JPS6366162A - N-(2-amino-3-alkoxy(or aralkyloxy)benzoyl)-l-prolinal acetal and production thereof - Google Patents

Abstract

NEW MATERIAL:N-(2-amino-3-alkoxy(or aralkyloxy)benzoyl)-L-prolinal acetal of formula I (R is alkyl or aralkyl; R1 and R2 are alkyl). EXAMPLE:N-(2-amino-3-methoxybenzoyl)-L-prolinal dimethyl acetal. USE:A production intermediate for a pyrrolo-1,4-benzodiazepine compound having pharmacological activities such as antitumor activity, antibacterial activity, etc. PREPARATION:An N-protected-L-prolinal is converted to N-protected-L-prolinal acetal of formula II by acetalization, the protecting group is removed and the obtained L-prolinal acetal is made to react with 2-amino-3-alkoxy(or aralkyloxy) benzoic acid of formula III in the presence of a condensation agent to obtain the objective compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides a new chemical substance, N-(2-amino-3-
alkoxy(or aralkyloxy)benzoyl)-
This invention relates to L-prolinal acetal and its production method.

More specifically, general formula (I) (wherein R represents an alkyl group or an aralkyl group, R
and R2 each independently represent an alkyl group) and a method for producing the same.

The new chemical substance of the present invention is expected to have pharmacological activities such as antitumor and antibacterial properties.
It is useful as an intermediate for chemically producing benzodiazepine compounds.

That is, when the N-(2-amino-3-alkoxy(or aralkyloxy)benzoyl)-L-prolinal acetal of the present invention is reacted with indole under predetermined conditions, O-alkyl( or aralkyl) tirivarine, and further cleavage of the ether bond can produce tirivarine.

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

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

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

The only method for chemically converting tilivarine or its precursor, O-alkoxyteilibaline, is
Hohr, N. and Budzikiewicz, H.
(Tetrahedro Vol. 3814)
7 (I982)) is known.

In this method, N-benzyloxycarbonyl-L-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-(I-prolyl)indole is condensed with 2-nitro-3-benzyloxy (or methoxy)benzoic acid, and then reduced and cyclized to produce teilivaline or O-methyltiribaline. . However, this method tends to involve racemization of the proline nucleus to a considerable extent in the reaction of the acid chloride of N-benzyloxycarbonyl-L-proline with the Grignard reagent of indole. In addition, teilibarin is a compound with the steric structure shown below (VA), but this method has poor stereoselectivity in the final step of reduction and cyclization, and a large amount of the compound with the structure B, which is an epimer of A, is produced. generate.

For example, according to the above-mentioned literature, A:B=48:52 for O-methyltilivarine, and A:B=8:92 for teilivarine.

Therefore, separation from isomers becomes complicated.

We investigated a new method for producing O-alkyl (or O-aralkyl) tiribaline stereoselectively without racemization of the proline nucleus during the production process.

As a result, the novel compound of the present invention, namely N-
We have succeeded in producing (2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal acetal, and have found that tiribaline can be efficiently produced using this compound as a raw material.

That is, the present inventors discovered that this N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L
-Prolinal acetal was treated with a silylating agent such as trimedelsilyl chloride in a solvent, and then subjected to a condensation reaction with indole in the presence of a Lewis acid such as zinc chloride. O with three-dimensional structure
It has been unexpectedly discovered that -alkyl (or O-aralkyl) tiribaline can be produced in good yield.

(Means for Solving the Problems) As described above, the present invention provides a compound extremely useful as a 113m intermediate of tilivarine and a method for producing the same.

That is, the present invention provides N-(2-amino- 3-Alkoxy (or aralkyloxy) benzoyl iL-prolinal acetal and the method for producing this compound (see ■ and ■ below)
).

■ N-protected N-protected by acetalizing L-prolinal and represented by the general formula (I[) (wherein R and R2 each independently represent an alkyl group, and X represents a protecting group) -[- After conversion to prolinal acetal, the protecting group is removed to give monoprolinal acetal, and this compound is then represented by the general formula (III> (wherein R does not represent an alkyl group or an aralkyl group). Formula (I) (wherein R
represents an alkyl group or an aralkyl group, R Onibi R2
each independently represents an alkyl group)
A method for producing (2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal acetal (hereinafter referred to as the first method), and ■General formula (TV) (wherein, R is an alkyl group) 2-21 to lo-3-alkoxy (or aralkyloxy) benzoic acid represented by -alkoxy(or aralkyloxy)benzoyl)-seproline algyl ester, and then converting the ester group of this compound to a formyl group to form the general formula (V) (wherein R represents an alkyl group or an aralkyl group). ) of the general formula (I
> (wherein, R represents an alkyl group or an aralkyl group, R
A method for producing N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal acetal (hereinafter referred to as the second method) ).

Specifically, the N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal acetal represented by the general formula (I) of the present invention includes N-(2-amino- 3-Me1-oxy)benzoyl-prolinal acetal, N-(2-amino-3-ethoxy)benzoyl-prolinal acetal, l
l-(2-Amino-3-butoxy)benzoyl-1-prolinal acetal, N-(2-amino-3-propoxy)benzoyl-prolinal acetal, N
-(2-amino-3-penzyl-1-di)benzoyl-prolinal acetal, N-(2-amino-3
-isopropoxy)benzoyl-prolinal acetal, N-(2-amino-3-p-methoxybenzyloxy)benzoyl-1-prolinal acetal, N
-(2-amino-3-t-butoxy)benzoyl-1-
-prolinal acetal, N-(2-amino-3-phenoxy)benzoyl-prolinal acetal, and the like.

A first method of producing these compounds is as follows.

N-1-L-prolinal used in this method is obtained by protecting the imino group of prolinal 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-1-L-prolinal is first acetalized to give N-1-L-prolinal acetal of general formula (II).

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

As a specific example, a method of reacting with an alcohol having 1 to 4 carbon atoms under an acidic catalyst, a method of using an or-l-ester, 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%, preferably from 1.0 to 20 mol%, based on the raw material N-protected-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 the presence of a catalyst such as cerium chloride, ammonium chloride, cesium chloride, ammonium nitrate, hydrochloric acid, sulfuric acid, iron chloride, p-toluenesulfonic acid or a strongly acidic ion exchange resin in an alcohol solvent. The reaction is carried out with at least an equivalent amount, preferably at least 1.1 equivalents, of orthoester and at a temperature ranging from 0° C. or higher, preferably 20° C. or higher, to the boiling point of the solvent. Examples of orthoesters include orthoformates or orthosilicate esters, such as methyl orthoformate, ethyl orthoformate, propyl orthoformate, ethyl orthoformate, methyl orthosilicate, ethyl orthosilicate, and propyl orthosilicate. Alternatively, orthoalkyl esters having 1 to 4 carbon atoms such as butyl orthosilicate are often used.

The amount of the catalyst used is, but not limited to, 0.1 to 2 equivalents, preferably 1 equivalent, based on the raw material N-H!-L-prolinal.

As a method for removing iJJ 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 using an okiyari or unsubstituted benzyloxycarbonyl group 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. Ru.

In this case, the organic solvent used is not particularly limited as long as it is inert to the reaction; examples include lower alcohol solvents such as methanol or ethanol, carbonized solvents such as benzene, toluene, hexane, heptane or cyclohexane, etc. Hydrogen solvents, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, ester solvents such as ethyl acetate or butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, etc. Examples include nitrogen-containing solvents.

Further, the palladium catalyst is used in an amount of 0.1% by weight or more, preferably 0.5% by weight or more, based on the N-protected-L-prolinal acetal, and the upper limit is not particularly limited, but is 50% by weight.
It is sufficient to use:

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-3rd
It is preferable that the amount is 1 equivalent or more based on the butoxycarbonyl-prolinal acetal, and the contact temperature with the acid is 0.
℃ to the boiling point of the solvent.

As described above, L-prolinal acecur is produced in 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 It can also be used in the next reaction in the form of a residue obtained by evaporating the solvent to dryness.

L-prolinal acetal and 2- of the general formula (I[[)
The reaction with amino-3-alkoxy (or aralkyloxy)benzoic 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, carbonyl diimidazole, diethyl phosphoric cyanide, and diphenyl phosphoric azide. The amount of these condensing agents used is 1 equivalent or more based on L-prolinal acetal or 2-amino-3-alkoxy (or aralkyloxy)benzoic 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-alkoxy(
Alternatively, aralkyloxy)benzoyl)-L-prolinal acetal is produced. This product is processed from the reaction solution by an appropriate method to obtain a crude product, and then purified using various purification methods.
For example, a purified product can be obtained by means such as silica gel column chromatography.

Further, a second method for producing the compound of the present invention is as follows.

This method uses 2-nitro-3-alkoxy (or aralkyloxy)benzoic acid represented by the general formula (IV) and L-proline alkyl ester as raw materials, and as the L-proline alkyl ester, Lower alkyl esters are used, especially methyl or ethyl esters.

The reaction operation is generally as follows.

First, 2-nitro-3-alkoxy (or aralkyloxy)benzoic acid and L-proline alkyl ester are condensed in the presence of a condensing agent to form N-(2-nitro-3-alkoxy (or aralkyloxy)benzoyl iL). −
Manufacture proline alkyl ester. This condensation reaction is carried out in an organic solvent, and the organic solvent used, the type and amount of the condensing agent used, and the condensation conditions such as reaction temperature and time may be the same as in the first method described above.

The N-(2-nitro-3-alkoxy (or aralkyloxy)benzoyl)-L-proline alkyl ester obtained by the above method is obtained by converting the ester group to a formyl group and converting the ester group into a formyl group. (or aralkyloxy)benzoyl iL-prolinal.

This conversion reaction is preferably a two-step method in which the ester group is first converted into a methylol group and then converted into a formyl group.

The method for converting an ester group into a methylol group is in a lower alcohol solvent such as methanol or ethanol, in an ether solvent such as tetrahydrofuran or dioxane, or in ethylene glycol monomethyl ether, ethylene glycol nanyl ether, ethylene glycol dimedyl ether, etc. It is preferable to carry out the reaction using metal boron hydride as a reducing agent in a glycol-based solvent at a temperature ranging from -20°C to the boiling point of the solvent.

As the metal boron hydride, mono-lithium boron hydride is often used. The amount used is more than the theoretical amount based on the raw material ester compound.

This reaction can be accelerated by adding salts such as lithium chloride, lithium bromide, or aluminum chloride.

The methylol group is then converted to formyl group using various oxidizing agents. For example, chromic acid anhydride, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-acetic anhydride, dimethyl sulfoxide-N,N'-dicyclohexylcarbodiimide can be used for oxidation, and among them, dimethyl sulfoxide has a medium stoichiometric amount or more. By using the pyridine/sulfur trioxide complex, the corresponding formyl compound can be derived in good yield under mild conditions. The reaction temperature is 0-50°C.

The thus obtained N-(2-nitro-3-alkoxy (or aralkyloxy)benzoyl iL-prolinal is then acetalized to N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl-L-prolinal). - Prolinal acetal. This acetalization can be carried out according to the first method.

Finally, the desired N-(2-amino-3
-Alkoxy (or aralkyloxy)benzoyl 1
m-prolinal acecur can be obtained.

Various reduction reactions for reducing a nitro group to an amino group can be applied to this reduction method.

In particular, a catalytic reduction method in an organic solvent is most suitable.

Palladium or platinum are suitable as reduction catalysts in this process. These may be used in the form of being supported on various carriers such as carbon or silica, or in the form of platinum oxide in the case of platinum.

The most common use of these reduction catalysts is N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L
-0.1% by weight or more based on prolinal acetal,
Preferably, it is 0.2 weight % or more, and there is no particular restriction on the upper limit, and it is sufficient if it is used at 30 ffi amount % or less.

The reaction temperature can be arbitrarily selected from 0°C to the boiling point of the solvent.

The crude product of the target product obtained as described above can be purified by various methods. For example, a highly pure target product can be isolated using means such as column chromatography.

(Effects) The present invention provides novel chemical substances that are extremely useful as intermediates for producing various chemical substances whose core structure is pyrrolobenzodiazepine, which is expected to have pharmacological activities such as antitumor and antibacterial properties. provide.

Using this novel compound of the present invention, tilivarine having pharmacological effects such as antitumor or antibacterial properties can be provided.

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

Example 1 Synthesis of N-benzyloxycarbonyl dimethylacetal N-benzyloxycarbonyl-prolinal 4.
Add 50 rrdl (20 imol) of a 0.4 M methanol solution of cerium chloride to 66 g (20 mmol), and then add 15 ml of methyl orthoformate while stirring at room temperature.
3d was dropped. After stirring at room temperature for 30 minutes, the mixture was reacted at 50° C. for 15 hours. The reaction solution was added to 200 d of 5% sodium hydrogen carbonate, and extracted three times with 200 d of ether.

Add the extract to water ioo* and saturated saline 100#11! After washing with water, it was dried with anhydrous sodium sulfate. Filtration and evaporation of the filtrate to dryness under reduced pressure yielded crude N-benzyloxycarbonyl-di-prolinal dimethyl acetal 5.0
1 g (yield 98.7%) was obtained. Of this, 1.901g
was purified by silica gel column chromatography (developing agent: ethyl acetate: n-hexane-1:2 (volume ratio)),
1,765 g (yield: 83.2%) of pure product was obtained as a colorless oil.

Infrared absorption spectrum (cIR-1): 2950, 7
0O NMR spectrum (δ) 1,5-2.4 (4H, multiplet) 3,1-3.9 (multiplet) 3,4 (-multiplet) Total 8H3, 9-4.
2 (IH, multiplet) 4, 7 (IH, - multiplet) 5, 2 (2H, multiplet) 7, 4 (51-1, multiplet) Example 2 N-(2-amino-3-methoxy Synthesis of (benzoyl)-L-prolinal dimethyl acetal N-benzyloxycarbonyl-prolinol dimethyl acetal i,og was dissolved in 20d of tetrahydrofuran, 5% palladium on carbon-17 was added, and hydrogen was passed through at room temperature for 3 hours. .

Filter out the catalyst and use 15ml! The catalyst was washed with 100 ml of tetrahydrofuran.

The filtrate and washing liquid were combined, Molecular Sieves 4Δ was added, and the mixture was slowly stirred. Add to this 0.5d of triethylamine
, 334 rng of 2-amino-3-methoxybenzhonzoic acid was added, and then 587 rng of diethyl IJ acid cyanide was added under water cooling.
2 mg of tetrahydrofuran solution was added, and the reaction was stirred at 0° C. for 1 hour and then at room temperature overnight. The reaction solution was distilled under reduced pressure, extracted with 200 d of benzene-ethyl acetate (I: 2), and the extract was diluted with saturated hydrogen carbonate, 1 helium, 50 d, water 5
After washing with 50 ml of saturated saline solution and drying over anhydrous sulfuric acid, the solvent was evaporated to dryness under reduced pressure to obtain 1.058 g of a crude product.

Ethyl acetate: Purified by silica gel column chromatography using a solvent of n-hexane-1=2 (volume) to obtain N-(2-amino-3-methoxybenzoyl) as a colorless oil.
-L-prolinal dimethyl acetal 503η was obtained (yield 85.4%).

Infrared absorption spectrum 1~le<cm-1); 3460.3
360. 2970. 1615, NMR spectrum (δppm) 1.05-2.57 (4H1 multiplet) 3.17-3.
73 (multiple line) 3.48 (-multiple line) total 8 H3,5
311! ) 3.9 (3H1-double line) 4.23-5.
17 (multiplet) 4.78 (-weight>6.5-7.1 (31-1, multiplet) MaSS spectrum (m/e: 29/I (M'), 262.
230, 219.193. 150.75 = -173 (C=1.2, methanol) Example 3 Synthesis of N-tertiary butoxyluponyl-L-prolinal dimethyl acecure N-tertiary 71-xycarbonyl-L-prolinal 7
0.4M of cerium chloride in 97mg (4, mmol)
10 ml (4 mmol) of methanol solution was added, and 3.1 g of methyl orthoformate was added dropwise with stirring at room temperature. After stirring at room temperature for 30 minutes, the mixture was reacted at 50° C. for 21 hours. The reaction solution was poured into 80 d of a 5% aqueous sodium bicarbonate solution, extracted three times with 80 d of ether, and the extract was washed with 30 d of 10% citric acid, 30 d of water, and 30 ml of saturated brine, and then dried over anhydrous sodium sulfate. After separation by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 781 m9 of crude N-tert-butoxycarbonyl-L-prolinal dimedylacecure.
Obtained.

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

Infrared absorption spectrum (shi008jcm-1>: 29
6 Example 4 Synthesis of N-(2-amino-3-methoxybenzoyl)-L-prolinal dimethyl acecure N obtained in Example 3
- Tertiary butoxycarbonyl-L-prolinal dimethyl acetal 325 mg (L, 32 mmol) to 10
% hydrogen chloride-methanol solution was added and the reaction was allowed to proceed at room temperature for 1 hour to remove the protecting group. The reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in 9d of tetrahydrofuran, triethylamine Yura Thiefs 4A was added, and the mixture was slowly stirred for 15 minutes. In this, 18 2-amino-3-methoxybenzoic acid
4 mg (I.1 mmol) was added and stirred. Next, under cooling in an ice water bath, diethyl phosphate cyanide 215m9 < 1
, 3 2+++ mol) in tetrahydrofuran solution 1
d was added dropwise and reacted at 0° C. for 1 hour and further at room temperature for 40 minutes. Tetrahydrofuran was distilled off under reduced pressure, the residual aroma was dissolved in a benzene-ethyl acetate (I:2) mixing groove W100d, and the molecular sieves were filtered off. The organic layer was washed with saturated sodium bicarbonate (20Id), water (20d), and saturated brine, and then dried over anhydrous sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated to dryness under reduced pressure to obtain 453 mg of a crude product. N-(2-
272 m9 of (amino-3-methoxybenzoyl)-L-brolinal dimedylacetal (yield: 84%) was obtained.

The spectral data of this product were consistent with those obtained in Example 2.

Example 5 N-(2-amino-3-benzyloxybenzoyl)-
1 Prolinal dimethyl acetal.

148 mg of N-tert-butoxycarbonyl-monoprolinal dimethyl acetal obtained in Example 3<0.6+n
10% aqueous chloride-methanol 1- was added to H), and the mixture was stirred and reacted at room temperature for 30 minutes. The reaction solution was concentrated to dryness under reduced pressure.

Dissolve the residue in 4d of tetrahydrofuran and add 0.17rff of triethylamine! (I, 2+nH) and Molecular Sieves 4A were added and stirred slowly for 15 minutes. Here 2-amino-3-benzyloxybenzoic W 122m
Next, a tetrahydrofuran solution of 98m9 (0.6mM) of diethyl phosphate cyanide was added dropwise in a water bath, and the reaction was stirred for 1 hour at O°C and 1 hour at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. Then, the residue was dissolved in benzene-ethyl acetate (I: 2') 50rd, and the 4 molar sieves were filtered off. The organic layer was washed with 10 d of saturated sodium bicarbonate, 10 d of water, and 1' od of saturated saline, and then the organic layer was dried and concentrated with anhydrous thorium sulfate to remove the crude product 2.
．． 25Rg was obtained. Ethyl acetate to hegylene (I:1)
Silica gel column chromatography was performed using silica gel as a solvent to obtain N~(2-amino-3-benzyloxybenzoyl)-L-prolinal dimethylacetal 142In.
g, (7.7% yield) was obtained.

Infrared absorption spectrum (KBrCm-1) = 3,450
．． 3350. 28.00° NMR spectrum (solvent CD, C, Q3 δ) 2-(4
, 1-j, multiplet), 3.4.5 (3H1-multiplet), 3, . 50
(31-1, - double line), 4.5, , (4H,
multiplet) 1,.

, 4.70 (2H, - double line), 5.10
(2nd day, - double line), 6.7-7. ．． 4. (3) 1, multiplet), 7.4.
(5) (, - double line) Example 6 N-(2-nitro-3,-methoxybenzoyl)-1-
Proline methyl ester.

15.9 g of 2-nitro-3-methoxybenzoic acid (80,
, 6n+mol) and -proline methyl ester 12
．． -5W (96.8 mmol) was dissolved in 160 ml of N,N-dimethylformamide, and then dissolved in 20 ml of N,N-dimethylformamide solution of 4 g (I12.8 mmol) of diethyl phosphoric acid cyanide 18", 4 g (I12.8 mmol) under water cooling, and triethylamine. 11., 4. q (,, 112!,
A 20 m solution of N,N-dimethylbormamide (8 mmol) was added dropwise. After reacting at 0°C for 30 minutes or at room temperature for 2 days, the reaction solution was diluted with 750 d of a mixed solution of ethyl acetate and benzene (volume ratio 2:1), and mixed with ζ 10% aqueous citric acid solution, water, and saturated hydrogen carbonate solution. It was washed successively with a ~lium aqueous solution, water, and then 200 d of saturated saline moss. After drying the organic layer with anhydrous thorium sulfuric acid, the solvent was distilled off under reduced pressure.
The residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give pale yellow crystals of N-,(2,-nitro-3-methoxybenzoyl)-L-proline methyl ester 8./1
9' (yield 7'4.1%) was obtained.

mp100-101°C Infrared absorption spectrum (・νKB'cm-1>: 2
950.1725, NMR spectrum (solvent CDCfJ δ) 1.83~
2.50 (41-11 multiplet), 3.37-3.75 (
2 to 1, multiplet), 3.80 (3H1-multiplet), 3.97 (3) (I-multiplet), 4.
23-4.85 (IH, multiplet), 6.97-7.3
7 (3H, multiplet) Example 7 N-(2-nitro-3-methoxybenzoyl)-2-hydroxymethyl-1-pyrrolidine Under an argon atmosphere, N-(2-nitro-3-methoxybenzoyl)-2-hydroxymethyl-1-pyrrolidine obtained in Example 6 -methoxybenzoyl)-L-proline methyl ester 2.06 g (6,6
8 mmol) of tetrahydro7ran 17d at 0°C.
Sodium borohydride 6321yi (I0,7m
mol) and lithium chloride 708m9 (I6,7mmol)
Add ethanol 34#d! and keep it below 5℃. was dripped. After reacting at 0°C for 2 hours and at room temperature for 19 hours,
Add 30Id of 10% citric acid aqueous solution, extract with a mixed solvent of ethyl acetate-benzene (2:1), and add the extract to saturated aqueous sodium bicarbonate solution and 3C each of saturated saline)
After washing with +1112 times, it was dried with anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residual aroma was purified by silica gel column chromatography using a mixed solvent of ethyl acetate-n-hexane (I0:i>) to obtain a yellow oily N-(2-nitro-3-methoxy 1.67 g (yield: 89.1%) of benzoyl-2-hydroxymethyl-L-pyrrolidine was obtained.

Infrared absorption spectrum (ν”””cm-1>: 335
0.2930° 1620° NMR spectrum (solvent CDCfJ δ) 1.65~
2.42 (41-1, multiplet) 3.25-3.58 (
2+-1, multiplet) 3.58 to 3.93 (2H, multiplet) 3.97 (3H, - multiplet tIA) 4.0
8~4.63 (2 to 1 multiplet) 6.92~7.77
(3H, multiple ffA) 36 Example 8 N-(2-nitro-3-methoxybenzoyl)-di-prolinal dimethyl acetal Under argon flow, N-(2-nitro-3-methoxybenzoyl) obtained in Example 7 benzoyl)
-2-hydroxymethyl-L-pyrrolidine 13.25y
(46.6 mmol) of dimethyl sulfoxy 50 m! !
Add 14.2 g of triethylamine (I40m) to the solution at room temperature.
mol) and 22.3 g of pyridine/sulfur trichloride (I
150 d of a dimethyl sulfoxide solution (40 mmol) was added thereto, and the mixture was reacted for 10 minutes with stirring. Pour the reaction solution into ice water 500ml
d and extracted three times with 150 d of ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen solution, water, and then 801 d of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a reddish-brown candy-like N-(2-nido-o-3-methoxybenzoyl).
-L-prolinal 9.9 g (yield 76.7%) was obtained. To this, 0.4M cerium chloride methanol solution 1
15d, then 33.5m methyl orthoformate at room temperature.
was added dropwise, and the reaction was allowed to proceed at room temperature for 30 minutes and then at 55-60°C for 4 hours. The reaction solution was diluted with 5% aqueous sodium hydrogen carbonate solution.
00d and extracted four times with ether 160d. The extract was washed successively with 300ml of water and 25ml of saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual aroma was purified by silica gel column chromatography using a mixed solvent of ethyl acetate-n-hexane (I:1) to obtain N-(2-nitro-3-methoxybenzoyl)-1-prolinal dimethyl acetal as a pale brown oil. 9.
18 g (yield 79%) was obtained.

Infrared absorption spectrum (ν””cm-1>: 2920
．． 2820° 63O NMR spectrum (solvent CDCJ δ) 1.93~
2.45 (4)1. multiplet) 3.08 to 3.83 (
2H, multiplet) 3.58 (3H1-multiplet)
3.62 (3H, - double line) 4.07
(3H, - double line) 4.28-4.67 (IH,
doublet) 6.73 to 7.65 (3H, multiplet) --2
06,5° (C=9.5, methanol) Example 9 N-(2-Amino-3-methoxybenzoyl)-di-prolinal dimethyl acetal.

Palladium black 2001B15F was added to ethanol 6d and activated under a hydrogen stream. This was obtained in Example 8 with N-
(2-nitro-3-methoxybenzoyl)-prolinal dimethyl acetal 1.05g (3.1smol
) was added thereto, and the mixture was reacted for 18 hours under a hydrogen stream. The catalyst was filtered and the solvent was distilled off to give a pale brown oily N-(2-amino-3-methoxybenzoyl iL-
Prolinal dimethyl acetal 939η (yield 98.
5%). It was confirmed that this product was the same as that obtained in Example 2.

Claims (1)

[Claims] 1) General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R represents an alkyl group or an aralkyl group, and R_1 and R_2 each independently represent an alkyl group. N-(2-amino-3-alkoxy(
or aralkyloxy)benzoyl)-L-prolinal acetal. 2) N-protected-L-prolinal is acetalized to form the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 each independently represent an alkyl group, N-protected-L represented by
- After converting to prolinal acetal, the protecting group is removed to form L-prolinal acetal, and this compound is then converted to the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R is General formula (I) ▲Math. , chemical formulas, tables, etc.▼(I) (In the formula, R represents an alkyl group or an aralkyl group, and R
^1 and R^2 each independently represent an alkyl group. 3) General formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) 2-nitro-3-alkoxy (or aralkyloxy) represented by (in the formula, R represents an alkyl group or an aralkyl group) Benzoic acid is condensed with L-proline alkyl ester in the presence of a condensing agent to produce N-(2-nitro-3-alkoxy (or aralkyloxy)benzoyl)-L-
Proline alkyl ester is obtained, and then the ester group of this compound is converted to a formyl group to form the general formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R represents an alkyl group or an aralkyl group. ) is converted into N-(2-nitro-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal, which is then acetalized and then reduced. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼(I) (In the formula, R represents an alkyl group or an aralkyl group, and R
A method for producing N-(2-amino-3-alkoxy (or aralkyloxy)benzoyl)-L-prolinal acetal represented by (_1 and R_2 each independently represent an alkyl group).