A method for synthesizing 3-hydroxy-2'-chloroacetophenone derivative as a phenylephrine intermediate

Abstract

The invention relates to the technical field of chemical intermediates, and specifically discloses a method for synthesizing 3-hydroxy-2'-chloroacetophenone, an intermediate of phenylephrine, and an analog thereof. The invention starts from m-hydroxybenzoic acid, and protects the hydroxyl group of the m-hydroxybenzoic acid to obtain compound 1. In a nitrogen atmosphere, the compound 1 is activated by a carboxylic acid activation reagent, and then reacts with a diazo reagent, and then hydrogen chloride gas is introduced or concentrated hydrochloric acid and a hydrogen chloride organic solvent are added to fully mix and react to obtain a compound shown in formula 2. Compared with the prior art, the invention starts from m-hydroxybenzoic acid, a cheap industrial raw material, and protects the hydroxyl group of the m-hydroxybenzoic acid to obtain compound 1. In the synthesis path, the reaction conditions are mild, the atomic utilization rate is high, the final product yield is high, the three wastes are less, and the compound is environmentally friendly, and the compound has the application value of large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of intermediates, and in particular to a method for synthesizing a phenylephrine intermediate 3-hydroxy-2'-chloroacetophenone derivative. Background Art

[0002] Phenylephrine is an α1 receptor agonist drug with vasoconstriction and is widely used in clinical practice. In 1927, German chemist Helmut Legerlotz first synthesized phenylephrine and later isolated its chiral isomers. The α carbon of the side chain of phenylephrine (PE) is a chiral carbon atom, and its R(-)-isomer has a much stronger α1-adrenergic receptor agonist effect than the S(+)-isomer. Clinically, R-type phenylephrine is widely used in paroxysmal supraventricular tachycardia, treatment of shock and maintenance of blood pressure during anesthesia; it can also be used for mydriasis examinations in ophthalmic examinations. Compound preparations in combination with antihistamines are mainly used for symptoms such as headache, fever, sore limbs, sneezing, and sore throat caused by colds. R-type phenylephrine is also showing an increasing trend in clinical use. Its structure is as follows:

[0003] At present, the main methods for synthesizing R-phenylephrine are as follows: chiral resolution, enzyme catalysis, asymmetric hydrogenation, etc. The currently reported methods have low yields, large amounts of three wastes, easy environmental pollution, and low ee values ​​of the products, which have certain deficiencies in industrial production applications.

[0004] Chiral resolution method: L-(+)-tartaric acid is widely used as a resolution agent. After chiral resolution, S-type phenylephrine-L-(+)-tartrate crystals are obtained. After ammonia alkalization, S-type phenylephrine is obtained by washing with water and drying. R-type phenylephrine-L-(+)-tartrate remains in the mother liquor and is recovered by adding ammonia water to obtain R-type phenylephrine. The obtained S-type phenylephrine is racemized under acidic or alkaline conditions and can be resolved again, thereby improving the overall yield. The process steps are cumbersome, the amount of three wastes is huge, and it is not environmentally friendly. For specific literature, see: Bao WN, Pan HF, Zhang ZH, et al. Isolation of the stable strain Labrys sp. BK-8 for L-(+)-tartaric acid production [J]. Journal of Bioscience and Bioengineering, 2014, 118 (1): 1-5.

[0005] Asymmetric hydrogenation method: With the development of asymmetric hydrogenation technology, chemists have continuously improved the synthesis process of phenylephrine, and more and more manufacturers are using asymmetric synthesis methods to prepare R-phenylephrine. Among the common asymmetric synthesis methods for preparing R-phenylephrine, the earliest studied and most widely used is the asymmetric hydrogenation method. In addition, the Sharpless asymmetric dihydroxylation method and the Salen catalytic aldehyde Henry reaction method are also effective ways to synthesize R-phenylephrine. In 2008, Hossein (WO2009086283) first reported a method for synthesizing S-phenylephrine by asymmetric catalytic hydrogenation using a ruthenium chiral bisphosphine catalyst. They used α-methylamino-m-hydroxyacetophenone as the raw material, formed sulfate, and then used ruthenium-chiral bisphosphine catalyst for asymmetric catalytic hydrogenation, and then neutralized it with ammonia to obtain R-phenylephrine, and the optical purity of the product was 95% ee. The asymmetric hydrogenation of α-methylamino-m-hydroxyacetophenone was catalyzed by a ruthenium biligand catalyst [(R)-Xyl-P-Phos RuCl2(R)-DAIPEN] to obtain R-type phenylephrine; (R)-Xyl-P-Phos is a C chiral bisphosphine ligand, (R)-DAIPEN is a chiral diamine ligand, the reaction time is 16h, and the optical purity of the product is 96% ee.

[0006] In 2010, McGarrity et al. (Tetrahedron: Asymmetry, 2010 (21): 2479-2486) directly used a ruthenium dual ligand catalyst [(R)-Xyl-P-Phos RuCl2(R)-DAIPEN] to catalyze the asymmetric hydrogenation of α-methylamino-m-hydroxyacetophenone to obtain R-type phenylephrine; (R)-Xyl-P-Phos is a carbon chiral diphosphine ligand, (R)-DAIPEN is a chiral diamine ligand, the reaction time is 16h, and the optical purity of the product is 96% ee.

[0007] In 2011, Feng Wenhua et al. (CN 102234237) used commercial (R)-BINAP-Ru(II) catalysts to synthesize L-phenylephrine. (R)-BINAP is a C-chiral bidentate diphosphine ligand. The optical purity of the crude product obtained by reduction is 75%ee, and it can reach 96%ee after methanol crystallization. The reaction of the above literature is shown in reaction formula I:

[0008] Reaction I The ee value of the product obtained by the existing process is relatively low. With the improvement of the quality requirements for drugs, the ee value of the product is more required to be 99%. Chiral catalysts are expensive, and there is still room for improvement in the catalyst conversion rate.

[0009] Enzyme catalysis technology: In 2013, Breuer et al. (US8617854) of BASF Europe disclosed a method for synthesizing R-type phenylephrine catalyzed by alcohol dehydrogenase of Azoarbrio species EBN1. The enzyme can be recombinantly prepared in Escherichia coli. The route is to use m-hydroxyacetophenone as the starting material, which reacts with sulfonyl chloride in the presence of propanol to obtain α-chloro-3-hydroxyacetophenone. Then, the alcohol dehydrogenase of Azoarbrio species EBN1 is used as a biocatalyst, and NADP is used as an electron donor. In the presence of glucose dehydrogenase and 2-butanol, α-chloro-3-hydroxyacetophenone is reduced to a chiral alcohol, and methylamine is aminated to obtain L-phenylephrine. The optical purity of the product is greater than 99% ee. The reaction route is shown in Reaction Formula II:

[0010] Reaction II The document reports that the fifth concentration should not exceed 8.5g / L, and it is necessary to use a process of continuous feeding and continuous extraction of (R)-2-chloro-1-(3-hydroxyphenyl)ethanol generated in the reaction solution with methyl tert-butyl ether. The amount of (R)-2-chloro-1-(3-hydroxyphenyl)ethanol finally generated per 1000mL reaction solution does not exceed 175g. This process produces a large amount of organic solvent waste liquid, places great pressure on environmental protection, and increases reaction costs and environmental pollution costs. This low-concentration, long-term, and environmentally unfriendly enzyme catalysis process does not have the application value for large-scale industrial production.

[0011] 3-Hydroxy-2'-chloroacetophenone is a key intermediate in the synthesis of phenylephrine, and its cost determines the cost of L-phenylephrine hydrochloride. Therefore, it is of great significance to develop a technology for efficiently preparing 3-hydroxy-2'-chloroacetophenone and realizing the application of industrial production of R-phenylephrine, improve the production efficiency and quality of drug R-phenylephrine, reduce costs, and reduce the generation of three wastes. Summary of the invention

[0012] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a method for synthesizing a phenylephrine intermediate derivative, characterized in that it comprises: The compound of formula 1, , mixing the compound of formula 1 with a carboxylic acid activating reagent, controlling the temperature, adding a diazo reagent to react, and then adding hydrogen chloride to obtain a compound of formula 2;

[0013] The R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or substituted ester, substituted or unsubstituted heterocyclic group; Said R2 is selected from hydroxyl group and hydrogen; The n is selected from an integer of 0 to 2.

[0014] In some specific embodiments of the first aspect, the carboxylic acid activating agent is selected from N,N'-carbonyldiimidazole, the compound of formula 1 is mixed with N,N'-carbonyldiimidazole, and the temperature is controlled to obtain a compound of formula 3, such as:

[0015] A diazo reagent is then added to react, and then hydrogen chloride is added to obtain a compound of formula 2;

[0016] In some specific embodiments of the first aspect, the R1 is selected from an alkoxy group, wherein the alkoxy structure is -O(CO)R a , the R a is selected from substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl, and substituted or unsubstituted aryl.

[0017] In some specific embodiments of the first aspect of the present invention, the R1 is relative to The groups are located at the ortho, meta, and para positions.

[0018] In some specific embodiments of the first aspect of the present invention, the R2 is relative to The groups are located at the ortho, meta, and para positions.

[0019] In some specific embodiments of the first aspect, the hydrogen chloride is selected from hydrogen chloride gas, hydrogen chloride organic solution, and hydrogen chloride aqueous solution.

[0020] In some specific embodiments of the first aspect, the temperature of the temperature control is -5~5°C, in some embodiments, the temperature of the temperature control is -2°C, in some embodiments, the temperature of the temperature control is 0°C, and in some embodiments, the temperature of the temperature control is 2°C.

[0021] In some specific embodiments of the first aspect, the carboxylic acid activating agent is selected from one of thionyl chloride, oxalyl chloride, and alkyl chloroformate.

[0022] In some specific embodiments of the first aspect, the carboxylic acid activating reagent is selected from alkyl chloroformate, the compound of formula 1 is mixed with an organic base, and then the alkyl chloroformate is added, and the organic base is selected from triethylamine.

[0023] In some specific embodiments of the first aspect, the diazo reagent is selected from trimethylsilyldiazomethane and diazomethane.

[0024] In some specific embodiments of the first aspect, the diazo reagent is an organic solution of diazomethane or a diazomethane / nitrogen mixture, and the organic solution of diazomethane is prepared by: S1: Alkaline aqueous solution is mixed with organic solvent, and the temperature is controlled. S2: adding 1-methyl-3-nitro-1-nitrosoguanidine or N-methyl-N-nitroso-p-toluenesulfonamide in batches, separating the liquids to obtain an organic phase, and obtaining an organic phase of diazomethane.

[0025] The diazomethane / nitrogen mixed gas configuration method is: S1: 1-methyl-3-nitro-1-nitrosoguanidine or N-methyl-N-nitroso-p-toluenesulfonamide is mixed with an organic solvent and the temperature is controlled. S2: After adding the aqueous solution of alkali dropwise, high-purity nitrogen is bubbled to form a diazomethane / nitrogen mixed gas.

[0026] Advantages of the present invention: The invention provides a method for preparing 3-hydroxy-2'-chloroacetophenone, an intermediate of phenylephrine, or 3,4-dihydroxy-2'-chloroacetophenone, an intermediate of a hemostatic drug Anluoxue or a mimetic adrenaline drug Quanxiling. Compared with the prior art, the invention adopts m-hydroxybenzoic acid, an inexpensive industrial raw material, and protects the hydroxyl group of the m-hydroxybenzoic acid to obtain compound 1. During the synthesis path, the reaction conditions are mild, the atomic utilization rate is high, the final product yield is high, the three wastes are produced in a small amount, and the method is environmentally friendly, and the method has the application value of large-scale industrial production. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application belong to the scope of protection of the present application.

[0028] A method for preparing a phenylephrine intermediate derivative, starting from m-hydroxybenzoic acid, a cheap industrial raw material, protecting the hydroxyl group of m-hydroxybenzoic acid to obtain compound 1; activating the compound shown in formula 1 with a carboxylic acid activating reagent under a nitrogen atmosphere, and then reacting with a diazo reagent under alkaline conditions, introducing hydrogen chloride gas or adding concentrated hydrochloric acid and hydrogen chloride organic solvent to fully mix and react to obtain a compound shown in formula 2;

[0029] Example 1: Synthesis of Compound 1a

[0030] Add 200 mL of acetic anhydride and m-hydroxybenzoic acid (2 mol) to a 2L flask, and add m-hydroxybenzoic acid while stirring. After adding the materials, heat and stir until reflux, the solution becomes clear, and take samples for detection after reflux reaction for 5 hours. Stop heating after the m-hydroxybenzoic acid reacts completely. After the temperature drops to room temperature, pour the reaction solution into a container filled with 3 L of ice water, stirring while pouring. During the treatment, a large amount of white solid precipitates. After the reaction solution and ice water are completely mixed, continue stirring for 15 minutes, filter, wash the filter cake with water, and vacuum dry to obtain compound 1a with a yield of 92% and a purity of 99.1%.

[0031] Example 2: Synthesis of Compound 1b

[0032] Add 200 mL of propionic anhydride and m-hydroxybenzoic acid (2 mol) to a 2L flask, and add m-hydroxybenzoic acid while stirring. After adding the materials, heat and stir to 140°C, the solution becomes clear, and samples are taken for detection after 5 hours of reaction. Stop heating after the m-hydroxybenzoic acid reacts completely. After the temperature drops to room temperature, pour the reaction solution into a 3L ice water kettle, stirring while pouring. During the treatment, a large amount of white solid precipitates. After the reaction solution and ice water are completely mixed, continue stirring for 15 minutes, filter, wash the filter cake with water, and vacuum dry to obtain compound 1b with a yield of 88% and a purity of 98.9% detected by HPLC.

[0033] Example 3: Synthesis of Compound 1c

[0034] Add 200L of butyric anhydride and m-hydroxybenzoic acid (1 mol) to a 2L flask, and add m-hydroxybenzoic acid while stirring. After adding the materials, heat and stir to 140°C, the solution becomes clear, and samples are taken for detection after 5 hours of reaction. Stop heating after the m-hydroxybenzoic acid reacts completely. After the temperature drops to room temperature, pour the reaction solution into a container filled with 3L of ice water, stirring while pouring. During the treatment, a large amount of white solid precipitates. After the reaction solution and ice water are completely mixed, continue stirring for 15 minutes, filter, wash the filter cake with water, and vacuum dry to obtain compound 1c with a yield of 90% and a purity of 98.5% detected by HPLC.

[0035] Example 4: Synthesis of Compound 1e

[0036] Add 200mL of tetrahydrofuran and m-hydroxybenzoic acid (1mol) to a 2L flask. After the addition of m-hydroxybenzoic acid is completed, add benzoyl chloride (1.5mol) dropwise while stirring. After adding the materials, heat and stir until reflux, the solution becomes clear, and sample and test after 5 hours of reaction. Stop heating after the m-hydroxybenzoic acid reacts completely. After the temperature drops to room temperature, pour the reaction solution into a 3L ice water container, stirring while pouring. During the treatment, a large amount of white solid precipitates. After the reaction solution and ice water are completely mixed, continue stirring for 15 minutes, filter, wash the filter cake with water, and vacuum dry to obtain compound 1e, HPLC purity: 99.4%, yield 83%.

[0037] Example 5: The first synthesis method of compound 2a

[0038] Add compound 1a (0.75 mol) and thionyl chloride (81.5 mL, 1.12 mol) to a 1L flask, heat and reflux for 2 hours, remove the excess thionyl chloride by distillation under reduced pressure with toluene three times, using 50 mL of toluene each time. Dissolve the concentrated acyl chloride in methyl tert-butyl ether (200 mL), control the reaction temperature at -5~0 °C, and set aside.

[0039] A tetrahydrofuran solution of trimethylsilyldiazomethane (2.0 M, 750 mL, 1.5 mol) was added dropwise to the above-mentioned acyl chloride solution. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the monitoring reaction was completed, the reaction solution was poured into 250 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 200 ml of tetrahydrofuran, slowly added to 100 ml of concentrated hydrochloric acid, and stirred at -10~0°C for more than 1 hour. After the reaction was completed, the reaction was quenched with 250 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 86% and a purity of 84.3% as determined by HPLC.

[0040] Example 6: Synthesis of Compound 2a Second Synthesis Method

[0041] Compound 1b (0.75 mol), dichloromethane (4V) and 0.1 ml N,N'-dimethylformamide were mixed, the temperature was controlled at 0~5°C, and oxalyl chloride (95.5 mL, 1.12 mol) was added dropwise. The concentrated acyl chloride was dissolved in methyl tert-butyl ether (200 mL), the reaction temperature was controlled at -5~0 °C, and it was set aside.

[0042] A tetrahydrofuran solution of trimethylsilyldiazomethane (2.0 M, 750 mL, 1.5 mol) was added dropwise to the above-mentioned acyl chloride solution. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the monitoring reaction was completed, the reaction solution was poured into 250 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 200 ml of tetrahydrofuran, slowly added to 100 ml of concentrated hydrochloric acid, and stirred at -10~0°C for more than 1 hour. After the reaction was completed, the reaction was quenched with 250 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 88% and a purity of 85.7% as determined by HPLC.

[0043] Example 7: The third synthesis method of compound 2a

[0044] Compound 1c (0.75 mol), dichloromethane (4V) and triethylamine (0.825 mol) were mixed, the temperature was controlled at 0~5℃, isobutyl chloroformate (0.8 mol) was added dropwise, and the temperature was raised to room temperature after 2 hours of reaction. TLC was used to track the reaction until it was complete. Purified water 2V was added to wash twice, the organic phase was retained, and dried over sodium sulfate. After the filtrate was concentrated, tetrahydrofuran (4V) was added to dissolve it to obtain a tetrahydrofuran solution of the mixed anhydride intermediate, which was cooled to 0~5℃.

[0045] A tetrahydrofuran solution of trimethylsilyldiazomethane (2.0 M, 750 mL, 1.5 mol) was added dropwise to the tetrahydrofuran solution of the above-mentioned mixed anhydride intermediate. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the monitoring reaction was completed, the reaction solution was poured into 250 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 200 ml of tetrahydrofuran, slowly added to 100 ml of concentrated hydrochloric acid, and stirred at -10~0°C for more than 1 hour. After the reaction was completed, the reaction was quenched with 250 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 91% and a purity of 86.2% as determined by HPLC.

[0046] Example 8: The fourth synthesis method of compound 2a

[0047] Compound 1e (0.75 mol) and thionyl chloride (1.12 mol) were added to a 2L flask, heated under reflux for 2 hours, and the excess thionyl chloride was removed by distillation under reduced pressure with toluene three times, with 50 ml of toluene used each time. The acyl chloride obtained after concentration was dissolved in methyl tert-butyl ether (200 mL), and the reaction temperature was controlled at -5~0°C. The acyl chloride methyl tert-butyl ether solution obtained in the above reaction was set aside.

[0048] Dissolve potassium hydroxide (1.5 mol) solid in 210 ml water. After complete dissolution, add 750 ml methyl tert-butyl ether. Place the mixture in a 1L three-necked flask, cool to -5~0℃, and add the precursor 1-methyl-3-nitro-1-nitrosoguanidine (1.5 mol) in batches. At this time, the methyl tert-butyl ether layer gradually turns yellow. After N-methyl-N-nitroso-p-toluenesulfonamide is added and dissolved completely, stirring can be stopped and the upper methyl tert-butyl ether phase can be carefully poured into a constant pressure funnel for use.

[0049] The diazomethane (2.0 M, 750 mL, 1.5 mol) methyl tert-butyl ether solution was slowly added dropwise to the above-mentioned acyl chloride methyl tert-butyl ether solution, and the temperature was controlled at 0~10°C. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the reaction was monitored, the reaction solution was poured into 250 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 200 ml of tetrahydrofuran, slowly added to 100 ml of concentrated hydrochloric acid, and stirred at -10~0°C for more than 1 hour. After the reaction was completed, the reaction was quenched with 250 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 90% and a purity of 98.5% as determined by HPLC.

[0050] Example 9: The fifth synthesis method of compound 2a

[0051] Compound 1a (0.75 mol), dichloromethane (4V) and triethylamine (0.825 mol) were mixed, the temperature was controlled at 0~5℃, isobutyl chloroformate (0.8 mol) was added dropwise, and the temperature was raised to room temperature after 2 hours of reaction. TLC was used to track the reaction until it was complete. Purified water 2V was added to wash twice, the organic phase was retained, and dried over sodium sulfate. After the filtrate was concentrated, methyl tert-butyl ether (4V) was added to dissolve to obtain the activated mixed anhydride of compound 1a, and the mixture was cooled to 0~5℃.

[0052] Dissolve potassium hydroxide (1.5 mol) solid in 210 ml water. After complete dissolution, add 750 ml of methyl tert-butyl ether. Place the mixture in a 1L three-necked flask, cool to -5~0℃, and add the precursor N-methyl-N-nitroso-p-toluenesulfonamide (1.5 mol) in batches. At this time, the methyl tert-butyl ether layer gradually turns yellow. After N-methyl-N-nitroso-p-toluenesulfonamide is completely added and dissolved, stop stirring and carefully pour the upper methyl tert-butyl ether phase into a constant pressure funnel for use to obtain a methyl tert-butyl ether solution of diazomethane.

[0053] The diazomethane (2.0 M, 750 mL, 1.5 mol) methyl tert-butyl ether solution was slowly added dropwise to the activated mixed anhydride of the above-mentioned compound 1a, and the temperature was controlled at 0~10°C. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the monitoring reaction was completed, the reaction solution was poured into 250 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 200 ml of tetrahydrofuran, slowly added to 100 ml of concentrated hydrochloric acid, and stirred at -10~0°C for more than 1 hour. After the reaction was completed, the reaction was quenched with 250 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 95% and a purity of 98.7% as determined by HPLC.

[0054] Example 10: The sixth synthesis method of compound 2a

[0055] Add compound 1b (0.5 mol) and thionyl chloride (54 mL, 0.75 mol) to a 2L flask, heat and reflux for 2 hours, remove the excess thionyl chloride with toluene under reduced pressure three times, 50 ml of toluene each time. Dissolve the concentrated acyl chloride in methyl tert-butyl ether (200 mL), control the reaction temperature at -5~0 °C, and set aside.

[0056] Dissolve potassium hydroxide (1.0 mol) solid in 140 ml water. After complete dissolution, add 500 ml of methyl tert-butyl ether. Place the mixture in a 1L three-necked flask, cool to -5~0℃, and add the precursor N-methyl-N-nitroso-p-toluenesulfonamide (1.0 mol) in batches. At this time, the methyl tert-butyl ether layer gradually turns yellow. After N-methyl-N-nitroso-p-toluenesulfonamide is completely added and dissolved, stop stirring and carefully pour the upper methyl tert-butyl ether phase into a constant pressure funnel for use to obtain a methyl tert-butyl ether solution of diazomethane.

[0057] The diazomethane (2.0 M, 500 mL, 1.0 mol) methyl tert-butyl ether solution was slowly added dropwise to the above-mentioned acyl chloride methyl tert-butyl ether solution, and the temperature was controlled at 0-10 °C. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the reaction was monitored, the reaction solution was poured into 400 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 150 ml of tetrahydrofuran, slowly added to 125 ml of concentrated hydrochloric acid, and stirred at -10-0 °C for more than 1 hour. After the reaction was completed, the reaction was quenched with 400 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane with a yield of 90% and a purity of 97.6% as determined by HPLC.

[0058] Example 11: Synthesis of Compound 2f

[0059] Compound 1f (0.5 mol), dichloromethane (4V) and triethylamine (0.55 mol) were mixed, the temperature was controlled at 0~5 ℃, isobutyl chloroformate (0.6 mol) was added dropwise, and the temperature was raised to room temperature after 2 hours of reaction. TLC was followed until the reaction was complete. Purified water 2V was added to wash twice, the organic phase was retained, and dried over sodium sulfate. After the filtrate was concentrated, methyl tert-butyl ether (4V) was added to dissolve to obtain the activated mixed anhydride mixture of compound 1f, which was cooled to 0~5 ℃.

[0060] Dissolve potassium hydroxide (1.0 mol) solid in 140 ml water. After complete dissolution, add 500 ml of methyl tert-butyl ether. Place the mixture in a 1L three-necked flask, cool to -5~0℃, and add the precursor N-methyl-N-nitroso-p-toluenesulfonamide (1.0 mol) in batches. At this time, the methyl tert-butyl ether layer gradually turns yellow. After N-methyl-N-nitroso-p-toluenesulfonamide is completely added and dissolved, stop stirring and carefully pour the upper methyl tert-butyl ether phase into a constant pressure funnel for use to obtain a methyl tert-butyl ether solution of diazomethane.

[0061] The diazomethane (2.0 M, 500 mL, 1.0 mol) methyl tert-butyl ether solution was slowly added dropwise to the activated mixed anhydride of the above compound 1f, and the temperature was controlled at 0~10 °C. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the reaction was monitored, the reaction solution was poured into 400 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure to obtain an oily liquid. The oily liquid was dissolved in 150 ml of tetrahydrofuran, slowly added to 125 ml of concentrated hydrochloric acid, and stirred at -10~0 °C for more than 1 hour. After the reaction was completed, the reaction was quenched with 400 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2f was obtained by slurrying with n-hexane with a yield of 93% and a purity of 98.2% as determined by HPLC. Mass Spectrometry MS / [M+H] + :187.6, 1 H NMR (400 MHz, DMSO-d6) δ : 9.78 (s,1H), 9.29 (s, 1H), 7.54 (d, J =7.2 Hz 2H), 6.83 (d, J =7.2 Hz 1H), 4.80 (s,2H).

[0062] Embodiment 12:

[0063] Add m-hydroxybenzoic acid (1 mol) and dichloromethane (4V) to a 2L flask, and add N,N'-carbonyldiimidazole (1.2 eq.) while stirring. After adding the materials, stir and react at room temperature for 5 hours. The solution becomes clear. TLC shows that the raw material reacts completely. Add purified water (3V) to wash twice, dry with sodium sulfate, and concentrate under reduced pressure to a viscous liquid to obtain a crude compound 3a with a purity of 98.3%, which is ready for use.

[0064]

[0065] The crude compound 3a (1.0 mol) was dissolved in methyl tert-butyl ether (4V) and cooled to 0-5 °C.

[0066] Dissolve potassium hydroxide (2.0 mol) solid in 280 ml water. After complete dissolution, add 1000 ml of methyl tert-butyl ether. Place the mixture in a 2L three-necked flask, cool to -5~0℃, and add the precursor N-methyl-N-nitroso-p-toluenesulfonamide (2.0 mol) in batches. At this time, the methyl tert-butyl ether layer gradually turns yellow. After N-methyl-N-nitroso-p-toluenesulfonamide is completely added and dissolved, stop stirring and carefully pour the upper methyl tert-butyl ether phase into a constant pressure funnel for use to obtain a methyl tert-butyl ether solution of diazomethane.

[0067] The diazomethane (2.0 M, 1000 mL, 2.0 mol) methyl tert-butyl ether solution was slowly added dropwise to the methyl tert-butyl ether solution of 3a above, and the temperature was controlled at 0-10 °C. After the addition was completed, the reaction temperature was returned to room temperature and the reaction was continued to stir for 1 hour. After the reaction was monitored, the reaction solution was poured into 400 ml of saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried with magnesium sulfate, filtered and the solvent was removed by vacuum distillation to obtain an oily liquid. The oily liquid was dissolved in 300 ml of tetrahydrofuran, slowly added to 250 ml of concentrated hydrochloric acid, and stirred at -10-0 °C for more than 1 hour. After the reaction was completed, the reaction was quenched with 800 ml of ice water, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by n-hexane slurrying with a yield of 92% and a purity of 98.2% as determined by HPLC.

[0068] Example 13: Seventh Synthesis Method of Compound 2a

[0069] Compound 1a (0.75 mol), dichloromethane (4V) and triethylamine (0.825 mol) were mixed, the temperature was controlled at 0~5℃, isobutyl chloroformate (0.8 mol) was added dropwise, and the temperature was raised to room temperature after 2 hours of reaction. TLC was followed until the reaction was complete. Purified water 2V was added to wash twice, the organic phase was retained, dried over sodium sulfate, the filtrate was concentrated, methyl tert-butyl ether (4V) was added to dissolve, and the activated mixed anhydride mixture of compound 1a was obtained, and cooled to -20℃.

[0070] The precursor N-methyl-N-nitroso-p-toluenesulfonamide (1.5 mol) was dissolved in N,N'-dimethylacetamide, and the temperature was controlled at 0~5°C; potassium hydroxide (1.5 mol) solid was dissolved in 210 ml water, and after complete dissolution, it was added dropwise to the above diazomethane precursor solution, and the temperature was controlled at 0~10°C. At the same time, the generated diazomethane gas was passed into the activated mixed anhydride of compound 1a through a nitrogen flow, and the temperature was controlled at -20 ~ -10°C; after the addition of the alkali solution, the reaction was continued for 2 hours. After the monitoring reaction was completed, 100 ml of concentrated hydrochloric acid was slowly added and stirred at -10~0°C for more than 1 hour. After the reaction was completed, 250 ml of ice water was used to quench the reaction, the organic phase was separated, the aqueous phase was extracted three times with methyl tert-butyl ether, the organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a slurry solid. Compound 2a was obtained by slurrying with n-hexane, with a yield of 96% and a purity of 98.9% detected by HPLC.

[0071] The above description is only a preferred embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims

1. A method for synthesizing a phenylephrine intermediate derivative, characterized in that: include, The compound of formula 1, , mixing the compound of formula 1 with a carboxylic acid activating reagent, controlling the temperature, adding a diazo reagent to react, and then adding hydrogen chloride to obtain a compound of formula 2; ； The R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or substituted ester, substituted or unsubstituted heterocyclic group; Said R2 is selected from hydroxyl group and hydrogen; The n is selected from an integer of 0 to 2.

2. The method for synthesizing the intermediate derivative of phenylephrine according to claim 1, characterized in that: The R1 is selected from alkoxy, the alkoxy structure is -O(CO)R a , the R a is selected from substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl, and substituted or unsubstituted aryl.

3. The method for synthesizing a phenylephrine intermediate derivative according to any one of claims 1 or 2, characterized in that: The R1 and R2 are located at the ortho position, meta position, or para position.

4. The method for synthesizing the intermediate derivative of phenylephrine according to claims 1 to 3, characterized in that: The carboxylic acid activating agent is selected from N, N'-carbonyldiimidazole, the compound of formula 1 is mixed with N, N'-carbonyldiimidazole, and the temperature is controlled to obtain a compound of formula 3, such as: ； A diazo reagent is then added to react, and then hydrogen chloride is added to obtain a compound of formula 2; 。 5. The method for synthesizing the intermediate derivative of phenylephrine according to any one of claims 1 to 4, characterized in that: The hydrogen chloride is selected from hydrogen chloride gas, hydrogen chloride organic solution, and hydrogen chloride aqueous solution.

6. The method for synthesizing the intermediate derivative of phenylephrine according to any one of claims 1 to 5, characterized in that: The temperature of the temperature control is -5~5°C, preferably 0°C.

7. The method for synthesizing the intermediate derivative of phenylephrine according to claim 1, characterized in that: The carboxylic acid activating agent is selected from one of thionyl chloride, oxalyl chloride and alkyl chloroformate.

8. The method for synthesizing the intermediate derivative of phenylephrine according to claim 7, characterized in that: The carboxylic acid activating agent is selected from alkyl chloroformate, the compound of formula 1 is mixed with an organic base, and then the alkyl chloroformate is added, and the organic base is selected from triethylamine.

9. The method for synthesizing the phenylephrine intermediate derivative according to any one of claims 1 to 8, characterized in that: The diazo reagent is selected from trimethylsilyldiazomethane and diazomethane.

10. The method for synthesizing the intermediate derivative of phenylephrine according to claim 9, characterized in that: The diazo reagent is an organic solution of diazomethane or a diazomethane / nitrogen mixture. The organic solution of diazomethane is prepared as follows: S1: Alkaline aqueous solution is mixed with organic solvent, and the temperature is controlled. S2: adding 1-methyl-3-nitro-1-nitrosoguanidine or N-methyl-N-nitroso-p-toluenesulfonamide in batches, separating the liquids to obtain an organic phase, and obtaining an organic phase of diazomethane; The diazomethane / nitrogen mixed gas configuration method is: S1: 1-methyl-3-nitro-1-nitrosoguanidine or N-methyl-N-nitroso-p-toluenesulfonamide is mixed with an organic solvent and the temperature is controlled. S2: After adding the aqueous solution of alkali dropwise, high-purity nitrogen is bubbled to form a diazomethane / nitrogen mixed gas.

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