JPH11349565A - Method for producing pyridonecarboxylic acid derivative and intermediate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an intermediate for producing pyridonecarboxylic acid derivatives. SOLUTION: This new compound, 1-t-butoxycarbonyl-trans-3-benzylamino-4- hydroxypyrrolidine, is shown by formula I (Boc is t-butoxycarbonyl; Ph is phenyl), being obtained, for example, by the following procedure: t-butyl carbamate is reacted with cis-1,4-dichloro-2-butene in the presence of sodium hydride to form 1-t-butoxycarbonyl-3-pyrroline, which is then reacted with N- bromosuccinimide to form a compound of formula II, which, in turn, reacted with a base and benzylamine. The other objective pyridonecarboxylic acid derivative of formula III is obtained by the following procedure: the compound of formula I is subjected to optical resolution using (+)-mandelic acid and then treated with a base followed by ciebenzylation and Boc group introduction, methylation, and then elimination of the Boc group to form a compound of formula IV, which is then reacted with a compound of formula V L is an eliminable group; R is H or the like) followed by hydrolysis or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing a pyridonecarboxylic acid derivative having the following structure (hereinafter sometimes referred to as the final target compound or compound (C)), and a method for producing the intermediate itself. And a method for producing a final target compound or a physiologically acceptable salt thereof from an intermediate thereof.

[0002]

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[0003]

BACKGROUND OF THE INVENTION Problems to be Solved by the Invention
JP-A-220424 describes that the pyridonecarboxylic acid derivative [compound (C)] represented by the above [Chemical Formula 12] is extremely excellent as an anticancer agent. This compound (C) is obtained by converting 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester with (+)-trans-
Produced by reacting 3-tert-butoxycarbonylamino-4-methoxypyrrolidine (B ′);
It is described in Example B-2 of the publication that the latter raw material (B ') is produced according to the following reaction formula shown in [Formula 13].

[0004] In the present specification, "Boc" means a tert-butoxycarbonyl group, and "Ph"
“A” means a phenyl group.

[0005]

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However, the conventional method represented by the above-mentioned reaction formula [Formula 13] is not always satisfactory as an industrial production method. For example, the conventional method is industrial in that the N-methylation and the O-methylation are separately performed as a whole, and that the yield (52%) in the optical resolution in the conventional method is rather low. It was not satisfactory as a typical manufacturing method.

[0007] The yield in the optical resolution is calculated assuming that half of the racemic form used is obtained as an optically active substance, as 100%.

The starting compound (A ') in the above-mentioned conventional method can be produced by the method described in JP-A-2-69474, that is, the method represented by the following chemical formula (14). it can.

[0009]

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The method for producing the intermediate represented by the above formula [Chemical Formula 14] is inevitable that a column purification method must be used for purifying each product, and the method for converting an azide group to an amino group is not applicable. The use of lithium aluminum hydride, which is not easy, has been difficult to employ as an industrial production method.

[0011]

The inventors of the present invention have made intensive studies to solve the problems in the conventional method, and as a result, have completed the present invention which is excellent as an industrial production method.

The present invention provides the following formula (A)

[0013]

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1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine or an acid addition salt thereof.

The compound (A) is a compound which is believed not to be specifically described in the literature, and can be industrially produced by the method of the present invention, ie, the following production method (I) or (II). Can be manufactured.

Production method (I): Production of intermediate (A)
The production method (I) comprises the following steps 1-3, and details such as reaction conditions of each step are described in Examples below.

[Step 1]: This step is performed by a ring-closure reaction.
This is a step of forming pyrroline. That is, this step is performed in the presence of sodium hydride by the following formula (1)

[0018]

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Cis-1,4-dichloro-2-represented by
Butene is reacted with tert-butyl carbamate to give 1-te
It can be carried out by using rt-butoxycarbonyl-3-pyrroline. The yield of this step is about 50-60%.

[Step 2}: This step is a step relating to bromination and hydroxylation. That is, this step is Step 1.
Is reacted with N-bromosuccinimide to give the following formula (2)

[0021]

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The reaction can be carried out by using 1-tert-butoxycarbonyl-trans-3-bromo-4-hydroxypyrrolidine represented by the formula: Compound (2) obtained is
Usually, it is used as a raw material in the next step without purification.

[Step 3]: This step relates to benzyl amination. That is, in this step, the desired 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (A) is obtained by reacting the compound obtained in step 2 with a base such as sodium hydroxide and then with benzylamine. Can be implemented. The yield from the previous step 2 to the present step 3 is around 50%.

Production Method (II): Production of Intermediate A --Production Method (II) comprises the following steps 4 and 5, and details such as reaction conditions of each step are described in Examples below.

[Step 4]: This step relates to the introduction of a Boc group. That is, this step is represented by the following equation (3)

[0026]

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In this method, a Boc group is introduced at the 1-position of 3-pyrroline to form 1-tert-butoxycarbonyl-3-pyrroline. The Boc group is introduced by using, for example, ditert-butyl dicarbonate.

[Step 5]: This step relates to oxidation and benzyl amination. That is, in this step, the compound obtained in step 4 is oxidized to give the following formula (4)

[0029]

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The reaction can be carried out by reacting the compound with benzylamine to give 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (A). Oxidation is usually
The reaction is performed using m-chloroperbenzoic acid.

Steps 4 and 5 above can be carried out continuously without purification of the intermediate product, in which case the overall yield is about 40%.

Production method (III): Production of intermediate B --The present invention also relates to (3S, 4S) -3-methoxy-4-methylaminopyrrolidine which is a direct intermediate in the production of pyridonecarboxylic acid. B) or a method for producing an acid addition salt thereof. That is, the present invention sequentially performs the following steps 6-9, wherein the following formula (B)

[0033]

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It is intended to provide a method for producing (3S, 4S) -3-methoxy-4-methylaminopyrrolidine or an acid addition salt thereof represented by the formula:

[Step 6]: This step relates to optical resolution, and the following formula (A)

[0036]

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After optically resolving 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine represented by the following formula with (+)-mandelic acid, it is treated with a base to give free (+)- 1-tert-butoxycarbonyl- (3S, 4S) -3-benzylamino-4-
It can be carried out by using hydroxypyrrolidine.

In this step 6, the compound (A) and a slightly excessive amount of (+)-mandelic acid are dissolved in a solvent such as a mixture of acetonitrile and water and left at room temperature for several hours to precipitate mandelic acid salt. Is purified by recrystallization several times, and the purified mandelic acid salt is treated with a base such as potassium carbonate to give an optically active form of compound (A), ie, free (+)-1-tert-butoxycarbonyl- (3S, 4
S) -3-Benzylamino-4-hydroxypyrrolidine can be obtained. The recrystallization of mandelate is usually
The reaction is performed using a mixture of acetonitrile and water (20: 1, V / V). The yield of this step is about 70-80%.

[Step 7]: This step relates to elimination of a benzyl group and introduction of a Boc group. That is, in this step, the compound obtained in Step 6 is subjected to a debenzylation reaction and Boc
Following the group introduction reaction, the following formula (5)

[0040]

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(+)-1-tert-butoxycarbonyl- (3S, 4S) -3-tert-butoxycarbonylamino-4-hydroxypyrrolidine represented by the formula:

The debenzylation reaction here can be carried out, for example, by catalytic reduction using palladium-carbon as a catalyst, and ditert-butyl dicarbonate is used to introduce a Boc group. This step can be performed almost quantitatively.

[Step 8]: This step relates to methylation. That is, in this step, in the presence of sodium hydride, the compound obtained in step 7 is methylated to give the following formula (6)

[0044]

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(+)-1-tert-butoxycarbonyl- (3S, 4S) -3-[(N-tert-butoxycarbonyl-N-methyl) amino] -4-methoxycypyrrolidine Can be implemented.

More specifically, this step can be carried out by adding methyl iodide to anhydrous dimethylformaldehyde in which sodium hydride is suspended, and slowly adding dropwise a solution containing the compound obtained in the previous step to this. -Methylation and O-methylation can be performed simultaneously and almost quantitatively.

[Step 9]: This step relates to elimination of the Boc group. That is, in this step, the Boc group of the compound obtained in Step 8 is eliminated to form the target compound (B),
Then, if desired, the reaction can be carried out by converting the free base to an acid addition salt when it is obtained, and converting the acid addition salt to a free base when the acid base is obtained.

This step can be carried out by a conventional method. However, the compound obtained in the preceding step is treated with p-toluenesulfonic acid to remove the Boc group and, at the same time, to obtain a di-p-toluenesulfonic acid salt having excellent crystallinity. It is preferable to obtain the target product as
The yield of this step is about 90% or more.

The total yield of process (III) is about 55-65%.

Production method (IV): Production of final product (C)
The intermediate (B) thus obtained, ie (3S, 4
S) -3-methoxy-4-methylaminopyrrolidine or an acid addition salt thereof binds at the 1-position to the 7-position of the pyridonecarboxylic acid even though the amino group at the 3-position is not protected. be able to.

That is, the present invention is characterized in that the following steps 10 and 11 are sequentially performed.

[0052]

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(+)-1,4-dihydro-7 represented by
-[(3S, 4S) -3-methoxy-4-methylamino-1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,8-naphthyridine-3-carboxylic acid or a physiologically acceptable salt thereof And a method for producing a salt.

[Step 10]: This step is performed according to the production method (III).
(3S, 4S) -3-methoxy-4- produced by
Methylaminopyrrolidine (B) or an acid addition salt thereof and the following formula (7)

[0055]

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(Wherein, L represents a leaving group and R represents a hydrogen atom or a lower alkyl group) or a salt thereof. The compound obtained in this step 10 is used as a starting material for the next step 11 with or without purification.

[Step 11]: In this step, when the compound obtained in the preceding step 10 is a lower alkyl ester, it is hydrolyzed, and when a free form is obtained, it is optionally physiologically acceptable. It consists of converting to a salt and, if desired, converting it to the free form when a salt is obtained.

[0058]

Next, the present invention will be described in more detail with reference to examples.

Production method (I): Production of intermediate (A) -[Step 1]: Production of 1-tert-butoxycarbonyl-3-pyrroline--Sodium hydride (60% in mineral oil) 4.20 g
Was washed with 40 ml of n-hexane to remove mineral oil, and 60 ml of anhydrous dimethylformamide was added to form a suspension. Add cis-1,4-dichloro-2-butene (purity 95%) to this suspension 8.2.
After adding 8 g, 5 g of tert-butyl carbamate dissolved in 60 ml of anhydrous dimethylformamide was added dropwise. At room temperature
After stirring for 40 minutes, the mixture was stirred at 65 ° C for 5 hours. The mixture was neutralized with a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. After washing with saturated saline four times and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-tert-butoxycarbonyl-
7.5 g of a mixture of 3-pyrroline and ethyl acetate was obtained as an oil. ^The yield was calculated to be 55% from the result of ¹ H-NMR.

¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.48 (s, 9
H), 4.06-4.19 (m, 4H), 5.70-5.84 (m, 2H)

[Step 2]: Production of 1-tert-butoxycarbonyl-trans-3-bromo-4-hydroxypyrrolidine (2)-3.75 g (including ethyl acetate) of the compound obtained in the previous step was treated with dimethyl sulfoxide. 10 ml and water 0.
Dissolve in 5 ml, and add 1N-bromosuccinimide under ice-cooling.
4 g was added little by little. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate and washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 1-tert-
3.4 g of butoxycarbonyl-trans-3-bromo-4-hydroxypyrrolidine were obtained as an oil.

[Step 3]: Production of 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (A)-The crude product obtained in the preceding step was added to the crude product obtained in the previous step in 14 ml of a 1N aqueous sodium hydroxide solution. Was added and stirred at room temperature for 1 hour. Next, 3.1 g of benzylamine was added, and the mixture was stirred at 65 ° C. overnight. After cooling the reaction solution on ice, the precipitated crystals were collected by filtration, washed with acetonitrile, and washed with intermediate (A), ie, 1-te
1.6 g of rt-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (yield from step 2)
49%).

Melting point: 141-143 ° C. IR (KBr): 3250, 1670, 1605 cm ^-1 . ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.46 (s, 9H), 3.10-3.35
(m, 3H), 3.57-3.75 (m, 2H), 3.82 (d, 2H, J = 5.0Hz),
4.06-4.15 (m, 1H), 7.21-7.38 (m, 5H)

Production method (II): Production of intermediate (A)
Steps 4 and 5 were performed sequentially. That is, 399 g of 3-pyrroline (purity: 93.9%) was dissolved in 5800 ml of chloroform, and 1.32 kg of di-tert-butyl dicarbonate was added over 1.5 hours while stirring with ice cooling. After raising the temperature to room temperature and stirring for further 17 hours, m-chloroperbenzoic acid (purity 75
%) 1.46 kg was added over 6 hours. The temperature was raised to room temperature, and the mixture was stirred for 2 days. The precipitate was filtered, 1000 ml of a saturated aqueous solution of sodium thiosulfate was added to the filtrate, and the mixture was stirred for 30 minutes. The organic layer was separated, washed twice with 5% aqueous potassium carbonate solution (5000 ml) and further with saturated saline (3000 ml), and the solvent was distilled off under reduced pressure. At room temperature, 1540 ml of water and benzylamine 1540 were added to the residue.
ml was added. After stirring the reaction solution for 2 hours, it was stirred at 65 ° C. for 3 hours. 2000 ml of water and 9000 ml of ethyl acetate are added to the reaction solution.
Was added, and the mixture was stirred. The organic layer was separated, washed twice with 2500 ml of water, and the solvent was distilled off under reduced pressure. Diisopropyl ether (6000 ml) was added to the residue to obtain 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (42% yield).

Melting point: 140-141 ° C. IR (KBr): 3250, 1670, 1605 cm ^-1 . ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.46 (s, 9H), 3.10-3.35
(m, 3H), 3.57-3.75 (m, 2H), 3.82 (d, 2H, J = 5.0Hz),
4.06-4.15 (m, 1H), 7.21-7.38 (m, 5H)

Production method (III): Production of intermediate (B)
[Step 6-1]: Production of mandelic acid salt of (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-benzylamino-4-hydroxypyrrolidine--Production method (I) or (II) 1-tert-butoxycarbonyl-trans-3-benzylamino-4 produced in any of the above
714 g of -hydroxy-3-pyrrolidine (A) and (+)
-411 g of mandelic acid in 7500 ml of acetonitrile and 62 ml of water
And left at room temperature for 3.5 hours. The precipitated crystals are collected by filtration and mixed with acetonitrile and water (20: 1, V / V
) Was recrystallized three times to obtain the mandelic acid salt of (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-benzylamino-4-hydroxypyrrolidine.

Melting point: 189-191 ° C. ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (s, 9H), 2.91-3.1
8 (m, 3H), 3.22-3.50 (m, 4H), 3.72 (s, 1H), 3.95-4.02
(m, 1H), 4.98 (s, 1H), 4.98-5.18 (m, 1H), 7.19-7.44
(m, 10H)

[Step 6-2]: (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-benzylamino-4
-Production of hydroxypyrrolidine- The compound obtained in the preceding step was made alkaline by adding 3000 ml of a 9% aqueous potassium carbonate solution, and extracted three times with ethyl acetate (7000 ml in total). After washing with saturated saline (1500 ml) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized by adding 1700 ml of diisopropyl ether, and the crystals were collected by filtration to give (+)-1-tert-butoxycarbonyl- (3S, 4S
) -3-Benzylamino-4-hydroxypyrrolidine 2
74 g (77% yield from step 6-1) were obtained.

Melting point: 69-70 ° C. [Α] _D ²⁹ = + 18.0 ° (c = 0.50, MeOH). IR (KBr): 3250, 1670, 1605 cm ^-1 . ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.46 (s, 9H), 3.10-3.35
(m, 3H), 3.57-3.75 (m, 2H), 3.82 (d, 2H, J = 5.0Hz),
4.06-4.15 (m, 1H), 7.21-7.38 (m, 5H)

[Step 7] Production of (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-tert-butoxycarbonylamino-4-hydroxypyrrolidine (5)
274 g of the compound obtained in the preceding step was dissolved in 1200 ml of n-butanol, 13.7 g of 5% palladium-carbon was added, and hydrogenated at 15-50 ° C. The catalyst was filtered off with suction, and ethanol 8 was added to the filtrate.
After adding 00 ml, under ice cooling, ditert-butyl dicarbonate 215 g
Was added over 10 minutes. The temperature was raised to room temperature and stirred for 16 hours, and the reaction solution was evaporated to dryness under reduced pressure. The residue was crystallized by adding 1800 ml of diisopropyl ether, and the crystals were collected by filtration to give (+)-1-tert-butoxycarbonyl- (3S, 4S)-
278 g (98% yield) of 3-tert-butoxycarbonylamino-4-hydroxypyrrolidine were obtained.

Melting point: 148-149 ° C. [Α] _D ²⁹ = + 1.80 ° (c = 1.00, MeOH). IR (KBr): 3470, 3300, 1670 cm ^-1 . ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 1.46 (s, 9
H), 3.10-3.38 (m, 2H), 3.61-4.01 (m, 3H), 4.16-4.29
(m, 1H), 4.59-4.85 (m, 1H)

[Step 8]: (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-[(N-tert-butoxycarbonyl-N-methyl) amino] -4-methoxypyrrolidine (6) Preparation of 66.4 g of sodium hydride (in 60% mineral oil) was washed twice with 700 ml of n-hexane to remove the mineral oil, and then 1400 ml of anhydrous dimethylformamide was added to form a suspension. After adding 283 g of methyl iodide to the suspension under ice cooling, 1000 ml of anhydrous dimethylformamide in which 200 g of the compound obtained in the step 7 was dissolved was added dropwise over 1 hour. The temperature was raised to room temperature, stirred for 19 hours, neutralized with 2700 ml of a 2% acetic acid aqueous solution, and extracted three times with toluene (4500 ml in total). After washing three times with 1000 ml of a saturated saline solution, the resultant was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and (+)-1-
tert-butoxycarbonyl- (3S, 4S) -3-tert-
[(N-butoxycarbonyl-N-methyl) amino]-
218 g of 4-methoxypyrrolidine was obtained quantitatively as a colorless oil.

[Α] _D ²⁹ = + 9.03 ° (c = 0.55, MeOH
). IR (NaCl): 2980, 1690 cm ^-1 . ¹ H NMR (200 MHz, CDCl ₃ ) δ: 1.47 (s, 9H), 1.48 (s, 9
H), 2.79 (s, 3H), 3.21-3.39 (m, 2H), 3.39 (s, 3H), 3.
53-3.74 (m, 2H), 3.80-3.89 (m, 1H), 4.40-4.52 (m, 1H)

[Step 9]: (3S, 4S) -3-methoxy-
Preparation of di-p-toluenesulfonate of 4-methylaminopyrrolidine (B)-3,200 ml of a mixture of 218 g of the compound obtained in the preceding step and tetrahydrofuran-methanol (3: 1, V / V)
And 289 g of p-toluenesulfonic acid monohydrate was added. After stirring for 30 minutes, the mixture was stirred at 60 ° C. for 3 hours and left at room temperature. After cooling on ice, the precipitated crystals were collected by filtration and (+)-(3S, 4
S) -3-Methoxy-4-methylaminopyrrolidine di-p
-286 g of toluenesulfonic acid (91% yield) were obtained.

Melting point: 163-164 ° C. [Α] _D ²⁹ = + 10.4 ° (c = 1.05, MeOH). IR (KBr): 3060, 1617, 1570 cm ^-1 . ¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 2.70 (s, 3H), 3.22-3.4
8 (m, 3H), 3.32 (s, 3H), 3.60-4.71 (m, 1H), 3.79-3.90
(m, 1H), 4.19-4.26 (m, 1H)

Production method (IV): Production of final target product (C) [Step 10]: 7-substitution reaction-(+) obtained in Step 9
95.3 g of (3S, 4S) -3-methoxy-4-methylaminopyrrolidine dip-toluenesulfonic acid was suspended in 600 ml of acetonitrile, and 120 ml of triethylamine was suspended under ice-cooling.
Was added. After stirring for 15 minutes, 7-chloro-1,4-dihydro-4-oxo-1- (2-thiazolyl) -1,8
-Naphthyridine-3-carboxylic acid ethyl ester 60.3 g
Was added. After stirring for 1 hour at room temperature, acetonitrile 15
0 ml was added and the mixture was stirred at the same temperature for 1 day. The precipitated crystals are collected by filtration, washed with acetonitrile, and washed with (-)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4-methylamino-1-pyrrolidinyl] -4-oxo-1. -(2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester was obtained.

Melting point: 184-185 ° C. [Α] _D ²⁸ = -16.9 ° (c = 0.50, chloroform)

[Step 11]: Preparation of final target-430 ml of 0.5N sodium hydroxide aqueous solution was added to the ester obtained in the previous step.
And ethanol (12 ml), and the mixture was stirred at room temperature for 2 days. 21 ml of 28% aqueous ammonia and 34.5 ml of 50% aqueous acetic acid were added to the reaction solution,
Stirred at 80 ° C. for 2 hours. After cooling on ice, the precipitated crystals are collected by filtration, washed successively with water and ethanol, and washed with (+)-1,4-dihydro-7-[(3S, 4S) -3-methoxy-4-methylamino-1-pyrrolidinyl. ] -4-oxo-1- (2
-Thiazolyl) -1,8-naphthyridine-3-carboxylic acid (64.8 g, 90% yield from step 10) was obtained.

Melting point: 278-280 ° C. (decomposition). [Α] _D ²⁹ = + 58.5 ° (c = 1.00, 1N NaOH)

[0080]

The method of the present invention is far superior to the conventional method as an industrial production method.

Claims (5)

[Claims] (1) The following formula (A): (Wherein Boc means a tert-butoxycarbonyl group, and Ph means a phenyl group)
-Butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine or an acid addition salt thereof. 2. A process for producing 1-tert-butoxycarbonyl-trans-3-benzylamino-4-hydroxypyrrolidine (A), which comprises sequentially performing the following steps 1-3: [Step 1]: hydrogen In the presence of sodium chloride, the following formula (1) Tert-1,4-dichloro-2-butene represented by tert
Step of reacting 1-tert-butoxycarbonyl-3-pyrroline by reacting -butylcarbamate [Step 2]: reacting the compound obtained in Step 1 with N-bromosuccinimide to obtain the following formula (2) 3] (In the formula, Boc means a tert-butoxycarbonyl group) 1-tert-butoxycarbonyl-trans-3-bromo-4-hydroxypyrrolidine represented by the following formula: [Step 3]: obtained in Step 2 The compound is reacted with a base and then with benzylamine to give 1-tert-butoxycarbonyl-
Step of forming trans-3-benzylamino-4-hydroxypyrrolidine (A). 3. The following steps 4 and 5 are sequentially performed: 1-tert-butoxycarbonyl-trans-3
Method for producing -benzylamino-4-hydroxypyrrolidine (A): [Step 4]: The following formula (3): A step of introducing a tert-butoxycarbonyl group (hereinafter referred to as a Boc group in this section) at the 1-position of 3-pyrroline represented by the formula (1) to form 1-tert-butoxycarbonyl-3-pyrroline; [Step 5]: Step 4 The compound obtained in the above is oxidized to give the following formula (4): And reacted with benzylamine to give 1-tert-butoxycarbonyl-trans-3-
A step of forming benzylamino-4-hydroxypyrrolidine (A). 4. The following step (6) is performed sequentially: Method for producing (3S, 4S) -3-methoxy-4-methylaminopyrrolidine or an acid addition salt thereof represented by the following formula: [Step 6]: Formula (A): (In the formula, Boc means a tert-butoxycarbonyl group, and Ph means a phenyl group; the same applies hereinafter in this section.) 1-tert-butoxycarbonyl-trans-3-benzylamino-4- The hydroxypyrrolidine (A) is subjected to optical resolution with (+)-mandelic acid, and then treated with a base to give free (+)-1-tert-butoxycarbonyl- (3S, 4S) -3-benzylamino-4-.
[Step 7]: subjecting the compound obtained in step 6 to a debenzylation reaction and a Boc group introduction reaction to give the following formula (5): (+)-1-tert-butoxycarbonyl- represented by
(3S, 4S) -3-tert-butoxycarbonylamino-4-hydroxypyrrolidine [Step 8]: The compound obtained in Step 7 is methylated in the presence of sodium hydride to give the following formula (6) 9 (+)-1-tert-butoxycarbonyl- represented by
(3S, 4S) -3- [N-tert-butoxycarbonyl-N-methyl) amino] -4-methoxypyrrolidine [Step 9]: removing the Boc group of the compound obtained in Step 8 Converting the compound to an acid addition salt when a free base is obtained, and then converting it to a free base when an acid addition salt is obtained, if desired. 5. The following formula (C) characterized by sequentially performing the following steps 10 and 11: (+)-1,4-dihydro-7-[(3S,
4S) -3-Methoxy-4-methylamino-1-pyrrolidinyl] -4-oxo-1- (2-thiazolyl) -1,
Method for producing 8-naphthyridine-3-carboxylic acid or a physiologically acceptable salt thereof [Step 10]: (3S, 4S) -3-methoxy-4-methyl produced by the method according to claim 4. Aminopyrrolidine (B) or an acid addition salt thereof and the following formula (7): (Wherein L represents a leaving group, R represents a hydrogen atom or a lower alkyl group) or a salt thereof, [Step 11] wherein the compound obtained in Step 10 is When it is a lower alkyl ester, it is hydrolyzed, and when a free form is obtained, it is optionally converted to a physiologically acceptable salt, and when a salt is obtained, it is converted to a free form as desired. The process of converting.