A compound for preparing aselixone and a method for preparing the same

Abstract

The application discloses a compound for preparing asahikon, and a structural formula [II] is as follows: a preparation method comprises the following steps: the compound [II] is obtained through amide condensation catalyst reaction of compound [III] and 4-methanesulfonylaniline in a solvent, and a reaction formula is as follows: the compound and the preparation method provided by the application have the advantages of milder reaction condition, more stable process, higher yield, and an effective synthesis path which is favorable for asahikon localization is provided.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a compound for preparing isalidon and a method for preparing it. Background Technology

[0002] Esalidomide is an oral, nonsteroidal, selective, novel mineralocorticoid receptor (MR) blocker used to treat hypertension. Its racemic form was first reported by Exelixis in patent WO2006 / 012642, entitled "Pyrrole Derivative as a Pharmaceutical Preparation," dated July 30, 2005. Its transisomer was proposed by Daiichi Sankyo in patent WO2008 / 126831, entitled "Transisomer of a Pyrrole Derivative," dated April 8, 2008. The complete synthetic route is as follows:

[0003]

[0004] Compound 1 is the same compound as isalidon [Ⅰ].

[0005] The main drawback of this route is that the preparation of methyl 4-methyl-5-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrrole-3-carboxylic acid requires purification by column chromatography, and the finished product needs to be separated by liquid chromatography. The overall yield is only 3.69%, making it difficult to achieve industrialization.

[0006] WO2014168103A1 uses ethyl cyanoacetate instead of methyl cyanoacetate, and thionyl chloride / hydrogen chloride / sulfuric acid catalytic ring closure instead of Raney nickel catalytic ring closure. The imine of pyrrolidine undergoes hydroxyethylation after ring closure. The final liquid-phase resolution step of WO2008 / 126831 is replaced by resolution with an active amine in the intermediate steps. The specific route is as follows:

[0007]

[0008] The reactions involved in this route are all conventional, and the post-processing methods are all standard operations, making it highly industrializable. However, a drawback is that the preparation of compound 18 from compound 8 uses thionyl chloride and sulfuric acid, and the residual sulfide can easily cause catalyst poisoning during the preparation of compound 17 from compound 18. Furthermore, the Chinese patent CN106916092B (WO2014168103A1) protects the resolving reagents cinconidine, quinine, cinconidine, quinidine, and intermediate 1631030-72-2 and its S-configuration quinine salt, which will not expire until April 6, 2034, hindering the domestic production of the drug.

[0009] WO2015030010A1, ethylene carbonate replaced with ethyl bromoacetate, was hydrolyzed to give 1665283-34-0, which was then resolved with active amines such as cinchonine, followed by reduction with sodium borohydride-boron trifluoride to give 1665290-31-2. Ethyl magnesium bromide catalyzed the reaction with 4-(methanesulfonyl)aniline, quenched with hydrochloric acid, and then extracted and concentrated with isobutyl acetate. The final product was purified with methylcyclohexane to obtain isalidomide. The specific synthetic route is as follows:

[0010]

[0011] The main drawback of this route is that the carboxylic acid reduction uses a sodium borohydride + trifluoroethyl ether reduction system, which produces highly toxic boroethane gas during the reaction. It also uses highly reactive Grignard reagents, which can easily increase side reactions.

[0012] Indian patent IN202121024569 reports the separation of the pyrrole ring before reduction of the chlorine at the 2-position, with the specific synthetic route as follows:

[0013]

[0014] After the route is split, the pyrrole ring 2-position chlorine is reduced, which increases the activity and steric hindrance of the carboxylic acid, making it more conducive to the split. The drawback is that the carboxylic acid is relatively strong, and direct palladium reduction on carbon can easily cause catalyst deactivation. Summary of the Invention

[0015] In view of the shortcomings of the prior art, the technical problem to be solved by this patent application is how to provide a compound for the preparation of isalidomone with mild reaction conditions, stable process and high yield, and a method for its preparation.

[0016] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0017] A compound used to prepare isalidon has the following structural formula [II]:

[0018]

[0019] A method for preparing a compound for preparing isalitonene includes the following steps:

[0020] Compound [II] is obtained by reacting compound [III] with 4-methanesulfonylaniline in a solvent with an amide condensation agent and an acid-binding agent as catalyzed, as shown in the following reaction formula;

[0021]

[0022] The solvent is one or a mixture of several solvents selected from tetrahydrofuran, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, methyl tert-butyl ether, or toluene.

[0023] The amide condensing agent is one or two of CDI, DCC, DMAP, EDCI, DIC, HOBt, HOAt, oxaloyl chloride, or thionyl chloride, preferably oxaloyl chloride, CDI, and DCC.

[0024] The acid-binding agent is triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc., preferably triethylamine, N,N-diisopropylethylamine or pyridine.

[0025] After the reaction, the compound was extracted with ester, ether, chlorinated hydrocarbon, or aromatic solvents and concentrated to obtain compound [II]. Compound [II] can be purified by column chromatography.

[0026] The ester solvent is ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethyl formate, propyl formate, etc., with ethyl acetate being preferred.

[0027] The ether solvent is diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, etc., preferably methyl tert-butyl ether.

[0028] The chlorinated hydrocarbon solvent is dichloromethane, chloroform, 1,2-dichloroethane, etc., with dichloromethane being preferred.

[0029] The aromatic solvent is benzene, toluene, chlorobenzene, xylene, etc., with toluene being preferred.

[0030] If oxaloyl chloride is chosen as the amide condensing agent, the [Ⅱa] intermediate compound is produced, with the following structural formula:

[0031]

[0032] Compound [Ⅱa] is hydrolyzed in an alkaline solution at a suitable temperature in a hydrolysis solvent to form compound [Ⅱ]. The compound is then extracted with ester, ether, chlorinated hydrocarbon, or aromatic solvents and concentrated to obtain a relatively pure compound [Ⅱ].

[0033] The hydrolysis solvent is methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., preferably tetrahydrofuran.

[0034] The alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or lithium hydroxide, preferably an aqueous solution of sodium hydroxide or potassium hydroxide.

[0035] Compound [II] was prepared into isalidon [I] by catalytic reduction, as shown in the following reaction formula:

[0036]

[0037] The catalyst used for catalytic reduction is either palladium on carbon or Raney nickel metal catalyst.

[0038] The reducing agent used in catalytic reduction is hydrogen, formic acid, or formate.

[0039] The solvent used for catalytic reduction is water, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0040] In summary, the compound and preparation method provided by this invention have milder reaction conditions, more stable processes, and higher yields, providing an effective synthetic route that is conducive to the domestic production of isalidomide. Attached Figure Description

[0041] Figure 1 For compound [Ⅲ] 1 H-NMR spectrum.

[0042] Figure 2 For compound [II] 1 H-NMR spectrum.

[0043] Figure 3 The image shows the MS spectrum of compound [Ⅱ].

[0044] Figure 4 For compound [Ⅰ] 1 H-NMR spectrum. Detailed Implementation

[0045] The present invention will now be described in further detail with reference to the accompanying drawings. In the description of the present invention, it should be understood that directional terms such as "upper," "lower," "top," and "bottom" indicate directions or positional relationships based on the directions or positional relationships shown in the accompanying drawings. These terms are used only for the convenience of describing the present invention and simplifying the description. Unless otherwise stated, these directional terms do not indicate or imply that the device or element referred to must have a specific orientation or be constructed and operated in a specific orientation, and therefore should not be construed as limiting the scope of protection of the present invention. The directional terms "inner" and "outer" refer to the inner or outer contours relative to the outline of each component itself.

[0046] A compound for preparing asalidone, (5S)-2-chloro-1-(2-hydroxyethyl)-4-methyl-N-[4-(methanesulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, has the following structural formula [II]:

[0047]

[0048] A method for preparing a compound for preparing isalitonene includes the following steps:

[0049] Compound [II] is obtained by reacting compound [III] with 4-methanesulfonylaniline in a solvent with an amide condensation agent and an acid-binding agent as catalyzed, as shown in the following reaction formula;

[0050]

[0051] In practice, the solvent is one or a mixture of several solvents selected from tetrahydrofuran, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, methyl tert-butyl ether, or toluene.

[0052] In practice, the amide condensing agent is one or two of CDI, DCC, DMAP, EDCI, DIC, HOBt, HOAt, oxaloyl chloride, or thionyl chloride, preferably oxaloyl chloride, CDI, and DCC.

[0053] In practice, the acid-binding agent is triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc., preferably triethylamine, N,N-diisopropylethylamine or pyridine.

[0054] After the reaction, the compound was extracted with ester, ether, chlorinated hydrocarbon, or aromatic solvents and concentrated to obtain compound [II]. Compound [II] can be purified by column chromatography.

[0055] In practice, the ester solvent is ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethyl formate, propyl formate, etc., with ethyl acetate being preferred.

[0056] In practice, the ether solvent is diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, etc., preferably methyl tert-butyl ether.

[0057] In practice, the chlorinated hydrocarbon solvent is dichloromethane, chloroform, 1,2-dichloroethane, etc., with dichloromethane being preferred.

[0058] In practice, the aromatic solvent is benzene, toluene, chlorobenzene, xylene, etc., with toluene being preferred.

[0059] If oxaloyl chloride is chosen as the amide condensing agent, the [Ⅱa] intermediate compound is produced, with the following structural formula:

[0060]

[0061] Compound [Ⅱa] is hydrolyzed in an alkaline solution at a suitable temperature in a hydrolysis solvent to form compound [Ⅱ]. The compound is then extracted with ester, ether, chlorinated hydrocarbon, or aromatic solvents and concentrated to obtain a relatively pure compound [Ⅱ].

[0062] In practice, the hydrolysis solvent is methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., preferably tetrahydrofuran.

[0063] In practice, the alkaline solution is an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of potassium carbonate, an aqueous solution of sodium carbonate, an aqueous solution of lithium hydroxide, etc., preferably an aqueous solution of sodium hydroxide and an aqueous solution of potassium hydroxide.

[0064] In practice, compound [II] is reduced to isalidomide [I] via catalytic reduction, as shown in the following reaction formula:

[0065]

[0066] The catalyst used for catalytic reduction is palladium on carbon or Raney nickel metal catalyst. Preferably, it is 5% to 10% palladium on carbon.

[0067] In practice, the reducing agent used for catalytic reduction is hydrogen, formic acid, or formate. Sodium formate and hydrogen are preferred.

[0068] In practice, the solvent used for catalytic reduction is water, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide. Water, methanol, ethanol, and tetrahydrofuran are preferred.

[0069] The abbreviations are explained as follows:

[0070] CDI: N,N'-carbonyldiimidazole;

[0071] DCC: N,N'-Dicyclohexylcarbodiimide;

[0072] DMAP: 4-Dimethylaminopyridine;

[0073] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0074] DIC: N,N'-Diisopropylcarbodiimide;

[0075] HOBt: 1-Hydroxybenzotriazole;

[0076] HOAt: N-hydroxy-7-azabenzotriazole.

[0077] Preparation of compound [Ⅲ]:

[0078]

[0079] Compound [Ⅲ] was prepared according to Examples 1 to 6 of Indian Patent IN202121024569, with an isomer content of less than 2%. 1 HNMR (600MHz, DMSO): δ 12.21 (s, 1H), 7.89 (d, J = 7.7Hz, 1H), 7.79 (t, J = 7.4Hz, 1H), 7.73 (t, J = 7.7Hz, 1H), 7.54 (d, J = 7.5Hz, 1H), 4.98 (br, 1H), 3.86 (m, 1H), 3.42 (m, 3H), 1.85 (s, 3H). See appendix for details. Figure 1 .

[0080] Preparation of compound [II] (using oxaloyl chloride):

[0081]

[0082] In a 5L three-necked flask, 400g (1.15mol) of compound [Ⅲ], 3.6L of dichloromethane, and 0.4L (4.73mol) of oxaloyl chloride were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was distilled under reduced pressure until the flow stopped to obtain a concentrate. 3.6L of tetrahydrofuran and 360g (1.83mol) of 4-methanesulfonylaniline were added to the concentrate, and 1L of N,N-diisopropylethylamine was added dropwise at room temperature. The mixture was then heated to reflux until the reaction was complete as detected by TLC (developing solvent: petroleum ether-ethyl acetate (3:1), and the reaction solution was diluted with methanol). The mixture was cooled to room temperature and concentrated under reduced pressure until the flow stopped to obtain wet N-{[4-(methanesulfonyl)phenyl]amino}oxalic acid 2-((S)-2-chloro-3-methyl-4-[4-(methanesulfonyl)phenyl]carbamoyl}-2-[2-(trifluoromethyl)phenyl]-1H-pyrrole-1-yl) ethyl ester.

[0083] Add 4.5 L of tetrahydrofuran, 300 g (3.6 mol) of 48% potassium hydroxide aqueous solution, and 3.6 L of water to a reaction flask containing wet N-{[4-(methylsulfonyl)phenyl]amino}oxalan 2-((S)-2-chloro-3-methyl-4-[4-(methylsulfonyl)phenyl]carbamoyl}-2-[2-(trifluoromethyl)phenyl]-1H-pyrrole-1-yl)ethyl ester. Heat to 35-45 °C and react until complete as detected by TLC (developing solvent: petroleum ether-ethyl acetate (3:1), reaction solution diluted with methanol). After the reaction is complete, cool to room temperature, add 2 L of ethyl acetate, stir well, separate the layers, and concentrate the organic phase to dryness under reduced pressure at 40 °C. Add 600 mL of ethanol to the concentrate, add 7.5 L of water dropwise at 35-45 °C, stir to crystallize, cool to 0-10 °C, filter, and dry the filter cake to obtain formula (II), which can be directly used for the next reaction without purification. Alternatively, it can be purified by column chromatography (eluent: n-hexane-ethyl acetate (10-1:1), collect the fraction, concentrate and obtain a relatively pure compound [II]. 1 HNMR (600MHz, DMSO): δ 10.30 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.92 (d, J = 7.8Hz, 1H), 7.88 (d, J = 8.8Hz, 2H), 7.81 (d, J = 7.4Hz, 1H), 7.76 (d, J = 7.7Hz, 1H), 7.53 (d, J = 7.5Hz, 1H), 4.90 (s, 1H), 3.87 (m, 1H), 3.46 (s, 3H), 3.17 (s, 3H), 1.83 (s, 3H). See appendix for details. Figure 2 MS(+ESI): 501.09 (M+H, isotopes: 502.09 and 503.09), 1001.17 (2M+H, 1003.17), see appendix for details. Figure 3 .

[0084] Preparation of compound [II] (using CDI catalysis):

[0085]

[0086] 40 g (0.12 mol) of compound [III] and 20.5 g of 4-methanesulfonylaniline were added to a 1 L three-necked reaction flask.

[0087] (0.12 mol), 400 ml of dichloromethane and 20.0 g (1.2 mol) of CDI, incubated overnight at room temperature. Add 400 ml of water, stir and separate the layers. Concentrate the organic layer to dryness. The next reaction can be carried out directly without purification. Alternatively, column chromatography can be used for purification (eluent: n-hexane-ethyl acetate (10-1:1). Collect the fraction and concentrate to obtain a relatively pure compound [II].

[0088] Preparation of isalidon[Ⅰ] (reduction of sodium formate by palladium on carbon):

[0089]

[0090] 260 g of compound [II], 2 L of ethanol, 140 g of sodium formate, and 30 g of 5% palladium on carbon were added to a 5 L three-necked round-bottom flask. The mixture was heated to 55-65 °C and stirred until the reaction was complete as detected by TLC (developing solvent: ethyl acetate-petroleum ether (1:1)). After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain isalidon [I]. 1 ¹H NMR (600 MHz, CDCl₃): δ 8.11 (s, 1H), 7.80 (m, 5H), 7.62 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 3.71 (m, 2H), 3.64 (m, 2H), 3.03 (s, 3H), 2.05 (s, 3H). See appendix for details. Figure 4 .

[0091] Isalidone[Ⅰ] can be purified by a mixture of ethanol and water, or by ethyl acetate and n-hexane, with an isomer content of less than 0.1%.

[0092] Preparation of isalidon[Ⅰ] (palladium-carbon catalytic hydrogenation):

[0093]

[0094] 260 g of compound [II], 2 L of ethanol, and 30 g of 5% palladium on carbon were added to a 5 L three-necked round-bottom flask. Air was replaced with nitrogen, and nitrogen was replaced with hydrogen. The mixture was heated to 55-65 °C under normal pressure and stirred until the reaction was complete as detected by TLC (developing solvent: ethyl acetate-petroleum ether (1:1)). The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain isalidon [I].

[0095] Finally, it should be noted that those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A compound for preparing isalidon, characterized in that, The structural formula [II] is as follows: [Ⅱ]。 2. A method for preparing a compound for preparing isalitonene, characterized in that, Includes the following steps: Compound [II] is obtained by reacting compound [III] with 4-methanesulfonylaniline in a solvent with an amide condensation agent and an acid-binding agent as catalyzed, as shown in the following reaction formula; 。 3. The method for preparing a compound for preparing isalitone according to claim 2, characterized in that, The solvent is one or a mixture of several solvents selected from tetrahydrofuran, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, methyl tert-butyl ether, or toluene.

4. The method for preparing a compound for preparing isalidon according to claim 2, characterized in that, The amide condensing agent is one or two of CDI, DCC, DMAP, EDCI, DIC, HOBt, HOAt, oxaloyl chloride, or thionyl chloride.

5. A method for preparing a compound for preparing isalidon according to claim 2, characterized in that, The acid-binding agent is one of triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.

6. A method for preparing isalidon from the compound according to claim 1, characterized in that, The compound [II] was prepared into isalidon [I] by catalytic reduction, as shown in the following reaction formula: 。 7. The method for preparing isthalidone according to claim 6, characterized in that, The catalysts used for catalytic reduction are palladium on carbon or Raney nickel metal catalysts.

8. The method for preparing isalitone according to claim 6, characterized in that, The reducing agent used in catalytic reduction is hydrogen, formic acid, or formate.

9. The method for preparing isalitone according to claim 6, characterized in that, The solvents used for catalytic reduction are water, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide.

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