WO2023033097A1

WO2023033097A1 - Method for producing heterocyclic sulfonamide derivative, and synthetic intermediate thereof

Info

Publication number: WO2023033097A1
Application number: PCT/JP2022/032904
Authority: WO
Inventors: 一喜西脇; 康樹國島
Original assignee: Ｅａファーマ株式会社
Priority date: 2021-09-02
Filing date: 2022-09-01
Publication date: 2023-03-09

Abstract

The present disclosure provides a method that is suitable for the industrial production of a compound (1) and that enables production of same at a high purity and a high yield.　The present disclosure pertains to a method for producing the compound (1) through the following route.

Description

Method for producing heterocyclic sulfonamide derivative, and synthetic intermediate thereof

The present disclosure provides (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2, The present invention relates to a method for producing a heterocyclic sulfonamide derivative represented by 3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide, and a synthetic intermediate thereof.

(2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4- Heterocyclic sulfonamide derivatives typified by tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1) described later) regulate the function of Transient Receptor Potential Ankyrin 1 (TRPA1) and are effective in treating pain diseases. , digestive system diseases, pulmonary diseases, skin diseases, inflammatory diseases, bladder diseases and neurological diseases (Patent Document 1).

In Patent Document 1, compound (1) comprises (2S)-1-(benzofuran-2-ylsulfonyl)pyrrolidine-2-carboxylic acid (compound (2) described later) and 5-(aminomethyl)-3- It is produced by reaction with isopropyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione hydrochloride (compound (3) described later), but its isolation is by chromatographic photography (see Example 1).

Compound (3), which is a starting material, is described in Patent Document 1 by reacting (1) thymine and 1-iodo-4-(trifluoromethyl)benzene at 140° C. in the presence of copper (I) iodide. (2) reacting the resulting 5-methyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione with 2-iodopropane, (3) obtaining 3-Isopropyl-5-methyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione was treated with N in the presence of 2,2′-azobisisobutyronitrile. -bromination with bromosuccinimide to give (4) 5-(bromomethyl)-3-isopropyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)- Reaction of the dione with sodium azide followed by reaction with Boc ₂ O in the presence of palladium on carbon under a hydrogen atmosphere (5) yielded N-[[3-isopropyl-2,4-dioxo-1 tert-Butyl-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl]methyl]carbamate is treated with an acid to produce a hydrochloride salt (see Example C-1). Except for the final step, isolation has been performed by chromatography. In addition, the total yield of compound (3) is not as high as about 2%.
Furthermore, in Patent Document 1, compound (2), which is a starting material, is produced by reacting L-proline with benzofuran-2-sulfonyl chloride (see Example B-1). It is difficult to say that the purity is good.

Thus, the production method described in Patent Document 1 requires high temperature (140 ° C.) heating; there is a risk of reaction runaway due to the use of a radical initiator; Explosive hazard from effluent; large-scale reactions must be split up to reduce hazard; isolation procedure is not convenient; total yield and purity are unsatisfactory ; Therefore, it is difficult to say that the method is suitable for industrial production of compound (1). Moreover, the above-mentioned problems are the same in the industrial production of heterocyclic sulfonamide derivatives having a structure similar to compound (1).

WO2017135462

An object of the present disclosure is to provide a method for producing a heterocyclic sulfonamide derivative represented by compound (1) in a method suitable for industrial production with a high total yield and high purity.

As a result of intensive studies on the above problems, the present inventors have found that ethyl N-(cyanoacetyl) carbamate is used as a production route for compound (3), which is a starting material, when compound (1) is produced as a heterocyclic sulfonamide derivative. As a starting material, a novel compound 3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (described later By adopting a route via compound (3-1)), compound (3) can be obtained in a high overall yield in a safe reaction without heating to a high temperature such as 140 ° C. and without using dangerous reagents. It has been found that the compound (3) can be produced and can be easily isolated by a crystallization operation. In addition, as a production route of compound (2), by adopting a route via a novel compound, benzyl (benzofuran-2-ylsulfonyl)-L-prolinate (compound (2-1) described later), It was found that compound (2) can be obtained in high yield as pure crystals. Furthermore, the inventors have also found that by adopting a crystallization process suitable for compound (1), compound (1) can be easily obtained as crystals of high purity and excellent storage stability. Therefore, the invention was completed.

One aspect of the present disclosure includes the following.
[1] A method for producing a compound of formula (1) (hereinafter also referred to as compound (1)), comprising the following step (a);

Step (a): reacting a compound of formula (2) or a salt thereof (hereinafter also referred to as compound (2)) with a compound of formula (3) or a salt thereof (hereinafter also referred to as compound (3)), and then A step of crystallizing the compound of formula (1) from the obtained reaction solution.
[2] The production method according to [1] above, further comprising the following step (c5);

Step (c5): A step of subjecting the compound of formula (3-1) (hereinafter also referred to as compound (3-1)) to a reduction reaction to produce the compound of formula (3) or a salt thereof.
[3] The production method according to [2] above, further comprising the following steps (c3) and (c4);

Step (c3): subjecting the compound of formula (3-3) or a salt thereof (hereinafter also referred to as compound (3-3)) to an intramolecular cyclization reaction, followed by
Step (c4): A step of subjecting the produced compound of formula (3-2) (hereinafter also referred to as compound (3-2)) to an N-isopropylation reaction to produce a compound of formula (3-1).
[4] The production method according to [3] above, further comprising the following step (c2);

Step (c2): A compound of formula (3-4) (hereinafter also referred to as compound (3-4)) is reacted with 4-(trifluoromethyl)aniline or a salt thereof to give a compound of formula (3-3). A process for producing a compound or a salt thereof.
[5] The production method according to [4] above, further comprising the following step (c1);

Step (c1): A step of reacting a compound of formula (3-5) (hereinafter also referred to as compound (3-5)) with ethyl orthoformate to produce a compound of formula (3-4).
[6] The production method according to any one of [1] to [5] above, further comprising the following step (b2);

Step (b2): A step of subjecting the compound of formula (2-1) (hereinafter also referred to as compound (2-1)) to a deprotection reaction to produce the compound of formula (2) or a salt thereof.
[7] The production method according to [6] above, further comprising the following step (b1);

Step (b1): reacting a compound of formula (2-2) (hereinafter also referred to as compound (2-2)) with L-proline benzyl ester or a salt thereof to produce a compound of formula (2-1) process.
[8] A compound of formula (3-1).

[9] A compound of formula (2-1).

[10] Characterized by having peaks at diffraction angles (2θ) of at least 14.0°, 14.9°, 16.5°, 21.0° and 22.7° in a powder X-ray diffraction pattern , a crystal of the compound of formula (1).

According to the present disclosure, a heterocyclic sulfonamide typified by compound (1) can be obtained in a safe reaction without heating to a high temperature such as 140° C. and without the use of hazardous reagents, in a high total yield and high purity. Derivatives can be produced and can be easily obtained as crystals with excellent storage stability by an appropriate crystallization operation. It is useful as a method suitable for industrial production of amide derivatives.

FIG. 1 shows (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl) obtained in Example 8. 2 shows a powder X-ray diffraction pattern of crystals of phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1)).

Hereinafter, the production method of the present disclosure will be described in detail using the case of producing compound (1) as an example, but the present disclosure is not limited to the case of producing compound (1).
In the present disclosure, compound (1) is produced by the following step (a).

Step (a) is a step of reacting compound (2) and compound (3), and then crystallizing compound (1) from the resulting reaction solution.
Compounds (2) and (3) can be produced by known methods, but from the viewpoint of industrial production, they are preferably produced by the methods described below.
The amount of compound (2) to be used is generally 1.0-1.1 mol, preferably 1.0-1.05 mol, per 1 mol of compound (3).

The reaction is carried out in a solvent in the presence of a condensing agent.
Condensing agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-[3-(dimethylamino) Propyl]-3-ethylcarbodiimide, N,N'-carbonyldiimidazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate and the like. The amount of the condensing agent to be used is generally 1.0-1.2 mol, preferably 1.0-1.1 mol, per 1 mol of compound (3).
When compound (3) is an acid addition salt, the reaction is carried out in the presence of a base.
Examples of the base include organic bases such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine. The amount of the base to be used is generally 2.0-4.0 mol, preferably 2.5-3.0 mol, per 1 mol of the acid addition salt of compound (3).
Solvents include ether solvents such as tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane; N,N-dimethylformamide, N , N-dimethylacetamide, amide solvents such as N-methylpyrrolidone; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone; halogen solvents such as dichloromethane and 1,2-dichloroethane; nitriles such as acetonitrile system solvent; an organic base solvent such as pyridine, and the like.
The reaction is usually carried out in the range of 0-40°C, preferably in the range of 0-30°C. The reaction time is usually 1 to 24 hours, preferably 3 to 5 hours, depending on the reaction temperature.

Alternatively, the reaction may be carried out by converting compound (2) into a reactive derivative and then reacting it with compound (3).
Reactive derivatives of compound (2) include acid chlorides and acid anhydrides. For example, acid chlorides can be prepared by reaction with thionyl chloride, oxalyl chloride, and the like.
The subsequent reaction with compound (3) is usually carried out in a solvent in the presence of a base.
Examples of the base include organic bases such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine. The amount of the base to be used is generally 2.0-4.0 mol, preferably 2.5-3.0 mol, per 1 mol of compound (3).
Solvents include ether solvents such as tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane; N,N-dimethylformamide, N , N-dimethylacetamide, amide solvents such as N-methylpyrrolidone; ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone; halogen solvents such as dichloromethane and 1,2-dichloroethane; nitriles such as acetonitrile system solvent; an organic base solvent such as pyridine, and the like.
The reaction is usually carried out at -20 to 40°C, preferably -10 to 30°C. The reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.

After the completion of the reaction, the compound (1) can be obtained as highly pure crystals by performing post-treatments such as liquid separation and concentration, and then performing a crystallization operation suitable for the compound (1). A crystallization operation suitable for compound (1) is a step of crystallization in a specific solvent, followed by an aging operation step to obtain crystal nuclei with higher purity and crystallinity, and a final yield of It is preferable to carry out step by step the aging operation step to improve the After the step of aging (by adding water to the methanol solution), and then the step of further aging usually in the range of 15 to 35 ° C., preferably in the range of 20 to 30 ° C. (adding water ) and more preferably. It may be recrystallized if necessary.
The crystal is a crystal having peaks at diffraction angles (2θ) of at least 14.0°, 14.9°, 16.4°, 21.0° and 22.8° in a powder X-ray diffraction pattern; Preferably diffraction angles of 6.1°, 12.1°, 14.0°, 14.9°, 16.4°, 18.2°, 21.0°, 22.8° and 24.0° It is a crystal with a peak at (2θ).
Such crystals of compound (1) are excellent in storage stability, as shown in Examples described later, and thus such crystals are very useful as crystals of active pharmaceutical ingredients.

Compound (2) can be produced by a known method, but by producing the following routes of steps (b1) and (b2) via novel compound (2-1), high-purity crystals can be obtained. As a compound (2) can be obtained in good yield. In addition, in the step (b2), by using the same catalyst as in the step (c5), which will be described later, efficiency is improved, and a production method more suitable for industrial production can be realized.

Step (b1) is a step of reacting compound (2-2) with L-proline benzyl ester or a salt thereof to produce compound (2-1).
The reaction is carried out in the presence of a base in a solvent.
Compound (2-2) is commercially available.
The amount of L-proline benzyl ester or its salt to be used is generally 1.0-1.2 mol, preferably 1.0-1.1 mol, per 1 mol of compound (2-2).
Examples of the base include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine. The amount of the base to be used is generally 2.0-4.0 mol, preferably 2.5-3.0 mol, per 1 mol of compound (2-2).
Solvents used in step (b1) include aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, xylene, and cumene; , 2-dimethoxyethane, 1,4-dioxane and other ether solvents; N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and other amide solvents; acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl ketone solvents such as butyl ketone; halogen solvents such as dichloromethane and 1,2-dichloroethane; nitrile solvents such as acetonitrile; organic base solvents such as pyridine;
The reaction is usually carried out in the range of -20 to 40°C, preferably in the range of 0 to 30°C. The reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.
After the completion of the reaction, the compound (2-1) is obtained as high-purity crystals by subjecting the compound (2-1) to post-treatments such as liquid separation and concentration, followed by a crystallization operation suitable for the compound (2-1). can be done. A crystallization operation suitable for compound (2-1) is preferably carried out stepwise in a specific solvent, a step of crystallization, a step of aging, and a step of further aging under cooling. In an ethanol solvent, first, a step of crystallizing usually in the range of 25 to 50°C, then a step of maturing in the range of usually 35 to 50°C, then usually cooling to the range of 0 to 10°C and further It is more preferable to include a step of aging. It may be recrystallized if necessary.

Step (b2) is a step of subjecting compound (2-1) to a deprotection reaction to produce compound (2).
The reaction is carried out in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere at normal to medium pressure (5 atmospheres).
Palladium catalysts include palladium-carbon, palladium hydroxide-carbon and the like. The amount of palladium catalyst used is usually a catalytic amount. 10 w/w %) to 0.15 w/w (15 weight percent, 15 w/w %).
Examples of the solvent used in step (b2) include alcoholic solvents such as methanol, ethanol, propanol and isopropanol.
The reaction may be carried out in the presence of a base, if necessary.
Examples of bases include organic bases such as N,N-diisopropylethylamine, triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine. The amount of the base to be used is generally 0.1-2.0 mol, preferably 0.9-1.1 mol, per 1 mol of compound (2-1).
The reaction is usually carried out in the range of 10-50°C, preferably in the range of 20-30°C. The reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.
After completion of the reaction, after post-treatment such as liquid separation operation and concentration, the compound (2 ) can be obtained as high-purity crystals. It may be recrystallized if necessary.

Through the above steps (b1) and (b2), the compound (2-1) can be obtained as high-purity crystals at a high yield. It has the advantage of being readily available.

The compound (3) can be produced by a known method, but the compound (3-5) shown below is used as a starting material, and the steps (c1) to (c5) via the novel compound (3-1) By the production route, it can be produced in a high overall yield in a safe reaction without heating to a high temperature such as 140° C. and without the use of dangerous reagents, and can be easily isolated by a crystallization operation. In addition, by performing step (c4) continuously in one pot without isolating the product after step (c3), operability is improved and a production method more suitable for industrial production can be realized.

Step (c1) is a step of reacting compound (3-5) with ethyl orthoformate to produce compound (3-4).
The reaction is carried out in acetic anhydride.
Compound (3-5) and ethyl orthoformate are commercially available.
The amount of ethyl orthoformate to be used is generally 1.0-20 mol, preferably 1.0-4.0 mol, per 1 mol of compound (3-5).
The reaction is usually carried out in the range of 90-130°C, preferably in the range of 100-120°C. The reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.
After completion of the reaction, compound (3-4) can be obtained as crystals by a crystallization operation using methyl tert-butyl ether. It may be recrystallized if necessary.

Step (c2) is a step of reacting compound (3-4) with 4-(trifluoromethyl)aniline or a salt thereof to produce compound (3-3).
The reaction is carried out in a solvent.
4-(Trifluoromethyl)aniline is commercially available. The amount of 4-(trifluoromethyl)aniline or a salt thereof to be used is generally 1.0-3.0 mol, preferably 1.0-1.2 mol, per 1 mol of compound (3-4). .
Examples of the solvent used in step (c2) include alcoholic solvents such as ethanol, methanol, propanol and isopropanol.
The reaction is usually carried out in the range of 60-100°C, preferably in the range of 70-90°C. The reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.
After completion of the reaction, the compound (3-3) can be obtained as crystals by crystallization. It may be recrystallized if necessary.

Step (c3) is a step of subjecting compound (3-3) to an intramolecular cyclization reaction to produce compound (3-2).
The reaction is carried out in the presence of a base in a solvent.
Examples of the base include organic bases such as triethylamine and N,N-diisopropylethylamine. The amount of the base to be used is generally 0.1-2.0 mol, preferably 0.3-1.0 mol, per 1 mol of compound (3-3).
Solvents used in step (c3) include amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert ether solvents such as -butyl methyl ether, 1,2-dimethoxyethane and 1,4-dioxane; halogen solvents such as dichloromethane and 1,2-dichloroethane; and nitrile solvents such as acetonitrile.
The reaction is usually carried out in the range of 80-120°C, preferably in the range of 90-120°C. The reaction time is usually 1 to 24 hours, preferably 2 to 6 hours, depending on the reaction temperature.
After completion of the reaction, the reaction solution is directly subjected to the next step (c4) without isolating compound (3-2).

Step (c4) is a step of subjecting compound (3-2) to an N-isopropylation reaction to produce compound (3-1).
The reaction is carried out by reacting compound (3-2) with isopropyl halide in the presence of a base in a solvent. Specifically, it is carried out by adding a base and isopropyl halide to the reaction solution obtained in step (c3).
Isopropyl halides include isopropyl iodide and isopropyl bromide. The amount of isopropyl halide to be used is generally 1.0-3.0 mol, preferably 1.0-1.5 mol, per 1 mol of compound (3-2).
as a base. Inorganic bases such as potassium carbonate, sodium hydrogencarbonate and sodium carbonate are included. The amount of the base to be used is generally 2.0-4.0 mol, preferably 2.0-3.0 mol, per 1 mol of compound (3-2).
The reaction is usually carried out in the range of 10-80°C, preferably in the range of 40-60°C. The reaction time is usually 1 hour to 48 hours, preferably 12 hours to 24 hours, depending on the reaction temperature.
After completion of the reaction, compound (3-1) can be obtained as crystals by a crystallization operation using ethanol-water. It may be recrystallized if necessary.

Step (c5) is a step of subjecting compound (3-1) to a reduction reaction to produce compound (3).
The reaction is carried out in a solvent in the presence of a palladium catalyst and concentrated sulfuric acid in a normal to medium pressure (5 atm) hydrogen atmosphere.
Palladium catalysts include palladium-carbon, palladium hydroxide-carbon and the like. The amount of palladium catalyst used is usually a catalytic amount. 1 w/w%) to 0.05 w/w (5 weight percent, 5 w/w%).
The amount of concentrated sulfuric acid to be used is preferably 1 to 10 mol per 1 mol of compound (3-1).
Solvents used in step (c5) include alcohol solvents such as methanol, ethanol, propanol and isopropanol, tetrahydrofuran, methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane. , 1,4-dioxane; and ester solvents such as ethyl acetate and methyl acetate. Moreover, hydrogen chloride, methanesulfonic acid, etc. are mentioned as an acid to add.
The reaction is usually carried out in the range of 0-90°C, preferably in the range of 10-40°C. The reaction time is usually 1 to 24 hours, preferably 1 to 12 hours, depending on the reaction temperature.
After completion of the reaction, post-treatments such as liquid separation and concentration are performed, and then hydrochloric acid is added dropwise in alcohol (eg, 2-propanol) to obtain compound (3) as a hydrochloride. It may be recrystallized if necessary.

The route from step (c1) to step (c5) has no reaction that requires heating to a high temperature such as 140°C; no reaction that uses a radical initiator or dangerous reagents such as sodium azide; The target product can be obtained by a simple crystallization operation without the need for chromatography; the total yield of the above five steps is higher than that of the step described in Patent Document 1; Steps (c3) and (c4) is performed in one pot, the operability of the entire reaction is improved;

As described above, the production method of the present disclosure has been described with the case of producing compound (1) as an example. It can be used for the production of derivatives. More specifically, among the heterocyclic sulfonamide derivatives described in Patent Document 1, heterocyclic sulfonamide derivatives containing a dioxopyrimidine ring in the structure (specifically, Examples 1 to 12, 16 to 19, 23-26, 29-36 and 38-41). No. 2004/0010002, the entire disclosure of which is incorporated herein by reference, and those skilled in the art, in light of the description herein and the description of US Pat. high yields and high purities.

At least one aspect of the present disclosure will be described in detail below with reference to examples, but the present disclosure is not limited to the following examples.

(Analysis conditions)
The analyzes in the following examples were carried out according to conventional methods using the following measurement equipment.
(1) ^1H -NMR
Device: JNM-ECZ400S, manufactured by JEOL

(2) High Performance Liquid Chromatography (HPLC)
(2-1) Compound (1)
Detector: Ultraviolet absorption photometer (measurement wavelength: 214 nm)
Column: KINETEX XB-C18, 5μm, 100 x 4.6mm
Column temperature: Constant temperature around 35°C Mobile phase A: TFA: water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0 mL/min
Measurement time: 16min

(2-2) Until reaction confirmation of compounds (3-4) to (3-3) Detector: UV absorption photometer (measurement wavelength: 200 nm)
Column: Agilent Zorbax Bonus-RP, 3.5μm (4.6mm id×150mm)
Column temperature: Constant temperature around 35°C Mobile phase A: TFA: distilled water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0mL/min
Analysis time: 16 minutes

(2-3) After confirming the reaction of compound (3-3) to compound (3-2)
Detector: Ultraviolet absorption photometer (measurement wavelength: 200 nm)
Column: phenomenonnex Kinetex XB-C18, 5μm (4.6mm id×100mm)
Column temperature: Constant temperature around 35°C Mobile phase A: TFA: distilled water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0mL/min
Analysis time: 16 minutes

(2-4) compound (3-1)
Detector: Ultraviolet absorption photometer (measurement wavelength: 214 nm)
Column: phenomenonnex Kinetex XB-C18, 5μm (4.6mm id×100mm)
Column temperature: Constant temperature around 35°C Mobile phase A: TFA: distilled water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0mL/min
Analysis time: 16 minutes

(2-5) Compound (3)
Detector: Ultraviolet absorption photometer (measurement wavelength: 214 nm)
Column: Agilent Zorbax Bonus-RP, 3.5μm (4.6mm id×150mm)
Column temperature: Constant temperature around 35°C Mobile phase A: TFA: distilled water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0mL/min
Analysis time: 16 minutes

(2-6) compound (2-1) and compound (2)
Detector: Ultraviolet absorption photometer (measurement wavelength: 216 nm)
Column: YMC Pack ODS A, 5μm (4.6mm id×150mm)
Column temperature: Constant temperature around 40°C Mobile phase A: TFA: distilled water = 0.05: 100
Mobile phase B: TFA: acetonitrile = 0.05:100

Flow rate: 1.0mL/min
Analysis time: 30 minutes

Example 1 Production of ethyl (E)-(2-cyano-3-ethoxyacryloyl) carbamate (compound (3-4))

Ethyl N-(cyanoacetyl)carbamate (also known as N-cyanoacetylurethane) (compound (3-5)) (8.5 g), acetic anhydride (22.9 g) and triethyl orthoformate (16.1 g) under a nitrogen atmosphere. ) and stirred at 100-115° C. for 1 hour. The reaction solution was cooled to 45 to 55° C. and stirred for 1 hour after crystal precipitation was confirmed. Methyl tert-butyl ether (31.5 g) was added dropwise at 40-50°C over 1 hour, then cooled to 0-10°C and stirred for 12 hours. Precipitated crystals were collected by filtration and washed with methyl tert-butyl ether (18.9 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give ethyl (E)-(2-cyano-3-ethoxyacryloyl)carbamate (compound (3-4)) (10.1 g, yield 88%). got
¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm), 1.23 (t, J=7.2 Hz, 3 H), 1.33 (t, J=7.2 Hz, 3 H), 4.14 (q, J =7.2 Hz, 2 H), 4.39 (q, J=7.2 Hz, 2 H), 8.41 (s, 1 H), 10.61 (s, 1 H).

Example 2 Production of ethyl (2-cyano-3-{[4-(trifluoromethyl)phenyl]amino}acryloyl)carbamate (compound (3-3))

Ethyl (E)-(2-cyano-3-ethoxyacryloyl)carbamate (compound (3-4)) (8.0 g), ethanol (75.7 g) and 4-(trifluoromethyl)aniline under nitrogen atmosphere (6.7 g) were mixed and stirred at 75-85° C. for 1 hour. The reaction was cooled to 20-30° C. and stirred for 18 hours. Precipitated crystals were collected by filtration and washed with ethanol (12.6 g). The obtained wet crystals were dried at 50° C. under reduced pressure to give ethyl (2-cyano-3-{[4-(trifluoromethyl)phenyl]amino}acryloyl)carbamate (compound (3-3)) (11. 1 g, 90% yield).
¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm), 1.24-1.27 (m, 3 H), 4.15 (q, J=7.2 Hz, 2 H), 7.68 (d, J=8.8 Hz , 2 H), 7.77 (d, J=8.8 Hz, 2 H), 8.54 (d, J=12.8 Hz, 1 H), 10.59 (s, 1 H), 10.74 (d, J=12.8 Hz, 1 H ).

Example 3 of 3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound (3-1)) manufacturing

Under a nitrogen atmosphere, ethyl (2-cyano-3-{[4-(trifluoromethyl)phenyl]amino}acryloyl)carbamate (compound (3-3)) (10.0 g), N,N-dimethylformamide (70 .8 g) and triethylamine (1.5 g) were mixed and stirred at 90-110° C. for 2 hours. The reaction solution is cooled to 30° C. or less, and 2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (compound (3- An N,N-dimethylformamide solution of 2)) was obtained. Potassium carbonate (8.5 g) and 2-iodopropane (6.8 g) were mixed with this solution, washed with N,N-dimethylformamide (4.7 g), and stirred at 45-55° C. for 21 hours. After cooling to 30° C. or lower, water (129 g) and ethyl acetate (77.4 g) were added, and the organic layer was separated. The organic layer was washed twice with 20% brine (86 mL), and the organic layer was separated. The organic layer was concentrated below 60° C. to about 26 mL, and ethanol (67.9 g) was added. It was concentrated to about 43 mL at 60° C. or lower, and ethanol (67.9 g) was added. The mixture was concentrated at 60°C or lower to about 43 to 77 mL until crystals precipitated, ethanol was added to about 86 mL, and the crystals were dissolved at 45 to 60°C. After adding dropwise water (22.0 g) at 50-60° C. over 1 hour, the mixture was cooled to 20-30° C. and stirred for 15 hours. Precipitated crystals were collected by filtration and washed with ethanol water prepared from ethanol (13.6 g) and water (4.3 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give 3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5. - carbonitrile (compound (3-1)) (6.4 g, yield 65%).
¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm), 1.40 (d, J=6.8 Hz, 6 H), 5.02-5.05 (m, 1 H), 7.74 (d, J=8.4 Hz , 2 H), 7.94 (d, J=8.4 Hz, 2 H), 8.86 (s, 1 H).

Example 4 Production of 5-(aminomethyl)-3-isopropyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione hydrochloride (compound (3))

3-Isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3,4 was mixed with 98% concentrated sulfuric acid (23.3 g) in methanol (59.3 g). -Tetrahydropyrimidine-5-carbonitrile (compound (3-1)) (15.0 g) and 10% palladium on carbon (0.15 g, dry equivalent) were added. The mixture was sequentially replaced with nitrogen and hydrogen, maintained at a pressure of 0.2-0.3 MPa at 20-30° C., and stirred for 4.5 hours. After purging with nitrogen, the reaction solution was filtered and washed with methanol (11.9 g). A 10% aqueous sodium hydroxide solution (204 g) was added dropwise at 30° C. or lower, ethyl acetate (269 g) was added, and the organic layer was separated. The organic layer was washed with 10% brine (150 g) and separated. The organic layer was concentrated below 50° C. to about 150 mL, and ethyl acetate (135 g) was added. The mixture was concentrated to about 120 mL at 50° C. or below, and 2-propanol (17.7 g) was added. After 35% hydrochloric acid (4.8 g) was added dropwise at 35-45°C over 30 minutes, the mixture was cooled to 0-10°C and stirred for 5.5 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (26.9 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give 5-(aminomethyl)-3-isopropyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione. A hydrochloride (compound (3)) (12.6 g, yield 75%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm), 1.39-1.44 (m, 6 H), 3.74 (s, 2 H), 5.10-5.16 (m, 1 H), 7.74 (d , J=8.8 Hz, 2 H), 7.94 (d, J=8.8 Hz, 2 H), 8.18 (s, 1 H), 8.34 (s, 2 H).

Example 5 Production of benzyl (benzofuran-2-ylsulfonyl)-L-prolinate (compound (2-1))

Toluene (86.5 g) was added to 1-benzofuran-2-sulfonyl chloride (compound (2-2)) (20.0 g) and dissolved in a nitrogen atmosphere. This solution was added dropwise to a solution of L-proline benzyl ester hydrochloride (24.5 g) and triethylamine (23.4 g) in toluene (86.5 g) over 1 hour at 30°C or lower. and stirred at 20-30°C for 30 minutes. 5% brine (147 g) was added at 30° C. or lower, and the organic layer was separated. The organic layer was washed with 5% brine (147 g) and 17.5% hydrochloric acid (9.6 g), and the organic layer was separated. The organic layer was concentrated below 50° C. to about 40 mL and ethanol (237 g) was added. Crystals were precipitated at 25 to 50°C, stirred at 35 to 50°C for 1 hour, cooled to 0 to 10°C, and stirred for 18 hours. Precipitated crystals were collected by filtration and washed with cold ethanol (31.6 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give benzyl (benzofuran-2-ylsulfonyl)-L-prolinate (compound (2-1)) (31.2 g, yield 88%, purity 100.0). %) was obtained.
¹ H-NMR (400 MHz, chloroform-d), δ (ppm), 1.80-1.83 (m, 1 H), 1.99-2.10 (m, 3 H), 3.48-3.54 (m, 1 H), 3.68- 3.74 (m, 1H), 4.57 (dd, J=4.0, 8.0Hz, 1H), 5.12 (d, J=12.4Hz, 1H), 5.19 (d, J=12.4Hz, 1H), 7.33 -7.39 (m, 7 H), 7.44-7.49 (m, 1 H), 7.54 (dd, J=0.8, 8.4 Hz, 1 H), 7.68 (dd, J=0.8, 7.2 Hz, 1 H).

Example 6 Preparation of (2S)-1-(benzofuran-2-ylsulfonyl)pyrrolidine-2-carboxylic acid (compound (2))

Benzyl (benzofuran-2-ylsulfonyl)-L-prolinate (compound (2-1)) (16.0 g) obtained in Example 5, 10% palladium carbon (1.6 g, dry equivalent), triethylamine ( 4.2 g) and methanol (63.3 g) were mixed. The mixture was sequentially replaced with nitrogen and hydrogen, and stirred for 2 hours while maintaining a pressure of 0.1 MPa at 20-30°C. After purging with nitrogen, the reaction solution was filtered and washed with methanol (25.3 g). The mixture was concentrated to about 32 mL at 50°C or lower, water (80.0 g) and ethyl acetate (101 g) were added at 30°C or lower, and the aqueous layer was separated. Water (32.0 g) and sodium hydroxide (0.3 g) were added to the organic layer, the aqueous layer was separated, and the obtained aqueous layers were mixed. Ethyl acetate (86.4 g) and 17.5% hydrochloric acid (10.4 g) were added to the aqueous layer, and the organic layer was separated. Water (64.0 g) was added to the organic layer, and the organic layer was separated. The organic layer was concentrated below 50° C. to about 32 mL, and ethanol (63.1 g) was added. Concentrate to about 48 mL at 50° C. or less and add ethanol (63.1 g). Concentrate to about 48 mL at 50° C. or lower, add water (32.0 g) at 50° C. or lower, and cool to 10 to 30° C. to precipitate crystals. Stir at 20-30° C. for 2 hours, cool to 0-10° C. and stir for 16 hours. Precipitated crystals were collected by filtration and washed with cold ethanol water prepared from ethanol (6.3 g) and water (8.0 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give (2S)-1-(benzofuran-2-ylsulfonyl)pyrrolidine-2-carboxylic acid (compound (2)) (10.9 g, yield 89%). , purity 99.9%).
¹ H-NMR (400 MHz, chloroform-d), δ (ppm), 1.81-1.88 (m, 1 H), 2.01-2.19 (m, 3 H), 3.45-3.52 (m, 1 H), 3.68- 3.73 (m, 1 H), 4.54 (dd, J=4.0, 8.4 Hz, 1 H), 7.35-7.39 (m, 1 H), 7.44-7.52 (m, 3 H), 7.57-7.59 (m, 1 H), 7.71 (d, J=8.0Hz, 1H).

Example 7 Crude (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2, Preparation of 3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (crude compound (1))

5-(Aminomethyl)-3-isopropyl-1-[4-(trifluoromethyl)phenyl]pyrimidine-2,4(1H,3H)-dione hydrochloride ( compound (3)) (10.0 g), (2S)-1-(benzofuran-2-ylsulfonyl)pyrrolidine-2-carboxylic acid obtained in Example 6 (compound (2)) (8.28 g) and Tetrahydrofuran (80.0 g) was mixed. N,N-diisopropylethylamine (8.88 g) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro at 0-20°C Phosphate (11.5 g) was added, washed in with tetrahydrofuran (8.9 g), and stirred at 0-20° C. for 3 hours. 0.5 M hydrochloric acid (60.6 g) and ethyl acetate (54.0 g) were added at 0 to 20° C., and the organic layer was separated. The organic layer was washed four times with 0.5M aqueous sodium hydroxide solution (61.2 g) at 30°C or lower. A 5% sodium chloride aqueous solution (63.1 g) and ethyl acetate (45.1 g) were added to the organic layer at 30°C or lower, and the organic layer was separated. A 5% sodium chloride aqueous solution (63.1 g) was added at 30° C. or lower, and the organic layer was separated. The organic layer was concentrated at 50°C or less until no more solvent was distilled off, methanol (39.7 g) and water (15.0 g) were added, and dissolved at 30-65°C. After cooling to 25-40° C. to deposit crystals, the mixture was stirred at 30-40° C. for 20 hours. After cooling to 20-30° C., water (10.0 g) was added dropwise over 30 minutes and stirred for 1 hour. Precipitated crystals were collected by filtration and washed with methanol water prepared from methanol (11.9 g) and water (5.0 g) and water (20.0 g) in that order. The obtained wet crystals were dried under reduced pressure at 50° C. to give crude (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4- (Trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (crude compound (1)) (15.5 g, 93% yield) was obtained. .

Example 8 (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3 ,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1)) crystal production

Crude (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoro Methyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (crude compound (1)) (10.0 g) and methanol (27.8 g) are mixed and Dissolved at 50-65°C. Water (6.0 g) was added, and the mixture was cooled to 25-40°C to precipitate crystals, and then stirred at 30-40°C for 17 hours. After cooling to 20-30° C., water (4.0 g) was added dropwise over 20 minutes and stirred for 1 hour. Precipitated crystals were collected by filtration and washed with aqueous methanol prepared from methanol (11.9 g) and water (5.0 g). The obtained wet crystals were dried under reduced pressure at 50° C. to give (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-( Trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1)) (9.4 g, yield 94%, purity 100.0% ) was obtained as crystals.
¹ H-NMR (400 MHz, DMSO-d ₆ ), δ (ppm), 1.43 (d, J=6.8 Hz, 6 H), 1.59-1.62 (m, 1 H), 1.82-1.90 (m, 3 H ), 3.30-3.38 (m, 1 H), 3.52-3.57 (m, 1 H), 4.01-4.05 (m, 2 H), 4.23 (dd, J=4.0, 8.0 Hz, 1 H), 5.09-5.14 (m, 1H), 7.40-7.43 (m, 1H), 7.53-7.58 (m, 2H), 7.66-7.68 (m, 3H), 7.73 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0 Hz, 1 H), 7.87 (d, J=7.6 Hz, 2 H), 8.38 (t, J=5.6 Hz, 1 H).

The resulting (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2,3 ,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1)) was measured for a powder X-ray diffraction pattern.
The measurement conditions for the powder X-ray diffraction pattern are as follows.
Powder X-ray diffractometer: RINT2200Ultima+/PC (manufactured by Rigaku)
Compound (1) was filled and molded in a sample holder to obtain a measurement sample, and the measurement was performed under the following conditions.
<Measurement conditions>
Sample table: Standard sample table Anticathode (counter electrode): Copper (Cu)
Scan axis: 2θ/θ
Scanning mode: Continuous scanning range (2θ): 5-40°
Sampling width: 0.02°
Scan speed: 4°/min
Tube voltage (X-ray voltage): 40 kV
Tube current (X-ray current): 40 mA
Divergence slit: 1°
Scattering slit: 1°
Light receiving slit: 0.3 mm
FIG. 1 shows the powder X-ray diffraction pattern, and Table 7 shows the diffraction angle and intensity of each peak number.

Further, the obtained (2S)-1-(benzofuran-2-ylsulfonyl)-N-({3-isopropyl-2,4-dioxo-1-[4-(trifluoromethyl)phenyl]-1,2 ,3,4-tetrahydropyrimidin-5-yl}methyl)pyrrolidine-2-carboxamide (compound (1)) crystals were stored under conditions of 25° C./60% RH for 24 months, and the moisture content (in terms of dehydrated product) was determined. ) was measured. The water content was measured by the Karl Fischer method, and the content was measured by the HPLC method using a column filled with octadecylated silylated silica gel for liquid chromatography. Table 9 shows the results.
No change over time was observed in water content and content, and it was stable for 24 months at 25°C/60% RH. Therefore, this crystalline form is considered to be useful as a crystalline form of drug substances.

The measurement conditions for water content are as follows.
Anolyte for moisture measurement: Hydranal Coulomat AK
Catholyte for moisture determination: Hydranal Coulomat CG-K
After quickly putting the specimen into the electrolysis cell, stir the inside of the electrolysis cell, and after the specimen is completely dissolved (about 3 minutes), electrolyze it while stirring, and the water content obtained from the amount of electricity consumed. read.

The measurement conditions for the content are as follows.
compound (1)
Detector: Ultraviolet absorption photometer (measurement wavelength: 254 nm)
Column: CORTECS ^™ C18, 2.7μm (4.6mm id×75mm)
Column temperature: constant temperature around 40°C Mobile phase A: 25 mM ammonium acetate solution (pH 5)
1.93 g of ammonium acetate was weighed, dissolved in 1000 mL of water, and adjusted to pH 5.0 by adding acetic acid.
Mobile phase B: acetonitrile

Flow rate: 0.3 mL/min
Analysis time: 25 minutes

According to the present disclosure, compound (1) can be produced in a high total yield and high purity in a safe reaction without heating to a high temperature such as 140 ° C. and without using dangerous reagents, and the compound ( Since it can be easily isolated by a crystallization operation suitable for 1) and can be obtained as crystals with excellent storage stability, the production method of the present disclosure is suitable for industrial production of compound (1) as a drug substance. It is useful as a suitable method.
In addition, according to the present disclosure, heterocyclic sulfonamide derivatives having a structure similar to compound (1) can also be produced in high yield and with high purity. It is also useful as a method suitable for industrial production of

This application is based on Japanese Patent Application No. 2021-143476 filed on September 2, 2021 in Japan, the contents of which are all incorporated herein.

Claims

A process for preparing a compound of formula (1), comprising the following step (a);

Step (a): A step of reacting the compound of formula (2) or a salt thereof with the compound of formula (3) or a salt thereof, and then crystallizing the compound of formula (1) from the resulting reaction mixture.
The manufacturing method according to claim 1, further comprising the following step (c5);

Step (c5): A step of subjecting the compound of formula (3-1) to a reduction reaction to produce the compound of formula (3) or a salt thereof.
The production method according to claim 2, further comprising the following steps (c3) and (c4);

Step (c3): subjecting the compound of formula (3-3) or a salt thereof to an intramolecular cyclization reaction, followed by
Step (c4): A step of subjecting the produced compound of formula (3-2) to an N-isopropylation reaction to produce a compound of formula (3-1).
The manufacturing method according to claim 3, further comprising the following step (c2);

Step (c2): A step of reacting the compound of formula (3-4) with 4-(trifluoromethyl)aniline or a salt thereof to produce the compound of formula (3-3) or a salt thereof.
The production method according to claim 4, further comprising the following step (c1);

Step (c1): A step of reacting a compound of formula (3-5) with ethyl orthoformate to produce a compound of formula (3-4).
The production method according to any one of claims 1 to 5, further comprising the following step (b2);

Step (b2): A step of subjecting the compound of formula (2-1) to a deprotection reaction to produce the compound of formula (2) or a salt thereof.
The manufacturing method according to claim 6, further comprising the following step (b1);

Step (b1): A step of reacting a compound of formula (2-2) with L-proline benzyl ester or a salt thereof to produce a compound of formula (2-1).
A compound of formula (3-1).
A compound of formula (2-1).
The formula ( A crystal of the compound of 1).