Preparation method of cyclopofol intermediate cyclopropyl [2-hydroxy-3-(propyl-2-yl) phenyl] ketone

Abstract

The invention discloses a preparation method of a cyclopofol intermediate B (cyclopropyl [2-hydroxy-3-(propyl-2-yl) phenyl] ketone) and cyclopofol. The preparation method comprises the following steps: esterifying 2-isopropyl phenol serving as a starting material and cyclopropylformyl chloride to obtain a compound A, carrying out rearrangement reaction on the compound A through aluminum trichloride to obtain an intermediate compound B, carrying out ylide reaction on the intermediate compound B and methyltriphenylphosphorus bromide to obtain a compound C, and carrying out recrystallization on the compound C to obtain a compound D; splitting (R)-(+)-1-phenylethyl isocyanate to obtain a compound E ({[(1R)-1-phenylethyl] amino} methanoic acid-6-[(1R)-1-cyclopropylethyl]-2-(propyl-2-yl) phenyl ester with a single configuration, wherein {[(1R)-1-phenylethyl] amino} methanoic acid-6-[(1R)-1-cyclopropylethyl]-2-(propyl-2-yl) phenyl ester; the purity of the finished cyclopofol finished product obtained through refining can reach 99.9%, the cost is low, operation is easy and convenient, and industrial production is easy.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and relates to a method for preparing propofol, in particular to a method for preparing a propofol intermediate cyclopropyl[2-hydroxy-3-(propan-2-yl)phenyl]methanone with high purity and low cost. Background Art

[0002] Ciprofol (2-(1R)-1-cyclopropylethyl-6-isopropylphenol) is a Class 1 innovative intravenous anesthetic independently developed by Sichuan Hiseko Pharmaceutical Co., Ltd., a wholly-owned subsidiary of China Hiseko Pharmaceutical Group. As China's first innovative Class 1 intravenous anesthetic with an independent compound, its research and development began in 2012 and took 8 years to be approved for marketing in China in December 2020. The first indication was sedation during gastrointestinal endoscopy, and it has been gradually expanded to general anesthesia induction / maintenance, bronchoscopic diagnosis and treatment sedation, ICU sedation, gynecological outpatient surgery anesthesia and other scenarios, and is advancing into Phase III clinical trials in the United States.

[0003] Its chemical structure is shown below:

[0004]

[0005] There are several methods for synthesizing cyclamate at present:

[0006] Original research route (patent document CN105820040A): 2-isopropylphenol is used as the starting material, which is etherified with crotyl alcohol to produce compound 1. This is then subjected to high-temperature Claisen rearrangement to prepare chiral compound 2. This is then reacted with (R)-(+)-1-phenylethyl isocyanate to produce compound 3. Diiodomethane is used to obtain a three-membered ring chiral compound 4, which is then purified and hydrolyzed to produce the finished product of propofol.

[0007]

[0008] The main problems of this preparation method are: the Claisen rearrangement reaction temperature needs to be high, there are many isomer impurities, and the yield of this route is low.

[0009] The route reported in patent document CN118791364A: the intermediate cyclopropyl[2-hydroxy-3-(propan-2-yl)phenyl]methanone is used to further prepare cyclopropene. This route uses 2-isopropylphenol as the starting material, which is brominated with N-bromosuccinimide (NBS), esterified with cyclopropylcarbonyl chloride, and then subjected to Fries migration with aluminum chloride to obtain the intermediate [5-bromo-2-hydroxy-3-(prop-2-yl)phenyl](cyclopropyl)methanone. Palladium-carbon hydrogenation is then performed to obtain the intermediate cyclopropyl[2-hydroxy-3-(prop-2-yl)phenyl]methanone, which undergoes a ylide reaction with methyltriphenylphosphonium bromide to obtain 2-(1-cyclopropylvinyl)-6-(prop-2-yl)phenol. This is then resolved with (R)-(+)-1-phenylethyl isocyanate to obtain a single-configuration {[(1R)-1-phenylethyl]amino}methane-6-[(1R)-1-cyclopropylethyl]-2-(prop-2-yl)phenyl ester. After purification, the product can be obtained by hydrolysis, and finally the target product, the propyloctylphenol finished drug substance, is purified.

[0010]

[0011] Although this preparation method has readily available raw materials and is simple to operate, the following problems still exist: 1. When N-bromosuccinimide (NBS) is used for bromination, ortho-position impurities are generated and the product needs to be purified with 4-dimethylaminopyridine (DMAP), which reduces the yield; 2. The bromination and debromination steps extend the overall synthesis route and result in a low overall reaction yield; 3. The reaction requires the use of palladium on carbon, which increases the reaction cost and the reaction risk.

[0012] Based on the many defects of the preparation methods of propylcarbamazepine disclosed in the prior art, there is an urgent need for a preparation method of propylcarbamazepine with low preparation cost, short reaction steps and easy industrial production. Summary of the Invention

[0013] In view of the shortcomings of the prior art, the present invention aims to provide a method for preparing propylcyclanil suitable for industrial production.

[0014] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0015] 2-Isopropylphenol is used as the starting material, and after esterification with cyclopropylcarbonyl chloride, compound A is obtained. Compound A undergoes rearrangement reaction to obtain intermediate compound B. Intermediate compound B then undergoes ylide reaction with methyltriphenylphosphonium bromide to obtain compound C, which is then resolved with (R)-(+)-1-phenylethyl isocyanate to obtain a single-configuration compound E, which is further hydrolyzed to obtain cyclopentol.

[0016] The reaction route is as follows:

[0017]

[0018] Specifically, the present invention provides a method for preparing a propofol intermediate compound B (cyclopropyl[2-hydroxy-3-(propan-2-yl)phenyl]methanone), the method comprising the following steps:

[0019] S1: 2-isopropylphenol is esterified with cyclopropanecarbonyl chloride in the presence of triethylamine to obtain compound A;

[0020] S2: Compound A undergoes rearrangement reaction under the action of Lewis acid to obtain intermediate compound B;

[0021] The reaction route is as follows:

[0022]

[0023] As a specific embodiment, in step S1, 2-isopropylphenol is esterified with cyclopropanecarbonyl chloride in triethylamine and dichloromethane solvent to obtain compound A, and the reaction temperature is 0-10°C.

[0024] As a specific embodiment, in step S2, compound A undergoes rearrangement reaction in the presence of a Lewis acid and a reaction solvent at a certain reaction temperature to obtain an intermediate compound B.

[0025] Wherein, the Lewis acid in step S2 is selected from any one of aluminum trichloride, titanium tetrachloride, trifluoromethanesulfonic acid, ferric chloride, and zinc chloride,

[0026] Preferably, the Lewis acid in step S2 is selected from aluminum trichloride and titanium tetrachloride.

[0027] Wherein, the molar ratio of compound A to Lewis acid in step S2 is 1:0.5 to 1:2,

[0028] As a preference, the molar ratio of compound A to Lewis acid in step S2 is 1:0.9 to 1:1.1.

[0029] Wherein, the reaction solvent of step S2 is any one of dichloromethane, carbon disulfide, nitromethane, and nitrobenzene,

[0030] As a preference, the reaction solvent in step S2 is dichloromethane.

[0031] Wherein, the reaction temperature of step S2 is 110-130°C,

[0032] As a preference, the reaction temperature of step S2 is 120°C.

[0033] Another aspect of the present invention provides a method for preparing propofol.

[0034] In the above-mentioned method for preparing the propylacin intermediate compound B, the intermediate compound B undergoes a ylide reaction with methyltriphenylphosphonium bromide to prepare compound C, compound C undergoes a hydrogenation reaction under the action of [Ru] catalyst to prepare compound D, compound D reacts with (1R)-1-phenylethyl isocyanate under the action of triethylamine to prepare compound E, and compound E is hydrolyzed under alkaline conditions to prepare propylacin.

[0035] The [Ru] catalyst is cyclooctadiene ruthenium dichloride, and the ligand is R-(+)-1,1-binaphthyl-2,2-bisdiphenylphosphine.

[0036] The advantages of the present invention are:

[0037] 1. The reaction raw materials are easily available, the operation is continuous and simple, the cost is low, and the product purity and yield are high;

[0038] 2. During the preparation of the intermediate compound B cyclopropyl[2-hydroxy-3-(propan-2-yl)phenyl]methanone, there is no need to protect the para position, and the ortho position migration can be directly performed with a high conversion rate.

[0039] 3. Compared with the method reported in patent document CN118791364A, the bromination and debromination steps are reduced, the reaction steps are reduced, the amount of three wastes is greatly reduced, time and labor costs are saved, the raw material cost accounts for a low proportion, it is easy to industrialize production, and no palladium carbon is required, which is safer. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0041] Figure 1 NMR spectrum of intermediate compound B prepared under the conditions of method 1 in Example 2 of the present invention; DETAILED DESCRIPTION

[0042] The synthetic route of propofol of the present invention is as follows:

[0043]

[0044] The present invention will be described in detail below with reference to the examples. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that those skilled in the art may make several adjustments and improvements without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0045] Example 1. Preparation of Compound A

[0046] 100 g of 2-isopropylphenol (0.73 mol) and 148.3 g of triethylamine (1.46 mol) were weighed and placed in a 1 L three-necked reaction flask. 500 ml of dichloromethane was added and stirred evenly. The temperature was lowered to 0-10°C, and 84.43 g of cyclopropanecarbonyl chloride (0.80 mol) was slowly added dropwise. The mixture was kept warm for 1-2 hours. 500 ml of 1N hydrochloric acid was added and stirred to separate the liquids. The mixture was washed once with 250 ml of water. The organic phase was concentrated to obtain 149 g of a colorless oil (Compound A) (HPLC 98.50%, molar yield 99.47%).

[0047] Example 2. Preparation of Compound B

[0048] Method 1:

[0049] 100 g of compound A (0.49 mol) was weighed into a 1 L single-necked flask, 500 mL of dichloromethane and 58.8 g of aluminum chloride (0.44 mol) were added, and the mixture was stirred and refluxed for 30 minutes. The organic phase was concentrated, then the temperature was raised to 120 ° C. and the reaction was continued for 1 hour. The temperature was lowered to 100 ° C. 200 mL of toluene was added. After dissolution, the organic phase was poured into 500 mL of ice water and cooled to below 30 ° C. 500 mL of ethyl acetate was added, stirred and separated, and washed again with 500 mL of water. The organic phase was concentrated and poured into 600 g of 200-300 mesh silica gel pad. It was rinsed with 2 L of n-heptane and the organic phase was concentrated to obtain 44.6 g of yellow oily compound (B) (HPLC 99.2%, molar yield 44.6%).

[0050] MS: m / z = 203.2 [MH] -

[0051] 1 H NMR(400MHz, DMSO-d)δ13.03(s,1H),8.07~8.09(dd,1H),7.50~7.51(dd,1H),6.97~7.00(t,1H) ,3.27~3.35(m,1H),2.99~3.04(m,1H),1.19~1.21(d,6H),1.17~1.19(m,2H),1.13~1.16(m,2H).

[0052] Method 2:

[0053] 10 g of compound A (0.049 mol) was weighed into a 250 mL single-necked flask, 50 mL of dichloromethane and 5.88 g of aluminum chloride (0.044 mol) were added, and the mixture was stirred and refluxed for 30 minutes. The organic phase was concentrated, and then the temperature was raised to 140 ° C. and the reaction was continued for 1 hour. The temperature was lowered to 100 ° C. 20 mL of toluene was added. After dissolution, the organic phase was poured into 100 mL of ice water, 100 mL of ethyl acetate was added, stirred and separated, and washed again with 100 mL of water. The organic phase was concentrated and the concentrated organic phase was poured into 60 g of 200-300 mesh silica gel pad, rinsed with 500 mL of n-heptane, and the organic phase was concentrated to obtain 2.95 g of yellow oily compound (B) (HPLC 99.1%, molar yield 29.5%).

[0054] Method 3:

[0055] 10 g of compound A (0.049 mol) was weighed into a 250 mL single-necked flask, 50 mL of dichloromethane and 5.88 g of aluminum chloride (0.044 mol) were added, and the mixture was stirred and refluxed for 30 minutes. The organic phase was concentrated, and then the temperature was raised to 100 ° C. and the reaction was carried out for 1 hour. 20 mL of toluene was added and dissolved. The organic phase was poured into 100 mL of ice water, 100 mL of ethyl acetate was added, stirred and separated, and washed again with 100 mL of water. The organic phase was concentrated and poured into a 60 g 200-300 mesh silica gel pad. It was eluted with 500 mL of n-heptane and the organic phase was concentrated to obtain 3.17 g of compound (B) as a yellow oil (HPLC 99.1%, molar yield 31.7%).

[0056] Method 4:

[0057] 10 g of compound A (0.049 mol) was weighed into a 250 mL single-necked flask, 50 mL of dichloromethane and 5.88 g of aluminum chloride (0.044 mol) were added, and the mixture was stirred and refluxed for 30 minutes. The organic phase was concentrated, and then the temperature was raised to 70 ° C. and the reaction was carried out for 1 hour. 20 mL of toluene was added and dissolved. The organic phase was poured into 100 mL of ice water, 100 mL of ethyl acetate was added, stirred and separated, and washed again with 100 mL of water. The organic phase was concentrated and poured into a 60 g 200-300 mesh silica gel pad. It was eluted with 500 mL of n-heptane and the organic phase was concentrated to obtain 0.71 g of compound (B) as a yellow oil (HPLC 99.1%, molar yield 7.1%).

[0058] Method 5:

[0059] 10 g of compound A (0.049 mol) was weighed into a 250 mL single-necked flask, 9.26 g of titanium tetrachloride (0.049 mol) was added, and the temperature was then raised to 100 ° C. The reaction was allowed to proceed for 1 h. 50 mL of toluene was added and dissolved. The organic phase was poured into 100 mL of ice water, 100 mL of ethyl acetate was added, stirred and separated, and washed again with 100 mL of water. The organic phase was concentrated and poured into a 60 g 200-300 mesh silica gel pad. The concentrated organic phase was rinsed with 500 mL of n-heptane and the organic phase was concentrated to obtain 3.47 g of compound (B) as a yellow oil (HPLC 99.3%, molar yield 34.7%).

[0060] Method 6:

[0061] 8 g of compound A was weighed into a 100 mL single-necked flask, 15 g of trifluoromethanesulfonic acid was added, and the temperature was then raised to 50° C. and the reaction was allowed to proceed for 1 h. 80 mL of dichloromethane was added, and the organic phase was poured into 100 mL of ice water, stirred for separation, and washed again with 100 mL of water. The organic phase was concentrated and poured onto a 50 g 200-300 mesh silica gel pad. The concentrated organic phase was rinsed with 400 mL of n-heptane and the organic phase was concentrated to obtain 1.41 g of compound (B) as a yellow oil (HPLC 98.9%, molar yield 14.1%).

[0062] Method 7:

[0063] 10 g of compound A (0.049 mol) was weighed into a 250 mL single-necked flask, 50 mL of carbon disulfide and 6.5 g of aluminum chloride (0.049 mol) were added, and the mixture was stirred and refluxed for 30 minutes. The organic phase was concentrated, and then the temperature was raised to 120 ° C. and the reaction was continued for 1 hour. The temperature was lowered to 100 ° C. 20 mL of toluene was added. After dissolution, the organic phase was poured into 100 mL of ice water, 100 mL of ethyl acetate was added, stirred and separated, and washed again with 100 mL of water. The organic phase was concentrated and poured into a 60 g 200-300 mesh silica gel pad. The concentrated organic phase was rinsed with 500 mL of n-heptane and the organic phase was concentrated to obtain 3.56 g of compound (B) as a yellow oil (HPLC 99.1%, molar yield 35.6%).

[0064] Example 3. Preparation of Compound C

[0065] To a reaction flask containing 15 g (0.073 mol) of compound (B), add 225 ml of tetrahydrofuran solvent, 78.7 g (0.221 mol) of methyltriphenylphosphonium bromide, and 28.8 g (0.257 mol) of potassium tert-butoxide in portions with stirring. Stir for 30 minutes after addition, then raise the temperature to 60-65°C and incubate for reaction. After 2-3 hours, TLC analysis indicates complete conversion of compound B. The reaction temperature is lowered to 0-10°C, and 300 ml of purified water, 300 ml of n-heptane, and then 45 ml of methanol are slowly added to the reaction solution. Stir and separate the layers. The aqueous phase is extracted with 300 ml of n-heptane, and the combined organic phases are washed with 300 ml of saturated brine. After separation, the organic phase is dried and concentrated to obtain 30 g of crude compound C (containing triphenylphosphine oxide). To the crude compound were added 60 g of 200-300 mesh silica gel powder and 300 mL of n-heptane, stirred for 30 minutes, filtered, and the filter cake was rinsed with 100 mL of n-heptane. The organic phase was concentrated, and the filtrate was concentrated to obtain compound (C) (14.2 g of 2-(1-cyclopropylvinyl)-6-isopropylphenol) (yield 94.67%, purity 98.60%; MS: m / z = 203.3 [M+H]+).

[0066] Example 4. Preparation of Compound D

[0067] 0.27 g (0.001 mol, 0.002 eq) of cyclooctadiene ruthenium dichloride was added to a 100 ml single-necked round-bottom flask, followed by 20 ml of ethanol and R-(+)-1,1-binaphthyl-2,2-bisdiphenylphosphine (0.63 g, 0.002 eq). The atmosphere was replaced with nitrogen three times, and the reaction was heated at reflux for 1 h. The ethanol solvent was then concentrated under reduced pressure to obtain the [Ru] catalyst. To a 1 L hydrogenation reactor, 10 g (0.05 mol, 1 eq) of compound (C) and 0.5 L of tert-butyl alcohol were added. The freshly prepared [Ru] catalyst was then added with stirring. The atmosphere was replaced with nitrogen and then hydrogen three times, with a hydrogen atmosphere of 3-4 MPa. The reaction was carried out at 25-30°C for 10 h. After the reaction was complete, a sample was taken for HPLC analysis. The catalyst was filtered, the organic phase was concentrated, and stored at low temperature.

[0068] Example 5. Preparation of Compound E

[0069] To the reaction flask of compound D prepared in Example 4, 50 mL of n-heptane solvent was added, and 2.6 g of triethylamine and 10.5 g of (1R)-1-phenylethyl isocyanate were added with stirring. The mixture was refluxed for 2 hours, then cooled to 10-15°C for crystallization for 1 hour, filtered, and the filter cake was rinsed with n-heptane. 13 g of a white solid carbamate compound was obtained. 45 ml of n-heptane was added to the white solid, heated to 65-70°C, dissolved, and then naturally cooled to 0-5°C. Crystallization occurred for 1 hour, and filtered to obtain 11.5 g of compound (E) {[(1R)-1-phenylethyl]amino}methane-6-[(1R)-1-cyclopropylethyl]-2-(prop-2-yl)phenyl ester as a white solid (HPLC purity 99.62%, yield 66.8%; MS: m / z = 352.5 [M+H]). + )

[0070] Example 6, Preparation of Propofol Finished Product

[0071] To 10 g of compound (E) was added 50 ml of n-heptane, followed by 5 g of solid sodium hydroxide under nitrogen, and the mixture was heated to reflux for 2-3 hours. TLC monitored the complete conversion. The reaction mixture was cooled to 10-15°C, and 50 ml of purified water was slowly added. The mixture was stirred under nitrogen for 30 minutes, filtered through celite, and rinsed with n-heptane. After separation, the aqueous phase was back-extracted once with 20 ml of n-heptane. The combined organic phases were washed with 30 ml of purified water, dried, and concentrated to yield 5 g of the finished product, Propofol. (Yield: 85.9%; MS: m / z = 205.3 [M+H]+)

[0072] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various variations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing cyclopropyl[2-hydroxy-3-(propan-2-yl)phenyl]methanone, an intermediate of propofol, characterized in that: The method comprises the following steps: S1: 2-isopropylphenol is esterified with cyclopropanecarbonyl chloride in the presence of triethylamine to obtain compound A; S2: Compound A undergoes rearrangement reaction under the action of Lewis acid to obtain intermediate compound B; The reaction route is as follows:

2. The method for preparing a propofol intermediate according to claim 1, wherein In step S1, 2-isopropylphenol is esterified with cyclopropanecarbonyl chloride in triethylamine and dichloromethane solvent to obtain compound A. The reaction temperature is 0-10°C.

3. The method for preparing the propofol intermediate according to claim 1, wherein In step S2, compound A undergoes rearrangement reaction in the presence of Lewis acid and reaction solvent at a certain reaction temperature to obtain intermediate compound B.

4. The method for preparing a propofol intermediate according to claim 1, wherein In step S2, the Lewis acid is selected from any one of aluminum trichloride, titanium tetrachloride, trifluoromethanesulfonic acid, ferric chloride, and zinc chloride.

5. The method for preparing the propofol intermediate according to claim 4, wherein: In step S2, the Lewis acid is selected from any one of aluminum trichloride and titanium tetrachloride.

6. The method for preparing a propofol intermediate according to claim 1, wherein: In step S2, the molar ratio of compound A to Lewis acid is 1:0.5 to 1:

2.

7. The method for preparing a propofol intermediate according to claim 1, wherein: The reaction solvent in step S2 is any one of dichloromethane, carbon disulfide, nitromethane, and nitrobenzene.

8. The method for preparing a propofol intermediate according to claim 1, wherein: The reaction temperature of step S2 is 110-130°C.

9. The synthesis method according to claim 1 or 2 is used to prepare the intermediate compound B, and further prepare propylparaben.

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