JP2000273084A - Production of n-hydroxy-pyrrole-2-carboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce N-hydroxy-pyrrole-2-carboxylic acid preferentially as the formation of the 6-membered ring by-product is suppressed by stopping the reduction reaction of a nitro keto ester at the step of the hydroxylamine and allowing the hydroxylamine to cyclizing at the step. SOLUTION: The nitro keto ester of formula I (R1 to R3 are each H, an alkyl, an aryl or the like; R4 is alkyl) is treated with a reducing agent to give N-hydroxy-pyrrole-2-carboxylic acid. The reducing agent preferably can stop the reduction reaction of a nitro compound at the step of hydroxylamine, for example, tin (II) halide, zinc/acid, palladium/sodium hypophosphite or the like can be cited. The resultant compound of formula II is treated with another reducing agent [preferably titanium (III) halide to give the objective pyrrole-2- carboxylic acid of formula III. These reduction reactions may be carried out in succession.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing N-hydroxy-pyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid which are useful as intermediates for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art JP-A-7-188166 describes a tricyclic indole-2-carboxylic acid derivative useful as a selective antagonist of a glycine moiety of an NMDA receptor.
It also describes the production of an indole-2-carboxylic acid derivative by treating a nitroketoester with an aqueous solution of titanium trichloride.

[0003]

When a nitroketoester is treated with an aqueous solution of titanium trichloride or iron / hydrochloric acid,
Along with the indole-2-carboxylic acid derivative cyclized as a 5-membered ring, 2,3-dihydroxyquinoline cyclized as a 6-membered ring is produced as a by-product, so that the yield is poor.
Also, a purification step is required. For example, (2-iodo-4
-Chloro-6-nitrophenyl) pyruvate methyl
Under reflux with heating, reduction with iron / hydrochloric acid produces 10 to 20% of the corresponding 2,3-dihydroxyquinoline, and reduction with an aqueous solution of titanium trichloride at room temperature produces 30 to 40% of the corresponding 2,3-dihydroxyquinoline. I was born. Therefore, the problem to be solved by the present invention is to suppress the generation of by-products,
An object of the present invention is to provide a method capable of producing high-purity N-hydroxy-pyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid at a high yield.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that when a nitroketoester is reduced to an aminoketoester and cyclized, the nitroketoester and pyrrole-2-carboxylic acid are reacted together. Although a by-product of a six-membered ring is also formed, when the reduction reaction of the nitroketoester is completely or temporarily stopped at the stage of the hydroxylamine compound, and the cyclization is performed there, a corresponding by-product of the six-membered ring is formed. Is suppressed, N-hydroxy-pyrrole-2-carboxylic acid is preferentially formed, and further reduction is performed, whereby pyrrole-2-carboxylic acid of high purity can be produced at a high yield. Thus, the present invention has been completed.

[0005] That is, the present invention is as follows. [1] Equation 1:

[Formula 11] By treating a nitroketoester of formula with a reducing agent:

Embedded image A method for producing N-hydroxy-pyrrole-2-carboxylic acid represented by the formula: [Wherein, R ¹ , R ² and R ³ independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. However, R ¹ and R ² together form two adjacent
R ² and R ³ together may represent an aromatic ring that may be substituted with two carbon atoms and / or R ² and R ³ may be substituted with a cycloalkane or substituted with two adjacent carbon atoms May represent a heterocycloalkane. R ⁴ represents an optionally substituted alkyl. ]

[2] Equation:

Embedded image By treating a nitroketoester of the formula with a reducing agent:

Embedded image The method for producing N-hydroxy-pyrrole-2-carboxylic acid represented by [1]. [In the formula, R ⁴ represents an optionally substituted alkyl. R ⁵ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. R ⁶ and R ⁷ are
Independently a hydrogen atom, a halogen atom, a cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, a carboxyl, an optionally substituted carbamoyl, an optionally substituted alkoxycarbonyl,
Represents aryl or heteroaryl. However, R ⁵ and R ⁶ may together represent a cycloalkane which may be substituted with two adjacent carbon atoms or a heterocycloalkane which may be substituted. [3] The reducing agent is tin (II) halide, zinc / acid, palladium / sodium hypophosphite, palladium / trialkylsilane hydride or palladium / formic acid or ammonium formate [1] or [2]. The manufacturing method as described.

[4] Equation 1:

Embedded image By treating the nitroketoester represented by the formula with a reducing agent, the formula:

Embedded image By treating with an N-hydroxy-pyrrole-2-carboxylic acid represented by
formula:

Embedded image A method for producing a pyrrole-2-carboxylic acid represented by the formula: [Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. ]

[5] Equation:

Embedded image By treating the nitroketoester represented by the formula with a reducing agent, the formula:

Embedded image By treating with an N-hydroxy-pyrrole-2-carboxylic acid represented by
formula:

Embedded image The method according to [4], wherein pyrrole-2-carboxylic acid is represented by the formula: [Wherein, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as described above. [6] The reducing agent is tin (II) halide, zinc / acid, palladium / sodium hypophosphite, palladium / trialkylsilane hydride or palladium / formic acid or ammonium formate [4] or [5]. The process for producing pyrrole-2-carboxylic acid according to the above. [7] The pyrrole-2 according to any one of [4] to [6], wherein the another reducing agent is a titanium (III) halide or iron.
-A process for producing carboxylic acids.

[0009] Examples of the "alkyl" include linear or branched alkyl having 6 or less carbon atoms, and specifically, methyl, ethyl, propyl, 1-methylethyl, butyl,
2-methylpropyl, pentyl, 1,2-dimethylpropyl, hexyl, 3-methylpentyl and the like.
Examples of "alkoxy" include straight-chain or branched-chain alkoxy having 6 or less carbon atoms, and specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, 2
-Dimethylpropoxy, hexyloxy, 3-methylpentoxy and the like. As "alkanoyl",
For example, straight-chain or branched-chain alkanoyl having 6 or less carbon atoms may be mentioned, and specific examples include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like. The “cycloalkane” includes, for example,
To 8 cycloalkane rings, specifically, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like. As "heterocycloalkane",
For example, a 5-membered or 6-membered heterocycloalkane containing 1 to 3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom can be mentioned. Examples of the 5-membered heterocycloalkane include 1 or 2 arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as pyrrolidine, pyrroline, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydrothiophene, and dioxolane. 5-membered heterocycloalkanes containing 10 atoms. Examples of the 6-membered heterocycloalkane include one or two atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as piperidine, piperazine, morpholine, tetrahydropyran, and dioxane. 6
Membered heterocycloalkanes.

The “substituent” of the substituted alkyl, substituted cycloalkane, substituted heterocycloalkane, optionally substituted alkoxy and optionally substituted alkoxycarbonyl includes, for example, halogen atom, cyano, alkoxy,
Examples include optionally substituted amino, carboxyl, optionally substituted carbamoyl, optionally substituted alkoxycarbonyl, aryl, heteroaryl and the like. One or more of these substituents may be independently substituted.

[0011] The "aryl" includes aryl having 6 to 10 carbon atoms, specifically, phenyl, naphthyl and the like. As the “heteroaryl”, for example, a 5-membered ring or a 6-membered ring containing 1 to 3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom
Membered heteroaryl and the like. Examples of the 5-membered heteroaryl include pyrrolyl, thienyl, furyl,
5-membered heteroaryl containing one or two atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, such as imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, thiazolyl and oxazolyl. Examples of the 6-membered heteroaryl include a 6-membered heteroaryl containing 1 to 3 nitrogen atoms, and specific examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
As the “aromatic ring”, for example, a 5-membered ring or a 6-membered ring containing 1 to 3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom
And a membered heteroaromatic ring. The 5-membered heteroaromatic ring is arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as pyrrole, thiophene, furan, imidazole, pyrazole, isothiazole, isoxazole, thiazole, and oxazole. 5-membered heteroaromatic rings containing one or two atoms are included. As the 6-membered heteroaromatic ring, one nitrogen atom
Examples thereof include a 6-membered heteroaromatic ring containing from 3 to 3, and specific examples include pyridine, pyrazine, pyrimidine, pyridazine, and triazine.

[0012] The "substituent" of the substituted aryl and the substituted aromatic ring includes, for example, a halogen atom, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, substituted Carbamoyl, optionally substituted alkoxycarbonyl, aryl, heteroaryl and the like. One or more of these substituents may be independently substituted.

[0013] Examples of the substituted amino include amino substituted with one or two alkyl, aryl, or alkanoyl. As the substituted carbamoyl, 1 or 2
Carbamoyl substituted with a single alkyl or aryl. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

As the "reducing agent", a reducing agent capable of stopping the reaction at the stage of the hydroxylamine compound in the reduction reaction of the nitro compound, that is, completely or temporarily at the stage of the hydroxylamine compound in the reduction reaction of the nitro compound. And a reducing agent which has a lower reduction rate from a nitro compound to a hydroxylamine compound than a reduction rate from a hydroxylamine compound to an amine compound. Specifically, tin (II) halides such as tin (II) chloride, zinc /
Examples include acetic acid, zinc / acid such as zinc / ammonium chloride, and the like. Further, a reducing agent capable of stopping the reduction of the nitro compound at the stage of the hydroxylamine compound by controlling the equivalent of the hydrogen source can also be used. As the hydrogen source, specifically, sodium hypophosphite,
Examples include hydrogenated trialkylsilanes, formic acid, ammonium formate, and the like, and examples thereof include reducing agents in which these hydrogen sources are used in a stoichiometric amount and combined with a palladium reagent such as palladium carbon. "Another reducing agent" includes N-hydroxy-
Examples of a reducing agent that can reduce the pyrrole compound to a pyrrole compound include, for example, titanium halides such as titanium trichloride.
(III), iron, Raney nickel and the like.

Hereinafter, the production method of the present invention will be described.

Embedded image [Wherein, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as described above. By treating the nitroketoester of Formula 1 with a reducing agent,
N-hydroxy-pyrrole-2-carboxylic acid of Formula 2 can be prepared. The reaction conditions are the "reducing agent" used.
References (J. March, Advanced Organic
Chemistry, Fourth Ed., 1216-1218 (1992)) and the like can be carried out in accordance with the usual conditions. For example, when tin (II) chloride is used, the amount of tin (II) chloride used is 2 to the nitroketoester of the formula 1.
To 5 mol, preferably 2.2 to 3 mol. As a reaction solvent, dimethoxyethane, THF
And hydrophilic organic solvents such as amides such as DMF and the like. The amount of the organic solvent used is, for example, 5 to 20 times the weight of the nitroketoester of the formula 1. The reaction temperature is, for example, in the range of 0 to 50 ° C. Subsequently, the N-hydroxy-pyrrole-2-carboxylic acid of formula 2 can be treated with another reducing agent to give pyrrole-2 of formula 3
A carboxylic acid can be produced. The reaction conditions vary depending on the “other reducing agent” used, but are described in the literature (J. Mar.
ch, Advanced Organic Chemistry, Fourth Ed., 1216-1
218 (1992)) and the like. For example, when titanium trichloride is used, the amount of titanium trichloride used is 2 to 10 mol based on N-hydroxy-pyrrole-2-carboxylic acid of the formula 2, preferably 2.5 to 3 mol. Mole.
Examples of the reaction solvent include ethers such as dimethoxyethane and THF, alcohols such as methanol and ethanol, and DMF.
And the like, and hydrophilic organic solvents such as ketones such as acetone, and the like. The amount of the solvent used is, for example, 5 to 20 times the weight of the nitroketoester of the formula 1. The reaction temperature is, for example, in the range of 0 to 30 ° C. It is preferred to use titanium trichloride as the aqueous solution. In addition, two steps can be continuously performed from the nitroketoester of the formula 1.

[0016]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Reaction step A

Embedded image

[A-1]3-iodo-4-chloro-6-nitrotoluene  Under a nitrogen stream, 4-chloro-2-nitrotoluene (343 g, 2.00
 mol) in concentrated sulfuric acid (1960 g, 20.0 mol, 10 eq.)
Was. To this solution, add ice_Two(204 g, 0.800 mol, 0.4
eq.) and NaIO_Three(158 g, 0.800 mol, 0.4eq.)
It was added slowly and stirred for 6 hours. Ice-cool the reaction
Below, slowly add water (2 L), and add toluene (2.5 L).
Extracted. Organic layer is 10% Na_TwoS_TwoO_ThreeTreat with aqueous solution and add water (1
 L, twice), NaHCO_ThreeWash with aqueous solution (1 L, 2 times)_Two
SO_FourAnd concentrated to give crude A-1 (548 g, purity 62).
%) As a yellow liquid. This product must be purified.
Used for the next reaction without.¹ H-NMR (270MHz, CDCl_Three) δ: 2.56 (3H, s), 7.74 (1H,
d, J = 2.0Hz), 8.06 (1H, d, J = 2.0Hz).

[A-2](2-Iodo-4-chloro-6-nitrophenyl) pyr
Methyl borate  In a nitrogen atmosphere, adjusted KOMe (188 g, 2.69 mol, 4 e
q.) / methanol (560 mL) solution and toluene (280 m
L) and (CO_TwoCH_Three)_Two(318 g, 2.69 mol, 4 eq.)
And stirred at room temperature for 20 minutes. The above crude A-1 was added to this solution.
(200 g) in toluene (280 mL) at room temperature
And stirred for 4 hours. Appropriately with methanol (200-300 mL)
While diluting, pour into stirred 5N hydrochloric acid (600 mL) under ice-cooling.
Slowly injected. Ethyl acetate (1 L) and water (600 mL)
, And the mixture was separated and extracted with ethyl acetate / tolue.
(2: 1, 300 mL). Combine the organic layers
Concentrate, add toluene (500 mL) and concentrate again.
Thus, crude A-2 (374 g) was obtained as a brown liquid substance.
Was. This was used for the next reaction without purification.¹ H-NMR (270MHz, CDCl_Three) δ: 3.95 (3H, s), 4.70 (2H,
s), 8.01 (1H, d, J = 2.0Hz), 8.15 (1H, d, J = 2.0Hz).

[A-2](2-Iodo-4-chloro-6-nitrophenyl) pyr
Methyl borate  Under a nitrogen atmosphere, 28% NaOMe / methanol solution (324 g, 1.
68 mol, 5 eq.), (CO_TwoCH_Three)_Two(199 g, 1.68 mol, 5 e
q.) and stirred at room temperature for 30 minutes. Add this solution to
A solution of crude A-1 (100 g) in methanol (340 mL)
The mixture was added dropwise at room temperature and stirred for 16 hours. Methanol (100-200 m
5N hydrochloric acid (300 L
 mL). Ethyl acetate / toluene
(2: 1, 750 mL) and water (400 mL), and perform liquid separation extraction.
The aqueous layer was reconstituted with ethyl acetate / toluene (2: 1, 150 mL).
Extracted. Combine the organic layers and concentrate, then add toluene
(300 mL) and concentrated again to give crude A-2 (165
 g) was obtained as a brown liquid. This product must be purified.
Used for the next reaction without.

[A-3]4-iodo-6-chloroindole-2-carboxylic acid
Chill  Under a nitrogen stream, SnCl_Two H_TwoO (299 g, 1.33 mol, 3 eq.) / Di
In a methoxyethane (410 mL) solution, the above crude A-
2 Add a solution of 220 g of dimethoxyethane (410 mL)
The mixture was dropped and stirred for 1 hour. Then add ice to this solution
Under cooling, 20% TiCl _ThreeSlowly add aqueous solution (682 g, 0.884 mol)
The mixture was added dropwise and stirred for 1 hour. Ethyl acetate / toluene (2:
1) Add (2.4 L) and 6N hydrochloric acid (1.4 L) and warm to room temperature
After that, liquid separation was performed. Wash the organic layer with 1N hydrochloric acid (1.4 L)
And the solvent was distilled off to obtain crude A-3 (158 g).
Was. This crude A-3 was suspended in acetonitrile (1.55 L).
And heat to reflux for 30 minutes, and further stir at around 30 ° C for 1 hour.
Was. The precipitate is collected by filtration, and the precipitate is filtered with ice-cold acetonitrile (15
Wash with 0 mL, 60 mL x 2) and dry under reduced pressure to obtain A-
3 (75.9 g, 51% yield from 4-chloro-2-nitrotoluene)
Was obtained as a pale yellow solid.¹ H-NMR (270 MHz, d₆-DMSO) δ: 3.89 (3H, s), 6.91 (1H,
 s), 7.48 (1H, m), 7.56 (1H, d, J = 2.0Hz), 12.5 (1
H, br.s).

[A-4]4- (2-formylethyl) -6-chloroindole-
Methyl 2-carboxylate  Under a nitrogen atmosphere, A-3 (87.5 g, 261 mmol) / DMF (440
 mL) solution into NaHCO_Three(43.9 g, 522 mmol, 2.0 eq.),
Benzyltriethylammonium chloride (59.5g, 261 mmo
l, 1.0 eq.), Pd (OAc)_Two(1.17 g, 5.22 mmol, 0.02 e
q.) and allyl alcohol (30.3 g, 522 mmol, 2.0
eq.) and stirred at 40-50 ° C. for 2 hours. Reaction chamber
Allow to cool to warm, Na_TwoS_TwoO_Three.5H_TwoO (2.6 g, 10.4 mmol) in water
(18 mL) solution was added and stirred vigorously at room temperature for 20 minutes.
Next, activated carbon (4.4 g) was added, and the mixture was stirred for 15 minutes.
I have. The filtrate was washed with DMF (60 mL) and the resulting filtrate
And washing solution, and add water (1.5 L) while stirring under ice-cooling.
The mixture was slowly added dropwise and stirred at room temperature for 30 minutes. Filter the solid
Wash with water (300 mL, twice) and dry under reduced pressure.
Thus, A-4 (62.5 g) was obtained as a yellow-white solid.¹ H-NMR (270MHz, CDCl_Three) δ: 2.90 (2H, t, J = 7.4Hz), 3.
20 (2H, t, J = 7.4Hz), 3.96 (3H, s), 6.96 (1H, d, J =
1.7Hz), 7.22 (1H, d, J = 1.7Hz), 7.29 (1H, d, J = 1.3H
z), 9.06 (1H, br.s), 9.86 (1H, t, J = 1.0Hz).

[A-5]4- (4-ethoxycarbonyl-3-butenyl) -6
Chloroindole-2-carboxylate  At room temperature under a nitrogen atmosphere, t-BuOK (39.9 g, 356 mmol, 1.
1 eq.) In THF (516 mL).
Honoacetate (79.8 g, 356 mmol, 1.1 eq.)
The mixture was dropped and stirred for 30 minutes. At room temperature, A-
4 (86.0 g, 324 mmol) in THF (860 mL)
The mixture was dropped and stirred for 1.5 hours. Add water (1.2L) and add vinegar
Extract with ethyl acetate / toluene (1: 1) (1.8 L)
(1.2L x 2), and washed twice and concentrated to give A-5
(111 g) was obtained as a white solid.¹ H-NMR (270MHz, CDCl_Three) δ: 1.29 (3H, t, J = 7.2Hz), 2.
63 (2H, m), 3.02 (2H, m), 3.96 (3H, s), 4.19 (2H,
q, J = 7.2Hz), 5.87 (1H, d, J = 15.8Hz), 6.95 (1H, d,
J = 1.65Hz), 7.02 (1H, dt, J = 15.8,6.9Hz), 7.21 (1H,
t, J = 1.0Hz), 7.29 (1H, s), 9.02 (1H, br.s).

[A-6]3-Iodo-4- (4-ethoxycarbonyl-3-bute
Nyl) -6-chloroindole-2-carboxylate methyl  Under a nitrogen stream, under water cooling, NaI (53.6 g, 357 mmol, 1.2 e
q.) was added to DMF (400 mL) and stirred, and NCS (4
7.7 g, 357 mmol, 1.2 eq.) / DMF (400 mL) solution
It was added slowly and stirred at room temperature for 1 hour. This reaction mixture
A-5 (100 g, 298 mmol) in DMF (400 mL)
The solution was slowly added dropwise and stirred at room temperature for 2 hours. 1 in the reaction solution
0% Na_TwoS_TwoO_ThreeAqueous solution (600 mL) and water (2200 mL) slowly
The mixture was added dropwise and stirred at room temperature for 2 hours. Filter off the solid and add water (5
After washing and drying under reduced pressure, A-6 (128 mL
g, 93%) as a pale yellow solid.¹ H-NMR (270MHz, CDCl_Three) δ: 1.31 (3H, t, J = 7.2Hz), 2.
61 (2H, m), 3.44 (2H, m), 3.99 (3H, s), 4.21 (2H, m
q, J = 7.2Hz), 5.94 (1H, d, J = 15.8Hz), 6.94 (1H, d,
J = 1.7Hz), 7.10 (1H, dt, J = 15.8,6.9Hz), 7.32 (1H,
d, J = 1.7Hz), 9.35 (1H, br.s).

[A-7]3-ethoxycarbonylmethylidene-1,3,4,5-
Tetrahydrobenz [c, d] indole-2-carbo
Methyl acid  Under a nitrogen atmosphere, A-6 (6.00 g, 13.0 mmol) and Pd (PP
h_Three)_Four(300 mg, 0.26 mmol, 0.02 eq.) In DMF at room temperature.
(60 mL). Ag_ThreePO_Four(4.35 g, 10.4 mmol) and
Water (12 mL) was added, and the mixture was stirred at 87 to 89 ° C for 3.5 hours. this
The reaction mixture was allowed to cool, and activated carbon (300 mg) was added.
Stir for 15 minutes. Filtrate, and filter the residue with ethyl acetate / tolue.
(1: 1) (50 mL), and combine the filtrate and washing solution.
Furthermore, ethyl acetate / toluene (1: 1) (50 mL) and water (50 m
L) was added and the mixture was separated. Wash the organic layer with water (30 mL x 2)
Activated carbon (300 mg) and MgSO_FourAdd, stir and filter
And concentrated under reduced pressure to give A-7 (4.67 g) as a brown solid
As obtained.

[A-8]3-ethoxycarbonylmethyl-1,3,4,5-tetra
Lahydrobenz [c, d] indole-2-carboxylic acid
Methyl  Under nitrogen atmosphere, A-6 (45.0 g, 97.5 mmol) / Monoc
Heat the lorobenzene (1.8 L) solution to reflux and add hydrogen
Tri-n-butyltin bromide (34.0 g, 117 mmol, 1.2 eq.)
Azobisisobutyronitrile (4.00 g, 24.4 mmol, 0.2
5 eq.) / Monochlorobenzene (200 mL) solution
Then, the mixture was stirred under reflux for 1 hour. Release the reaction mixture to room temperature
After cooling, the solvent was distilled off under reduced pressure, acetonitrile (300 mL),
Add hexane (300 mL) and activated carbon (4.5 g),
Stirred vigorously at warm for 30 minutes. After that, it was filtered and
Separate the tolyl layer and separate the hexane layer with acetonitrile.
(100 mL). Transfer the combined acetonitrile layer to
Wash with xane (300 mL x 3) to reduce the acetonitrile layer.
A-8 (31.3 g) was obtained by pressure concentration.

[A-8]3-ethoxycarbonylmethyl-1,3,4,5-tetra
Lahydrobenz [c, d] indole-2-carboxylic acid
Methyl  Under a nitrogen atmosphere, A-7 (1.72 g, 5.14 mmol) was added to THF.
(12 mL) and methanol (0.640 mL, 15.8 mmo)
l, 3.1 eq.) and samarium (1.58 g, 10.5 mmol, 2.0 e)
q.). The reaction mixture is added to iodine (1.
21 g, 4.78 mmol, 0.9 eq.) / THF (5 mL)
The mixture was dropped dropwise and stirred for 2 hours. Triethylamine (1.3
3 mL, 9.56 mmol, 2.0 eq.) And bring the reaction mixture to room temperature.
And stirred for 3 hours. The reaction mixture is brought to 0-5 ° C with 1N salt
Acid (30 mL) is slowly added dropwise, and ethyl acetate (30 mL) is added.
In addition, the mixture was vigorously stirred at room temperature for 15 minutes to separate the layers. Organic layer
1N hydrochloric acid (15 mL x 2), 10% Na_TwoS_TwoO_ThreeAqueous solution (15 mL x
2 times), washed with saturated saline (10 mL) and activated carbon (85 m
g) and MgSO_Four(260 mg) and stir at room temperature for 10 minutes.
Was. A-8 (1.67 g) was obtained by filtration and concentration under reduced pressure.
Was.¹ H-NMR (270MHz, CDCl_Three) δ: 1.28 (3H, t, J = 7.3Hz), 2.
01 (1H, m), 2.17 (1H, m), 2.48 (1H, dd, J = 14.9,10.5
Hz), 2.73 (1H, dd, J = 14.9,4.0Hz), 2.82 (1H, m), 3.0
0 (1H, m), 3.92 (1H, m), 3.95 (3H, s), 4.18 (2H,
q, J = 7.3Hz), 6.88 (1H, s), 7.17 (1H, s), 8.70 (1H,
 br.s).

[A-9]3-carboxylmethyl-1,3,4,5-tetrahydrido
Robbens [c, d] indole-2-carboxylate methyl  Under a nitrogen atmosphere, A-8 (122.8 g, 365.7 mmol) was treated with acetic acid.
(620 mL) at 80 ° C, add concentrated hydrochloric acid (245 mL),
The mixture was stirred at 80 ° C for 3.5 hours. Cool to room temperature and add water (1250 m
L) and extracted with THF / ethyl acetate (1: 3) (4900 mL).
Issued. After washing the organic layer with water (1250 mL x 2),
Add charcoal (6.5 g), stir at room temperature for 10 minutes, filter,
After concentration under reduced pressure, crude A-9 (111.3 g) was obtained. Crude A-9 (1
Acetonitrile (490 mL) was added to 11.3 g) and refluxed for 1 hour
Then, the mixture was allowed to cool to room temperature, and the precipitated crystals were collected by filtration and washed with acetone.
Wash with tonitrile (60 mL x 3) and dry under reduced pressure
A-9 (57.8 g, 55.8%) was obtained as white crystals.¹ H-NMR (270 MHz, d₆-DMSO) δ: 1.88 (1H, m), 2.11 (1H,
 br.d, J = 12.5Hz), 2.37 (1H, dd, J = 15.2, 10.6Hz), 2.
56 (1H, dd, J = 15.2, 4.3Hz), 2.80 (1H, br.d, J = 17.2H
z), 2.94 (1H, br.t, J = 13.9Hz), 3.77 (1H, m), 3.88
(3H, s), 6.84 (1H, s), 7.17 (1H, s), 11.60 (1H, s),
 12.17 (1H, br.s).

[A-10]3- (S) -3-carboxylmethyl-1,3,4,5
-Tetrahydrobenz [c, d] indole-2-cal
Methyl bonate  Under a nitrogen atmosphere, A-9 (21.0 g, 68.24 mmol) was
Add to pill alcohol (1050 mL), dissolve under reflux,
(-)-Norephedrine (10.32 g, 68.24 mmol) / isop
Add a propyl alcohol (210 mL) solution and heat to reflux for 10 minutes
And cooled slowly and stirred at room temperature. Filter the crystals
Wash with ice-cold isopropyl alcohol (50 mL x 2),
By drying under reduced pressure, L-(-)-norephed of crude A-10 was obtained.
The phosphorus salt (14.78 g, 79.7% ee) was obtained. Under nitrogen atmosphere, coarse
L-(-)-Norephedrine salt of A-10 (29.4 g, 78.6% e
e) to isopropyl alcohol (590 mL) and add for 4 hours.
Heated to reflux, cooled slowly and stirred at room temperature. Crystal
Filter and wash with ice-cold isopropyl alcohol (60 mL x 2)
Purify and dry under reduced pressure to obtain A-10 L-(-)-norefe
Obtained as the drin salt (25.11 g, 98.5% ee). L-10 of A-10
64.19 g of (-)-norephedrine salt was added to 500 mL of 1N hydrochloric acid and acetic acid.
The residue was dissolved in 2 L of ethyl / THF (3: 1) and separated. This
The organic layer was washed with water (500 mL x 2), activated carbon (3.0 g) and M
gSO_Four, And the mixture was filtered.The solvent was distilled off.
After washing with nitrile and drying under reduced pressure, A-10 (4
1.89 g, 97.3%, 98.1% ee).¹ H-NMR (270 MHz, d₆-DMSO) δ: 1.88 (1H, m), 2.11 (1H,
 br.d, J = 12.5Hz), 2.37 (1H, dd, J = 15.2, 10.6Hz), 2.
56 (1H, dd, J = 15.2, 4.3Hz), 2.80 (1H, br.d, J = 17.2H
z), 2.94 (1H, br.t, J = 13.9Hz), 3.77 (1H, m), 3.88
(3H, s), 6.84 (1H, s), 7.17 (1H, s), 11.60 (1H, s),
 12.17 (1H, br.s).

Reaction step B

Embedded image

[B-1]S-2-hydroxypropionic acid morpholinoamide  Under a nitrogen atmosphere, stirred L-methyl lactate (50.0 g, 0.48 m
ol) and morpholine (46 mL, 0.528 mol) under ice-cooling.
Slowly add 0% sodium hydride (1.92 g, 0.048 mol).
Then, the mixture was stirred at 50 ° C. for 3 hours. Add toluene and evaporate under reduced pressure
This operation was repeated three times to obtain B-1.

[B-2]S-2-tosyloxypropionic acid morpholinoamide  Under nitrogen, 60% sodium hydride (20.17 g, 0.504 mol)
When the suspension in THF (400 mL) was cooled on ice,
The obtained B-1 / THF (400 mL) solution is slowly dropped.
Then, the temperature was gradually raised and the mixture was stirred at 50 ° C. for 30 minutes. This reaction mixture
Was cooled on ice and p-toluenesulfonyl chloride (109.87 g, 0.
576 mol) / THF (400 mL) solution was slowly added dropwise.
While stirring. 1N hydrochloric acid was added to the reaction mixture to adjust the pH to 1.
And extracted with about 500 mL of ethyl acetate. Saturate the organic layer with water
Wash with brine and wash with MgSO_Four, Filtered and evaporated under reduced pressure.
Was. About 100 ml of diethyl ether was added to the obtained concentrated residue.
About 30 mL of xan is added, and the precipitated crystals are collected by filtration.
After washing with chill ether and drying, B-2 (10
9.7 g) were obtained.¹ H-NMR (270 MHz, CDCl_Three) δ: 7.81 (d, 2H, J = 8.3Hz),
7.35 (d, 2H, J = 8.3Hz), 5.27 (q, 1H, J = 6.6Hz), 3.63
(m, 4H), 3.57 (m, 3H), 3.42 (m, 1H), 2.46 (s, 3H),
 1.47 (d, 3H, J = 6.6Hz).

[B-3]5-hydroxymethyl-2-nitrophenol  Under a nitrogen atmosphere, 3-hydroxy-4-nitrobenzoic acid
(50.0 g, 0.273 mol) to dichloroethane (1000 mL).
And trimethoxyborane (45.39 g, 0.437 mol)
Boron iodide diethyl ether complex (61.99 g, 0.437 mo
l) and boranepyridine complex (38.05 g, 0.410 mol)
Was slowly added dropwise and stirred at room temperature for 4 hours. Reaction mixture
Was cooled on ice, methanol (100 mL) was added dropwise, and the mixture was stirred and
Distilled off. Add toluene (400 mL) and add 1N sodium hydroxide
Extracted three times with an aqueous solution of ethanol (300 mL). Combine the aqueous layers and concentrate
Adjust the pH to 1 with acid and extract with ethyl acetate (500 mL and 300 mL).
Was. The organic layer was washed with water (300 mL x 2) and saturated saline,
gSO_Four, And filtered, and the solvent was distilled off to obtain B-3 (4
3.25 g, 93.6%).¹ H-NMR (270 MHz, CDCl_Three) δ: 10.65 (s, 1H), 8.09 (d,
1H, J = 8.6Hz), 7.17 (d, 1H, J = 1.7Hz), 6.96 (dd, 1H,
J = 8.6, 1.7Hz), 4.77 (s, 2H), 1.94 (br.s, 1H).

[B-4]2- (1-R-morpholinocarbonylethoxy) -4-
Hydroxymethyl nitrobenzene  Under a nitrogen atmosphere, B-3 (43.00 g, 0.254 mol) and B-2 (8
3.58 g, 0.267 mol) in DMF (150 mL)
Add potassium (52.71 g, 0.381 mol) and stir at 50 ° C for 6 hours.
Stirred. About 400 mL of water is added to the reaction mixture, and
Extracted twice with 300 mL of methane. 5% carbonic acid combined organic layers
Wash with aqueous potassium solution, 1N aqueous hydrochloric acid and water, MgSO_FourDry with
Then, the mixture was filtered and the solvent was distilled off to give B-4 (93.24 g, 11
8%, 99.3% ee).¹ H-NMR (270 MHz, CDCl_Three) δ: 7.80 (d, 1H, J = 8.3Hz),
7.11 (d, 1H, J = 1.6Hz), 7.02 (dd, 1H, J = 8.3, 1.6Hz),
 5.09 (q, 1H, J = 6.9Hz), 4.72 (d, 2H, J = 5.6Hz), 4.1
5 (t, 1H, J = 5.6Hz), 3.87 (m, 1H), 3.68 (m, 4H), 3.
51 (m, 3H), 1.67 (d, 3H, J = 6.9Hz).

[B-5]2- (1-R-morpholinocarbonylethoxy) -4-
Methanesulfonyloxymethylnitrobenzene  Under nitrogen atmosphere, B-4 (93.0 g, 0.300 mmol)
Dissolve in methane (500 mL) and triethylamine (50.1
mL, 0.360 mol) and add methanesulfonyl chloride under ice-cooling.
Ride (36.05 g, 0.315 mol) was slowly added dropwise and stirred.
Was. About 300 mL of 1N aqueous hydrochloric acid was added to the reaction mixture, and the mixture was separated.
And the organic layer was washed with water and dried over MgSO_FourDry, filter and dissolve
The solvent was distilled off to obtain B-5 (96.97 g, 83.3%).¹ H-NMR (270 MHz, CDCl_Three) δ: 7.85 (d, 1H, J = 8.2Hz),
7.11 (d, 1H, J = 1.7Hz), 7.09 (dd, 1H, J = 8.2, 1.7Hz),
 5.24 (s, 2H), 5.08 (q, 1H, J = 6.9Hz), 3.92 (m, 1H),
 3.69 (m, 4H), 3.48 (m, 3H), 3.09 (s, 3H), 1.70
(d, 3H, J = 6.9Hz).

[B-6]2- (1-R-morpholinocarbonylethoxy) -4-
Phthalimidomethylnitrobenzene  Under nitrogen, B-5 (96.74 g, 0.249 mol) was added to DMF (800 m
L) dissolved in potassium phthalimide (50.75
g, 0.274 mol) and stirred at room temperature for 1.5 hours. Reaction mixture
Add 1000 mL of water to the mixture, and add ethyl acetate / toluene (2: 1)
Was extracted twice with 700 mL. Combine the organic layers and add water (40
(3 x 0 mL x 3)) and saturated brine, wash with MgSO_FourAnd dry
After that, the solvent was distilled off to obtain 107.9 g of a concentrated residue. This concentration
About 400 mL of diethyl ether and 50 mL of toluene
In addition, crystallized, and the precipitated crystals are collected by filtration and diethyl ether
And dried under reduced pressure to give B-6 (73.61 g).
I got¹ H-NMR (270 MHz, CDCl_Three) δ: 7.87 (m, 2H), 7.80 (d,
1H, J = 7.3Hz), 7.75 (m, 2H), 7.10 (d, 1H, J = 1.7Hz),
7.08 (dd, 1H, J = 7.3, 1.7Hz), 5.02 (q, 1H, J = 6.9H
z), 4.88 (d, 1H, J = 15.2Hz), 4.81 (d, 1H, J = 15.2H
z), 3.88 (m, 1H), 3.71-3.51 (m, 4H), 3.49-3.31 (m,
 3H), 1.65 (d, 3H, J = 6.9Hz).

[B-7]2- (1-R-morpholinocarbonylethoxy) -4-
Aminomethylnitrobenzene  Under a nitrogen atmosphere, B-6 (73.4 g, 0.167 mol) / THF (80
Hydrazine monohydrate (32.4 mL, 0.668 mol)
And p-toluenesulfonic acid monohydrate (3.18 g, 0.0167 mol)
Was added and stirred under reflux for about 6 hours. Bring the reaction mixture to room temperature
And add 1000 mL of 5% aqueous potassium carbonate solution to pH
And extract with dichloromethane (500 mL x 2 times, 200 mL)
did. Combine the organic layers and wash with 1 L of water, MgSO_FourDry with
Then, the mixture was filtered and the solvent was distilled off to give B-7 (47.30 g, 9
1.5%).¹ H-NMR (270 MHz, CDCl_Three) δ: 7.83 (d, 1H, J = 8.3Hz),
7.13 (s, 1H), 7.05 (d, 1H, J = 8.3Hz), 5.09 (q, 1H, J
= 6.9Hz), 3.96 (m, 1H), 3.93 (s, 2H), 3.69 (m, 4H),
 3.56-3.38 (m, 3H), 1.69 (d, 3H, J = 6.9Hz), 1.50 (b
r.s, 2H).

[B-8]2- (1-R-morpholinocarbonylethoxy) -4-
t-butoxycarbonylaminomethylnitrobenzene  Under nitrogen atmosphere, B-7 (47.10 g, 0.152 mol) / ethyl acetate
(Boc)_TwoO (36.56 g, 0.167 mol)
And stirred at room temperature for about 1 hour. The solvent is distilled off and toluene
Add about 400 mL, dissolve under heating, stir at room temperature,
The mixture was stirred under ice cooling for 2 hours, and the crystals were collected by filtration and washed with toluene.
And dried at 50 ° C. under reduced pressure to give B-8 (58.09 g,
93.2%, 99.7% ee).¹ H-NMR (270 MHz, CDCl_Three) δ: 7.82 (d, 1H, J = 8.6Hz),
7.00 (m, 2H), 5.07 (m, 1H), 5.06 (q, 1H, J = 6.9Hz),
4.32 (d, 2H, J = 6.4Hz), 3.91 (m, 1H), 3.69 (m, 4H),
 3.55-3.37 (m, 3H), 1.68 (d, 3H, J = 6.9Hz), 1.46
(s, 9H).

[B-9]2- (1-R-morpholinocarbonylethoxy) -4-
t-butoxycarbonylaminomethylaniline  Under a nitrogen atmosphere, B-8 (20.0 g, 48.85 mmol) / ethyl acetate
5.0% 10% Pd / C (50% wet)
The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Under nitrogen atmosphere, M
gSO_FourAnd dried with Celite, and filtered off with Pd / C using Celite.
And B-9 (19.44 g, 105%) was distilled off.
Obtained.¹ H-NMR (270 MHz, CDCl_Three) δ: 6.73 (d, 1H, J = 7.6Hz),
6.70 (s, 1H), 6.66 (d, 1H, J = 7.6Hz), 4.98 (q, 1H, J
= 6.6Hz), 4.80 (br.s, 1H), 4.14 (d, 2H, J = 7.3Hz),
3.89 (br.s, 2H), 3.63-3.52 (m, 8H), 1.60 (d, 3H, J
= 6.6Hz), 1.45 (s, 9H).

[B-10]2- (1-R-morpholinocarbonylethoxy) -4-
Phthalimidomethylaniline  10% was added to a solution of B-6 (11.0 g, 25 mmol) / DMF (77 mL).
 Add Pd / C (50% wet, 2.0g) and add hydrogen gas at 40 ° C 3.
Stir for 5 hours. The reaction solution was filtered through celite,
The upper material was washed with DMF (10 mL × 2). Water (75 mL) in the filtrate
, And cooled to room temperature, and the precipitated crystals were collected by filtration.
0 mL x 2) and THF (10 mL x 2), then dry under reduced pressure.
Thereby, B-10 (8.71 g, 85%) was obtained.¹ H-NMR (270 MHz, CDCl_Three) δ: 7.71-7.78 (m, 2H), 7.59
-7.65 (m, 2H), 6.85 (dd, 1H, J = 1.8, 7.9Hz), 6.79
(d, 1H, J = 1.8Hz), 6.57 (d, 1H, J = 7.9Hz), 4.95 (q, 1
H, J = 6.7Hz), 4.62 (s, 2H), 3.83 (bs, 2H), 3.41-3.6
8 (m, 8H), 1.52 (d, 3H, J = 6.7Hz).

Reaction step C

Embedded image

[C-1]3- (S) -3- (2- (1-R-morpholinocarboni)
Ruethoxy) -4-t-butoxycarbonylaminomethyl
Ruphenyl) aminocarbonylmethyl-1,3,4,5
-Tetrahydrobenz [c, d] indole-2-cal
Methyl bonate  Under a nitrogen atmosphere, A-10 (39.0 g, 127 mmol) was added to ethyl acetate.
(390 mL) and DMF (0.196 mL).
Xalyl chloride (16.9 g, 133 mmol) is slowly added dropwise.
Then, the mixture was stirred at room temperature for 2 hours. Solvent and excess oxide
The chloride was distilled off and dissolved again in 260 mL of ethyl acetate.
I let you. B-9 (57.68 g, 152 mmol) / ethyl acetate solution
(About 880 mL) with triethylamine (26.5 mL, 190 mmol).
In addition, under ice cooling, activated A-10 / vinegar prepared above
Ethyl acid solution was slowly added dropwise and stirred for 1 hour under ice cooling
The mixture was further stirred at room temperature for 1 hour. 5% sulfuric acid aqueous solution in the reaction mixture
Aqueous potassium hydroxide solution (500 mL) was added to adjust the pH to 2, and acetic acid was added.
800 mL of chill was added for extraction. The organic layer was saturated with 500 mL of water.
Wash with 400 mL of aqueous sodium bicarbonate, 500 mL of water and 200 mL of saturated saline, and add M
gSO_Four, And the solvent was distilled off to obtain crude C-1.
(88.51 g) was obtained. This crude C-1 was added to 450 mL of toluene.
Heat to dissolve, cool slowly, and stir at room temperature.
Stirred. The crystals are collected by filtration, washed together with the filtrate, and toluene 80 m
After washing twice with L and drying under reduced pressure at 40 ° C., C-1 (83.
04 g, 97.7%).¹ H-NMR (270 MHz, CDCl_Three) δ: 9.02 (s, 1H), 8.82 (s,
1H), 8.36 (d, 1H, J = 8.3Hz), 7.18 (s, 1H), 6.93 (d,
 1H, J = 8.3Hz), 6.86 (m, 1H), 4.95 (q, 1H, J = 6.6H
z), 4.88 (m, 1H), 4.23 (m, 2H), 4.03 (m, 1H), 3.83
 (s, 3H), 3.59 (m, 6H), 3.43 (m, 2H), 3.12 (m, 1H),
 2.84 (m, 2H), 2.59 (dd, 1H, J = 14.0, 10.1Hz), 2.29
 (m, 1H), 2.04 (m, 1H), 1.57 (d, 3H, J = 6.6Hz), 1.4
6 (s, 9H).

[C-2]3- (S) -3- [2- (1-R-morpholinocarboni
Ruethoxy) -4-phthalimidomethylphenyl] ami
Nocarbonylmethyl-1,3,4,5-tetrahydrobe
[C, d] indole-2-carboxylate methyl  Ethyl chloroformate (1.2 mL) / THF (6 mL) solution was added to -13
C. and cooled to A-10 (3.69 g) and triethylamine (1.
A solution (86 mL) / THF (9 mL) was added dropwise and stirred for 30 minutes.
A solution of B-10 (5.40 g) / DMF (65 mL) was added dropwise.
Then, the mixture was stirred at 0 to 5 ° C for 1 hour and at room temperature overnight. Reaction mixture
Water (45 mL) and saturated saline (5 mL) were added to ethyl acetate (60 m
L). The aqueous layer is further extracted with ethyl acetate (35 mL)
And combine the organic layers with 2.5% KHSO_FourAqueous solution (30 mL), saline
(15 mL), saturated aqueous sodium bicarbonate (15 mL), and saturated saline (15 mL)
Was cleaned. Na_TwoSO_Four, Concentrated under reduced pressure and crystallized.
And add hexane and stir.
By drying, C-2 (8.03 g, 96%) was obtained.¹ H-NMR (300 MHz, CDCl_Three) δ: 8.81 (s, 1H), 8.62 (s,
1H), 8.28 (d, 1H, J = 8.4Hz), 7.70-7.80 (m, 2H), 7.6
0-7.70 (m, 2H), 7.19 (s, 1H), 7.18 (d, 1H, J = 8.4H
z), 6.94 (d, 1H, J = 1.8Hz), 6.79 (bs, 1H), 4.93 (q,
 1H, J = 6.6Hz), 4.64 (d, 1H, J = 14.5 Hz), 4.62 (d, 1
H, J = 14.5Hz), 3.80-3.99 (m, 1H), 3.78 (s, 3H), 3.3
5-3.60 (m, 8H), 2.95-3.08 (m, 1H), 2.68-2.78 (m, 2
H), 2.49 (dd, 1H, J = 14.1, 10.1Hz), 2.15-2.25 (m, 1
H), 1.88-2.02 (m, 1H), 1.49 (d, 3H, J = 6.6Hz).

[C-1]3- (S) -3- [2- (1-R-morpholinocarboni
Ruethoxy) -4-t-butoxycarbonylaminomethyl
Ruphenyl] aminocarbonylmethyl-1,3,4,5
-Tetrahydrobenz [c, d] indole-2-cal
Methyl bonate  Dissolve C-2 (1.60 g) in THF (4 mL) and methanol (8 mL).
Then, add hydrazine monohydrate (0.56 mL) and add
Stirred for hours. Water (6 mL) and saturated aqueous sodium bicarbonate (5 mL) were added to the reaction solution.
In addition, the mixture was extracted with ethyl acetate (20 mL). Add vinegar to the water layer
Extract with ethyl acetate (10 mL), combine the organic layers and add saturated sodium bicarbonate
Wash with water and saturated saline_TwoSO_FourAnd the solvent is distilled off.
Then, a residue (1.365 g) was obtained. This concentrated residue (678 mg) is
Dissolved in ethyl acetate (7 mL)_TwoO (286 mg) / ethyl acetate
(0.5 mL) solution was added and stirred at room temperature. After 1 hour, remove the solvent
By distilling off and adding toluene (4 mL) for crystallization,
C-1 (740 mg) was obtained.

[C-3]3- (S) -3- (2- (1-R-carboxethoxy)
B) -4-t-butoxycarbonylaminomethylphenyl
L) aminocarbonylmethyl-1,3,4,5-tetra
Hydrobenz [c, d] indole-2-carboxylic acid  Under a nitrogen atmosphere, C-1 (86.4 g, 129 mmol) was added to THF (440
 mL) and methanol (440 mL), and 2N lithium hydroxide
An aqueous solution (440 mL) was added, and the mixture was stirred at room temperature for 16 hours. reaction
The mixture was concentrated under reduced pressure, and the aqueous phase was washed three times with 300 mL of toluene.
And add potassium hydrogen sulfate (145 g) / water (1 L) solution
pH 2 and ethyl acetate / THF (3: 1) (1000 mL and 500 m
L × 2). Combine the organic layers and saturate with 700 mL of water.
After washing with 300 mL of a saline solution, 4.0 g of activated carbon and MgSO_Four 1.0 g
In addition, the mixture is stirred, filtered, and evaporated to remove crude C-
3 (73.06 g) was obtained. Crude C-3 (72.0 g) in acetonitrile
Heat to reflux, slowly cool, and add
The mixture was stirred at room temperature for an hour. Filter the crystals and wash with the filtrate.
Then, wash with ice-cold acetonitrile (30 mL x 3) and dry under reduced pressure.
By drying, C-3 (70.25 g, 94.3%) was obtained.¹ H-NMR (270 MHz, CDCl_Three) δ: 12.99 (br.s, 2H), 11.42
 (s, 1H), 9.07 (s, 1H), 7.89 (d, 1H, J = 8.3Hz), 7.3
1 (m, 1H), 7.15 (s, 1H), 6.84 (m, 3H), 4.75 (q, 1H,
 J = 6.6Hz), 4.04 (m, 2H), 3.87 (m, 1H), 3.10 (m, 1
H), 2.81-2.62 (m, 3H), 2.13 (m, 1H), 1.85 (m, 1H),
 1.56 (d, 3H, J = 6.6Hz), 1.40 (s, 9H).

[C-4]3- (S) -3- (2- (1-R-carboxethoxy)
B) -4-aminomethylphenyl) aminocarbonyl
Cyl-1,3,4,5-tetrahydrobenz [c, d]
Indole-2-carboxylic acid hydrochloride  C-3 (70.0 g, 119 mmol) was added to vinegar at room temperature under a nitrogen atmosphere.
In addition to 280 mL of acid, add 1N hydrochloric acid / acetic acid (240 mL, 239 mmol).
And stirred at room temperature for 2 hours. Add toluene (1040 mL)
After stirring for 30 minutes, the solid is collected by filtration and washed three times with 50 mL of toluene.
Then, by drying under reduced pressure, C-4 (61.24 g, 98.9
%).¹ H-NMR (270 MHz, d₆-DMSO) δ: 12.83 (br.s, 2H), 11.
42 (s, 1H), 9.16 (s, 1H), 8.39 (br.s, 3H), 8.05
(d, 1H, J = 8.2Hz), 7.21 (d, 1H, J = 1.7Hz), 7.15 (s, 1
H), 7.07 (dd, 1H, J = 8.2, 1.7Hz), 6.82 (s, 1H), 4.8
4 (q, 1H, J = 6.9Hz), 3.93 (m, 3H), 3.10 (m, 1H), 2.
81-2.59 (m, 3H), 2.09 (m, 1H), 1.86 (m, 1H), 1.58
(d, 3H, J = 6.9Hz).

[C-5]3- (S) -3- [2- (1-R-carboxethoxy)
B) -4-Aminomethylphenyl] aminocarbonyl
Cyl-1,3,4,5-tetrahydrobenz [c, d]
Indole-2-carboxylic acid hydrochloride monohydrate  Isopropanol (4 mL) and water (0.4 mL) in C-4 (400 mg)
And stir at 80 ° C for 1 hour, cool to room temperature, and
Stirred. C-5 (261 mg) was obtained by filtering the crystals.
Was. Melting point: 232-237 ° C (decomposition)

[0047]

According to the present invention, high-purity N-hydroxy-pyrrole-2-carboxylic acid and pyrrole-2-carboxylic acid can be produced at a high yield while suppressing generation of by-products.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Ryu Nagata 3-1-198 Kasuganaka, Konohana-ku, Osaka F-term (reference) in Sumitomo Pharmaceutical Co., Ltd. 4C204 AB02 BB04 CB03 CB21 DB25 EB02 EB03 FB01 FB33

Claims (7)

[Claims] [Claim 1] Formula: By treating a nitroketoester represented by the formula with a reducing agent: A method for producing N-hydroxy-pyrrole-2-carboxylic acid represented by the formula: [Wherein, R ¹ , R ² and R ³ independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. However, R ¹ and R ² together form two adjacent
R ² and R ³ together may represent an aromatic ring that may be substituted with two carbon atoms and / or R ² and R ³ may be substituted with a cycloalkane or substituted with two adjacent carbon atoms May represent a heterocycloalkane. R ⁴ represents an optionally substituted alkyl. ] [Claim 2] Formula: embedded image By treating a nitroketoester represented by the formula with a reducing agent: The method according to claim 1, wherein N-hydroxy-pyrrole-2-carboxylic acid represented by the formula: [In the formula, R ⁴ represents an optionally substituted alkyl. R ⁵ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. R ⁶ and R
⁷ is independently a hydrogen atom, a halogen atom, a cyano, an optionally substituted alkyl, an optionally substituted alkoxy,
Represents optionally substituted amino, carboxyl, optionally substituted carbamoyl, optionally substituted alkoxycarbonyl, aryl or heteroaryl. However,
R ⁵ and R ⁶ together may represent an optionally substituted cycloalkane or an optionally substituted heterocycloalkane with two adjacent carbon atoms. ] 3. The method according to claim 1, wherein the reducing agent is tin (II) halide, zinc /
Acid, palladium / sodium hypophosphite, palladium /
The method according to claim 1 or 2, wherein the method is hydrogenated trialkylsilane, palladium / formic acid, or ammonium formate. (4) Formula: embedded image By treating the nitroketoester represented by the formula with a reducing agent, the formula: By treating with an N-hydroxy-pyrrole-2-carboxylic acid represented by
Formula: A method for producing a pyrrole-2-carboxylic acid represented by the formula: [Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meaning as in claim 1]. ] 5. The formula: embedded image By treating the nitroketoester represented by the formula with a reducing agent, the formula: By treating with an N-hydroxy-pyrrole-2-carboxylic acid represented by
Formula: The method for producing pyrrole-2-carboxylic acid represented by the formula: [Wherein, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as in claim 2]. ] 6. The method according to claim 6, wherein the reducing agent is tin (II) halide, zinc /
Acid, palladium / sodium hypophosphite, palladium /
The production method according to claim 4 or 5, wherein the production method is hydrogenated trialkylsilane, palladium / formic acid, or ammonium formate. 7. Another reducing agent is titanium (III) halide,
The production method according to any one of claims 4 to 7, wherein the production method is Raney nickel or iron.