Preparation process of esmolol hydrochloride

Abstract

The invention aims to provide a method for preparing an esmolol hydrochloride key intermediate as shown in a formula II: # imgabs0 #. The method comprises the following steps: putting methyl p-hydroxyphenylpropionate and epoxy chloropropane into a mixed solvent of acetone and a small amount of dimethyl sulfoxide, and heating and refluxing;

Description

Technical Field

[0001] The invention relates to a preparation method of a key intermediate in a novel esmolol hydrochloride preparation process and application of the key intermediate in the preparation of an esmolol hydrochloride bulk drug. Background Art

[0002] Esmolol hydrochloride is a commonly used intravenous antihypertensive drug in clinical practice. To ensure patient safety, as an intravenous raw material, its quality requirements are particularly high.

[0003] The synthetic route of esmolol hydrochloride is as follows:

[0004]

[0005] The second step of this process is to react methyl p-hydroxyphenylpropionate with epichlorohydrin to prepare 3-[4-(2,3-epoxypropoxy)phenyl]methyl propionate (structure as shown in formula II), which is the key to controlling product quality. In the current process, phenolic hydroxyl ortho-substituted byproduct II' is easily formed, which requires rectification, and even multiple rectifications can be removed. Rectification in production is heavily dependent on rectification kettle and Roots pump system, and it is difficult to do process verification and process handover. When mass production is carried out, it is difficult to achieve process control. Therefore, 3-[4-(2,3-epoxypropoxy)phenyl]methyl propionate (structure as shown in formula II) is the key intermediate for preparing esmolol hydrochloride.

[0006] After extensive process research, the inventors found that adding a small amount of dimethyl sulfoxide to the solvent acetone in the second step reaction can avoid the formation of by-product II'; the product prepared by this process can be directly used in the next step reaction without distillation. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing the key intermediate of esmolol hydrochloride represented by formula II:

[0008]

[0009] The method includes:

[0010] Methyl p-hydroxyphenylpropionate is reacted with epichlorohydrin in a solvent of acetone and a small amount of dimethyl sulfoxide; preferably, the ratio of acetone to dimethyl sulfoxide is 10:1 to 30:1 (volume ratio); more preferably, the ratio of acetone to dimethyl sulfoxide is 15:1 to 25:1 (volume ratio). DETAILED DESCRIPTION

[0011] The present invention can be further described with reference to the following examples; however, these examples should not be construed as limiting the scope of the present invention.

[0012] Reference Example 1 Preparation of methyl p-hydroxyphenylpropionate (I)

[0013] Reaction ingredients:

[0014] Serial number Material Name unit Feeding Ingredient ratio Remark 1 Para-hydroxyphenylpropionic acid Kg 1.88 1 Add from the feeding port 2 Methanol L 16 excess Add from the feeding port 3 Concentrated sulfuric acid L 0.06 Moderate Add by dropping funnel to control the dripping rate 4 Toluene L 6 / Add from the feeding port

[0015] Operating procedures:

[0016] ① Clean, install and debug the reactor to normal;

[0017] ② Feeding: Add p-hydroxyphenylpropionic acid into the reactor from the feeding port;

[0018] ③Reaction operation: Start stirring, add the amount of methanol, continue stirring, and slowly add the amount of methanol

[0019] After adding concentrated sulfuric acid, heat under reflux for 20 hours, and evaporate the methanol after the reaction is completed;

[0020] ④ Dissolve the residue with toluene, place in a separator, wash three times with water (1500ml / time), and

[0021] Dry for 3 hours, filter, evaporate the filtrate to remove the solvent toluene, and then fractionate under reduced pressure to collect 100-110℃ / 5-6

[0022] mmHg fraction, and 1.92 kg of methyl p-hydroxyphenylpropionate (I) was obtained.

[0023] Reference Example 2 Preparation of methyl 3-[4-(2,3-epoxypropoxy)phenyl]propanoate (II)

[0024] Reaction ingredients:

[0025] Serial number Material Name unit Feeding Ingredient ratio Remark 1 Methyl p-hydroxyphenylpropionate (I) Kg 1.8 1 Add from the feeding port 2 Epichlorohydrin L 2.4 excess Add from the feeding port 3 Anhydrous potassium carbonate Kg 2.1 1.7 Add from the feeding port 4 acetone L 5 excess Add from the feeding port 5 Toluene L 6 / Add from the feeding port

[0026] Operating procedures:

[0027] ① Clean, install and debug the reactor to normal;

[0028] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0029] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0030] After the addition, heat to reflux for 20 hours;

[0031] ④ Treatment: Filter by suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500ml / time) and water (1500ml / time) in a separator, dry with anhydrous sodium sulfate for 3h, filter by suction, evaporate the toluene from the filtrate, and fractionate under reduced pressure to obtain a colorless product at 170-180℃ / 2-3mmHg.

[0032] 1.59 kg of oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II) was obtained, and the purity was 94.78% by HPLC. Reference Example 3 Preparation of esmolol hydrochloride (III)

[0033] Reaction ingredients:

[0034] Serial number Material Name unit Feeding Ingredient ratio (Kg / L) Remark 1 Intermediate II Kg 1.2 1 Add from the feeding port 2 Isopropylamine L 2.4 2 Add from the feeding port 3 Methanol L 2.4 2 Add from the feeding port 4 Butyl acetate L 7.2 6 Add from the feeding port

[0035] Operating procedures:

[0036] ① Clean, install and debug the reactor to normal;

[0037] ② Feeding: Add intermediate II according to the feeding amount;

[0038] ③Reaction operation: Start stirring, add the amount of methanol, continue stirring, slowly add isopropylamine, add

[0039] After completion, heat under reflux for 4 hours;

[0040] ④ Treatment: Evaporate methanol and excess isopropylamine, transfer the residue to a reactor, add butyl acetate, 40~

[0041] Stir with 0.5% activated carbon at 50℃ for 20min, filter hot, transfer the filtrate to a crystallization tank and pass HCl gas until pH is 2~

[0042] 3. Cool to 0-10°C and let stand for crystallization for more than 6 hours;

[0043] ⑤ The crystals were dried to obtain 1.02 kg of esmolol (III) hydrochloride with a HPLC purity of 93.28%.

[0044] Example 1 Preparation of the intermediate represented by formula II (method 1)

[0045]

[0046] Reaction ingredients:

[0047]

[0048] Operating procedures:

[0049] ① Clean, install and debug the reactor to normal;

[0050] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0051] ③ Reaction operation: start stirring, add the feed amount of acetone and dimethyl sulfoxide, continue stirring, slowly add epichlorohydrin, and heat under reflux for 20 hours after adding;

[0052] ④ Treatment: Filter with suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500 ml / time) and water (1500 ml / time) in a separatory vessel, dry over anhydrous sodium sulfate for 3 hours, filter with suction, evaporate the toluene from the filtrate, and obtain 1.99 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II),

[0053] The purity was 89.51% as determined by HPLC.

[0054] Example 2 Preparation of the intermediate represented by formula II (Method 2)

[0055] Reaction ingredients:

[0056]

[0057]

[0058] Operating procedures:

[0059] ① Clean, install and debug the reactor to normal;

[0060] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0061] ③ Reaction operation: start stirring, add the feed amount of acetone and dimethyl sulfoxide, continue stirring, slowly add epichlorohydrin, and heat under reflux for 20 hours after adding;

[0062] ④ Treatment: Filter with suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500 ml / time) and water (1500 ml / time) in a separatory vessel, dry with anhydrous sodium sulfate for 3 hours, filter with suction, evaporate the toluene from the filtrate, and obtain 1.92 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II),

[0063] The purity determined by HPLC was 92.69%.

[0064] Example 3 Preparation of the intermediate represented by formula II (method three)

[0065] Reaction ingredients:

[0066]

[0067] Operating procedures:

[0068] ① Clean, install and debug the reactor to normal;

[0069] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0070] ③ Reaction operation: start stirring, add the feed amount of acetone and dimethyl sulfoxide, continue stirring, slowly add epichlorohydrin, and heat under reflux for 20 hours after adding;

[0071] ④ Treatment: Filter with suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500 ml / time) and water (1500 ml / time) in a separatory vessel, dry over anhydrous sodium sulfate for 3 hours, filter with suction, evaporate the toluene from the filtrate, and obtain 2.03 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II),

[0072] The purity was 95.54% as determined by HPLC.

[0073] Example 4 Preparation of the intermediate represented by formula II (method 4)

[0074] Reaction ingredients:

[0075]

[0076] Operating procedures:

[0077] ① Clean, install and debug the reactor to normal;

[0078] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0079] ③ Reaction operation: start stirring, add the feed amount of acetone and dimethyl sulfoxide, continue stirring, slowly add epichlorohydrin, and heat under reflux for 20 hours after adding;

[0080] ④ Treatment: Filter with suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500 ml / time) and water (1500 ml / time) in a separatory vessel, dry over anhydrous sodium sulfate for 3 h, filter with suction, evaporate the toluene from the filtrate to obtain 2.01 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II),

[0081] The purity determined by HPLC was 91.62%.

[0082] Example 5 Preparation of the intermediate represented by formula II (method five)

[0083] Reaction ingredients:

[0084]

[0085] Operating procedures:

[0086] ① Clean, install and debug the reactor to normal;

[0087] ② Feeding: Add methyl p-hydroxyphenylpropionate and anhydrous potassium carbonate from the feeding port according to the feeding amount;

[0088] ③ Reaction operation: Start stirring, add the feed amount of acetone and dimethyl sulfoxide, continue stirring, slowly add epichlorohydrin, and heat under reflux for 10 hours after adding;

[0089] ④ Treatment: Filter with suction, evaporate the acetone from the filtrate, dissolve the residue with toluene, wash three times with 5% NaOH aqueous solution (500 ml / time) and water (1500 ml / time) in a separatory vessel, dry with anhydrous sodium sulfate for 3 h, filter with suction, evaporate the toluene from the filtrate to obtain 2.05 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II), with a purity of 96.40% detected by HPLC.

Claims

1. Method for preparing the key intermediate of esmolol hydrochloride shown in formula II: The method comprises the following steps: placing methyl p-hydroxyphenylpropionate and epichlorohydrin in a mixed solvent of acetone and a small amount of dimethyl sulfoxide, and heating and refluxing in the presence of anhydrous potassium carbonate.

2. According to the method for preparing the key intermediate II of esmolol hydrochloride in claim 1, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in a mixed solvent of acetone and dimethyl sulfoxide, and heated to reflux in the presence of anhydrous potassium carbonate; the volume ratio of acetone to dimethyl sulfoxide in the mixed solvent is 10:1 to 30:

1.

3. According to the method for preparing the key intermediate II of esmolol hydrochloride in claim 1, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in a mixed solvent of acetone and dimethyl sulfoxide, and heated to reflux in the presence of anhydrous potassium carbonate; the volume ratio of acetone to dimethyl sulfoxide in the mixed solvent is 15:1 to 25:

1.

4. According to the method for preparing the key intermediate II of esmolol hydrochloride according to claims 1-3, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in a mixed solvent of acetone and dimethyl sulfoxide, and heated to reflux in the presence of anhydrous potassium carbonate, and the reflux time is 5 to 25 hours.

5. According to the method for preparing the key intermediate II of esmolol hydrochloride according to claims 1-3, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in a mixed solvent of acetone and dimethyl sulfoxide, and heated to reflux in the presence of anhydrous potassium carbonate, and the reflux time is 8 to 12 hours.

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