Synthesis method of 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid

Abstract

The invention discloses a method for synthesizing 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, which belongs to the technical field of organic chemical synthesis. The method uses 6-chloronicotinic acid as a raw material, and undergoes some conventional simple reactions, such as esterification, substitution, chlorination and hydrolysis, to obtain a final product. The invention does not use highly corrosive reagents, has no isomerization phenomenon, has mild reaction conditions, is simple in production and operation, has low cost and high safety, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a method for synthesizing an avatrombopag intermediate, namely 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, which avoids the use of highly toxic and highly corrosive chlorination reagents and has mild reaction conditions, is safe, and is suitable for industrial production. Background Art

[0002] Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) used for thrombocytopenia. It can greatly improve the quality of life of patients with thrombocytopenia and has the characteristics of long-lasting efficacy, safety and convenience.

[0003] 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid is an important intermediate for the synthesis of avatrombopag. Currently, the synthesis method of 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid includes the following steps:

[0004] Non-patent document 1 discloses a three-step synthesis method. First, 5-chloro-6-hydroxynicotinic acid is synthesized using 6-hydroxynicotinic acid as a raw material, and then 5,6-dichloronicotinic acid is synthesized under phosphorus oxychloride conditions; secondly, ethyl isonicotinate is synthesized using isonicotinic acid as a raw material, and then reduced to synthesize ethyl 4-piperidinic acid under catalyst Pd / C conditions; finally, ethyl 4-piperidinic acid, 5,6-dichloronicotinic acid and triethylamine are mixed and reacted at 150° C. for 6 hours to obtain the target intermediate, and the total yield of the three steps is 36.8%.

[0005]

[0006] In the above method, phosphorus oxychloride is used for reaction under high temperature conditions, which is highly corrosive and toxic, and has potential safety hazards; the substitution reaction is carried out through the activity difference between the two chlorides, which is prone to side reactions, affecting the product quality and yield, and is not convenient for subsequent purification.

[0007] Patent document 1 discloses a method for preparing atrombopag. In order to overcome the problem of poor selectivity of dichlorobenzene, 6-amino-5-chloro-3-pyridinecarboxylic acid and 4-bromo-2-(2-bromoethyl)butyric acid methyl ester are used as raw materials to undergo a cyclization reaction under the action of a surfactant and an acid binding agent to obtain the intermediate 5-chloro-6-(4-methoxycarbonyl-1-piperidinyl)-3-pyridinecarboxylic acid, with a yield of 93.7%. The raw materials in this method are not easy to obtain and are relatively expensive, which is not conducive to industrial production. In addition, the cyclization reaction also has side reactions.

[0008] Non-patent literature 1: Gong Zhang et al., "Synthesis of Avatrombopag", Journal of Wuhan University of Technology, 2023, Vol. 45, No. 2, pp. 162-168.

[0009] Patent document 1: Chinese invention patent (CN 111620863 A). Summary of the invention

[0010] The main purpose of the present invention is to provide a method for synthesizing 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, which avoids the use of highly toxic and highly corrosive chlorination reagents and has mild reaction conditions, is safe and suitable for industrial production.

[0011] To achieve the above object, the present invention provides a method for synthesizing 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, comprising the following steps:

[0012]

[0013] (a) dissolving 6-chloronicotinic acid and 2-(trimethylsilyl)ethanol in an organic solvent A, adding a condensation reagent to carry out an esterification reaction to obtain an intermediate Ia;

[0014] (b) dissolving the intermediate Ia, ethyl 4-piperidinylcarboxylate and a base in an organic solvent B to carry out a substitution reaction to obtain an intermediate Ib;

[0015] (c) dissolving the intermediate Ib in an organic solvent C, adding a chlorination agent, and performing a chlorination reaction to obtain an intermediate Ic;

[0016] (d) The intermediate Ib is dissolved in an organic solvent D, and a fluoride is added to carry out a hydrolysis reaction to obtain the target product Id.

[0017] Preferably, the condensation reagent is selected from one of N,N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, and N,N'-di-tert-butylcarbodiimide; the chlorination reagent is one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid; the fluoride is one of tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, and ammonium fluoride.

[0018] Preferably, the base is one of sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, and N,N-diisopropylethylamine.

[0019] Preferably, the organic solvent A is selected from one or more of dichloromethane and tetrahydrofuran; the organic solvent B is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dioxane, and dimethyl sulfoxide; the organic solvent C is selected from one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dioxane; and the organic solvent D is tetrahydrofuran.

[0020] Preferably, the esterification reaction temperature is -5°C to 5°C, preferably 0°C, and the esterification reaction time is 0.5h to 1.5h, preferably 1.0 h; the substitution reaction temperature is 60°C to 150°C, preferably 80°C, and the substitution reaction time is 1h to 4h, preferably 3.0 h; the chlorination reaction temperature is 10°C to 40°C, preferably 25°C, and the chlorination reaction time is 0.5h to 1.5h, preferably 1.0 h; the hydrolysis reaction temperature is 10°C to 40°C, preferably 25°C, and the hydrolysis reaction time is 1h to 4h, preferably 3.0 h.

[0021] The synthesis method of 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid provided by the present invention has the following advantages: 6-chloronicotinic acid is used as a raw material, and the final product is obtained by sequentially undergoing reactions such as esterification, substitution, chlorination and hydrolysis. The present invention does not use highly corrosive reagents, has no isomerization phenomenon, has mild reaction conditions, is simple in production operation, has low cost and high safety, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the hydrogen spectrum nuclear magnetic spectrum of the intermediate Id of the present invention.

[0023] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, rather than all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

[0025] The present invention provides a method for synthesizing 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, comprising the following steps:

[0026] (a) dissolving 6-chloronicotinic acid and 2-(trimethylsilyl)ethanol in an organic solvent A, adding a condensation reagent to carry out an esterification reaction to obtain an intermediate Ia;

[0027] Wherein, the organic solvent A is selected from one or more of dichloromethane and tetrahydrofuran, the condensation reagent is selected from one of N,N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide, and N,N'-di-tert-butylcarbodiimide, the esterification reaction temperature is -5°C to 5°C, preferably 0°C, and the esterification reaction time is 0.5h to 1.5h, preferably 1.0h;

[0028]

[0029] (b) dissolving the intermediate Ia, ethyl 4-piperidinylcarboxylate and a base in an organic solvent B to carry out a substitution reaction to obtain an intermediate Ib;

[0030] wherein the base is one of sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, and N,N-diisopropylethylamine; the organic solvent B is one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dioxane, and dimethyl sulfoxide; the substitution reaction temperature is 60°C to 150°C, preferably 80°C; and the substitution reaction time is 1h to 4h, preferably 3.0 h;

[0031]

[0032] (c) dissolving the intermediate Ib in an organic solvent C, adding a chlorination agent, and performing a chlorination reaction to obtain an intermediate Ic;

[0033] wherein the organic solvent C is selected from one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dioxane; the chlorination reagent is one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid; the chlorination reaction temperature is 10°C to 40°C, preferably 25°C; and the chlorination reaction time is 0.5h to 1.5h, preferably 1.0h;

[0034]

[0035] (d) The intermediate Ib is dissolved in an organic solvent D, and a fluoride is added to carry out a hydrolysis reaction to obtain the target product Id.

[0036] Wherein, the organic solvent D is tetrahydrofuran, the fluoride is one of tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride and ammonium fluoride, the hydrolysis reaction temperature is 10°C to 40°C, preferably 25°C, and the hydrolysis reaction time is 1h to 4h, preferably 3.0 h.

[0037]

[0038] Example 1

[0039] (a) Weigh 157.6 g of 6-chloronicotinic acid and 236.5 g of 2-(trimethylsilyl)ethanol and dissolve them in 800 mL of dichloromethane for esterification reaction. Slowly add 309.5 g of N,N'-dicyclohexylcarbodiimide in 200 mL of dichloromethane at 0°C. After the addition is complete, continue stirring for 1 hour to generate a large amount of white solid.

[0040] The reaction solution was filtered, and the filtrate was washed twice with water (600 mL×2), dried over anhydrous sodium sulfate, and spin-dried to obtain 348.6 g of crude intermediate Ia in the form of a yellow oil.

[0041] (b) 348.6 g of the crude intermediate Ia obtained in step (a) was dissolved in 1 L of N,N-dimethylformamide, and 235.8 g of ethyl 4-piperidincarboxylate and 318.0 g of sodium carbonate were added to carry out a substitution reaction at 80° C. for 3 h.

[0042] The reaction solution was cooled to room temperature, poured into 1L of water, extracted three times with ethyl acetate (500mL×3), the organic layers were combined, washed once with 1L of water, 500mL of 0.5M dilute hydrochloric acid, 1L of water, and 1L of saturated brine in sequence, dried over anhydrous sodium sulfate, and spin-dried to obtain 478.5g of crude intermediate Ib as a yellow oil.

[0043] (c) 478.5 g of the crude intermediate Ib obtained in step (b) was dissolved in 1 L of acetonitrile, and 200.3 g of N-chlorosuccinimide was added at room temperature (25° C.) to carry out chlorination reaction for 1 h to generate a white solid.

[0044] The reaction solution was filtered, and the filtrate was poured into 1 L of water, extracted three times with ethyl acetate (700 mL×3), and the organic layers were combined, washed once with 1 L of water and 1 L of saturated brine in sequence, and spin-dried to obtain 510.0 g of crude intermediate Ic as a yellow oil.

[0045] (d) 510.0 g of the crude intermediate Ic obtained in step (c) was dissolved in 1 L of tetrahydrofuran, and 784.4 g of tetrabutylammonium fluoride was added to carry out a hydrolysis reaction. The reaction time was 3 h at room temperature (25°C). The tetrahydrofuran was removed by rotary evaporation, 1 L of water was added to dilute, the pH was adjusted to 1 with concentrated hydrochloric acid, washed three times with ethyl acetate (300 mL×3), and the pH was adjusted to 5 with a 2M sodium hydroxide aqueous solution to precipitate a large amount of light yellow solid.

[0046] The reaction solution was filtered and the solid was washed twice with water to obtain 254.6 g of crude target product Id.

[0047] The crude product of target product Id was recrystallized with a mixed solvent of dichloromethane / n-hexane = 1 / 5, and finally 219.7 g of pure product was obtained, with a liquid phase purity of 99.2%, in the form of a white solid, and the total yield of the four-step reaction was 70.2%. Figure 1 As shown, where: H NMR spectrum 1 H NMR(400 MHz, DMSO-d6) (ppm): δ 8.63 (d,J=2.0Hz,1H), 8.05 (d,J=2.0Hz,1H), 4.08(q,J=7.2Hz,2H), 3.94 (ddd,J=13.2,4.0,4.0Hz,2H),3.00(ddd,J=12.4,12.4,2.8Hz,2H),2.57- 2.61(m,1H),1.90-1.95(m,2H),1.63-1.72(m,2H),1.19(t,J=7.2Hz,3H).

[0048] Example 2

[0049] (a) Weigh 15.8 g of 6-chloronicotinic acid, 23.7 g of 2-(trimethylsilyl)ethanol and 1.0 g of 4-dimethylaminopyridine respectively and dissolve them in 100 mL of dichloromethane for esterification reaction. Slowly add 31.0 g of N,N'-dicyclohexylcarbodiimide in 50 mL of dichloromethane at 0°C. After the addition is complete, continue stirring for 1 hour to generate a large amount of white solid.

[0050] The reaction solution was filtered, and the filtrate was washed twice with water (100 mL×2), dried over anhydrous sodium sulfate, and spin-dried to obtain 35.1 g of a crude intermediate Ia in the form of a yellow oil.

[0051] (b) 35.1 g of the crude intermediate Ia obtained in step (a) was dissolved in 100 mL of N,N-dimethylformamide, and 23.6 g of ethyl 4-piperidinylcarboxylate and 41.5 g of potassium carbonate were added to carry out a substitution reaction at 100° C. for 3 h.

[0052] The reaction solution was cooled to room temperature, poured into 150 mL of water, extracted three times with ethyl acetate (100 mL×3), the organic layers were combined, washed once with 150 mL of water, 50 mL of 0.5 M dilute hydrochloric acid, 150 mL of water, and 150 mL of saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 45.9 g of crude intermediate Ib as a yellow oil.

[0053] (c) 45.9 g of the crude intermediate Ib obtained in step (b) was dissolved in 100 mL of tetrahydrofuran, and 20.0 g of N-chlorosuccinimide was added at room temperature (25° C.) to carry out chlorination reaction for 1 h to generate a white solid.

[0054] The reaction solution was filtered, and the filtrate was poured into 200 mL of water, extracted three times with ethyl acetate (100 mL×3), and the organic layers were combined, washed once with 150 mL of water and 150 mL of saturated brine in sequence, and then spin-dried to obtain 49.6 g of crude intermediate Ic as a yellow oil.

[0055] (d) 49.6 g of the crude intermediate Ic obtained in step (c) was dissolved in 150 mL of tetrahydrofuran, and 27.9 g of tetramethylammonium fluoride was added to carry out a hydrolysis reaction. The reaction time was 3 h at room temperature (25°C). The tetrahydrofuran was removed by rotary evaporation, 200 mL of water was added to dilute, the pH was adjusted to 1 with concentrated hydrochloric acid, washed three times with ethyl acetate (100 mL×3), and the pH was adjusted to 5 with a 2M sodium hydroxide aqueous solution, and a large amount of light yellow solid was precipitated.

[0056] The reaction solution was filtered and the solid was washed twice with water to obtain 23.7 g of crude target product Id.

[0057] The crude target product Id was recrystallized with a mixed solvent of dichloromethane / n-hexane = 1 / 5 to finally obtain 18.8 g of pure product with a liquid phase purity of 98.6% in the form of a white solid. The total yield of the four-step reaction was 59.9%.

[0058] Example 3

[0059] The difference between this embodiment and embodiment 2 is that:

[0060] (a) A solution of 28.8 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in 50 mL of dichloromethane was slowly added dropwise to obtain 30.3 g of a crude intermediate Ia as a yellow oil.

[0061] (b) 30.3 g of the crude intermediate Ia obtained in step (a) was dissolved in 100 mL of N-methylpyrrolidone, and 23.6 g of ethyl 4-piperidincarboxylate and 30.4 g of triethylamine were added to carry out a substitution reaction at 60° C. to obtain 41.2 g of the crude intermediate Ib as a yellow oil.

[0062] (c) 41.2 g of the crude intermediate Ib obtained in step (b) was dissolved in 100 mL of N,N-dimethylformamide, and 13.9 g of trichloroisocyanuric acid was added at room temperature (25° C.) to carry out chlorination reaction to obtain 47.7 g of the crude intermediate Ic as a yellow oil.

[0063] (d) 47.7 g of the crude intermediate Ic obtained in step (c) was dissolved in 150 mL of tetrahydrofuran, and 78.4 g of tetraethylammonium fluoride was added to carry out a hydrolysis reaction to obtain 21.9 g of a crude target product Id.

[0064] Recrystallization finally gave 17.5 g of pure product, with the other conditions remaining unchanged.

[0065] The liquid phase purity is 98.8%, it is in the form of a white solid, and the total yield of the four-step reaction is 55.7%.

[0066] Example 4

[0067] The difference between this embodiment and embodiment 2 is that:

[0068] In (a), the organic solvent is tetrahydrofuran and the condensation reagent is 30.1 g of N,N'-diisopropylcarbodiimide.

[0069] (b) The base is sodium tert-butoxide and the organic solvent is N,N-dimethylacetamide.

[0070] In (c), the organic solvent is N-methylpyrrolidone and the chlorination reagent is 18.9 g of 1,3-dichloro-5,5-dimethylhydantoin.

[0071] The fluoride in (d) is 80 g of ammonium fluoride.

[0072] The rest of the conditions remain unchanged.

[0073] The liquid phase purity is 98.5%, it is in the form of a white solid, and the total yield of the four-step reaction is 54.1%.

[0074] Example 5

[0075] The difference between this embodiment and embodiment 2 is that:

[0076] In (a), the organic solvent is tetrahydrofuran and the condensation reagent is 28.5 g of N,N'-di-tert-butylcarbodiimide.

[0077] (b) The base is triethylamine and the organic solvent is dioxane.

[0078] In (c), the organic solvent is N,N-dimethylacetamide and the chlorination reagent is 18.9 g of 1,3-dichloro-5,5-dimethylhydantoin.

[0079] The fluoride in (d) is 80 g of ammonium fluoride.

[0080] The rest of the conditions remain unchanged.

[0081] The liquid phase purity is 98.0%, it is in the form of a white solid, and the total yield of the four-step reaction is 55.0%.

[0082] Example 6

[0083] The difference between this embodiment and embodiment 2 is that:

[0084] (a) Esterification reaction temperature is -5°C and esterification reaction time is 0.5h

[0085] (b) The base is N,N-diisopropylethylamine, the organic solvent is dimethyl sulfoxide, the reaction temperature is 150°C, and the reaction time is 1 h.

[0086] (c) The chlorination reaction temperature is 10°C and the reaction time is 0.5h.

[0087] (d) The hydrolysis reaction temperature was 10 °C and the reaction time was 1 h.

[0088] The rest of the conditions remain unchanged.

[0089] The liquid phase purity is 97.7%, it is in the form of a white solid, and the total yield of the four-step reaction is 44.4%.

[0090] Example 7

[0091] The difference between this embodiment and embodiment 2 is that:

[0092] (a) Esterification reaction temperature is 5°C and esterification reaction time is 1.5h

[0093] (b) The base is N,N-diisopropylethylamine, the organic solvent is dimethyl sulfoxide, the reaction temperature is 120°C, and the reaction time is 4 h.

[0094] (c) The chlorination reaction temperature is 40°C and the reaction time is 1.5 h.

[0095] (d) The hydrolysis reaction temperature was 40 °C and the reaction time was 4 h.

[0096] The rest of the conditions remain unchanged.

[0097] The liquid phase purity is 98.9%, it is in the form of a white solid, and the total yield of the four-step reaction is 43.8%.

[0098] Example 8

[0099] The difference between this embodiment and embodiment 2 is that:

[0100] (a) Esterification reaction temperature is 5°C and esterification reaction time is 1.5h

[0101] (b) The base is N,N-diisopropylethylamine, the organic solvent is dimethyl sulfoxide, the reaction temperature is 120°C, and the reaction time is 4 h.

[0102] (c) The chlorination reaction temperature is 40°C and the reaction time is 1.5 h.

[0103] (d) The hydrolysis reaction temperature was 40 °C and the reaction time was 4 h.

[0104] The rest of the conditions remain unchanged.

[0105] The liquid phase purity is 98.9%, it is in the form of a white solid, and the total yield of the four-step reaction is 43.8%.

[0106] It can be seen from the above examples that it is feasible to obtain 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid using 6-chloronicotinic acid as a raw material through chemical reactions such as esterification, substitution, chlorination and hydrolysis, and the highest yield can reach 70.2%.

Claims

1. A method for synthesizing 5-chloro-6-(4-(ethoxycarbonyl)piperidin-1-yl)nicotinic acid, characterized in that: The following steps are involved: ； (a) dissolving 6-chloronicotinic acid and 2-(trimethylsilyl)ethanol in an organic solvent A, adding a condensation reagent to carry out an esterification reaction to obtain an intermediate Ia; (b) dissolving the intermediate Ia, ethyl 4-piperidinylcarboxylate and a base in an organic solvent B to carry out a substitution reaction to obtain an intermediate Ib; (c) dissolving the intermediate Ib in an organic solvent C, adding a chlorination agent, and performing a chlorination reaction to obtain an intermediate Ic; (d) dissolving the intermediate Ib in an organic solvent D, adding a fluoride, and performing a hydrolysis reaction to obtain the target product Id; The chlorination agent is one of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid; The fluoride is tetrabutylammonium fluoride.

2. The method according to claim 1, characterized in that The condensation reagent is selected from one of N,N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-diisopropylcarbodiimide and N,N'-di-tert-butylcarbodiimide.

3. The method according to claim 1, characterized in that: The base is one of sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, triethylamine and N,N-diisopropylethylamine.

4. The method according to claim 1, characterized in that: The organic solvent A is selected from one or more of dichloromethane and tetrahydrofuran; the organic solvent B is selected from one or more of N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, dioxane, and dimethyl sulfoxide; the organic solvent C is selected from one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, and dioxane; and the organic solvent D is tetrahydrofuran.

5. The method according to any one of claims 1 to 4, characterized in that: The esterification reaction temperature is -5℃~5℃, and the esterification reaction time is 0.5h~1.5h; the substitution reaction temperature is 60℃~150℃, and the substitution reaction time is 1h~4h; the chlorination reaction temperature is 10℃~40℃, and the chlorination reaction time is 0.5h~1.5h; the hydrolysis reaction temperature is 10℃~40℃, and the hydrolysis reaction time is 1h~4h.

6. The method according to any one of claims 1 to 4, characterized in that: The esterification reaction temperature was 0°C, and the esterification reaction time was 1.0 h; the substitution reaction temperature was 80°C, and the substitution reaction time was 3.0 h; the chlorination reaction temperature was 25°C, and the chlorination reaction time was 1.0 h; the hydrolysis reaction temperature was 25°C, and the hydrolysis reaction time was 3.0 h.

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