A synthetic preparation process of pranoprofen

Abstract

The present invention discloses a synthetic preparation process of pranoprofen. Using 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as raw materials, first protect the carboxyl group of 2-(4-hydroxyphenyl)propionic acid, and then successively carry out condensation, dehydration, reduction, and hydrolysis to synthesize pranoprofen. The synthetic preparation process of pranoprofen in the present invention uses 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as starting materials, shortens the synthesis steps, is convenient for purification, and improves the total yield and purity of pranoprofen.

Description

Technical Field

[0001] The present invention relates to a synthesis preparation process of pranoprofen, belonging to the technical field of pranoprofen preparation. Background Art

[0002] Pranoprofen, chemically named 2-5H-[1]benzopyran[2,3-b]pyridin-7-ylpropionic acid, belongs to propionic acid non-steroidal anti-inflammatory drugs and has significant analgesic, anti-inflammatory, antipyretic and antirheumatic effects.

[0003] In the prior art, Jin Rongqing et al. published "Improvement of the Synthesis Research of Pranoprofen", which disclosed that using 2-chloronicotinic acid as a raw material, condensing with phenol under a strong base environment, then dehydrating pure water through polyphosphoric acid, reducing with potassium borohydride, and then undergoing acidic hydrolysis to obtain intermediate 4. After acylating intermediate 4 with chloroacetyl chloride, hydrolysis reaction occurs under alkaline conditions, and then acylating with sulfonyl chloride to finally obtain 7. As Figure 1 shown in the synthesis route, the synthesized pranoprofen is further purified and crystallized with ethanol to obtain refined pranoprofen. However, the pranoprofen prepared by this method has more steps, resulting in a lower total yield of pranoprofen. In addition, the purity is not high after ethanol purification and crystallization, which will affect the use of pranoprofen raw materials and their preparations. Summary of the Invention

[0004] At least aiming at one problem existing in the above prior art, the present invention provides a synthesis preparation process of pranoprofen.

[0005] In order to achieve the above purpose, the present invention adopts the following technical scheme: A synthesis preparation process of pranoprofen, using 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as raw materials, first protecting the carboxyl group of 2-(4-hydroxyphenyl)propionic acid, and then successively carrying out condensation, dehydration of pure water, reduction, and hydrolysis to synthesize and prepare pranoprofen.

[0006] Preferably, the process of the synthesis preparation process of pranoprofen is as follows:

[0007] (1) First, use trimethylsilylethanol to protect the carboxyl group of 2-(4-hydroxyphenyl)propionic acid to form intermediate I;

[0008] (2) Condense 2-chloronicotinic acid with intermediate I through a solid base catalyst to generate intermediate II;

[0009] (3) Dehydrate intermediate II with phosphorus oxychloride to generate intermediate III;

[0010] (4) Reduce intermediate III with potassium borohydride to generate intermediate IV;

[0011] (5) Intermediate IV undergoes acidic hydrolysis to obtain pranoprofen.

[0012] Preferably, the specific steps of the synthesis preparation process of Pranoprofen are as follows:

[0013] (1) Using dichloromethane as solvent, 2-(4-hydroxyphenyl)propionic acid, trimethylsilylethanol, triphosphine and azodicarboxylate were subjected to Mitsunobu reaction at a reaction temperature of 0-5°C. TLC showed that the raw material disappeared, and intermediate I was generated.

[0014] (2) Using tetrahydrofuran as solvent, 2-chloronicotinic acid, intermediate I and solid base catalyst are subjected to condensation reaction at a reaction temperature of 130-140°C and a reaction time of 1.5-2h to generate intermediate II;

[0015] (3) Intermediate II undergoes a dehydration reaction with phosphorus oxychloride at a temperature of 115-120°C for 4-5 hours to generate intermediate III;

[0016] (4) Using tetrahydrofuran as solvent, intermediate III is subjected to reduction reaction with potassium borohydride at a reaction temperature of 40-45°C for a reaction time of 5-6 hours to generate intermediate IV;

[0017] (5) Intermediate IV is hydrolyzed with trifluoroacetic acid and heated under reflux for 5 to 6 hours to generate pranoprofen.

[0018] Preferably, the molar ratio of 2-(4-hydroxyphenyl)propionic acid:trimethylsilylethanol:triphosphine:azodicarboxylate in step (1) is 1:1-1.2:1-1.3, preferably 1:1.1-1.2:1.2-1.3, and more preferably 1:1.06-1.2:1.1-1.3.

[0019] Preferably, the triphosphine in step (1) is triphenylphosphine, tri-tert-butylphosphine, tributylphosphine, etc.

[0020] Preferably, the azodicarboxylic acid ester in step (1) is diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, etc.

[0021] Preferably, the molar ratio of 2-chloronicotinic acid to intermediate I in step (2) is 1:1.2-1.4.

[0022] Preferably, the amount of the solid base catalyst used in step (2) is 20-30% by weight of 2-chloronicotinic acid.

[0023] Preferably, the solid base catalyst in step (2) is HND-64 solid super base catalyst, HND-63 solid super base catalyst, etc.

[0024] Preferably, the amount of phosphorus oxychloride used in step (3) is 1 to 2 times the mass of intermediate II.

[0025] Preferably, pure water is further included in step (4), and the amount of pure water used is 0.8 to 1.5 times the weight of intermediate III.

[0026] Preferably, the amount of potassium borohydride used in step (4) is 2 to 2.5 times the weight of intermediate III.

[0027] Preferably, the molar ratio of intermediate IV to trifluoroacetic acid in step (5) is 1:2 to 2.5.

[0028] Advantages of the present invention: The synthesis preparation process of pranoprofen of the present invention uses 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as the initial raw materials, providing a new route for the synthesis preparation of pranoprofen; moreover, with 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as the initial raw materials, the synthesis steps are shortened and purification is convenient, resulting in an increased total yield of pranoprofen and a high purity; the synthesis preparation process of pranoprofen of the present invention does not require a rearrangement reaction step, avoiding the use of irritating sulfonyl chloride and allyl chloride; the present invention uses a solid base catalyst, avoiding the use of dangerous and flammable sodium methoxide, sodium, etc., improving the safety of production; in addition, the synthesis preparation process of pranoprofen of the present invention uses 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as the initial raw materials, first protecting the carboxyl group of 2-(4-hydroxyphenyl)propionic acid, and then successively performing condensation, dehydration, reduction, and hydrolysis reactions, improving the raw material utilization rate and product yield. Description of the Drawings

[0029] Figure 1 It is a synthesis route diagram of pranoprofen in the prior art;

[0030] Figure 2 It is a synthesis route diagram of intermediate I of the present invention;

[0031] Figure 3 It is a synthesis route diagram of intermediate II of the present invention;

[0032] Figure 4 It is a synthesis route diagram of intermediate III of the present invention;

[0033] Figure 5 It is a synthesis route diagram of intermediate IV of the present invention;

[0034] Figure 6 It is a synthesis route diagram of pranoprofen of the present invention. Detailed Embodiments

[0035] The technical scheme in the implementation of the present invention is clearly and completely described below in conjunction with the accompanying drawings. The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to the conditions recommended by the normal conditions or the manufacturers. If the manufacturers are not specified in the reagents, instruments, and components used, they are all conventional products that can be purchased commercially.

[0036] Example

[0037] A synthetic preparation process of pranoprofen, the specific steps are as follows:

[0038] (1) Using dichloromethane as solvent, 2-(4-hydroxyphenyl)propionic acid, trimethylsilylethanol and triphosphine are added and mixed, stirred and maintained at a temperature of 0-5°C, and dichloromethane containing azodicarboxylate is added dropwise, and the temperature of the Mitsunobu reaction is controlled not to be higher than 5°C. When TLC monitoring shows that the raw material disappears, the reaction is completed, and the mixture is allowed to stand, and saturated brine is added for washing, and the mixture is dried with pure water and sulfuric acid. The organic phase is concentrated, and the residue is mixed with petroleum ether, and then placed at 0-5°C to precipitate crystals, filtered and washed with ethyl acetate and pure water in sequence, and dried in vacuo to obtain intermediate I;

[0039] (2) Using tetrahydrofuran as solvent, 2-chloronicotinic acid, intermediate I and solid base catalyst are subjected to condensation reaction at a reaction temperature of 135-140°C and a reaction time of 1.5-2h. The solid base catalyst is removed by filtering while hot, and tetrahydrofuran is removed by heat preservation. Pure water is first added to cool the mixture, and then an organic mixture of petroleum ether and ethyl acetate is added in a ratio of 1:2 for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4-5. The mixture is then placed at 0-5°C to precipitate crystals, filtered and washed with pure water, and dried in vacuo to obtain intermediate II.

[0040] (3) Intermediate II is subjected to a dehydration reaction with phosphorus oxychloride at a reaction temperature of 115-120°C to form a reflux for 4-5 hours, and then the phosphorus oxychloride is evaporated under reduced pressure, and then sodium carbonate solution is added to adjust the pH of the solution to 8-9. After sufficient stirring, the solution is placed at 0-5°C to precipitate crystals, which are filtered and washed with pure water, and then dried in a vacuum to obtain intermediate III;

[0041] (4) Using tetrahydrofuran as solvent, intermediate III is subjected to reduction reaction with pure water and potassium borohydride at a reaction temperature of 55-60°C for a reaction time of 5-6 hours. The tetrahydrofuran is then evaporated and pure water is added and stirred. The pH is adjusted to 6-7. The product is filtered and washed with pure water and dried in vacuo to obtain intermediate IV.

[0042] (5) Using isopropanol as solvent, the intermediate IV is subjected to a hydrolysis reaction with trifluoroacetic acid, heated under reflux, reacted for 5-6 hours, and then evaporated to dryness under reduced pressure. The residue is mixed with a 65% ethanol aqueous solution, heated and stirred to dissolve it, and then evaporated to dryness under reduced pressure. The residue is then stirred and mixed with a 3-5% ethanol aqueous solution, and then filtered and washed with the ethanol aqueous solution, and dried in vacuo to produce pranoprofen.

[0043] The triphosphine is one of triphenylphosphine, tri-tert-butylphosphine and tributylphosphine; the azodicarboxylic acid ester is one of diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0044] Among them, the solid base catalyst is HND-64 solid super base catalyst or HND-63 solid super base catalyst.

[0045] The purity determination of pranoprofen of the present invention is carried out by high performance liquid chromatography, wherein the chromatographic conditions and system suitability test are as follows: octadecylsilane bonded silica gel is used as a filler (5 μm, 4.6 mm×150 mm), acetonitrile-ammonium acetate solution (7.8 g of ammonium acetate is dissolved in 1000 mL of pure water, and the pH is adjusted to 4.5 with acetic acid) (32:68) is used as a mobile phase, the detection wavelength is 275 nm, the flow rate is 1.2 mL / min, and the column temperature is 25° C. The theoretical plate number calculated based on the pranoprofen peak should be not less than 2000.

[0046] Example 1 Preparation of Intermediate Ⅰ

[0047] Example 1-1, the specific process is as follows: 200ml of dichloromethane is used as a solvent, 24.9g (0.15mol) of 2-(4-hydroxyphenyl)propionic acid, 17.7g (0.15mol) of trimethylsilylethanol, and 43.23g (0.165mol) of triphenylphosphine are added and mixed, stirred and kept at a temperature of 0~5°C, 100ml of dichloromethane containing 28.71g (0.165mol) of diethyl azodicarboxylate is added dropwise, the Mitsunobu reaction temperature is controlled not to be higher than 5°C, TLC monitoring shows that the raw material disappears, the reaction is completed, and the mixture is allowed to stand, 200ml of saturated brine is added for washing, 400ml of sulfuric acid without pure water is dried, the organic phase is concentrated, the residue is mixed with 250ml of petroleum ether, and then placed at 0~5°C to precipitate crystals, filtered and washed with 100ml of ethyl acetate and 150ml of pure water in sequence, and dried in vacuo to obtain 36.63g of intermediate I, and the yield of this embodiment is 91.80%; the reaction formula is as follows Figure 1 Route Ⅰ shown.

[0048] Example 1-2. The specific process is as follows: Using 200 ml of dichloromethane as the solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 18.762 g (0.159 mol) of trimethylsilylethanol, and 43.23 g (0.165 mol) of triphenylphosphine were added and mixed. Stir and maintain the temperature at 0 - 5 °C. 100 ml of dichloromethane containing 28.71 g (0.165 mol) of diethyl azodicarboxylate was added dropwise, controlling the temperature of the Mitsunobu reaction not to exceed 5 °C. TLC monitoring showed that the raw materials disappeared, and the reaction ended. Let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0 - 5 °C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuum to obtain 37.47 of Intermediate I. The yield of this example was 93.91%.

[0049] Example 1-3. The specific process is as follows: Using 200 ml of dichloromethane as the solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilylethanol, and 43.23 g (0.165 mol) of triphenylphosphine were added and mixed. Stir and maintain the temperature at 0 - 5 °C. 100 ml of dichloromethane containing 28.71 g (0.165 mol) of diethyl azodicarboxylate was added dropwise, controlling the temperature of the Mitsunobu reaction not to exceed 5 °C. TLC monitoring showed that the raw materials disappeared, and the reaction ended. Let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0 - 5 °C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuum to obtain 37.86 of Intermediate I. The yield of this example was 94.89%.

[0050] Example 1-4. The specific process is as follows: Using 200 ml of dichloromethane as the solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 20.414 g (0.173 mol) of trimethylsilylethanol, and 43.23 g (0.165 mol) of triphenylphosphine were added and mixed. Stir and maintain the temperature at 0 - 5 °C. 100 ml of dichloromethane containing 28.71 g (0.165 mol) of diethyl azodicarboxylate was added dropwise, controlling the temperature of the Mitsunobu reaction not to exceed 5 °C. TLC monitoring showed that the raw materials disappeared, and the reaction ended. Let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0 - 5 °C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuum to obtain 38.48 g of Intermediate I. The yield of this example was 96.44%.

[0051] Examples 1-5, the specific process is as follows: Using 200 ml of dichloromethane as the solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 21.24 g (0.18 mol) of trimethylsilylethanol, and 43.23 g (0.165 mol) of triphenylphosphine were added and mixed. Stir and maintain the temperature at 0-5°C. 100 ml of dichloromethane containing 28.71 g (0.165 mol) of diethyl azodicarboxylate was added dropwise. Control the Mitsunobu reaction temperature not to exceed 5°C. TLC monitoring showed that the raw materials disappeared, and the reaction ended. Let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, and then place it at 0-5°C to precipitate crystals. Filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuo to obtain 38.53 g of Intermediate I. The yield of this example was 95.57%.

[0052] Examples 1-6, the specific process is as follows: Using 200 ml of dichloromethane as the solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilylethanol, and 39.3 g (0.15 mol) of triphenylphosphine were added and mixed. Stir and maintain the temperature at 0-5°C. 100 ml of dichloromethane containing 26.1 g (0.15 mol) of diethyl azodicarboxylate was added dropwise. Control the Mitsunobu reaction temperature not to exceed 5°C. TLC monitoring showed that the raw materials disappeared, and the reaction ended. Let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, and then place it at 0-5°C to precipitate crystals. Filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuo to obtain 35.88 g of Intermediate I. The yield of this example was 89.92%.

[0053] Examples 1-6, the specific process is as follows: Using 200 ml of dichloromethane as a solvent, add 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilylethanol, and 39.3 g (0.15 mol) of triphenylphosphine and mix them. Stir and maintain the temperature at 0-5°C. Dropwise add 100 ml of dichloromethane containing 26.1 g (0.15 mol) of diethyl azodicarboxylate, control the temperature of the Mitsunobu reaction not to exceed 5°C. TLC monitoring shows that the raw materials disappear, the reaction ends, let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0-5°C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuo to obtain 35.95 g of Intermediate Ⅰ. The yield of this example is 90.1%.

[0054] Examples 1-7, the specific process is as follows: Using 200 ml of dichloromethane as a solvent, add 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilylethanol, and 39.3 g (0.18 mol) of triphenylphosphine and mix them. Stir and maintain the temperature at 0-5°C. Dropwise add 100 ml of dichloromethane containing 26.1 g (0.18 mol) of diethyl azodicarboxylate, control the temperature of the Mitsunobu reaction not to exceed 5°C. TLC monitoring shows that the raw materials disappear, the reaction ends, let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0-5°C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuo to obtain 38.82 g of Intermediate Ⅰ. The yield of this example is 97.3%.

[0055] Examples 1-8, the specific process is as follows: Using 200 ml of dichloromethane as a solvent, add 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilylethanol, and 39.3 g (0.18 mol) of triphenylphosphine and mix them. Stir and maintain the temperature at 0-5°C. Dropwise add 100 ml of dichloromethane containing 26.1 g (0.18 mol) of diethyl azodicarboxylate, control the temperature of the Mitsunobu reaction not to exceed 5°C. TLC monitoring shows that the raw materials disappear, the reaction ends, let it stand, add 200 ml of saturated brine for washing, dry with 400 ml of anhydrous sulfuric acid, concentrate the organic phase, mix the residue with 250 ml of petroleum ether, then place it at 0-5°C to precipitate crystals, filter by suction and wash successively with 100 ml of ethyl acetate and 150 ml of pure water, and dry in vacuo to obtain 38.94 g of Intermediate Ⅰ. The yield of this example is 97.59%.

[0056] Example 1-9, the specific process is as follows: 200 ml of dichloromethane is used as a solvent, 24.9 g (0.15 mol) of 2-(4-hydroxyphenyl)propionic acid, 19.47 g (0.165 mol) of trimethylsilyl alcohol, and 34.95 g (0.173 mol) of tri-tert-butylphosphine are added and mixed, stirred and kept at a temperature of 0 to 5 ° C, 100 ml of dichloromethane containing 34.95 g (0.173 mol) of diisopropyl azodicarboxylate is added dropwise, and M is controlled. itsunobu The reaction temperature is not higher than 5°C. TLC monitoring shows that the raw material disappears, and the reaction is completed. The mixture is allowed to stand, and 200 ml of saturated brine is added for washing. The mixture is dried with 400 ml of anhydrous sulfuric acid. The organic phase is concentrated, and the residue is mixed with 250 ml of petroleum ether, and then placed at 0-5°C to precipitate crystals. The mixture is filtered and washed with 100 ml of ethyl acetate and 150 ml of pure water in sequence, and dried in vacuo to obtain 38.89 g of intermediate I. The yield of this embodiment is 97.47%.

[0057] According to the above-mentioned Examples 1-1 to 1-9, the molar ratio of 2-(4-hydroxyphenyl)propionic acid: trimethylsilylethanol: triphosphine: azodicarboxylate is selected to be 1:1~1.2:1~1.3, and the intermediate I has a higher yield. The amount of trimethylsilylethanol, triphosphine and azodicarboxylate is small, and the yield of intermediate I is low. The amount of trimethylsilylethanol, triphosphine and azodicarboxylate is large, which increases the cost of raw materials. The preferred molar ratio of 2-(4-hydroxyphenyl)propionic acid: trimethylsilylethanol: triphosphine: azodicarboxylate is 1:1.06~1.2:1.1~1.3, and the more preferred choice is 1:1.1~1.2:1.2~1.3.

[0058] Example 2 Preparation of Intermediate II

[0059] Example 2-1, the specific process is as follows: 150ml of tetrahydrofuran is used as a solvent, 15.75g (0.1mol) of 2-chloronicotinic acid and 31.92g (0.12mol) of intermediate I are stirred and dissolved, and then 3.94g of HND-64 solid superbase catalyst is added, and the reaction is heated to 135-140°C for condensation reaction. The reaction time is 1.5h, and then filtered while hot to remove the solid base catalyst, and the tetrahydrofuran is removed by heat preservation. 250ml of pure water is first added to cool, and then 250ml of an organic mixture of petroleum ether and ethyl acetate is added according to a 1:2 mixture for extraction, the pure water phase is taken and hydrochloric acid is added to adjust the pH to 4-5, and then placed at 0-5°C to precipitate crystals, filtered and washed with 80ml of pure water, and vacuum dried to obtain 35.19g of intermediate II. The yield of this embodiment is 90.93%; the reaction formula is as follows Figure 1 Route II shown.

[0060] Example 2-2: The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 33.25 g (0.125 mol) of Intermediate I are stirred and dissolved. Then, 3.94 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for a condensation reaction for 1.5 h. After that, it is filtered while hot to remove the solid base catalyst, and tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 35.55 g of Intermediate II. The yield of this example is 91.86%.

[0061] Example 2-3: The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.13 mol) of Intermediate I are stirred and dissolved. Then, 3.94 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for a condensation reaction for 1.5 h. After that, it is filtered while hot to remove the solid base catalyst, and tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 35.91 g of Intermediate II. The yield of this example is 92.79%.

[0062] Example 2-4: The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.135 mol) of Intermediate I are stirred and dissolved. Then, 3.94 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for a condensation reaction for 1.5 h. After that, it is filtered while hot to remove the solid base catalyst, and tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 36.07 g of Intermediate II. The yield of this example is 93.23%.

[0063] Example 2-5: The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 37.24 g (0.14 mol) of Intermediate I are stirred and dissolved. Then, 3.94 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for condensation reaction for 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture obtained by mixing petroleum ether and ethyl acetate in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 36.07 g of Intermediate II. The yield of this example is 93.31%.

[0064] Example 2-6: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.13 mol) of Intermediate I are stirred and dissolved. Then, 3.15 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for condensation reaction for 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture obtained by mixing petroleum ether and ethyl acetate in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 35.5 g of Intermediate II. The yield of this example is 91.73%.

[0065] Example 2-7: The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.13 mol) of Intermediate I are stirred and dissolved. Then, 4.72 g of HND-64 solid superbase catalyst is added, and the mixture is heated to 135 - 140 °C for condensation reaction for 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while maintaining the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture obtained by mixing petroleum ether and ethyl acetate in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, which are filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 36.07 g of Intermediate II. The yield of this example is 93.2%.

[0066] Example 2-8. The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.13 mol) of Intermediate I are stirred and dissolved. Then, 4.89 g of HND-64 solid superbase catalyst is added. The mixture is heated to 135 - 140 °C for the condensation reaction. The reaction time is 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while keeping the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, filtered by suction and washed with 80 ml of pure water, and dried in vacuum to obtain 36.09 g of Intermediate II. The yield of this example is 93.26%.

[0067] Example 2-9. The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 34.58 g (0.13 mol) of Intermediate I are stirred and dissolved. Then, 3.63 g of HND-63 solid superbase catalyst is added. The mixture is heated to 135 - 140 °C for the condensation reaction. The reaction time is 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while keeping the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, filtered by suction and washed with 80 ml of pure water, and dried in vacuum to obtain 35.72 g of Intermediate II. The yield of this example is 92.3%.

[0068] Comparative Example 2-1. The specific process is as follows: Using 150 ml of tetrahydrofuran as the solvent, 15.75 g (0.1 mol) of 2-chloronicotinic acid and 30.59 g (0.115 mol) of Intermediate I are stirred and dissolved. Then, 3.94 g of HND-64 solid superbase catalyst is added. The mixture is heated to 135 - 140 °C for the condensation reaction. The reaction time is 1.5 h. Then, it is filtered while it is hot to remove the solid base catalyst, and the tetrahydrofuran is removed while keeping the temperature. First, 250 ml of pure water is added to cool down, and then 250 ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added for extraction. The pure water phase is taken and hydrochloric acid is added to adjust the pH to 4 - 5. Then, it is placed at 0 - 5 °C to precipitate crystals, filtered by suction and washed with 80 ml of pure water, and dried in vacuum to obtain 34.58 g of Intermediate II. The yield of this example is 89.35%.

[0069] Comparative Example 2-2, the specific process is as follows: 150ml of tetrahydrofuran is used as a solvent, 15.75g (0.1mol) of 2-chloronicotinic acid, 34.58g (0.13mol) of intermediate I are stirred and dissolved, and then 2.84g of HND-64 solid superbase catalyst is added, and the reaction is heated to 135~140°C for condensation reaction. The reaction time is 1.5h, and then filtered while hot to remove the solid base catalyst, and the tetrahydrofuran is removed by heat preservation. 250ml of pure water is added to cool, and then 250ml of an organic mixture of petroleum ether and ethyl acetate mixed in a ratio of 1:2 is added to extract, the pure water phase is taken and hydrochloric acid is added to adjust the pH to 4~5, and then placed at 0~5°C to precipitate crystals, filtered and washed with 80ml of pure water, and dried in vacuo to obtain 34.61g of intermediate II, and the yield of this embodiment is 89.43%.

[0070] According to the above-mentioned Examples 2-1 to 2-9 and Comparative Examples 2-1 and 2-2, the molar ratio of 2-chloronicotinic acid: intermediate I is selected to be 1:1.2~1.4, the amount of the solid base catalyst is 20~30% by weight of the 2-chloronicotinic acid, and the intermediate II has a higher yield. The amount of intermediate I and the solid base catalyst is large, which increases the cost of raw materials. The amount of intermediate I and the solid base catalyst is small, and the yield of intermediate II is low. For this reason, the molar ratio of 2-chloronicotinic acid: intermediate I of the present invention is 1:1.2~1.4, and the amount of the solid base catalyst is 20~30% by weight of the 2-chloronicotinic acid, so that the yield of intermediate II is above 90%.

[0071] Example 3 Preparation of Intermediate III

[0072] Example 3-1, the specific process is as follows: 30.96g (0.08mol) of intermediate II and 30.96g of phosphorus oxychloride are heated to 115-120°C for dehydration reaction, the reflux time is 4h, and then the phosphorus oxychloride is evaporated under reduced pressure, and then 8% sodium carbonate solution is added to adjust the pH of the solution to 8-9, and the solution is fully stirred and placed at 0-5°C to precipitate crystals, filtered and washed with 100ml of pure water, and vacuum dried to obtain 26.89g of intermediate III. The yield of this example is 91.09%; the reaction formula is as follows Figure 1 Route III shown.

[0073] Example 3-2, the specific process is as follows: 30.96g (0.08mol) of intermediate II and 46.44g of phosphorus oxychloride are heated to 115-120°C for dehydration reaction, and the reflux time is 4h. The phosphorus oxychloride is then evaporated under reduced pressure, and then 8% sodium carbonate solution is added to adjust the solution pH to 8-9. After sufficient stirring, the solution is placed at 0-5°C to precipitate crystals, filtered and washed with 100ml of pure water, and vacuum dried to obtain 27.11g of intermediate III. The yield of this example is 91.83%.

[0074] Example 3-3. The specific process is as follows: 30.96 g (0.08 mol) of Intermediate II and 61.92 g of phosphorus oxychloride are heated to 115 - 120 °C for dehydration reaction. The reflux time is 4 h. After the reaction, phosphorus oxychloride is removed by distillation under reduced pressure. Then, 8% sodium carbonate solution is added to adjust the pH of the solution to 8 - 9. After sufficient stirring, the solution is placed at 0 - 5 °C to precipitate crystals. The crystals are filtered by suction and washed with 100 ml of pure water, and then dried in vacuum to obtain 27.21 g of Intermediate III. The yield of this example is 92.17%.

[0075] Comparative Example 3-1. The specific process is as follows: 30.96 g (0.08 mol) of Intermediate II and 46.44 g of polyphosphoric acid are heated to 115 - 120 °C for dehydration reaction. The reflux time is 4 h. 2 L of ice-cold pure water is added, and then sodium hydroxide is added to adjust the pH of the solution to 10. After sufficient stirring, the solution is placed at 0 - 5 °C to precipitate crystals. The crystals are filtered by suction and washed with 100 ml of pure water, and then dried in vacuum to obtain 25.92 g of Intermediate III. The yield of this step in the example is 87.8%.

[0076] According to the above Examples 3-1 to 3-3 and Comparative Example 3-1, phosphorus oxychloride is selected as the pure water removing agent, and its dosage is 1 - 2 times the mass of Intermediate II. Intermediate III has a relatively high yield, and the yield is above 91%.

[0077] Preparation of Intermediate IV in Example 4

[0078] Example 4-1. The specific process is as follows: Using 250 ml of tetrahydrofuran as the solvent, 25.83 g (0.07 mol) of Intermediate III and 25 g of pure water are mixed. Then, 9.45 g (0.14 mol) of potassium borohydride is added in batches. The mixture is heated to 55 - 60 °C for reduction reaction. The reaction time is 5 h. Then, tetrahydrofuran is removed by distillation. Then, 150 ml of pure water is added, stirred, and the pH is adjusted to 6 - 7. The mixture is filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 25.58 g of Intermediate IV. The yield of this example is 99.03%; the reaction formula is as shown in Route IV Figure 1 shown below.

[0079] Example 4-2. The specific process is as follows: Using 250 ml of tetrahydrofuran as the solvent, 25.83 g (0.07 mol) of Intermediate III and 25 g of pure water are mixed. Then, 7.56 g (0.14 mol) of potassium borohydride is added in batches. The mixture is heated to 55 - 60 °C for reduction reaction. The reaction time is 5 h. Then, tetrahydrofuran is removed by distillation. Then, 150 ml of pure water is added, stirred, and the pH is adjusted to 6 - 7. The mixture is filtered by suction and washed with 80 ml of pure water, and then dried in vacuum to obtain 25.65 g of Intermediate IV. The yield of this example is 99.3%.

[0080] Example 4-3. The specific process is as follows: Using 250 ml of tetrahydrofuran as the solvent, add 25.83 g (0.07 mol) of Intermediate III and 20.7 g of pure water and mix them. Then, add 7.56 g (0.14 mol) of potassium borohydride in batches. Heat the mixture to 55 - 60 °C for a reduction reaction for 5 h. After that, evaporate the tetrahydrofuran. Then, add 150 ml of pure water, stir, and adjust the pH to 6 - 7. Filter by suction and wash with 80 ml of pure water. Dry in vacuum to obtain 24.88 g of Intermediate IV. The yield of this example is 96.32%.

[0081] Example 4-4. The specific process is as follows: Using 250 ml of tetrahydrofuran as the solvent, add 25.83 g (0.07 mol) of Intermediate III and 32.3 g of pure water and mix them. Then, add 7.56 g (0.14 mol) of potassium borohydride in batches. Heat the mixture to 55 - 60 °C for a reduction reaction for 5 h. After that, evaporate the tetrahydrofuran. Then, add 150 ml of pure water, stir, and adjust the pH to 6 - 7. Filter by suction and wash with 80 ml of pure water. Dry in vacuum to obtain 25.41 g of Intermediate IV. The yield of this example is 98.37%.

[0082] Example 4-5. The specific process is as follows: Using 250 ml of tetrahydrofuran as the solvent, add 25.83 g (0.07 mol) of Intermediate III and 32.28 g of pure water and mix them. Then, add 7.56 g (0.14 mol) of potassium borohydride in batches. Heat the mixture to 55 - 60 °C for a reduction reaction for 5 h. After that, evaporate the tetrahydrofuran. Then, add 150 ml of pure water, stir, and adjust the pH to 6 - 7. Filter by suction and wash with 80 ml of pure water. Dry in vacuum to obtain 25.41 g of Intermediate IV. The yield of this example is 97.68%.

[0083] Comparative Example 4-1. The specific process is as follows: Using 250 ml of methanol as the solvent, add 25.83 g (0.07 mol) of Intermediate III and mix them. Then, add 7.56 g (0.14 mol) of potassium borohydride in batches. Heat the mixture to 55 - 60 °C for a reduction reaction for 5 h. After that, evaporate the tetrahydrofuran. Then, add 150 ml of pure water, stir, and adjust the pH to 6 - 7. Filter by suction and wash with 80 ml of pure water. Dry in vacuum to obtain 23.24 g of Intermediate IV. The yield of this example is 90%.

[0084] According to the above Examples 4-1 to 4-5 and Comparative Example 4, when tetrahydrofuran is selected as the solvent, the yield of Intermediate IV is above 96%. When the amount of pure water added is 1 times the weight of Intermediate III, the yield of Intermediate IV is higher.

[0085] Example 5 Preparation of Pranoprofen

[0086] Example 5-1. The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 17.1 g (0.15 mol) of trifluoroacetic acid, and carry out a hydrolysis reaction under heating and reflux for 5 h. Then, evaporate to dryness under reduced pressure. The residue is mixed with 200 ml of 65% aqueous ethanol solution, heated and stirred to dissolve it, then evaporated to dryness under reduced pressure again. Then, it is stirred and mixed with 200 ml of 5% aqueous ethanol solution, followed by suction filtration and washing with 100 ml of 5% aqueous ethanol solution, and then dried in vacuum to obtain 14.83 g of pranoprofen. The yield of this example is 96.83% and the purity is 99.86%; The reaction formula is as Figure 1 shown in Route V.

[0087] Example 5-2. The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 13.68 g (0.12 mol) of trifluoroacetic acid, and carry out a hydrolysis reaction under heating and reflux for 5 h. Then, evaporate to dryness under reduced pressure. The residue is mixed with 200 ml of 65% aqueous ethanol solution, heated and stirred to dissolve it, then evaporated to dryness under reduced pressure again. Then, it is stirred and mixed with 200 ml of 5% aqueous ethanol solution, followed by suction filtration and washing with 100 ml of 5% aqueous ethanol solution, and then dried in vacuum to obtain 14.56 g of pranoprofen. The yield of this example is 95.16% and the purity is 99.89%.

[0088] Example 5-3. The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 15.39 g (0.135 mol) of trifluoroacetic acid, and carry out a hydrolysis reaction under heating and reflux for 5 h. Then, evaporate to dryness under reduced pressure. The residue is mixed with 200 ml of 65% aqueous ethanol solution, heated and stirred to dissolve it, then evaporated to dryness under reduced pressure again. Then, it is stirred and mixed with 200 ml of 5% aqueous ethanol solution, followed by suction filtration and washing with 100 ml of 5% aqueous ethanol solution, and then dried in vacuum to obtain 14.78 g of pranoprofen. The yield of this example is 96.6% and the purity is 99.91%.

[0089] Example 5-4. The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 17.78 g (0.156 mol) of trifluoroacetic acid, and carry out a hydrolysis reaction under heating and reflux for 5 h. Then, evaporate to dryness under reduced pressure. The residue is mixed with 200 ml of 65% aqueous ethanol solution, heated and stirred to dissolve it, then evaporated to dryness under reduced pressure again. Then, it is stirred and mixed with 200 ml of 5% aqueous ethanol solution, followed by suction filtration and washing with 100 ml of 5% aqueous ethanol solution, and then dried in vacuum to obtain 14.89 g of pranoprofen. The yield of this example is 97.32% and the purity is 99.88%.

[0090] Example 5-5: The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 11.97 g (0.105 mol) of trifluoroacetic acid, heat under reflux for hydrolysis reaction for 5 h, then evaporate to dryness under reduced pressure. The residue is mixed with 200 ml of 65% ethanol aqueous solution, heated and stirred to dissolve it, then evaporated to dryness under reduced pressure again, and then stirred and mixed with 200 ml of 5% ethanol aqueous solution, followed by suction filtration and washing with 100 ml of 5% ethanol aqueous solution, and vacuum drying to obtain 13.08 g of pranoprofen. The yield of this example is 85.49% and the purity is 99.12%.

[0091] Comparative Example 5-1: The specific process is as follows: Using 150 ml of isopropanol as the solvent, add 22.26 g (0.06 mol) of Intermediate IV and 120 ml of concentrated sulfuric acid, heat under reflux for hydrolysis reaction for 5 h, then evaporate to dryness under reduced pressure. The residue is mixed with 300 ml of 65% ethanol aqueous solution, then solid sodium hydroxide is added and stirred to dissolve it until the pH reaches 10, followed by suction filtration and washing with 100 ml of 5% ethanol aqueous solution, and vacuum drying to obtain 12.27 g of pranoprofen. The yield of this step is 80.2% and the purity is 99.03%.

[0092] According to the above Examples 5-1 to 5-5 and Comparative Example 5-1, when trifluoroacetic acid is selected and the molar ratio of Intermediate IV to trifluoroacetic acid is 1:2 to 2.5, the yield of pranoprofen is above 95%. When the amount of trifluoroacetic acid is small, the yield and purity of pranoprofen both decrease. When the amount of trifluoroacetic acid is large, the raw material cost increases.

[0093] According to the above Examples 2 to 5, calculating the total yield of pranoprofen based on 2-chloronicotinic acid, the total yield is above 75.5% and the purity is greater than 99.8%.

[0094] In summary, for the synthetic preparation process of pranoprofen of the present invention, using 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propanoic acid as the initial raw materials, first performing carboxyl protection on 2-(4-hydroxyphenyl)propanoic acid, and then successively performing condensation, dehydration, reduction, and hydrolysis reactions, which improves the raw material utilization rate and product yield.

[0095] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and can be implemented in other specific forms without departing from the spirit and basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, it is intended to include all changes falling within the meaning and scope of the equivalent elements of the claims in the present invention.

[0096] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment contains only an independent technical solution. This narrative style of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A synthetic preparation process of pranoprofen, characterized in that, Using 2-chloronicotinic acid and 2-(4-hydroxyphenyl)propionic acid as raw materials, firstly protecting the carboxyl group of 2-(4-hydroxyphenyl)propionic acid, and then sequentially performing condensation, dehydration, reduction and hydrolysis to synthesize pranoprofen; The specific steps are as follows: (1) Using dichloromethane as solvent, 2-(4-hydroxyphenyl)propionic acid, trimethylsilylethanol, triphosphine and azodicarboxylate were subjected to Mitsunobu reaction at a reaction temperature of 0-5°C. TLC showed that the raw material disappeared, and intermediate I was generated. (2) Using tetrahydrofuran as solvent, 2-chloronicotinic acid, intermediate I and solid base catalyst are subjected to condensation reaction at a reaction temperature of 130-140°C and a reaction time of 1.5-2h to generate intermediate II; (3) Intermediate II undergoes a dehydration reaction with phosphorus oxychloride at a temperature of 115-120°C for 4-5 hours to generate intermediate III; (4) using tetrahydrofuran as solvent, the intermediate III is subjected to reduction reaction with potassium borohydride at a reaction temperature of 40-45° C. for a reaction time of 5-6 hours to generate the intermediate IV; further comprising pure water, the amount of which is 0.8-1.5 times the weight of the intermediate III; (5) Intermediate IV is subjected to a hydrolysis reaction with trifluoroacetic acid, heated under reflux, and reacted for 5 to 6 hours to generate pranoprofen; The molar ratio of intermediate IV to trifluoroacetic acid in step (5) is 1:2-2.5; The molar ratio of 2-chloronicotinic acid to intermediate I in step (2) is 1:1.2-1.4; the amount of the solid base catalyst used is 20-30% of the weight of 2-chloronicotinic acid; The solid base catalyst is one of HND-64 solid super base catalyst or HND-63 solid super base catalyst; The triphosphine is one of triphenylphosphine, tri-tert-butylphosphine or tributylphosphine; the azodicarboxylic acid ester is diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate; The reaction equation is as follows:

2. A synthetic preparation process of pranoprofen according to claim 1, characterized in that, The amount of phosphorus oxychloride used in step (3) is 1 to 2 times the mass of intermediate II.

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