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WO2023033097A1 - Procédé de production d'un dérivé de sulfonamide hétérocyclique et intermédiaire synthétique de celui-ci - Google Patents

Procédé de production d'un dérivé de sulfonamide hétérocyclique et intermédiaire synthétique de celui-ci Download PDF

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WO2023033097A1
WO2023033097A1 PCT/JP2022/032904 JP2022032904W WO2023033097A1 WO 2023033097 A1 WO2023033097 A1 WO 2023033097A1 JP 2022032904 W JP2022032904 W JP 2022032904W WO 2023033097 A1 WO2023033097 A1 WO 2023033097A1
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一喜 西脇
康樹 國島
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EA Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • 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.
  • 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.
  • compound (3) is not as high as about 2%.
  • 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.
  • 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).
  • 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.
  • compound (3) which is a starting material
  • compound (1) is produced as a heterocyclic sulfonamide derivative.
  • 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.
  • the compound (3) can be produced and can be easily isolated by a crystallization operation.
  • benzyl (benzofuran-2-ylsulfonyl)-L-prolinate compound (2-1) described later
  • compound (1) can be easily obtained as crystals of high purity and excellent storage stability. Therefore, the invention was completed.
  • a method for producing a compound of formula (1) comprising the following step (a);
  • compound (2) a compound of formula (2) or a salt thereof
  • compound (3) a compound of formula (3) or a salt thereof
  • 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.
  • compound (3-1) hereinafter also referred to as compound (3-1)
  • Step (c4) 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).
  • Step (c2) 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).
  • step (b2) 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.
  • step (b1) 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.
  • compound (2-2) hereinafter also referred to as compound (2-2)
  • L-proline benzyl ester or a salt thereof to produce a compound of formula (2-1) process.
  • 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)).
  • 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).
  • 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).
  • compound (3) is an acid addition salt
  • the reaction is carried out in the presence of a base.
  • 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
  • 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.
  • 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.
  • 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
  • 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 (2 ⁇ ) 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 (2 ⁇ ).
  • 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.
  • 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).
  • the base include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine.
  • 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
  • the reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature.
  • 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.
  • 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 %).
  • 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.
  • 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.
  • the compound (2 ) can be obtained as high-purity crystals. It may be recrystallized if necessary.
  • 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.
  • 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).
  • 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.
  • 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.
  • amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone
  • tetrahydrofuran methyltetrahydrofuran
  • tetrahydropyran diethyl ether
  • diisopropyl ether ter
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • Ethyl N-(cyanoacetyl)carbamate also known as N-cyanoacetylurethane (compound (3-5)
  • acetic anhydride 22.9 g
  • triethyl orthoformate 16.1 g
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • Sample table Standard sample table Anticathode (counter electrode): Copper (Cu) Scan axis: 2 ⁇ / ⁇ Scanning mode: Continuous scanning range (2 ⁇ ): 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
  • Table 7 shows the diffraction angle and intensity of each peak number.
  • 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.
  • Mobile phase B acetonitrile
  • 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.
  • 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

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé qui est approprié pour la production industrielle d'un composé (1) et qui permet la production de celui-ci à une pureté élevée et à un rendement élevé.　La présente invention concerne un procédé de production du composé (1) par le mode suivant.
PCT/JP2022/032904 2021-09-02 2022-09-01 Procédé de production d'un dérivé de sulfonamide hétérocyclique et intermédiaire synthétique de celui-ci Ceased WO2023033097A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54147923A (en) * 1978-04-03 1979-11-19 Zoecon Corp Novel composition and method
JP2014169285A (ja) * 2013-02-05 2014-09-18 Dainippon Sumitomo Pharma Co Ltd ウラシル誘導体からなる医薬
WO2017135462A1 (fr) * 2016-02-05 2017-08-10 Ｅａファーマ株式会社 Dérivé de sulfonamide hétérocyclique et médicament le contenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54147923A (en) * 1978-04-03 1979-11-19 Zoecon Corp Novel composition and method
JP2014169285A (ja) * 2013-02-05 2014-09-18 Dainippon Sumitomo Pharma Co Ltd ウラシル誘導体からなる医薬
WO2017135462A1 (fr) * 2016-02-05 2017-08-10 Ｅａファーマ株式会社 Dérivé de sulfonamide hétérocyclique et médicament le contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SENDA, SHIGEO; HIROTA, KOSAKU; NOTANI, JIYOJI: "Pyrimidine Derivatives and Related Compounds. XVI. Synthesis of 1,2-Disubstituted 5-Cyanouracil Derivatives and Related Compounds", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 20, no. 7, 1 January 1972 (1972-01-01), JP , pages 1380 - 1388, XP009544073, ISSN: 0009-2363, DOI: 10.1248/cpb.20.1380 *

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