Preparation of esmolol hydrochloride key intermediate

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 an acetone solvent, and heating and refluxing in the presence of anhydrous potassium carbonate and a small amount of triethylamine.

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 methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate (structure as shown in Formula II), which is the key to controlling product quality and is a key intermediate for preparing esmolol hydrochloride.

[0006] After extensive process research, the inventors found that the second step of the reaction of methyl p-hydroxyphenylpropionate with epichlorohydrin in an acetone solvent, in the presence of anhydrous potassium carbonate and a small amount of triethylamine, heating and refluxing can shorten the reaction process and improve the yield selectivity of the reaction. 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] The method comprises the following steps: placing methyl p-hydroxyphenylpropionate and epichlorohydrin in an acetone solvent, and heating and refluxing in the presence of anhydrous potassium carbonate and a small amount of triethylamine; preferably, the weight ratio of the anhydrous potassium carbonate to the triethylamine is 6:1 to 24:1; more preferably, the weight ratio of the anhydrous potassium carbonate to the triethylamine is 10:1 to 15:1. 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 Remark 1 Para-hydroxyphenylpropionic acid Kg 1.88 Add from the feeding port 2 Methanol L 16 Add from the feeding port 3 Concentrated sulfuric acid L 0.06 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 until it is 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 Remark 1 Methyl p-hydroxyphenylpropionate (I) Kg 1.8 Add from the feeding port 2 Epichlorohydrin L 2.4 Add from the feeding port 3 Anhydrous potassium carbonate Kg 2.1 Add from the feeding port 4 acetone L 5 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 until it is 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 Remark 1 Intermediate II Kg 1.2 Add from the feeding port 2 Isopropylamine L 2.4 Add from the feeding port 3 Methanol L 2.4 Add from the feeding port 4 Butyl acetate L 7.2 Add from the feeding port

[0035] Operating procedures:

[0036] ① Clean, install and debug the reactor until it is 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]

[0049] Operating procedures:

[0050] ① Clean, install and debug the reactor until it is normal;

[0051] ② Feeding: Add methyl p-hydroxyphenylpropionate, anhydrous potassium carbonate and triethylamine from the feeding port according to the feeding amount;

[0052] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0053] After the addition, heat to reflux for 20 hours;

[0054] 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.

[0055] 1.72 kg of oily product 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II) with a purity of 95.22% as determined by HPLC.

[0056] Example 2 Preparation of the intermediate represented by formula II (Method 2)

[0057] Reaction ingredients:

[0058] Serial number Material Name unit Feeding Remark 1 Methyl parahydroxyphenylpropionate Kg 1.8 Add from the feeding port 2 Epichlorohydrin L 2.4 Add from the feeding port 3 Anhydrous potassium carbonate Kg 2.1 Add from the feeding port 4 Triethylamine Kg 0.175 5 acetone L 5 Add from the feeding port 6 Toluene L 6 Add from the feeding port

[0059] Operating procedures:

[0060] ① Clean, install and debug the reactor until it is normal;

[0061] ② Feeding: Add methyl p-hydroxyphenylpropionate, anhydrous potassium carbonate and triethylamine from the feeding port according to the feeding amount;

[0062] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0063] After the addition, heat to reflux for 20 hours;

[0064] ④ Treatment: Filter by suction, evaporate the filtrate to remove acetone, dissolve the residue with toluene, and separate them with 5% NaOH in a separator.

[0065] The mixture was washed three times with aqueous solution (500 ml / time) and water (1500 ml / time), dried over anhydrous sodium sulfate for 3 hours, filtered, and the filtrate was evaporated to remove toluene. The residue was fractionated under reduced pressure to obtain a 170-180℃ / 2-3mmHg fraction to obtain a colorless

[0066] 1.90 kg of oily product 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II) with a purity of 94.82% as determined by HPLC.

[0067] Example 3 Preparation of the intermediate represented by formula II (method three)

[0068] Reaction ingredients:

[0069] Serial number Material Name unit Feeding Remark 1 Methyl parahydroxyphenylpropionate Kg 1.8 Add from the feeding port 2 Epichlorohydrin L 2.4 Add from the feeding port 3 Anhydrous potassium carbonate Kg 2.1 Add from the feeding port 4 Triethylamine Kg 0.0875 5 acetone L 5 Add from the feeding port 6 Toluene L 6 Add from the feeding port

[0070] Operating procedures:

[0071] ① Clean, install and debug the reactor until it is normal;

[0072] ② Feeding: Add methyl p-hydroxyphenylpropionate, anhydrous potassium carbonate and triethylamine from the feeding port according to the feeding amount;

[0073] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0074] After the addition, heat to reflux for 20 hours;

[0075] ④ Treatment: Filter by suction, evaporate the filtrate to remove acetone, dissolve the residue with toluene, and separate them with 5% NaOH in a separator.

[0076] The mixture was washed three times with aqueous solution (500 ml / time) and water (1500 ml / time), dried over anhydrous sodium sulfate for 3 hours, filtered, and the filtrate was evaporated to remove toluene. The residue was fractionated under reduced pressure to obtain a 170-180℃ / 2-3mmHg fraction to obtain a colorless

[0077] 1.72 kg of oily product 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II) with a purity of 95.08% as determined by HPLC.

[0078] Example 4 Preparation of the intermediate represented by formula II (method 4)

[0079] Reaction ingredients:

[0080] Serial number Material Name unit Feeding Remark 1 Methyl parahydroxyphenylpropionate Kg 1.8 Add from the feeding port 2 Epichlorohydrin L 2.4 Add from the feeding port 3 Anhydrous potassium carbonate Kg 2.1 Add from the feeding port 4 Triethylamine Kg 0.175 5 acetone L 5 Add from the feeding port 6 Toluene L 6 Add from the feeding port

[0081] Operating procedures:

[0082] ① Clean, install and debug the reactor until it is normal;

[0083] ② Feeding: Add methyl p-hydroxyphenylpropionate, anhydrous potassium carbonate and triethylamine from the feeding port according to the feeding amount;

[0084] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0085] After the addition, heat to reflux for 15 hours;

[0086] 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 to obtain 1.86 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II),

[0087] The purity determined by HPLC was 94.93%.

[0088] Example 5 Preparation of the intermediate represented by formula II (method five)

[0089] Reaction ingredients:

[0090]

[0091]

[0092] Operating procedures:

[0093] ① Clean, install and debug the reactor until it is normal;

[0094] ② Feeding: Add methyl p-hydroxyphenylpropionate, anhydrous potassium carbonate and triethylamine from the feeding port according to the feeding amount;

[0095] ③Reaction operation: Start stirring, add the feed amount of acetone, continue stirring, and slowly add epichlorohydrin.

[0096] After the addition, heat to reflux for 8 hours;

[0097] 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 1.96 kg of colorless oily 3-[4-(2,3-epoxypropoxy)phenyl]propionic acid methyl ester (II), with a purity of 95.64% 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 an acetone solvent, and heating under reflux in the presence of anhydrous potassium carbonate and a small amount of triethylamine.

2. According to the method for preparing the key intermediate II of esmolol hydrochloride of claim 1, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in an acetone solvent, and heated to reflux in the presence of anhydrous potassium carbonate and a small amount of triethylamine; the weight ratio of anhydrous potassium carbonate to triethylamine is 6:1 to 24:

1.

3. According to the method for preparing the key intermediate II of esmolol hydrochloride of claim 1, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in an acetone solvent, and heated to reflux in the presence of anhydrous potassium carbonate and a small amount of triethylamine; the weight ratio of anhydrous potassium carbonate to triethylamine is 10:1 to 15:

1.

4. According to the method for preparing the key intermediate II of esmolol hydrochloride of claims 1-3, methyl p-hydroxyphenylpropionate and epichlorohydrin are placed in an acetone solvent, heated to reflux in the presence of anhydrous potassium carbonate and a small amount of triethylamine, and the reflux time is 6 to 15 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 an acetone solvent, heated to reflux in the presence of anhydrous potassium carbonate and a small amount of triethylamine, and the reflux time is 6 to 10 hours.

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