CN107522654B

CN107522654B - Novel alpha-aminoamide derivatives and medicinal use thereof

Info

Publication number: CN107522654B
Application number: CN201610442910.4A
Authority: CN
Inventors: 史卫国; 李浩田; 樊士勇; 仲伯华
Original assignee: Institute of Pharmacology and Toxicology of AMMS
Current assignee: Institute of Pharmacology and Toxicology of AMMS
Priority date: 2016-06-21
Filing date: 2016-06-21
Publication date: 2020-09-01
Anticipated expiration: 2036-06-21
Also published as: CN107522654A

Abstract

The invention relates to a novel α -aminoamide derivative and medical application thereof, in particular to a α -aminoamide derivative shown in a structural formula I or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compounds as active ingredients, and application of the derivative or the pharmaceutically acceptable salt thereof in preparing analgesic drugs.

Description

Novel alpha-aminoamide derivatives and medicinal use thereof

Technical Field

The present invention relates to novel alpha-aminoamide derivatives or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds as active ingredients, and the use of the derivatives or pharmaceutically acceptable salts thereof for the preparation of analgesic drugs.

Background

Neuropathic pain (Neuropathic pain) is a chronic pain caused by damage or disease of the central or peripheral somatosensory nervous system, mainly manifested by spontaneous pain (persistent pain and paroxysmal pain) and induced pain (hyperalgesia and allodynia), and is characterized in that after the nervous system injury heals, the pain sense persists, and the daily life quality of a patient is seriously affected.

The neurogenic pain has wide causes, high morbidity, complex pathological mechanism and the lack of specific treatment drugs in clinic at present, which always troubles the medical field. It is estimated that only 1/4 patients have a greater than 50% relief of post-drug neuralgia and significant central system side effects. Traditional analgesics such as opioid receptor agonists show some effect only at high doses, which are addictive; although the non-steroidal anti-inflammatory drugs have no addiction, the efficacy on neuralgia is low, and the therapeutic purpose cannot be achieved. Therefore, high-efficiency and safe specific therapeutic drugs are urgently needed in clinic.

Ralfinamide is a selective Nav1.7 blocker, shows good treatment effect on various neuropathic pain animal models, and has the analgesic effect which is 20 times that of gabapentin and 80 times that of carbamazepine. The results of phase II clinical tests show that the medicine has good safety and tolerance and no addiction, and the orally administered dosage of 80-320mg/day shows obvious curative effect on various moderate and severe neuropathic pains. Is the only specific neuropathic pain treatment drug which is clinically proved to be effective in the phase II. However, the analgesic activity and target selectivity of Ralfinamide are to be further improved.

The present inventors designed to synthesize a series of novel α -aminoamide derivatives represented by structural formula I:

in structural formula I:

1.X₁when it is a nitrogen atom, X₂、X₃Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

2.X₂When it is a nitrogen atom, X₁、X₃Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

3.X₃When it is a nitrogen atom, X₁、X₂Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

4.X₁、X₂、X₃When all are carbon atoms, R₁、R₂、R₃、R₄、R₅Can be respectively or simultaneously hydrogen atom, methoxyl group, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

Biological evaluation results show that the target compound shows obvious analgesic effect on a mouse formalin model by intraperitoneal injection administration and intragastric administration, and the activity of the target compound is higher than that of a positive drug Ralfinamide.

Based on the above results, the present invention has been completed.

Disclosure of Invention

The present invention provides alpha-aminoamide compounds represented by structural formula I and non-toxic pharmaceutically acceptable salts thereof:

in structural formula I: x₁When it is a nitrogen atom, X₂、X₃Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type. X₂Is a nitrogen atomWhen, X₁、X₃Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type. X₃When it is a nitrogen atom, X₁、X₂Is a carbon atom, R₁、R₂、R₃、R₄、R₅Are each a hydrogen atom, R is a hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type. X₁、X₂、X₃When all are carbon atoms, R₁、R₂、R₃、R₄、R₅Can be respectively or simultaneously hydrogen atom, methoxyl group, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

The present invention also provides a target compound represented by formula Ia:

in the structural formula Ia, the connection position of the oxygen atom on the pyridine ring is ortho-position, meta-position or para-position, R is hydrogen atom or C₁-C₅Linear or branched alkyl groups of (a).

The present invention also provides a target compound represented by formula Ib:

in the structural formula Ib, the connection position of the oxygen atom on the pyridine ring is ortho-position, meta-position or para-position, R is hydrogen atom or C₁-C₅Linear or branched alkyl groups of (a).

The present invention also provides a target compound of formula Ic:

in the structural formula Ic, R₁、R₂、R₃、R₄、R₅Can be respectively or simultaneously hydrogen atom, methoxyl group, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

The present invention also provides a target compound represented by formula Id:

in the formula Id, R₁、R₂、R₃、R₄、R₅Can be respectively or simultaneously hydrogen atom, methoxyl group, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

The invention also provides a pharmaceutical composition containing the compounds shown in the formula I, the formula Ia, the formula Ib, the formula Ic and the formula Id and non-toxic pharmaceutically acceptable salts thereof as active ingredients and suitable excipients. These pharmaceutical compositions may be solutions, tablets, capsules or injections; these pharmaceutical compositions may be administered by injection route or orally.

The invention also provides application of the compounds shown in the formula I, the formula Ia, the formula Ib, the formula Ic and the formula Id and non-toxic pharmaceutically acceptable salts thereof as well as pharmaceutical compositions containing the compounds shown in the formula I, the formula Ia, the formula Ib, the formula Ic and the formula Id and non-toxic pharmaceutically acceptable salts thereof as active ingredients as analgesics.

Synthesizing target compound shown as formula Ia or Ib takes terephthalaldehyde (I-1) or isophthalaldehyde (I-2) as initial raw materials, and generates p-hydroxymethyl benzaldehyde (II-1) or isophthalaldehyde (II-2) through reduction reaction, wherein II-1 or II-2, N-bromosuccinimide (NBS) and triphenylphosphine (PPh)₃) The reaction is carried out to generate p-bromomethylbenzaldehyde (III-1) or m-bromomethylbenzaldehyde (III-2), III-1 or III-2 with hydroxypyridine, K₂CO₃Or Cs₂CO₃KI reaction to generate para-substituted ether intermediate (IV-1) or meta-substituted ether intermediate (IV-2), reacting IV-1 or IV-2 with α -aminoamide hydrochloride, sodium cyanoborohydride, triethylamine,

The type molecular sieve is subjected to a reductive amination reaction to obtain a target product Ia or Ib. The synthetic route is as follows:

The target compound shown as the formula Ic or Id is synthesized by taking terephthalaldehyde (I-1) or m-phthalaldehyde (I-2) as a starting material and generating p-hydroxymethylbenzaldehyde (II-1) or m-phthalaldehyde (II-2) through a reduction reaction, wherein the II-1 or II-2, N-bromosuccinimide (NBS) and triphenylphosphine (PPh)₃) Reaction to generate p-bromomethylbenzaldehyde (III-1) or m-bromomethylbenzaldehyde (III-2), III-1 or III-2, and further reacting with substituted phenol and K₂CO₃Or Cs₂CO₃KI reaction to generate para-substituted ether intermediate (IV-1) or meta-substituted ether intermediate (IV-2), reacting IV-1 or IV-2 with α -aminoamide hydrochloride, sodium cyanoborohydride, triethylamine,

The type molecular sieve is subjected to reductive amination reaction to obtain a target product Ic or Id. The synthetic route is as follows:

in the structural formula Ic, R₁、R₂、R₃、R₄、R₅Can be hydrogen atom, methoxy, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

In the formula Id, R₁、R₂、R₃、R₄、R₅Can be hydrogen atom, methoxy, ethoxy or halogen atom (F, Cl, Br), R is hydrogen atom or C₁-C₅The configuration of the carbon atom connected with R is R type or S type.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.

Example 1 Synthesis of (2S) -2- (4- (pyridin-2-yloxymethyl) benzyl) amino-propionamide (Ia-1)

Synthesis of 1.14-hydroxymethylbenzaldehyde (II-1)

A500 mL eggplant-shaped bottle was taken, 20g of terephthalaldehyde (0.15 mol; 4.0equiv), 100mL of ethanol and 150mL of tetrahydrofuran were sequentially added to the bottle, and the mixture was stirred and dissolved uniformly. Then 1.7g of sodium borohydride solid (9.3 mmol; 1.0equiv) was slowly added to the flask in one portion under ice bath conditions and reacted for more than 6h, followed by thin layer TLC spot plate and monitoring the progress of the reaction with UV analyzer (254 nm). And stopping the reaction after the point of the terephthalaldehyde raw material completely disappears, dropwise adding a 2mol/L hydrochloric acid solution prepared in advance for quenching, adjusting the pH value to 4-5, then carrying out rotary evaporation on the reaction liquid until the reaction liquid is dry, re-dissolving the obtained residue with water and ethyl acetate, and adding the re-dissolved residue into a separating funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out a drying agent, weighing about 30g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 3: 1, collecting the obtained monoaldehyde group reduction reaction product, and obtaining 17.6g of II-1 white solid with yield: 86.1 percent.

Synthesis of 1.24-bromomethylbenzaldehyde (III-1)

A500 mL eggplant-shaped bottle was peeled and 10.0g of intermediate II-1(0.073 mol; 1.0equiv) was weighed, dissolved in 150mL of methylene chloride, and then charged with 19.6g N-bromosuccinimide solid under stirring. Subsequently, triphenylphosphine solid was added to the eggplant-shaped bottle in four portions under ice-bath conditions, and a total amount of 38.5g (0.146 mol; 2.0equiv) was added, and at half an hour intervals for each portion, the ice-bath was removed after the addition of triphenylphosphine was completed, the reaction was continued at room temperature for more than 3 hours, and the progress of the reaction was monitored by a thin-layer TLC plate and an ultraviolet analyzer (254 nm). Stopping the reaction after the II-1 raw material point basically disappears, pouring the reaction solution into a beaker filled with 150ml of cold water, pouring the mixed solution of the organic phase and the aqueous phase into a separating funnel for extraction, extracting the aqueous phase with 150ml of dichloromethane, combining dichloromethane layers, and adding saturated sodium chloride aqueous solution for washing. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 15g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 99: 1, collecting the obtained benzyl alcohol hydroxyl bromination reaction product, and obtaining 8.5g of III-1 white solid with yield: 58.0 percent.

1.34 preparation of (pyridine-2-oxymethyl) -benzaldehyde (IV-1a)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.48g of 2-hydroxypyridine (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.22g of yellow solid IV-1a, and the yield is: 21.0 percent.

1.4 preparation of (2S) -2- (4- (pyridin-2-yloxymethyl) benzyl) amino-propionamide (Ia-1)

A250 mL eggplant-shaped bottle is taken, and 0.34g L-alaninamide hydrochloride (2.7 mmol; 1.0equiv), 0.13g sodium cyanoborohydride (2.2 mmol; 0.8equiv) and,

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 0.58g of intermediate IV-1a (2.7 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out desiccant, adding 4g of 60-100 mesh silica gel powder into the filtrate, rotary evaporating to dry sand, separating with silica gel column chromatography, and gradually eluting with dichloromethane and methanol (by gradient elution, the volume ratio of methanol and dichloromethane gradually increases from 0% to 5% within 50 min) to obtain final productThe compound Ia-1 was a tan solid, totaling 0.24g, in 30.6% yield. MS (ESI) m/z: (M + H +) 285.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.17-8.38(m, 2H), 7.01-7.46(m, 8H), 5.17(s, 2H), 3.54-3.72(m, 2H), 3.00-3.02(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 2 Synthesis of (2S) -2- (4- (pyridin-3-yloxymethyl) benzyl) amino-propionamide (Ia-2)

2.14 preparation of (pyridine-3-oxymethyl) -benzaldehyde (IV-1b)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.48g of 3-hydroxypyridine (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether forming reaction product, and obtaining 0.25g of yellow solid IV-1b in total, wherein the yield is as follows: 23.2 percent.

2.2 preparation of (2S) -2- (4- (pyridin-3-yloxymethyl) benzyl) amino-propionamide (Ia-2)

Adding type molecular sieve, 0.5ml triethylamine and 50ml methanol into a bottle, stirring at room temperature for reaction for 20min, and then quickly reacting0.58g of intermediate IV-1b (2.7 mmol; 1.0equiv) was added quickly, the reaction was continued for 12h by heating to 40 ℃ and the progress of the reaction was monitored by thin layer TLC spot plates and UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Ia-2 is a tan solid, the total amount is 0.22g, and the yield is 28.6%. MS (ESI) m/z: (M + H +) 285.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.19-8.42(m, 2H), 7.10-7.50(m, 8H), 5.15(s, 2H), 3.54-3.72(m, 2H), 3.00-3.02(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 3 Synthesis of (2S) -2- (4- (pyridin-3-yloxymethyl) benzyl) amino-propionamide (Ia-3)

3.14 preparation of (pyridine-4-oxymethyl) -benzaldehyde (IV-1c)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.48g of 4-hydroxypyridine (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.21g of yellow solid IV-1c in total, wherein the yield is as follows: 19.8 percent.

Preparation of (2S) -2- (4- (pyridin-4-yloxymethyl) benzyl) amino-propionamide (Ia-3)

Type molecular sieves, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 0.58g of intermediate IV-1c (2.7 mmol; 1.0equiv), heated to 40 deg.C and allowed to continue reacting for 12h, followed by thin layer TLC spotting, and monitoring the progress of the reaction with an ultraviolet analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Ia-3 is a tan solid, the total amount is 0.22g, and the yield is 28.6%. MS (ESI) m/z: (M + H +) 285.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.19-8.42(m, 2H), 7.10-7.50(m, 8H), 5.15(s, 2H), 3.54-3.72(m, 2H), 3.00-3.02(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 4 Synthesis of (2S) -2- (3- (pyridine-2-oxymethyl) benzyl) amino-propionamide (Ib-1)

Preparation of 4.13-hydroxymethylbenzaldehyde (II-2)

A500 mL eggplant-shaped bottle was taken, 20g of isophthalaldehyde (0.15 mol; 4.0equiv), 100mL of ethanol and 150mL of tetrahydrofuran were sequentially added to the bottle, and the mixture was stirred and dissolved uniformly. Then 1.7g of sodium borohydride solid (9.3 mmol; 1.0equiv) was slowly added to the flask in one portion under ice bath conditions and reacted for more than 6h, followed by thin layer TLC spot plate and monitoring the progress of the reaction with UV analyzer (254 nm). And stopping the reaction after the point of the terephthalaldehyde raw material completely disappears, dropwise adding a 2mol/L hydrochloric acid solution prepared in advance for quenching, adjusting the pH value to 4-5, then carrying out rotary evaporation on the reaction liquid until the reaction liquid is dry, re-dissolving the obtained residue with water and ethyl acetate, and adding the re-dissolved residue into a separating funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out a drying agent, weighing about 30g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 3: 1, collecting the obtained monoaldehyde group reduction reaction product, and obtaining 16.4g of II-2 white solid with yield: 80.2 percent.

Preparation of 4.23-bromomethylbenzaldehyde (III-2)

A500 mL eggplant-shaped bottle is taken, 10.0g of intermediate II-2(0.073 mol; 1.0equiv) is weighed out after peeling, 150mL of dichloromethane is added to dissolve 1b, and 19.6g N-bromosuccinimide solid is added under stirring. Subsequently, triphenylphosphine solid was added to the eggplant-shaped bottle in four portions under ice-bath conditions, and a total amount of 38.5g (0.146 mol; 2.0equiv) was added, and at half an hour intervals for each portion, the ice-bath was removed after the addition of triphenylphosphine was completed, the reaction was continued at room temperature for more than 3 hours, and the progress of the reaction was monitored by a thin-layer TLC plate and an ultraviolet analyzer (254 nm). Stopping the reaction after the II-2 raw material point basically disappears, pouring the reaction solution into a beaker filled with 150ml of cold water, pouring the mixed solution of the organic phase and the aqueous phase into a separating funnel for extraction, extracting the aqueous phase with 150ml of dichloromethane, combining dichloromethane layers, and adding saturated sodium chloride aqueous solution for washing. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 15g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 99: 1, collecting the obtained benzyl alcohol hydroxyl bromination reaction product, and obtaining 6.8g of III-2 white solid with yield: 46.8 percent.

4.3 preparation of 33- (pyridine-2-oxymethyl) -benzaldehyde (IV-2a)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.48g of 2-hydroxypyridine (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.27g of yellow solid IV-2a, and the yield is: 25.2 percent.

4.4 preparation of (2S) -2- (3- (pyridin-2-yloxymethyl) benzyl) amino-propionamide (Ib-1)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 0.58g of intermediate IV-2a (2.7 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with equal volume of ethyl acetate,the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ib-1 which is a tan solid, wherein the total amount is 0.24g, and the yield is 30.6%. MS (ESI) m/z: (M + H +) 285.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.06-8.31(m, 2H), 7.08-7.51(m, 8H), 5.13(s, 2H), 3.50-3.73(m, 2H), 3.00-3.03(m, 1H), 1.16(d, 3H, J ═ 6.7Hz).

Example 5 Synthesis of (2S) -2- (3- (pyridine-3-oxymethyl) benzyl) amino-propionamide (Ib-2)

Preparation of 13- (pyridine-3-oxymethyl) -benzaldehyde (IV-2b)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.48g of 3-hydroxypyridine (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.26g of yellow solid IV-2b, and the yield is as follows: 24.0 percent.

5.2 preparation of (2S) -2- (3- (pyridin-3-yloxymethyl) benzyl) amino-propionamide (Ib-2)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 0.58g of intermediate IV-2b (2.7 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ib-2 which is a tan solid, wherein the total amount is 0.22g, and the yield is 28.6%. MS (ESI) m/z: (M + H)⁺)285.2, respectively; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.98-8.29(m, 2H), 7.09-7.50(m, 8H), 5.13(s, 2H), 3.50-3.73(m, 2H), 3.00-3.03(m, 1H), 1.12(d, 3H, J ═ 6.7Hz).

Example 6 Synthesis of (2S) -2- (3- (pyridin-4-yloxymethyl) benzyl) amino-propionamide (Ib-3)

6.13 preparation of (pyridine-4-oxymethyl) -benzaldehyde (IV-2c)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.48g of 4-hydroxypyridine (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.24g of yellow solid IV-2c, and the yield is as follows: 22.2 percent.

Preparation of (2S) -2- (3- (pyridin-4-yloxymethyl) benzyl) amino-propionamide (Ib-3)

Type molecular sieves, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 0.58g of intermediate IV-2c (2.7 mmol; 1.0equiv), heated to 40 deg.C and allowed to continue reacting for 12h, followed by thin layer TLC spotting, and monitoring the progress of the reaction with an ultraviolet analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ib-3 which is a tan solid, wherein the total amount is 0.17g, and the yield is 22.5%. MS (ESI) m/z: (M + H +) 285.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d6)：7.96-8.27(m，2H)，7.09-7.50(m，8H)，5.13(s，2H)，3.50-3.73(m，2H)，3.00-3.02(m，1H)，1.13(d，3H，J＝6.7Hz)。

Example 7 Synthesis of (2S) -2- (4- (2-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-1)

7.14 Synthesis of- (2-fluorophenoxymethyl) -benzaldehyde (IV-3a)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.56g of 2-fluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed in the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.41g of light yellow solid IV-3a, and the yield is: 35.8 percent.

7.2 Synthesis of (2S) -2- (4- (2-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-1)

A250 mL eggplant-shaped bottle is taken, and 0.68g 0.68g L-alaninamide hydrochloride (5.4 mmol; 1.0equiv), 0.26g sodium cyanoborohydride (4.3 mmol; 0.8equiv) and,

Adding type molecular sieve, 0.5ml triethylamine and 50ml methanol into a bottle, stirring at room temperature for reaction for 20min, then quickly adding 1.24g intermediate IV-3a (5.4 mmol; 1.0equiv), heating to 40 deg.C, continuing reaction for 12h, spotting with thin-layer TLC, monitoring with ultraviolet analyzer (254nm)And (4) reaction progress. After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-1 which is a white solid, wherein the total amount is 0.47g, and the yield is 28.5%. MS (ESI) m/z: (M + H)⁺) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.34-7.38(m, 6H), 7.10(s, 2H), 6.77-6.91(m, 3H), 5.09(s, 2H), 3.52-3.70(m, 2H), 2.99-3.01(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 8 Synthesis of (2S) -2- (4- (3-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-2)

8.14 Synthesis of (3-fluorophenoxymethyl) -benzaldehyde (IV-3b)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.56g of 3-fluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed in the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.37g of light yellow solid IV-3b in total, wherein the yield is as follows: 32.4 percent.

Preparation of (2S) -2- (4- (3-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-2)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-3b (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-2 which is a white solid, wherein the total amount is 0.49g, and the yield is 30.1%. MS (ESI) m/z: (M + H +) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.31-7.35(m, 6H), 7.02(s, 2H), 6.81-6.93(m, 3H), 5.12(s, 2H), 3.45-3.60(m, 2H), 2.89-2.96(m, 1H), 1.21(d, 3H, J ═ 6.7Hz).

Example 9 Synthesis of (2S) -2- (4- (4-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-3)

9.14 preparation of (4-fluorophenoxymethyl) -benzaldehyde (IV-3c)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.56g of 4-fluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed in the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.42g of light yellow solid IV-3c in total, wherein the yield is as follows: 36.1 percent.

9.2 preparation of (2S) -2- (4- (4-fluorophenoxymethyl) benzyl) amino-propionamide (Ic-3)

Type molecular sieves, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-3c (5.4 mmol; 1.0equiv), heated to 40 deg.C and allowed to continue reacting for 12h, followed by thin layer TLC spotting, and monitoring the progress of the reaction with an ultraviolet analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering to remove desiccant, adding about 4g of 60-100 mesh silica gel powder into the filtrate, rotary evaporating to dry sand, separating by silica gel column chromatography, and eluting with dichloromethane and methanol (by gradient elution method, volume ratio of methanol to dichloromethane)Gradually increasing from 0% to 5% in 50 min) to give the final product Ic-3 as a white solid totaling 0.37g, 22.5% yield. MS (ESI) m/z: (M + H)⁺) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.30-7.65(m, 6H), 7.18(s, 2H), 6.84-7.00(m, 3H), 5.12(s, 2H), 3.45-3.60(m, 2H), 2.89-2.96(m, 1H), 1.21(d, 3H, J ═ 6.7Hz).

EXAMPLE 10 Synthesis of (2S) -2- (4- (2-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-4)

10.14 preparation of- (2-chlorophenoxymethyl) -benzaldehyde (IV-3d)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.64g of 2-chlorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, then heated to 58 ℃ for reflux reaction for 24 hours, a thin-layer TLC plate was placed, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.63g of light yellow solid IV-3d in total, wherein the yield is as follows: 50.8 percent.

10.2 preparation of (2S) -2- (4- (2-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-4)

A molecular sieve,0.5ml of triethylamine and 50ml of methanol were added to a flask and the reaction was stirred at room temperature for 20min, followed by the rapid addition of 1.33g of intermediate IV-3d (5.4 mmol; 1.0equiv), heating to 40 ℃ and continuing the reaction for 12h, and the progress of the reaction was monitored by thin-layer TLC spot plates and UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-4 which is a white solid, wherein the total amount is 0.69g, and the yield is 40.2%. MS (ESI) m/z: (M + H +) 318.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.34-7.38(m, 6H), 7.10(s, 2H), 6.77-6.91(m, 3H), 5.09(s, 2H), 3.52-3.70(m, 2H), 2.99-3.01(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

EXAMPLE 11 Synthesis of (2S) -2- (4- (3-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-5)

11.14 preparation of (3-chlorophenoxymethyl) -benzaldehyde (IV-3e)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.64g of 3-chlorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, then heated to 58 ℃ for reflux reaction for 24 hours, a thin-layer TLC plate was placed, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.53g of light yellow solid IV-3e, and the yield is as follows: 42.9 percent.

Preparation of (2S) -2- (4- (3-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-5)

Type molecular sieves, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.33g of intermediate IV-3e (5.4 mmol; 1.0equiv), heated to 40 deg.C and allowed to continue reacting for 12h, followed by thin layer TLC spotting, and monitoring the progress of the reaction with an ultraviolet analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-5 which is a white solid, wherein the total amount is 0.59g, and the yield is 34.3%. MS (ESI) m/z: (M + H +) 318.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.31-7.35(m, 6H), 7.02(s, 2H), 6.81-6.93(m, 3H), 5.12(s, 2H), 3.45-3.60(m, 2H), 2.89-2.96(m, 1H), 1.21(d, 3H, J ═ 6.7Hz).

EXAMPLE 12 Synthesis of (2S) -2- (4- (4-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-6)

12.14 preparation of (4-chlorophenoxymethyl) -benzaldehyde (IV-3f)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.64g of 4-chlorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, then heated to 58 ℃ for reflux reaction for 24 hours, a thin-layer TLC plate was placed, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.63g of light yellow solid IV-3f in total, wherein the yield is as follows: 51.1 percent.

Preparation of (2S) -2- (4- (4-chlorophenoxymethyl) benzyl) amino-propionamide (Ic-6)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.33g of intermediate IV-3f (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filter out the drying agent, balanceAdding about 4g of silica gel powder with 60-100 meshes into the filtrate, carrying out rotary evaporation until dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Ic-6 is a white solid, the total amount is 0.68g, and the yield is 39.5%. MS (ESI) m/z: (M + H +) 318.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.30-7.65(m, 6H), 7.18(s, 2H), 6.84-7.00(m, 3H), 5.12(s, 2H), 3.45-3.60(m, 2H), 2.89-2.96(m, 1H), 1.21(d, 3H, J ═ 6.7Hz).

Example 13 Synthesis of (2S) -2- (4- (2-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-7)

13.14 preparation of- (2-methoxyphenoxymethyl) -benzaldehyde (IV-3g)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.62g of 2-methoxyphenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv), and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.52g of light yellow solid IV-3g in total, wherein the yield is as follows: 43.0 percent.

13.2 preparation of (2S) -2- (4- (2-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-7)

A 250mL eggplant-shaped bottle is taken and 0.68g L-alaninamide hydrochloric acid is weighedSalt (5.4 mmol; 1.0equiv), 0.26g sodium cyanoborohydride (4.3 mmol; 0.8equiv),

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.31g of intermediate IV-3g (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-7 which is a white solid, wherein the total amount is 0.50g, and the yield is 29.5%. MS (ESI) m/z: (M + H +) 314.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.34-7.35(m, 4H), 7.00(s, 1H), 6.83-6.94(m, 4H), 5.00(s, 2H), 3.34-3.68(m, 5H), 2.97-3.01(m, 1H), 1.12(d, 3H, J ═ 6.7Hz).

Example 14 Synthesis of (2S) -2- (4- (3-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-8)

14.14 preparation of (4-methoxyphenoxymethyl) -benzaldehyde (IV-3h)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.62g of 4-methoxyphenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.42g of light yellow solid IV-1h in total, wherein the yield is as follows: 34.1 percent.

14.2 preparation of (2S) -2- (4- (3-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-8)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.31g of intermediate IV-3h (5.4 mmol; 1.0equiv), heated to 40 ℃ and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-8 which is a white solid, wherein the total amount is 0.54g, and the yield is 32.0%. MS (ESI) m/z: (M + H +) 314.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.35-7.37(m, 4H), 7.00(s, 1H), 6.83-6.94(m, 4H), 5.00(s, 2H), 3.34-3.68(m, 5H), 2.97-3.01(m, 1H), 1.11 (d)，3H，J＝6.7Hz).

Example 15 Synthesis of (2S) -2- (4- (4-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-9)

15.14 preparation of (4-methoxyphenoxymethyl) -benzaldehyde (IV-3i)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.62g of 4-methoxyphenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed and added to the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC spot plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.42g of light yellow solid IV-3i, and the yield is as follows: 34.1 percent.

15.2 preparation of (2S) -2- (4- (4-methoxyphenoxymethyl) benzyl) amino-propionamide (Ic-9)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.31g of intermediate IV-3i (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). Filtering the solution after the reaction is finished, and then rotatably evaporating the reaction liquid to be dryThe resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-9 which is a white solid, wherein the total amount is 0.46g, and the yield is 27.0%. MS (ESI) m/z: (M + H +) 314.2; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.35-7.36(m, 4H), 7.00(s, 1H), 6.83-6.94(m, 4H), 5.00(s, 2H), 3.34-3.68(m, 5H), 2.97-3.01(m, 1H), 1.12(d, 3H, J ═ 6.7Hz).

Example 16 Synthesis of (2S) -2- (4- (2, 3-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-10)

16.14 preparation of- (2, 3-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3j)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 2, 3-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.40g of light yellow solid IV-3j in total, wherein the yield is as follows: 32.0 percent.

16.2 preparation of (2S) -2- (4- (2, 3-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-10)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.34g of intermediate IV-3j (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-10 which is a white solid, wherein the total amount is 0.45g, and the yield is 33.3%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.26-7.56(m, 5H), 7.10(s, 2H), 6.52-6.81(m, 3H), 4.99(s, 2H), 3.40-3.65(m, 2H), 2.95-3.07(m, 1H), 1.20(d, 3H, J ═ 6.7Hz).

Example 17 Synthesis of (2S) -2- (4- (2, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-11)

17.14 preparation of- (2, 4-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3k)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 2, 4-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.39g of light yellow solid IV-3k, and the yield is: 31.0 percent.

17.2 preparation of (2S) -2- (4- (2, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-11)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3k (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering to remove desiccant, adding about 4g of 60-100 mesh silica gel powder into the filtrate, rotary evaporating to dry sand, separating with silica gel column chromatography, and gradually eluting with dichloromethane and methanol (by gradient elution, the volume ratio of methanol to dichloromethane is gradually 0% within 50minRising to 5%) to give the final product Ic-11 as a white solid, totaling 0.46g, in 34.0% yield. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.26-7.56(m, 5H), 7.12(s, 1H), 6.52-6.81(m, 3H), 4.99(s, 2H), 3.40-3.65(m, 2H), 2.95-3.07(m, 1H), 1.20(d, 3H, J ═ 6.7Hz).

EXAMPLE 18 Synthesis of (2S) -2- (4- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-12)

18.14 preparation of (3, 4-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3l)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 3, 4-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.46g of light yellow solid IV-3l in total, wherein the yield is: 36.5 percent.

Preparation of (2S) -2- (4- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-12)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to the flask and the reaction was stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3l (5.4 mmol; 1.0equiv), heating to 40 ℃ and continuing the reaction for 12h, thin layer TLC spot plates and monitoring the progress of the reaction with UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-12 which is a white solid, wherein the total amount is 0.49g, and the yield is 36.5%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 9.14(s, 2H), 7.91(s, 1H), 6.80-7.63(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.39(d, 3H, J ═ 6.7Hz).

EXAMPLE 19 Synthesis of (2S) -2- (4- (3, 5-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-13)

19.14 preparation of (3, 5-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3m)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 3, 5-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.43g of light yellow solid IV-3m in total, wherein the yield is as follows: 34.1 percent.

19.2 preparation of (2S) -2- (4- (3, 5-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-13)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.34g of intermediate IV-3m (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-13 which is a white solid, wherein the total amount is 0.50g, and the yield is 37.2%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 9.13(s, 2H), 7.88(s, 1H), 6.80-7.60(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.36(d, 3H, J ═ 6.7Hz).

EXAMPLE 20 Synthesis of (2S) -2- (4- (2, 6-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-14)

20.14 preparation of (2, 6-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3n)

A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 2, 6-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.37g of light yellow solid IV-3n in total, wherein the yield is: 29.8 percent.

20.2 preparation of (2S) -2- (4- (2, 6-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-14)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3n (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase is treated with anhydrous sodium sulfate orAnhydrous magnesium sulfate was dried overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-14 which is a white solid, wherein the total amount is 0.43g, and the yield is 31.8%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.90(s, 2H), 7.85(s, 1H), 6.89-7.65(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.36(d, 3H, J ═ 6.7Hz).

Example 21 Synthesis of (2R) -2- (4- (2, 3-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-15)

A250 mL eggplant-shaped bottle is taken, and 0.68g 0.68g D-alaninamide hydrochloride (5.4 mmol; 1.0equiv), 0.26g sodium cyanoborohydride (4.3 mmol; 0.8equiv) and,

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.34g of intermediate IV-3j (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry to prepare sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Ic-15 is a white solid, the total amount is 0.45g, and the yield is 33.3%. MS (E)SI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 1H-NMR (400MHz, DMSO-d 6): 7.26-7.56(m, 5H), 7.10(s, 2H), 6.52-6.81(m, 3H), 4.99(s, 2H), 3.40-3.65(m, 2H), 2.95-3.07(m, 1H), 1.20(d, 3H, J ═ 6.7Hz).

EXAMPLE 22 Synthesis of (2R) -2- (4- (2, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-16)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3k (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-16 which is a white solid, wherein the total amount is 0.46g, and the yield is 34.0%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.26-7.56(m, 5H), 7.12(s, 1H), 6.52-6.81(m, 3H), 4.99(s, 2H), 3.40-3.65(m, 2H), 2.95-3.07(m, 1H), 1.20(d, 3H, J ═ 6.7Hz).

EXAMPLE 23 Synthesis of (2R) -2- (4- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-17)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3l (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-17 which is a white solid, wherein the total amount is 0.49g, and the yield is 36.5%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 9.14(s, 2H), 7.91(s, 1H), 6.80-7.63(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.39(d, 3H, J ═ 6.7Hz).

EXAMPLE 24 Synthesis of (2R) -2- (4- (3, 5-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-18)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by rapid addition of 1.34g of intermediate IV-3m (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued reaction for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-18 which is a white solid, wherein the total amount is 0.50g, and the yield is 37.2%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 9.13(s, 2H), 7.88(s, 1H), 6.80-7.60(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.36(d, 3H, J ═ 6.7Hz).

EXAMPLE 25 Synthesis of (2R) -2- (4- (2, 6-difluorophenoxymethyl) benzyl) amino-propionamide (Ic-19)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3n (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction is completed, the solution is filtered, and then the reaction is carried outThe solution was evaporated to dryness and the residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of the methanol to the dichloromethane is gradually increased from 0% to 5% within 50 min), and obtaining a final product Ic-19 which is a white solid, wherein the total amount is 0.43g, and the yield is 31.8%. MS (ESI) m/z: (M + H +) 320.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 8.90(s, 2H), 7.85(s, 1H), 6.89-7.65(m, 7H), 5.08(s, 2H), 4.02-4.11(m, 2H), 3.72-3.74(m, 1H), 1.36(d, 3H, J ═ 6.7Hz).

Example 26 Synthesis of (2S) -2- (3- (2-fluorophenoxymethyl) benzyl) amino-propionamide (Id-1)

26.33 preparation of (2-fluorophenoxymethyl) -benzaldehyde (IV-4a)

A150 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.56g of 2-fluorophenol (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv), and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate which are 10: 1, collecting the obtained ether-forming reaction product to obtain 0.36g of light yellow solid IV-4a, and the yield is: 28.7 percent.

Preparation of (2S) -2- (3- (2-fluorophenoxymethyl) benzyl) amino-propionamide (Id-1)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-4a (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Id-1 is white solid, the total amount is 0.47g, and the yield is 28.5%. MS (ESI) m/z: (M + H +) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.34-7.38(m, 6H), 7.10(s, 2H), 6.77-6.91(m, 3H), 5.09(s, 2H), 3.52-3.70(m, 2H), 2.99-3.01(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 27 Synthesis of (2S) -2- (3- (3-fluorophenoxymethyl) benzyl) amino-propionamide (Id-2)

27.13 preparation of (3-fluorophenoxymethyl) -benzaldehyde (IV-4b)

A150 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.56g of 3-fluorophenol (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv), and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.37g of light yellow solid IV-4b in total, wherein the yield is as follows: 30.0 percent.

27.2 preparation of (2S) -2- (3- (3-fluorophenoxymethyl) benzyl) amino-propionamide (Id-2)

Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-4b (5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering to remove desiccant, adding 60-100 mesh silica gel powder 4g into the filtrate, rotary steaming to dry sand, separating with silica gel column chromatography, and elutingThe system is dichloromethane methanol (the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% in 50min by adopting a gradient elution method), and the obtained final product Id-2 is white solid, the total amount is 0.49g, and the yield is 30.1%. MS (ESI) m/z: (M + H)⁺) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.36-7.39(m, 6H), 7.12(s, 2H), 6.77-6.91(m, 3H), 5.09(s, 2H), 3.52-3.70(m, 2H), 2.99-3.01(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 28 Synthesis of (2S) -2- (3- (4-fluorophenoxymethyl) benzyl) amino-propionamide (Id-3)

28.13 preparation of (4-fluorophenoxymethyl) -benzaldehyde (IV-4c)

A150 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.56g of 4-fluorophenol (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv), and 40mL of N, N-dimethylformamide were weighed into the bottle, stirred uniformly, followed by heating to 40 ℃ for reaction overnight, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the residue redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of 60-100 mesh silica gel powder, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand preparation, carrying out silica gel column chromatography separation, selecting an elution system of petroleum ether and ethyl acetate of 10: 1, collecting the obtained ether-forming reaction product, and obtaining 0.39g of light yellow solid IV-4c in total, wherein the yield is as follows: 31.2 percent.

28.2 preparation of (2S) -2- (3- (4-fluorophenoxymethyl) benzyl) amino-propionamide (Id-3)

Type molecular sieves, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-4c (5.4 mmol; 1.0equiv), heated to 40 deg.C and allowed to continue reacting for 12h, followed by thin layer TLC spotting, and monitoring the progress of the reaction with an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by adopting a gradient elution method, the volume ratio of methanol to dichloromethane is gradually increased from 0% to 5% within 50 min), and the obtained final product Id-3 is a tan solid, the total amount is 0.37g, and the yield is 22.5%. MS (ESI) m/z: (M + H +) 302.1; hydrogen nuclear magnetic resonance spectroscopy: 1H-NMR (400MHz, DMSO-d 6): 7.35-7.38(m, 6H), 7.10(s, 2H), 6.77-6.91(m, 3H), 5.09(s, 2H), 3.53-3.74(m, 2H), 3.09-3.21(m, 1H), 1.13(d, 3H, J ═ 6.7Hz).

Example 29 evaluation of analgesic Effect of intraperitoneal administration (10mg/kg) in mouse formalin model

ICR (CD-1) male mice (with the weight of 22-25 g) are randomly divided into a blank group, a positive group and a test compound group, 6 mice in each group are subjected to intraperitoneal injection administration according to the dose of 10mg/kg and then are placed into a PVC observation box for adaptation. After 30min, the mouse was injected subcutaneously with 20 μ L of 2.7% formalin solution into the left hind paw, quickly returned to a PVC observation box for observation, and the time for the late-stage reaction (15-30min, phase II) mouse to lick the formalin-injected paw was recorded.

After the experiment was completed, the average of the phase II pain response time of each group of mice was calculated. The phase II pain inhibition rate of the positive drug group and the target product group can be calculated by the following formula:

drug pain inhibition (%) as ═ pain response time in blank group-pain response time in drug group)/pain response time in distilled water group × 100%

TABLE 1 intraperitoneal administration (10mg/kg) of the results

As can be seen from the results in Table 1, all compounds showed a certain analgesic activity at a dose of 10mg/kg, wherein the analgesic activity of the compounds Ib-2, Ic-4, Ic-7, Ic-8, Id-1, Id-2 administered intraperitoneally was significantly higher than that of the positive drug Ralfinamide.

Example 30 evaluation of analgesic Effect of intragastric administration (5mg/kg) in mouse formalin model

Mice were randomly divided into a blank group, a positive group, and a test compound group, 6 mice per group, and were administered by gavage at a dose of 5mg/kg, and then placed into a PVC observation box for adaptation. After 1 hour, the mouse was injected subcutaneously with 20 μ L of 2.7% formalin solution into the left hind paw, quickly returned to a PVC observation box for observation, and the time for the late-stage reaction (15-30min, phase II) mouse to lick the formalin-injected paw was recorded.

TABLE 2 results of the gavage (5mg/kg) experiment

Medicine	II phase reaction time (seconds)
		Blank group	120.0±18.6
Ib-2	80.3±11.1
		Ic-4	78.3±13.6
Ic-8	90.3±12.7
		Id-2	76.3±10.4
Ralfinamide	117.3±10.3

As can be seen from the results in Table 2, at 5mg/kg dose, the II phase reaction time of the compounds Ib-2, Ic-4, Ic-8 and Id-2 was significantly shorter than that of the blank group, and the analgesic effect of the positive drug Ralfinamide was substantially lost at 5mg/kg dose.

Example 31 evaluation of analgesic Effect of intraperitoneal administration (2mg/kg) in mouse formalin model

ICR (CD-1) male mice (with the weight of 22-25 g) are randomly divided into a blank group, a positive group and a test compound group, 6 mice in each group are administered according to the dose of 2mg/kg, and the mice are placed into a PVC observation box for adaptation after intraperitoneal injection. After 30min, the mouse was injected subcutaneously with 20 μ L of 2.7% formalin solution into the left hind paw, quickly returned to a PVC observation box for observation, and the time for the late-stage reaction (15-30min, phase II) mouse to lick the formalin-injected paw was recorded.

TABLE 3 intraperitoneal administration (2mg/kg) of the test results

Medicine	II phase reaction time (seconds)
		Blank group	125.3±16.4
Ib-2	58.7±11.7
		Ic-4	79.7±13.4
Ic-8	69.7±12.1
		Id-2	81.7±15.1
Ralfinamide	129.3±14.8

As can be seen from the results in Table 3, at the 2mg/kg dose, the II phase reaction time of the compounds Ib-2, Ic-4, Ic-8, Id-2 was significantly shorter than that of the blank group, and the analgesic effect of the positive drug Ralfinamide showed no analgesic effect at the 2mg/kg dose.

Example 32 evaluation of Nav1.7 channel blocking Effect

The experiment is based on the patch clamp technology, the selective inhibition capacity of the compound on the Nav1.7 channel is evaluated on an in vitro cell model, and the test concentration is 10 mu M.

TABLE 4 evaluation results of Nav1.7 channel blocking Effect

Medicine	Inhibition rate of inactive Nav1.7 channel
		Ralfinamide	66±5
Ib-2	34±1
		Ic-4	40±4
Ic-8	25±3
		Id-2	49±2

As can be seen from the results in Table 4, the compounds Ib-2, Ic-4, Ic-8 and Id-2 all have lower selective inhibition effect on Nav1.7 than Ralfinamide which is a positive drug in vitro, and the action mechanism is different from that of Ralfinamide, and Nav1.7 may not be the action target.

Example 33 evaluation of Nav1.8 channel blocking Effect

The experiment is based on the patch clamp technology, the selective inhibition capacity of the compound on the Nav1.8 channel is further evaluated on an in vitro cell model, and the test concentration is 10 mu M.

TABLE 5 evaluation results of Nav1.8 channel blocking Effect

As is clear from the results in Table 5, the compound Ic-8 showed a strong inhibitory activity against Nav1.8, while the other compounds showed a weak activity against Nav1.8.

Claims

1. The following compound, or a non-toxic pharmaceutically acceptable salt thereof, wherein the compound is:

2. a pharmaceutical composition comprising a compound of claim 1 or a non-toxic pharmaceutically acceptable salt thereof as an active ingredient, together with suitable excipients.

3. The pharmaceutical composition of claim 2, which is a solution, tablet or capsule.

4. The pharmaceutical composition of claim 2, which is an injection.

5. The pharmaceutical composition of claim 2, which is administered by injection route or orally.

6. Use of a compound according to claim 1 or a non-toxic pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 2 to 5 in the manufacture of an analgesic.

7. The use of claim 6 wherein the analgesic is an antineurogenic pain medication.