CN107903200A - A kind of preparation method of hyperlipidemia curative Ezetimibe - Google Patents

Abstract

The invention discloses a preparation method of ezetimibe, a drug for treating hyperlipidemia, and belongs to the field of drug synthesis. Using compound 2 as a raw material, ezetimibe 1 was prepared through four synthetic steps including carbonyl protection, cyclization, carbonyl reduction, and deprotection. Compared with the methods reported in the existing literature, the use of contaminating titanium reagents is avoided, the synthesis steps are reduced, the process stability is higher, and it is suitable for large-scale production.

Description

Preparation method of ezetimibe, a drug for treating hyperlipidemia

technical field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of ezetimibe, a drug for treating hyperlipidemia.

Background technique

Ezetimibe, also known as Ezetimibe, Ezetimibe or Ezetimibe, has a chemical name of (3R,4S)-1-(4-fluorophenyl)-3-{(3S )-3-(4-fluorophenyl)-3-hydroxypropyl}-4-(4-hydroxyphenyl)-2-azetidinone, CAS number: 163222-33-1, traits: white or Off-white crystalline powder, melting point: 164℃～166℃, molecular formula: C24H21F2NO3, molecular weight: 409.43, solubility: easily soluble in ethanol, isopropanol, acetone, methanol, ethyl acetate, etc., insoluble in water and petroleum ether , ether, etc.

Ezetimibe is a new type of cholesterol antagonist jointly developed by Merck and Schering-Plough, and it is a new type of blood lipid-lowering drug. It was launched in Germany for the first time in 2002, and was launched in the United States at the same time. It is the first new type of blood lipid-lowering drug with selective cholesterol absorption inhibitory effect approved by the FDA. It has been widely used in more than 90 countries and regions. Names: Ezetrol, Yishichun, Zetia. It has the advantages of less toxic and side effects, remarkable curative effect, etc., and has broad market prospects.

Ezetimibe acts locally on the epithelial cells of the small intestine, selectively inhibits the absorption of intestinal cholesterol and related sitosterol, reduces the cholesterol reaching the liver, reduces the storage of cholesterol in the liver and increases the plasma clearance of cholesterol. Ezetimibe mainly acts on exogenous cholesterol, but has no inhibitory effect on endogenous cholesterol. The compound drug "Vytorin" composed of Ezetimibe and Merck's simvastatin was officially approved by FDA in August 2004. The two single counterparts of "Vytorin" can reduce serum cholesterol. The difference is that simvastatin inhibits the enzyme that regulates cholesterol biosynthesis in vivo, while Ezetimibe inhibits the intestinal absorption of cholesterol from food. effective way to lower cholesterol. The combination of Ezetimibe and statins lowers cholesterol eight times more than statins alone. my country's demand for lipid-lowering drugs is increasing, especially the new drug ezetimibe, which is popular among patients and doctors. Therefore, it is necessary to develop an economical, environmentally friendly, and mass-produced ezetimibe The synthetic process route of has very important practical significance.

Therefore, on the basis of referring to the existing synthetic routes, it is very necessary to study a synthetic route with mild and good process conditions, high production efficiency, low input cost, simple operation, and easy industrial production. Add important materials and technical preparations to develop the market, so that it can be produced at a low price in the country in the future and widely used.

Contents of the invention

In order to solve the deficiencies of the prior art, the invention provides a preparation method of ezetimibe, a drug for treating hyperlipidemia.

A preparation method of ezetimibe, a drug for treating hyperlipidemia, is characterized in that it comprises the following steps: using compound 2 as a raw material, and preparing ezetimibe through carbonyl protection, cyclization reaction, carbonyl reduction, and deprotection.

The reaction equation is as follows:

Further, the protection step is to obtain compound 3 after reacting compound 2 with 1-1.1 eq ethylene glycol in n-hexane.

Further, the cyclization step is to cyclize compound 3 and compound 4 under the conditions of BSA and TBAF to obtain compound 5.

Further, the equivalent ratio of compound 3, compound 4, BSA and TBAF is 1-1.2:1-1.2:2:0.06. BSA is an abbreviation for N,O-bistrimethylsilylacetamide.

Further, the carbonyl reduction step is, in dichloromethane solvent, the reaction temperature is -5°C to 0°C, adding 0.10-0.15eq(R)-MeCBS and 1.0-1.5eq BH ₃ -S(CH ₃ ) ₂ Asymmetric reduction of compound 5 affords compound 6.

Further, the deprotection step is to add pyridine p-toluenesulfonate to compound 6 to deprotect THP to obtain product 1.

Further, the product 1 was recrystallized with isopropanol:water=1.0-1.7:1 (volume ratio) to obtain pure product 1 with a purity of more than 99.5%.

Further, the compound 4 is synthesized by refluxing p-fluoroaniline and an equivalent THP-protected p-hydroxybenzaldehyde in toluene to separate water, or adding 4A molecular sieve to dehydrate at room temperature to obtain compound 4.

Beneficial effects of the invention:

1. Compared with the methods reported in the existing literature, the cyclization step avoids the use of polluting titanium reagents, and THP is used to protect the hydroxyl groups, which is easy to remove and the overall process is more environmentally friendly.

2. After the crude product 1 is recrystallized from isopropanol: water, a product with a purity of more than 99.5% can be obtained.

3. The present invention has fewer synthesis steps, higher process stability, and is more suitable for large-scale production.

Detailed ways

Example 1

In the three-necked flask, add compound 2 (3.55g, 10.0mmol), ethylene glycol (0.68g, 11mmol) and 30mL of n-hexane into the three-necked flask to form a suspension, then add p-toluenesulfonic acid (9.0mmol), 25 ℃ reaction 6h. Add 0.5 g (6 mmol) sodium bicarbonate, stir for 30 min, and add 30 mL of 10% sodium hydroxide solution dropwise under ice-cooling. Airtight reaction at 25°C for 1 hour, after the reaction is complete, adjust the pH to 3-4 with 20% citric acid in an ice bath, extract twice with 40 mL of ethyl acetate, combine the organic phases, distill the ethyl acetate under reduced pressure, and recrystallize from n-hexane to obtain 3.61 g white solid compound 3, yield 90.5%, melting point: 101-102°C, [α] ²⁵ _D ＝+54.1°(c=1, CH ₂ Cl ₂ ); ¹ H NMR (400MHz, DMSO-d6): 1.43 -1.57(m,2H),1.76-1.84(m,2H),2.81(dt,J＝17.2,7.5Hz,1H),2.91(dt,J＝17.2,7.5Hz,1H),3.61-3.70(m ,2H),3.89-3.99(m,2H),4.14(dd,J＝8.7,3.6Hz,1H),4.72(t,J＝8.7Hz,1H),5.44(dd,J＝8.7,3.6Hz, 1H), 7.12-7.16(m, 2H), 7.24-7.29(m, 2H), 7.29-7.35(m, 1H), 7.35-7.39(m, 4H).

Add p-fluoroaniline (1.11g, 10mmol) and THP-protected p-hydroxybenzaldehyde (2.06g, 10mmol) into 150mL toluene to reflux and separate water. Crystallization gave compound 4 (2.694g), yield 90.1%.

Put compound 3 (3.99g, 10.0mmol) and compound 4 (2.99g, 10.0mmol) N,O-bistrimethylsilylacetamide (BSA, 4.06g, 20.0mmol) into 300mL of toluene and heat up to 60°C Stir until the suspension is clear, add tetrabutylammonium fluoride (TBAF, 0.1566g, 0.6mmol), keep warm at 60°C and stir for 5h until most of the raw materials disappear, add 10mL of acetic acid after cooling, concentrate under reduced pressure to remove toluene, and remove the remaining oil in vacuum Drying under low temperature gave intermediate 5 (4.42g, yield 90.01%).

Under nitrogen protection, in a dry three-necked flask, add 8 mL of dichloromethane, 7.46 mL (15 mmol) of BH ₃ S(CH ₃ ) ₂ , control the reaction temperature from -5°C to 0°C, and dropwise add (R)-Me CBS 1M toluene solution 1.5mL (1.5mmol), slowly add intermediate 5 (4.91g, 10.0mmol) methylene chloride solution 10mL dropwise, keep the temperature at -5°C to 0°C and continue stirring for 5h until the reaction is complete, Then slowly drop methanol successively to quench, wash with 4mol/L sulfuric acid solution, layer after stirring, wash the organic layer with 6mL of 0.5mol/L sulfuric acid solution and 22mL of 5% sodium sulfite aqueous solution respectively, and concentrate the organic layer to dryness to obtain sticky The liquid, namely intermediate 6 (4.775g, yield 92.01%, 98.4%dr).

In a dry three-necked flask, under the protection of nitrogen, add 8 mL of dichloromethane, 7.46 mL (15 mmol) of BH ₃ S(CH ₃ ) ₂ , maintain the reaction temperature at -5°C to 0°C, and dropwise add (R)-MeCBS1M Toluene solution 1.5mL (1.5mmol), slowly add intermediate 5 (4.91g, 10.0mmol) dichloromethane solution 10mL dropwise, after dropping, keep the temperature at -5°C to 0°C and continue stirring for 3h until the reaction is complete, then Slowly add methanol 1.5mL successively to quench, wash with 4mol/L sulfuric acid solution, separate layers after stirring, wash the organic layer with 0.5mol/L sulfuric acid solution and 5% sodium sulfite aqueous solution respectively, and concentrate the organic layer to dryness to obtain a slightly yellow oil The liquid intermediate 6 (4.537g, 92.03%, 98.4%dr) was directly used in the next reaction without purification.

Add intermediate 6 (4.93g, 10mmol) in the ethanol solution (30mL) in the reaction kettle, add pyridine p-toluenesulfonate (PPTS) (0.2g, 0.8mmol), reflux the solution for 1h, cool to 22-24 °C and diluted with a mixture of ether (10 mL) and _H2O (20 mL). The organic layer was _washed with water (20 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (3:1), to afford crude 1 (3.85 g, 94.1%).

Crude product 1 recrystallization purification method: Take the crude product of ezetimibe 1 (4.09g, 10mmol), dissolve it with 20mL of isopropanol under stirring at room temperature, slowly add 20mL of water, heat to 60°C, stir for 2h, cool to room temperature and suction filter, The resulting solid was dried in vacuum for 24 hours to obtain 3.52 g of ezetimibe, yield 86.23%, purity >99.8%, >99.9% dr, mp: 164.1-166.3°C, [α] ²⁵ _D = -28.0 (c = 0.34, MeOH ); ¹ H-NMR(400MHz,DMSO-d ₆ ):1.70-1.86(m,4H),3.07-3.08(m,1H),4.49-4.50(m,1H),4.81(d,J＝2.0Hz ,1H),5.27(d,J=4.4Hz,1H),6.76(d,J=8.3Hz,2H),7.11-7.32(m,10H),9.50(s,1H); ESI-MS m/z : calcd for C ₂₁ H ₁₇ ClN ₅ [M+H] ⁺ 410.3, found 410.3.

Example 2

In the three-necked flask, add compound 2 (35.5g, 100.0mmol), ethylene glycol (6.8g, 110mmol) and 300mL of n-hexane into the three-necked flask to form a suspension, then add p-toluenesulfonic acid (90mmol), and stir at room temperature reaction. After adding 5 g (60 mmol) of sodium bicarbonate, 300 mL of 10% sodium hydroxide solution was added dropwise under ice cooling. Airtight reaction at 25°C for 1 hour, after the reaction was completed, adjust the pH to 3-4 with 20% citric acid in an ice bath, extract twice with 400 mL of ethyl acetate, combine the organic phases, distill the ethyl acetate under reduced pressure, and recrystallize from n-hexane to obtain 36.07 g white solid compound 3, yield 90.42%, melting point: 101-102°C.

Add p-fluoroaniline (11.1g, 100mmol) and THP-protected p-hydroxybenzaldehyde (20.6g, 100mmol) into 850mL toluene to reflux and separate water. Crystallization gave compound 4 (27.06 g), yield 90.5%.

Put compound 3 (39.9g, 100.0mmol), compound 4 (29.9g, 100.0mmol) and N, O-bistrimethylsilylacetamide (BSA, 40.6g, 200.0mmol) into 1L of toluene, and heat up to 60 Stir at ℃ until the suspension is clear, add tetrabutylammonium fluoride (TBAF, 1.566g, 6mmol), keep warm at 60℃ and stir for 5h until most of the raw materials disappear, add 100mL acetic acid after cooling, concentrate under reduced pressure to remove toluene, and the remaining oil Drying under high temperature, 43.66g of intermediate 5 was obtained, the yield was 88.92%.

In a dry three-necked flask, under the protection of nitrogen, add 800mL of dichloromethane, 74.6mL (150mmol) of BH ₃ S(CH ₃ ) ₂ to react and stir, maintain the reaction temperature at -5°C to 0°C, add (R)- MeCBS 1M toluene solution 15mL (15mmol), slowly add intermediate 5 (549.1g, 100.0mmol) dichloromethane solution 1L dropwise, keep stirring at -5°C to 0°C until the reaction is complete, and then slowly Add methanol 250mL dropwise to quench, wash with 4mol/L sulfuric acid solution, wash the organic layer with 0.5mol/L sulfuric acid solution and 5% sodium sulfite aqueous solution respectively, and concentrate the organic layer to dryness to obtain intermediate 6 (45.3g, yield 91.97%) , directly used in the next reaction without purification.

Add intermediate 6 (49.3g, 100mmol) in ethanol solution (300mL) in the reaction kettle, add pyridine p-toluenesulfonate (PPTS) (2.08g, 8mmol); reflux the solution for 1h, and cool to 22-24°C , diluted with a mixture of ether (100 mL) and _H2O (200 mL). The organic layer _was washed with _H2O (200 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (3:1), to afford crude product 1 (38.4 g, yield 93.9%).

Crude product 1 Recrystallization and refining method: Take the crude product of ezetimibe (120g, 0.293mol), dissolve it with isopropanol (3.0L) under stirring at room temperature, slowly add water (2.5L), heat to 60°C, stir for 2h, cool After suction filtration at room temperature, the resulting solid was vacuum-dried for 24 hours to obtain 103 g of ezetimibe, with a yield of 86.18%, a purity greater than 99.9%, mp: 164.1-166.3°C, and the NMR data were the same as in Example 1.

Example 3

In the three-necked flask, add compound 2 (3.55kg, 10.0mol), ethylene glycol (0.68kg, 11mol) and 30L of n-hexane into the three-necked flask to form a suspension, then add p-toluenesulfonic acid (90mmol), and stir at room temperature reaction. After adding 0.5 kg (6 mol) of sodium bicarbonate, 30 L of 10% sodium hydroxide solution was added dropwise under ice cooling. Airtight reaction at 25°C for 1 hour, after the reaction is complete, adjust the pH to 3-4 with 20% citric acid in an ice bath, extract three times with 40 L of ethyl acetate, combine the organic phases, distill the ethyl acetate under reduced pressure, and recrystallize from n-hexane to obtain 3.599kg White solid compound 3, yield 90.2%, melting point: 101-102°C.

Add p-fluoroaniline (1.11kg, 10mol) and THP-protected p-hydroxybenzaldehyde (2.06kg, 10mol) into 45L toluene to reflux and divide water. Crystallization gave Compound 4 (2.7kg), with a yield of 90.3%.

Put compound 3 (3.99kg, 10.0mol), compound 4 (3.55kg, 10.0mol) and N, O-bistrimethylsilylacetamide (BSA, 4.06kg, 20.0mol) into 1L of toluene, and heat up to 60 Stir at ℃ until the suspension is clear, add tetrabutylammonium fluoride (TBAF, 1566g, 6mol), keep warm at 60℃ and stir for 3h until most of the raw materials disappear, cool, add 10L acetic acid, concentrate under reduced pressure to remove toluene, and the remaining oil Drying under the hood gave 4.36kg of intermediate 5 with a yield of 88.79%.

In the reaction kettle, under the protection of nitrogen, add 80L of dichloromethane, BH ₃ -S(CH ₃ ) ₂ 7.46L (15mol), maintain the reaction temperature from -5°C to 0°C, add (R)-MeCBS 1M toluene solution 1.5L (1.5mol), slowly add 1L of dichloromethane solution containing intermediate 5, 4.91kg (10mol) dropwise, keep the temperature below -5°C and continue stirring until the reaction is complete, then slowly add methanol dropwise in sequence 25L quenching, 5L pickling of 4mol/L sulfuric acid solution, layering after stirring, the organic layer was washed with 0.5mol/L sulfuric acid solution and 5% sodium sulfite aqueous solution respectively, and the organic layer was concentrated to dryness to obtain intermediate 6 (4.53kg, collected Yield 91.86%), directly used in the next reaction without purification.

Add intermediate 6 (2.465kg, 5mol) to the ethanol solution (30L) in the reaction kettle, add pyridine p-toluenesulfonate (PPTS) (20g, 0.08mol); reflux the solution for 1h, and cool to 22-24°C , diluted with a mixture of ethyl acetate (100 L) and _H2O (200 L). The organic layer was concentrated in vacuo. MTBE and heptane 1:6 (volume ratio) were stirred and beaten at -10°C, then filtered to obtain crude product 1 (1.92kg, yield 93.8%).

Crude product 1 Recrystallization and refining method: Take the crude product of ezetimibe (4.09kg, 10mol), dissolve it with isopropanol (25L) under stirring at room temperature, slowly add water (20L), heat to 60°C, stir for 2h, and cool to room temperature Suction filtration, the obtained solid was vacuum-dried for 24 hours to obtain 3.51 kg of ezetimibe, yield 86.12%, purity>99.6%, dr>99.9%, mp: 164.1-166.3°C, [α] ²⁵ _D =-27.2(c= 0.34, MeOH); NMR data are consistent with Example 1.

The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments, and that described in the above-mentioned embodiments and the specification only illustrates the principle of the present invention, and the present invention also has various aspects without departing from the scope of the principle of the present invention. Changes and improvements, these changes and improvements all fall within the protection scope of the present invention.

Claims (8)

1. a preparation method for hyperlipidemia therapeutic drug ezetimibe, is characterized in that, reaction equation is as follows: The method comprises the following steps: taking compound 2 as a raw material, and preparing ezetimibe 1 through carbonyl protection, cyclization reaction, carbonyl reduction, and deprotection. 2. according to the preparation method of a kind of hyperlipidemia treatment drug ezetimibe in claim 1, it is characterized in that: described protection step is, compound 2 is obtained compound after reacting with 1-1.1eq ethylene glycol in n-hexane 3. 3. The preparation method of ezetimibe, a drug for treating hyperlipidemia according to claim 1, characterized in that: the cyclization step is to cyclize compound 3 and compound 4 under the conditions of BSA and TBAF to obtain compound 5. 4. according to the preparation method of a kind of hyperlipidemia treatment drug ezetimibe in claim 3, it is characterized in that: described compound 3, compound 4, BSA and TBAF equivalent ratio are 1-1.2:1-1.2:2:0.06 . 5. According to the preparation method of ezetimibe, a drug for treating hyperlipidemia in claim 1, it is characterized in that: the carbonyl reduction step is, in dichloromethane solvent, the reaction temperature is -5 ° C to 0 ° C, adding Compound 5 was asymmetrically reduced by 0.10-0.15eq(R)-MeCBS and 1.0-1.5eq BH ₃ -S(CH ₃ ) ₂ to obtain compound 6. 6. According to the preparation method of a hyperlipidemia treatment drug ezetimibe in claim 1, it is characterized in that: the deprotection step is, adding pyridine p-toluenesulfonate to de-THP protection in compound 6 to obtain product 1 . 7. According to the preparation method of ezetimibe, a drug for treating hyperlipidemia in claim 1, it is characterized in that: the product 1 is recrystallized through isopropanol: water = 1.0-1.7: 1 to obtain a pure product with a purity of 99.5% or more 1. 8. according to the preparation method of a kind of hyperlipidemia therapeutic drug ezetimibe among the claim 1, it is characterized in that: described compound 4 is synthesized, and p-hydroxybenzaldehyde protected by THP of p-fluoroaniline and equivalence is refluxed in toluene Compound 4 was obtained after water separation or dehydration by adding 4A molecular sieve at room temperature.