A method for the synthesis of etomidate

Abstract

The present application relates to a kind of synthesis method of etomidate, starting material (R) -(1-(1-phenylethyl)-1H-5 imidazolyl) methanol is oxidized to obtain (R) -(1-(1-phenylethyl)-1H-5 imidazolyl) formaldehyde;Then in ethanol solvent, (R) -(1-(1-phenylethyl)-1H-5 imidazolyl) formaldehyde is oxidized to obtain etomidate by oxidizing agent potassium hydrogen peroxysulfate oxone complex salt, and by recrystallization, it is purified into clean etomidate crystal.The present application changes one-step oxidation in prior art into two-step oxidation, in oxidation process, its condition is mild, oxidizing agent is less, and conversion rate is high, and can be suitable for mass production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a method for synthesizing etomidate. Background Technology

[0002] Etomidate, scientifically known as R-(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-carboxylate, has the molecular formula C1. 14 H 16 N₂O₂, with a molecular weight of 244.12, has the structural formula shown below. It is a chiral imidazole compound, a non-barbiturate hypnotic intravenous general anesthetic, and one of the commonly used drugs for anesthesia induction. Among intravenous anesthetics, etomidate is the only one that does not interfere with cardiovascular stability. It can also reduce intracranial pressure and maintain cerebral perfusion, making it particularly suitable for elderly patients, those with coronary atherosclerotic heart disease, hypertension, and those in shock. Etomidate was synthesized in 1965 and introduced into clinical practice in 1972. Its clinical application has a history of nearly 50 years, and it has been on the market in China for 20 years since 2002. Its safety and efficacy have been widely proven.

[0003]

[0004] The above formula shows that in the prior art, chiral R-1-phenylethylamine hydrochloride (1) and 1,3-dihydroxyacetone dimer (2) are used as starting materials to obtain mercaptoimidazole derivatives (3) under reaction conditions such as potassium thiocyanate. Mercaptoimidazole derivatives (3) are oxidized by sodium nitrite to obtain imidazole methanol compounds (4). Compound 4 is oxidized and esterified under 40 equivalents of manganese dioxide as an oxidant to obtain the anesthetic etomidate. The key step of this route, from the oxidation reaction of compound 4 to the drug etomidate, although the oxidation of hydroxymethyl to carboxyl to obtain formate compounds seems to be a classic reaction, requires the use of highly toxic sodium cyanide as a catalyst and 40 equivalents of manganese dioxide as an oxidant because the hydroxymethyl group is attached to the imidazole group. This method has high production costs and is not suitable for large-scale production, and has obvious limitations in application. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing etomidate that is mild, environmentally friendly, and has a high yield, making it suitable for industrial-scale production.

[0006] A method for synthesizing etomidate, comprising the following steps:

[0007] (1) Provides (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol,

[0008] (2) (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol is oxidized to give (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde.

[0009] (3) Imidazole formaldehyde compounds are oxidized in alcohol solvents by potassium persulfate complex salt to obtain etomidate compounds.

[0010] The reaction conditions for step (3) are as follows: (R)-(1-(1-phenylethyl)-1H-5 imidazolyl)formaldehyde is mixed with potassium peroxymonosulfate oxone complex salt, an alcohol solvent is added, the tube is sealed and heated under reflux for 10-15 hours, cooled, the white solid is filtered off, the filtrate is concentrated and recrystallized to obtain etomidate compounds.

[0011] The alcohol solvent is ethanol.

[0012] The heating reflux temperature is 100°C, and the recrystallization solvent is petroleum ether and ethyl acetate in a volume ratio of 10:1.

[0013] The method of step (2) is to dissolve (R)-(1-(1-phenylethyl)-1H-5 imidazolyl)methanol in a haloalkane solvent, add the catalyst 2,2,6,6-tetramethylpiperidine oxide and the oxidant iodophenyldiacetic acid, react at room temperature, monitor the reaction until the end of the reaction with TCL, evaporate the solvent and recrystallize to obtain (R)-(1-(1-phenylethyl)-1H-5 imidazolyl)formaldehyde.

[0014] The amount of 2,2,6,6-tetramethylpiperidine oxide used is 10 mol% of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol, and the amount of iodophenyldiacetic acid used is 1.2 molar equivalents of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol.

[0015] Alternatively, the catalyst cuprous trifluoromethanesulfonate and the ligand bipyridine can be dissolved in acetonitrile, followed by the addition of the co-catalyst 2,2,6,6-tetramethylpiperidine oxide, and then (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol. The reaction is then purged with air until completion, water is added, and the mixture is extracted with ethyl acetate. The extractant is evaporated to dryness and recrystallized to obtain (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde.

[0016] The amount of 2,2,6,6-tetramethylpiperidine oxide used is 5 mol% of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol, and the haloalkane is dichloromethane.

[0017] The amounts of copper(II) trifluoromethanesulfonate and bipyridine added are 5 mol% copper(II) trifluoromethanesulfonate and 5 mol% bipyridine, respectively, of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol.

[0018] The solvent for recrystallization of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde is a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1.

[0019] The method of step (1) is as follows: add concentrated hydrochloric acid solution, dihydroxyacetone and potassium thiocyanate to a chiral R-1-phenylethylamine acetonitrile or isopropanol solution, react at 50-70℃ for 2-4 hours, cool and extract with ethyl acetate, and evaporate the solvent to obtain compound (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione; then add hydrogen peroxide dropwise with a haloalkane solvent under acidic conditions and react at 40-50℃. After the reaction is completed, adjust the pH to 10-12 with sodium hydroxide solution, extract with a haloalkane solvent, and evaporate the solvent to obtain (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol.

[0020] The haloalkane is dichloromethane, and the acidic condition is the addition of hydrochloric acid, phosphoric acid, acetic acid, or propionic acid to the reaction system.

[0021] The hydrogen peroxide is 30% hydrogen peroxide, and the amount added is 2.5 molar equivalents of (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione.

[0022] In existing technologies, hydroxymethyl groups are oxidized and esterified using manganese dioxide under potassium cyanide catalysis. Since hydroxymethyl is a substituent on imidazole, and the oxidation process is followed by direct esterification, the oxidation conditions are harsh. This invention first converts the hydroxymethyl group to an aldehyde group, and then oxidizes the aldehyde group to a carboxylic acid group in the presence of potassium bisulfate oxone complex salt as an oxidant, while simultaneously directly esterifying it into an ester. This invention transforms the one-step oxidation process of existing technologies into a two-step oxidation process. The oxidation conditions are mild, the oxidant is inexpensive and readily available, and the conversion rate is high, making it suitable for mass production.

[0023] The (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol in this invention can be synthesized using existing methods, but the method of this invention is preferred. This invention uses (R)-phenethylamine, dihydroxyacetone, and potassium thiocyanate as starting materials. After the reaction, the mixture is oxidized and desulfurized with hydrogen peroxide to obtain imidazolyl methanol compounds. The starting materials are simple and readily available, the reaction aids are inexpensive, and the product yield is high.

[0024] The present invention has two preferred methods for oxidizing hydroxymethyl to aldehyde. Both methods use low amounts of oxidant, are mild, and have high yields. Even though the present application uses a two-step oxidation process, it does not reduce the overall reaction yield. Detailed Implementation

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0026] All reagents used below are commercially available.

[0027] The technical solution adopted in this invention is: a novel method for preparing etomidate, comprising the following steps in sequence:

[0028] S1, the structure is R-1-phenylethylamine reacts with 1,3-dihydroxyacetone and potassium thiocyanate, and is then oxidized with 30% hydrogen peroxide to obtain...

[0029] S2, the compound obtained in the above steps Obtained through oxidation

[0030] S3, the compound obtained in the above steps Etomidate is obtained by oxidation in ethanol solvent using the oxidant potassium persulfate oxone complex salt.

[0031] The synthetic route for etomidate disclosed in this invention is as follows:

[0032]

[0033] Example 1: Preparation of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol (compound 3)

[0034] Acetonitrile (100 mL) was added to chiral R-1-phenylethylamine (100 mmol), and the mixture was stirred. At 0 °C, 37% HCl (8.3 mL, 100 mmol) was added. Then, acetic acid (8.3 mL), dihydroxyacetone (18 g, 200 mmol), and KSCN (9.7 g, 100 mmol) were added. The reaction mixture was reacted at 60 °C for 3 hours. After cooling, the mixture was extracted with ethyl acetate, and the solvent was evaporated to dryness to give compound (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione. Next, acetic acid (8.3 mL) was added in 100 mL of dichloromethane as a solvent, followed by the slow dropwise addition of 30% hydrogen peroxide (2.5 equiv). The reaction temperature was controlled at 40-50 °C. After the reaction was complete, the pH was adjusted to approximately 10-12 with 10% sodium hydroxide solution. After reacting for half an hour, the mixture was extracted three times with dichloromethane, and the combined organic phases were evaporated to dryness to give compound (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione. 19g, total yield 95%.

[0035] Example 2: Preparation of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde

[0036] Method 1: 10 g of compound (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol was dissolved in 200 mL of dichloromethane. Catalyst 2,2,6,6-tetramethylpiperidine oxide (10 mol%) and oxidant iodophenyldiacetic acid (19.1 g, 1.2 eq) were added, and the reaction was monitored by TCL until completion. After evaporating the dichloromethane solvent, the compound was recrystallized from 10:1 petroleum ether and ethyl acetate to obtain the compound. 9.4g, yield 95%. 1 H NMR (400MHz, Chloroform-d) δ9.72 (s, 1H), 7.83 (s, 2H), 7.34 (ddd, J = 13.0, 7.8, 6. 0Hz, 3H), 7.23 (dd, J=6.9, 1.8Hz, 2H), 6.30 (q, J=7.1Hz, 1H), 1.88 (d, J=7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ179.04,144.15,141.38,140.15,137.40,128.85,128.22,126.38,55.99,21.70.

[0037] Method 2: Copper(II) trifluoromethanesulfonate (5 mol%, 530 mg) and bipyridine (5 mol%, 390 mg) were dissolved in 250 ml of acetonitrile. 2,2,6,6-Tetramethylpiperidine oxide (5 mol%, 390 mg) was added, followed by (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol (10 g). The reaction was purged with air until completion. After finishing, 50 ml of water was added, and the mixture was extracted three times with ethyl acetate. Recrystallization yielded 9.9 g, with a yield of 99%.

[0038] Example 3: Preparation of etomidate

[0039] Method 1: Add 10g of the starting compound to the reaction flask The oxidant, potassium peroxymonosulfate oxone complex salt, was 4.5% (1.2 equiv, 37 g). Finally, 100 ml of anhydrous ethanol was added, the tube was sealed, and the mixture was heated to 100 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, the white solid residue was filtered off, and the solution was concentrated to obtain a white liquid. Recrystallization from petroleum ether and ethyl acetate (10:1) yielded 10.8 g of a white solid, with a yield of 93%.

[0040] Method 2: Add 10g of the starting compound (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde to the reaction flask. The oxidizing agent was potassium peroxymonosulfate oxone complex salt 4.5% (1.2 equiv, 37 g), and finally 100 ml of anhydrous ethanol was added. The mixture was heated to 60 °C and reacted for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, the white solid was filtered off, and the solution was concentrated to obtain a white liquid. No further reaction was observed.

[0041] Method 3: (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde (0.20 g, 1 mmol, 1 equiv) and zinc bromide (22.5 mg, 0.1 mmol, 10 mol%) were placed in a reaction flask. After adding 5 mL of anhydrous ethanol, 0.9 mL of hydrogen peroxide (30%) was slowly added dropwise (4 eq). The reaction was carried out at room temperature for 8 hours. Then, 3 mL of distilled water was added, and the product was extracted with ethyl acetate (3 × 10 mL). Only a partial reaction was observed, and the yield of etomidate was <10%.

[0042] Method 4: Diphenyldiselenes (2 mol%, 0.006 g) were treated with hydrogen peroxide (30%, 0.15 mL, 1.5 mmol) at room temperature until a colorless mixture was obtained, and then stirred at room temperature until the reaction mixture changed color. Then, (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde (0.20 g, 1 mmol, 1 equiv) and an appropriate amount of ethanol (2.5 mmol) were added. The reaction mixture was stirred at 50 °C for 2 h and extracted three times with ethyl acetate (3 × 20 mL). The collected organic layers were dried over Na₂SO₄, and the solvent was evaporated under reduced pressure; no product, etomidate, was obtained.

[0043] Method 5: An ethanol suspension (0.65 mL, 16 mmol, 16 equiv) of (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde (0.20 g, 1 mmol, 1 equiv) and (NH4)2S2O8 (0.35 g, 1.5 mmol, 1.5 equiv) was stirred at 60 °C for 4 h. After cooling to room temperature, the solid was dissolved in distilled water (10 mL), and the product was extracted with ethyl acetate (3 × 10 mL). The combined organic extract was concentrated and purified by silica gel column chromatography. The reaction was not carried out.

[0044] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the methods and techniques disclosed above without departing from the scope of the present invention to create equivalent embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for synthesizing etomidate, comprising the following steps: (1) Provides (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol, (2) (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol is oxidized to (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde. (3) Imidazole formaldehyde compounds are oxidized in alcohol solvents by potassium persulfate complex salt to obtain etomidate; The method of step (2) is as follows: (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol is dissolved in a haloalkane solvent, 2,2,6,6-tetramethylpiperidine oxide is added as a catalyst and iodophenyl diacetic acid as an oxidant, the reaction is monitored by TCL at room temperature until the reaction is completed, the solvent is evaporated, and recrystallized to obtain ( R )-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde; Alternatively, the catalyst cuprous trifluoromethanesulfonate and the ligand bipyridine can be dissolved in acetonitrile, followed by the addition of the co-catalyst 2,2,6,6-tetramethylpiperidine oxide, and then (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol. The reaction is then purged with air until completion, followed by the addition of water and extraction with ethyl acetate. The extractant is evaporated to dryness, and recrystallized to obtain (…). R )-(1-(1-phenylethyl)-1H-5-imidazolyl)formaldehyde; The reaction conditions for step (3) are: to ( R (1-(1-phenylethyl)-1H-5 imidazolyl)formaldehyde was mixed with potassium persulfate complex salt, an alcohol solvent was added, the tube was sealed and heated under reflux for 10-15 hours, cooled, the white solid was filtered off, the filtrate was concentrated and recrystallized to obtain etomidate compound.

2. According to the synthesis method of claim 1, the alcohol solvent is ethanol, the heating reflux temperature is 100°C, and the recrystallization solvent in step (3) is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 10:

1.

3. According to the synthesis method of claim 1, the amount of 2,2,6,6-tetramethylpiperidine oxide is 5-10 mol% of (R)-(1-(1-phenylethyl)-1H-5imidazolyl)methanol, the haloalkane in step (2) is dichloromethane, and the amount of iodophenyldiacetic acid is 1.2 molar equivalents of (R)-(1-(1-phenylethyl)-1H-5imidazolyl)methanol.

4. The synthesis method according to claim 1, wherein the amount of copper(II) trifluoromethanesulfonate and bipyridine added is 5 mol% copper(II) trifluoromethanesulfonate and 5 mol% bipyridine in (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol.

5. According to the synthesis method of claim 1, the solvent for recrystallization in step (2) is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:

1.

6. The synthesis method according to claim 1, wherein step (1) is performed in a chiral environment. R A solution of 1-phenylethylamine in acetonitrile or isopropanol was added with concentrated hydrochloric acid solution, dihydroxyacetone, and potassium thiocyanate. The mixture was refluxed for 2-4 hours, cooled, and extracted with ethyl acetate. The solvent was then evaporated to dryness to give compound (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione. Hydrogen peroxide was then added dropwise to the mixture in an acidic environment with a haloalkane solvent at 40-50 °C. After the reaction was completed, the pH was adjusted to 10-12 with sodium hydroxide solution. The mixture was then extracted with a haloalkane solvent, and the solvent was evaporated to dryness to give (R)-(1-(1-phenylethyl)-1H-5-imidazolyl)methanol.

7. The synthesis method according to claim 6, wherein the haloalkane in step (1) is dichloromethane, and the acidic condition is the addition of hydrochloric acid, phosphoric acid, acetic acid or propionic acid to the reaction system.

8. The synthesis method according to claim 6, wherein the hydrogen peroxide is 30% hydrogen peroxide, and the amount added is 2.5 molar equivalents of (R)-5-(hydroxymethyl)-1-(1-phenylethyl)-1,3-dihydro-2H-imidazol-2-thione.

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