Preparation method of imidazoline derivative or its salt

Abstract

The present disclosure relates to a method for preparing an imidazoline derivative or a salt thereof. Specifically, the present disclosure provides ( S A method for preparing )-4-(3-(4-(2,3-dihydroxypropoxy)phenyl)-4,4-dimethyl-5-keto-2-thioimidazoline-1-yl)-2-(trifluoromethyl)benzonitrile has good selectivity and yield.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a preparation method. Background Art

[0002] WO2014036897 discloses a new class of androgen receptor antagonists, the compound structure of which is shown in Formula I: At present, the synthesis method of this type of compound includes the steps of reacting an amino compound with a ketone and trimethylsilyl cyanide under the catalytic condition of trimethylsilyl trifluoromethanesulfonate to obtain a cyano compound, and performing a cyclization reaction between an isothiocyanato benzene ring compound and a cyano compound and hydrolyzing them under acidic conditions to obtain a thioimidazoline compound.

[0003] Among them, the intermediate IV obtained by the reaction of trimethylsilyl cyanide under the catalytic condition of trimethylsilyl trifluoromethanesulfonate has a yield of only 23%, and the total yield of the compound of formula I prepared by the above method is only 8.1%, which is not suitable for industrial production.

[0004] WO2011103202 discloses a method for synthesizing intermediate IV using p-aminophenol, magnesium sulfate and 2-hydroxy-2-methylpropionitrile as raw materials, which can increase the yield to 74%. However, 2-hydroxy-2-methylpropionitrile is a hazardous chemical listed in the "Catalogue of Hazardous Chemicals (2015 Edition)", which is highly toxic and not suitable for industrial scale-up production.

[0005] .

[0006] CN110684046B discloses a method for preparing a compound of formula I without using a catalyst. The yield of some steps in this route is relatively low, and the total yield of the compound of formula I is 16.5%.

[0007] .

[0008] At present, there is still a need to develop a method for industrially preparing the compound of formula I with high total yield, low cost and green environmental protection. Summary of the invention

[0009] The present disclosure provides a method for preparing a compound of formula II or a pharmaceutically acceptable salt thereof,

[0010] The method comprises the steps of reacting p-aminophenol with acetone and trimethylsilyl cyanide in the presence of an acid, .

[0011] In some embodiments, the acid is selected from the group consisting of hydrogen chloride, p-toluenesulfonic acid, citric acid, tartaric acid, malic acid, phosphoric acid.

[0012] In some embodiments, the acid is selected from p-toluenesulfonic acid.

[0013] In some embodiments, the acid is selected from hydrogen chloride.

[0014] In some embodiments, the molar ratio of p-aminophenol to acid is 1:0.1% to 1:5%, including but not limited to 1:0.1%, 1:0.2%, 1:0.3%, 1:0.4%, 1:0.5%, 1:0.6%, 1:0.7%, 1:0.8%, 1:0.9%, 1:1%, 1:2%, 1:3%, 1:4%, 1:5% or any value between two numbers. In some embodiments, the molar ratio of p-aminophenol to acid is 1:0.2% to 1:3%. In some embodiments, the molar ratio of p-aminophenol to acid is 1:0.2%. In some embodiments, the molar ratio of p-aminophenol to acid is 1:3%.

[0015] In certain embodiments, the molar ratio of p-aminophenol to p-toluenesulfonic acid is 1:0.2%.

[0016] In certain embodiments, the molar ratio of p-aminophenol to p-hydrogen chloride is 1:3%.

[0017] In some embodiments, the molar ratio of p-aminophenol to trimethylsilyl cyanide is 1:1 to 1:2, including but not limited to 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2 or any value between two numbers. In some embodiments, the molar ratio of p-aminophenol to trimethylsilyl cyanide is 1:1.2 to 1:1.5. In some embodiments, the molar ratio of p-aminophenol to trimethylsilyl cyanide is 1:1.3.

[0018] The present disclosure provides a method for preparing a compound of formula II, which can effectively remove impurities G and H while maintaining a high yield in an industrial-level operation. The compound of formula III is an impurity and is difficult to remove by column chromatography.

[0019] , .

[0020] The present disclosure provides a method for preparing a compound of formula II or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0021] 1) a crude product 1 of a compound of formula II obtained by reacting a compound of formula III with a compound of formula VI; 2) The crude compound 1 of formula II is recrystallized in a solvent system, wherein the solvent system is selected from any one of hydrocarbon solvents, ether solvents, alcohol solvents, nitrile solvents, ketone solvents, ester solvents or water, or a mixed solvent.

[0022] In an optional embodiment, the solvent system is selected from a mixed solvent of a hydrocarbon solvent, an alcohol solvent and water, the hydrocarbon solvent is selected from toluene, and the alcohol solvent is selected from methanol, ethanol, isopropanol, tert-butanol, propylene glycol, glycerol or benzyl alcohol.

[0023] In an optional embodiment, the solvent system is selected from a mixed solvent of a hydrocarbon solvent, an alcohol solvent and water, and the alcohol solvent is selected from methanol or ethanol.

[0024] In an optional embodiment, the alcohol solvent in the solvent system is selected from ethanol.

[0025] In an optional embodiment, the weight ratio of the hydrocarbon solvent to the alcohol solvent is selected from 1:10-1:25.

[0026] In an optional embodiment, the weight ratio of the hydrocarbon solvent to the alcohol solvent is selected from 1:15-1:19.

[0027] In an optional embodiment, the weight ratio of the hydrocarbon solvent to water is selected from 1:5-1:10.

[0028] In an optional embodiment, the weight ratio of the hydrocarbon solvent to water is selected from 1:8-1:10.

[0029] In an optional embodiment, the solvent system consisting of a mixed solvent of hydrocarbon solvents, alcohol solvents and water, the weight ratio of hydrocarbon solvents, alcohol solvents and water is 1:17:9.

[0030] In an optional embodiment, the solvent system consists of a mixed solvent of toluene, ethanol and water, and the weight ratio of toluene, ethanol and water is 1:17:9.

[0031] In an optional embodiment, the method for preparing the compound of formula II or a pharmaceutically acceptable salt thereof, the content of impurity G is less than 0.2%.

[0032] In an optional embodiment, the method for preparing the compound of formula II or a pharmaceutically acceptable salt thereof has an impurity H content of less than 1%.

[0033] The present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the method for preparing a compound of formula IV or formula II, further comprising the step of deprotecting the compound of formula II to obtain a compound of formula I, .

[0034] In an optional embodiment, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises the step of reacting a compound of formula IV with a compound of formula V to produce a compound of formula III, .

[0035] The present disclosure further provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the following steps: 1) reacting p-aminophenol with acetone and trimethylsilyl cyanide in the presence of an acid to generate a compound of formula IV, wherein the acid is selected from one of hydrogen chloride, p-toluenesulfonic acid, citric acid, tartaric acid and malic acid; 2) reacting the compound of formula IV with a compound of formula V to generate a compound of formula III; 3) reacting the compound of formula III with a compound of formula VI to generate a crude product of a compound of formula II, and recrystallizing the crude product through toluene: ethanol: water to obtain a compound of formula II; 4) deprotecting the compound of formula II to obtain a compound of formula I,

[0036] .

[0037] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the molar ratio of p-aminophenol to acid in step 1 is 1:0.1% to 1:5%, including but not limited to 1:0.1%, 1:0.2%, 1:0.3%, 1:0.4%, 1:0.5%, 1:0.6%, 1:0.7%, 1:0.8%, 1:0.9%, 1:1%, 1:2%, 1:3%, 1:4%, 1:5% or a value between any two numbers. In some embodiments, the molar ratio of p-aminophenol to acid is 1:0.2% to 1:3%. In some embodiments, the molar ratio of p-aminophenol to acid is 1:0.2%. In some embodiments, the molar ratio of p-aminophenol to acid is 1:3%.

[0038] In some embodiments, the molar ratio of p-aminophenol to p-toluenesulfonic acid in step 1 is 1:0.2%.

[0039] In some embodiments, the molar ratio of p-aminophenol to p-hydrogen chloride in step 1 is 1:3%.

[0040] In some embodiments, in the method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, the weight ratio of toluene:ethanol:water used for recrystallization of the crude product in step 3 is 1:17:9.

[0041] The preparation method disclosed in the present invention further comprises one or more steps of filtering, washing, drying, concentrating or recondensing.

[0042] Pharmaceutically acceptable salts of the disclosed compounds / intermediates include, but are not limited to, addition salts of the free state of the compounds / intermediates with acids or bases, and the acids used to form the salts include, but are not limited to, hydrogen chloride, p-toluenesulfonic acid, citric acid, tartaric acid, malic acid, and phosphoric acid. In some embodiments, pharmaceutically acceptable salts of the compounds / intermediates include, but are not limited to, hydrochlorides, citrates, malate, tartrates, and p-toluenesulfonates. DETAILED DESCRIPTION

[0043] The present disclosure will be explained in more detail below in conjunction with embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0044] Test conditions of the instruments used in the experiment:

[0045] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 400M NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0046] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMOUltimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0047] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC 2695-2489.

[0048] Silica gel column chromatography generally uses Yantai Huanghai 200~300 mesh silica gel as the carrier.

[0049] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0050] Example 1

[0051]

[0052] first step

[0053] 2-((4-Hydroxyphenyl)amino)-2-methylpropionitrile compound 1b

[0054] A 500L reactor was added with 260.0kg of acetone, 32.00kg of p-aminophenol, and 96g of p-toluenesulfonic acid, and the temperature was lowered to -20~0°C, and 37.76kg of trimethylsilyl cyanide was added dropwise, and the mixture was stirred at 15~25°C for reaction. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, 112.0kg of n-heptane was added, stirred, centrifuged, and the filter cake was dried to obtain 49kg of compound 1b with a yield of 95%.

[0055] Step 2

[0056] 4-(3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile compound 1c

[0057] To a 1000 L reactor, 320.0 kg of N,N-dimethylacetamide, 49 kg of compound 1b, and 70.00 kg of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile were added; 150 L of purified water and 30.00 kg of hydrochloric acid were added under stirring at -10 to 0°C; and the mixture was heated to reflux.

[0058] After the reaction was completed, purified water was added, centrifuged and filtered, the filter cake was slurried with purified water, centrifuged and filtered, the filter cake was refined with ethyl acetate and n-heptane, centrifuged and filtered, and the filter cake was dried to obtain 80.00 kg of compound 1c with a yield of 71% and a HPLC purity of 99.98%.

[0059] Step 3

[0060] (R)-4-(3-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile Compound 1d

[0061] Add 770.0 kg of toluene to a 2000L reactor, then add compound 1c obtained in the previous step, 36.48 kg of (R)-(-)-glycerol acetone, and 67.84 kg of tributylphosphine, and heat to 55-65°C. Add 79.68 kg of azodicarbonyl dipiperidine dissolved in 550.0 kg of toluene to the reactor. Stir the reaction at 60-70°C. After the reaction is completed, centrifuge and filter, and concentrate to dryness under reduced pressure. Add 32 kg of toluene and 533.6 kg of anhydrous ethanol to the reactor to purify 89.5 kg of compound 1d, with a yield of 87.3% and an HPLC purity of 98.733%.

[0062] Step 4

[0063] (S)-4-(3-(4-(2,3-dihydroxypropoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile compound 1

[0064] 275.0 kg of tetrahydrofuran was added to a 1000 L reactor, and then 57.00 kg of compound 1d was added, and the mixture was heated to 35-45 °C. 225 L of purified water and 45.00 kg of hydrochloric acid were added to the reactor, and the mixture was stirred for reaction. After the reaction was completed, 140 kg of compound was obtained by further treatment, with a yield of 76% and a HPLC purity of 99.80%.

[0065] Example 2

[0066] In order to investigate the impurity removal ability of the process step 3 of the present disclosure, the compound 1d obtained in the third step of Example 1 was subjected to HPLC impurity analysis, and the impurity content of the compound 1d obtained according to the process method of Example 1 of CN113929628A was compared. The results are shown in Table 1 below:

[0067] Table 1

[0068]

[0069] Example 3

[0070]

[0071] The method of preparing compound 1b in Example 1 was used to investigate the effect of different acids on the yield of compound 1b. The feed ratio of compound 1a and acid is shown in the table below.

[0072] Table 2

[0073]

[0074] It can be seen from the above table that p-toluenesulfonic acid, hydrogen chloride and citric acid can all obtain better yields at extremely low catalytic amounts.

Claims

1. Method for preparing a compound of formula IV or a pharmaceutically acceptable salt thereof , comprising the steps of reacting p-aminophenol with acetone and trimethylsilyl cyanide in the presence of an acid, The acid is selected from hydrogen chloride and p-toluenesulfonic acid, and the molar ratio of p-aminophenol to the acid is 1:0.1% to 1:5%.

2. Preparation method of the compound of formula I or its pharmaceutically acceptable salt , comprising the preparation method according to claim 1, further comprising a method for preparing a compound of formula II, wherein the method for preparing a compound of formula II comprises the following steps, Step 1) reacting a compound of formula III with a compound of formula VI to prepare a crude product 1 of a compound of formula II; Step 2) The crude product 1 is recrystallized in a mixed solvent of toluene:ethanol:water, wherein the weight ratio of toluene to ethanol in the mixed solvent is selected from 1:15-1:19, and the weight ratio of toluene to water is selected from 1:8-1:

10.

3. The preparation method according to claim 2, further comprising the step of deprotecting the compound of formula II to obtain the compound of formula I, .

4. The preparation method according to claim 2, comprising the following steps: Step 1) p-aminophenol reacts with acetone and trimethylsilyl cyanide in the presence of an acid to produce a compound of formula IV, wherein the acid is selected from one of hydrogen chloride, p-toluenesulfonic acid, citric acid, tartaric acid and malic acid; Step 2) reacting the compound of formula IV with the compound of formula V to generate the compound of formula III; Step 3) reacting the compound of formula III with the compound of formula VI to generate a crude compound of formula II, and recrystallizing the crude compound from toluene:ethanol:water in a weight ratio of 1:17:9 to obtain a compound of formula II; Step 4) Deprotecting the compound of formula II to obtain the compound of formula I, Wherein, in step 1, the molar ratio of p-aminophenol to acid is 1:0.1% to 1:5%.

5. The preparation method according to claim 4, characterized in that: In step 1, p-aminophenol reacts with acetone and trimethylsilyl cyanide in the presence of p-toluenesulfonic acid to generate a compound of formula IV, and the molar ratio of p-aminophenol to p-toluenesulfonic acid is 1:0.1% to 1:0.5%.

6. The preparation method according to claim 4, characterized in that: In step 1, p-aminophenol reacts with acetone and trimethylsilyl cyanide in the presence of hydrogen chloride to generate a compound of formula IV, and the molar ratio of p-aminophenol to hydrogen chloride is 1:1% to 1:5%.

Images