acetal and reacting the obtained L-prolinal acetal with 2-amino-3-hydroxybenzoic acid of formula III in the presence of a condensation agent.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides a new chemical substance, N-(2-amino-3-
The present invention relates to (hydroxybenzoyl)-1-prolinal acetal and a method for producing the same.

More specifically, N-(2-amino-3-hydroxybenzoyl)-L-prolinal acetal represented by general formula (I) (wherein R1 and R2 each independently represent an alkyl group) and its This is the manufacturing method.

The new chemical substance of the present invention is pyrrolo-1,4-
It is useful as an intermediate for chemically producing benzodiazepine compounds.

That is, tilivarine can be produced by reacting the N-(2-amino-3-hydroxybenzoyl)-di-prolinal acetal of the present invention with indole under predetermined conditions.

Moreover, this compound itself is expected to have various pharmacological activities.

(Prior Art and Problems to be Solved by the Invention) The compound of the present invention is a new compound, and there are no examples of its production.

The present inventors have focused on the pharmacological activity of pyrrolo-1,4-benzodiazepine compounds, particularly tiribaline, and have diligently investigated methods for chemically producing it efficiently.

The only method for chemically producing tirivarine is described by N. Hohr and Il, Bukzikin.
The method of Wicz et al. (Tetrahedron Vol.
38147 (1982)) is known.

In this method, N-benzyloxycarbonyl-proline is first converted into an acid chloride using Vilsmeier's reagent and reacted with indole's Grignard reagent, and then the protecting group is removed.
-(L-prolyl)indole is produced. Next, this 3-(L-prolyl)indole was converted into 2-nitro-3-
condensed with benzyloxy (or methoxy)benzoic acid,
In this method, tilivarine is then produced by reduction and cyclization.

However, this method tends to involve considerable racemization of the proline nucleus in the reaction of the acid chloride of N-benzyloxycarbonyl-proline with the Grignard reagent of indole. In addition, tilivarine is a compound having the following steric structure A, but in this method, the final step of reduction and cyclization has poor stereoselectivity, resulting in 4! of B, which is an epimer of A. ! A large amount of compounds with structure are produced.

For example, according to the above-mentioned literature, for O-methyltilivaline, A:B=4.8:52, and for teilivaline, A:B=8:92.

Therefore, separation from isomers becomes complicated.

Regarding a new production method to replace the above-mentioned method, in particular, a study on a method for stereoselectively producing VJ of 0-alkyl (or O-aralkyl) tiribaline without racemization of the proline nucleus in the production process. did. As a result, the novel compound of the present invention, namely N-(2-amino-3-hydroxybenzoyl)-L- of formula (I>
Successfully produced prolinal acetal. We have discovered that tilivarine can be efficiently produced using this compound as a raw material.

That is, we treated this N-(2-amino-3-hydroxybenzoyl iL-prolinal acetal with a silylating agent such as trimethylsilyl chloride in a solvent and then treated it in the presence of a Lewis acid such as zinc chloride. When a condensation reaction was carried out with indole, it was unexpectedly discovered that teilibaline having the steric structure of A could be produced in a good yield in one step.

(Means for Solving the Problems) As described above, the present invention provides a compound extremely useful as an intermediate for producing teilivaline and a method for producing the same.

That is, the present invention provides N-(2-amino-3-hydroxybenzoyl iL-prolinal acetal) represented by the general formula (I) (wherein R1 and R2 each independently represent an alkyl group), and The method for producing this compound is to acetalize N-ho!-L-prolinal to form the general formula (I[) (wherein R1 and R2 each independently represent an alkyl group, and X represents a protecting group). After converting into N-prolinal acetal represented by 14-prolinal acetal, the protecting group is removed to obtain L-prolinal acetal, and this compound is then converted into a compound represented by the general formula <I[l)O2H. N represented by the general formula (I) (wherein R1 and R2 each independently represent an alkyl group), which is characterized by reacting with 2-amino-3-hydroxybenzoic acid in the presence of a condensing agent. This is a method for producing -(2-amino-3-hydroxybenzoyl)-L-prolinal acetal.

Specific examples of the N-(2-amino-3-hydroxybenzoyl)-1-prolinal acetal represented by the general formula (I) of the present invention include dimethyl acetal, diethylacetal, and ethylene acetal. .

The method for producing these compounds is as follows.

It can be obtained by protecting the imino group of N-yt'-L-prolinal used in this method by a conventional method. As the protecting group, various protecting groups commonly used in peptide synthesis can be used. Among these, substituted or unsubstituted benzyloxycarbonyl groups or tertiary butoxycarbonyl groups are often used because of their ease of removal.

In this method, this N-protected 1-1-prolinal is first acetalized to give an N-protected-prolinal acetal of general formula (It).

As the acetalization method, various methods that can convert an aldehyde group into an acetal can be applied.

A concrete example of this is acidic contact! Below, a method of reacting with an alcohol having 1 to 4 carbon atoms, a method of using an orthoester, etc. can be applied.

Acidic catalysts used in such methods include hydrochloric acid,
Sulfuric acid, calcium chloride, ammonium chloride, hydrogen bromide,
Examples include polymer complexes of P-toluenesulfonic acid, boron trifluoride ether complex, phosphoric acid, ion exchange resins, and aluminum chloride.

The amount of these acidic catalysts used is usually very small and ranges from 0.5 to 30 mol % based on the raw material N-1-L-prolinal.

The reaction operation for this acetalization is not particularly limited, and a preferred mode of operation is to add the raw material to alcohol, and then add an acidic catalyst to raise the temperature to 0°C or higher, preferably 20°C.
The reaction may be carried out at a temperature ranging from °C to the boiling point of the solvent.

It is also possible to use a method in which the produced water is removed from the reaction system.

In addition, the method using orthoester is also carried out in an alcoholic solvent in the presence of a catalyst such as cerium chloride, ammonium chloride, cesium chloride, ammonium nitrate, hydrochloric acid, sulfuric acid, iron chloride, Pl-luenesulfonic acid or a strongly acidic ion exchange resin. The reaction is carried out with at least an equivalent amount, preferably at least 1.1 equivalents, of orthoester at a temperature of at least 0°C, preferably at least 20°C, and within the boiling point range of the solvent. Orthoesters include orthoformates or orthosilicate esters,
Specifically, methyl orthoformate, ethyl orthoformate, propyl orthoformate, ortho1! Orthoalkyl esters having 1 to 4 carbon atoms, such as butyl acid, methyl orthosilicate, ethyl orthosilicate, propyl orthosilicate, or ethyl orthosilicate, are often used.

The amount of the catalyst to be used is 0.1 to 2 equivalents, preferably 1 equivalent to the N-protected prolinal as the raw material.

As a method for removing the protecting group from the N-protected-L-prolinal acetal obtained by the above method, an optimal method corresponding to the protecting group may be applied. For example, when a substituted or unsubstituted benzyloxycarbonyl group is used as a protecting group, catalytic reduction in an organic solvent in the presence of a palladium catalyst such as palladium black, palladium on carbon, or palladium silica is often used. . In this case, the organic solvent used is not particularly limited as long as it is inert to the reaction, for example, lower alcohol solvents such as methanol or ethanol, carbonized solvents such as benzene, toluene, hexano, heptane or cyclohexane. Hydrogen solvents, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, ester solvents such as ethyl acetate or butyl acetate, and solvents such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone. Examples include nitrogen-based solvents.

Further, the palladium catalyst is 0.1% by weight or more, preferably 0.5% by weight or more, based on the N-protected di-prolinal acetal, and the upper limit is not particularly limited, but 50% by weight.
It is sufficient to use up to

The reduction temperature can be arbitrarily selected within the range of 0° C. to the boiling point of the solvent.

Further, when a tertiary butoxycarbonyl group is used as a protecting group, it can be removed by contact with an acid in a solvent inert to the reaction. As the acid, hydrogen chloride or trifluoroacetic acid is usually used. The amount used is N-3
1 equivalent or more is suitable for the butoxycarbonyl-L-prolinal acetal, and the contact temperature with the acid is 0 ° C.
to the boiling point of the solvent.

As described above, L-prolinal acetal is produced in the free form or in the form of an acid addition salt, which can be isolated and used in the next reaction, or left in solution without isolation, or in the form of a solvent. can be used in the next reaction in the form of a residue obtained by evaporation to dryness.

2-prolinal acetal and 2- of the general formula (I[[)
The reaction with amino-3-hydroxybenzoic acid is carried out in an organic solvent in the presence of a condensing agent.

The solvent used is not particularly limited as long as it is inert to the reaction, and for example, the same type of solvent as the solvent used in the reaction for deprotecting the group can be mentioned.

As the condensing agent, various condensing agents used in peptide synthesis can be used. Specifically, N.

Examples include N'-dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl phosphoric cyanide, and diphenyl phosphoric azide. The amount of these condensing agents used is L-prolinal acetal or 2-amino-3
-1 equivalent or more relative to hydroxybenzoic acid. The temperature of this condensation reaction is 80°C or less, preferably -20 to 50°C, in order to suppress racemization of the proline nucleus.

As described above, N-(2-amino-3-hydroxybenzoyl iL-prolinal acetal is produced. This product is treated with an appropriate method from the reaction solution to obtain a crude product, and then various purification methods are used. A purified product can be obtained by means such as silica gel column chromatography.

(Example) Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 N-(2-amino-3-hydroxybenzoyl)-L-
Synthesis of prolinal dimethyl acetal.

N-tertiary butoxycarbonyl-L-prolinal 79
To 7 mg (4 mmol) was added 10 ml (4 mmol) of a 0.4 M methanol solution of cerium chloride, and 3.11 ml of methyl orthoformate was added dropwise with stirring at room temperature. After stirring at room temperature for 30 minutes, the mixture was heated at 50°C for 21 hours. The reaction solution was poured into 5% aqueous sodium hydrogen carbonate solution 801, extracted three times with 80 ml of ether, and the extract was washed with 10% citric acid 301, water 301, and saturated brine 30 ml.
It was dried with anhydrous sodium sulfate. The filtrate was concentrated to dryness under reduced pressure to obtain crude N-tert-butoxyluponyl-L.
-prolinal dimethyl acetal at 781 ff1 (
I got J.

This was purified by silica gel column chromatography using a solvent of ethyl acetate-0-hexane = 1:5 to obtain a purified product as a colorless oil with a yield of 59%.

Infrared absorption spectrum (νne at cm −1
): 2960, 169O 10% hydrogen chloride-methanol 21 was added to N-tertiary butoxycarbonyl-monoprolinal dimethyl acetal 294+11 (] (1,21118), and the reaction was stirred at room temperature for 1 hour. After the reaction, the solvent is concentrated under reduced pressure to obtain prolinal dimethyl acetal hydrochloride.This and 2
-amino-3-hydroxybenzoic acid 153+aO (1mM
) was dissolved in dimethylformdiamide 81. 0 for this
284 g + o (2,2
mM) and stir for 10 minutes. Then, a solution of diethyl phosphate cyanide 1631 (J (11M)) in dimethylformamide 21 was stirred and reacted at 0°C for 1 hour and at room temperature for 2 hours.
A solution of 3n+H) in dimethylformamide 11 was added at room temperature, and the mixture was reacted with stirring at air temperature for 1.5 hours. After distilling off dimethylformamide under reduced pressure, the residue was dissolved in ethyl acetate-benzene (1
:1) Dissolve in 100+g, wash with saturated saline, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 315ml of reddish-brown eraser! I got 1. This was purified by silica gel column chromatography using a mixture of chloroform-methanol-benzene (15:1:3), and a yellow oil was obtained, N-(2-amino-3-hydroxybenzoyl)-L-
Prolinal dimethyl acetal 19411a (yield 6
9%).

Infrared absorption spectrum (cm”): 3450.3360.3180 2950, 162O NMR spectrum (solvent CDCl δ) 1.52-
2.32 (4)-1, multiplet) 4.24-4.60
(IH, multiplet) 4.60-5.04 (1H, multiplet) Example 2 N-benzyloxycarbonyl-L-prolinal 4.
To 66 g (20 mmol) was added 501 (20 mmol) of a 0.4 M methanol solution of cerium chloride, and then 15.311 l of methyl orthoformate was added dropwise while stirring at room temperature. After stirring at room temperature for 30 minutes, the mixture was reacted at 50° C. for 15 hours. The reaction solution was added to 200ml of 5%-1Ω-sodium hydrogen carbonate, and 20ml of ether was added.
Extracted 3 times with 0ml.

The extract was washed with 100 ml of water and 100 n+l of saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain 5.01 g (yield: 89.7%) of crude N-benzyloxycarbonyl acetal.

Of these, 1.9017 was subjected to silica gel column chromatography (developing agent: ethyl acetate di-n-hexane = 1:2 (
1.765 g (yield: 83.2%) of pure product was obtained as a colorless oil.

Infrared absorption spectrum (cm'): 2950, 1
70O NMR spectrum (δ) 1,5-2.4 (4H. multiplet) 3,1-3,9 (multiplet) 3,4 (-multiplet) Total 81-13, 9
~4.2(1)-1, multiplet) 4, 7 (11-1, -multiplet) 5, 2
(2H. Multiplet) 7, 4 (51-1. Multiplet) Dissolve 1.0 g of N-benzyloxycarbonyl dimethyl acetal in 20 ml of tetrahydrofuran, add 1 g of 5% palladium on carbon, and dissolve hydrogen at room temperature for 3 I passed the time. The catalyst is filtered out and 151 Te1~
The catalyst was washed with lahydrofuran.

The filtrate and washing liquid were combined to obtain a prolinal dimethyl acetal solution. N-(2
-Amino-3-hydroxybenzoyl)-L-prolinal dimethyl acetal was obtained.

Claims (1)

[Claims] 1. General formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 each independently represent an alkyl group) N-( 2-Amino-3-hydroxybenzoyl)-L-prolinal acetal. 2.N-protected-L-prolinal is acetalized to form the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_1 and R_2 each independently represent an alkyl group, and X is N-protected-, which represents a protecting group)
After converting to L-prolinal acetal, the protecting group is removed to obtain L-prolinal acetal, and then this compound is converted into 2 expressed by the general formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) -Amino-3-hydroxybenzoic acid and the general formula (I
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) N-(2-amino-3-hydroxybenzoyl)-L- (in the formula, R_1 and R_2 each independently represent an alkyl group) Method for producing prolinal acetal.