A method for synthesizing a key intermediate of pilocarpine

Abstract

The invention discloses a method for synthesizing a key intermediate of pilocarpine. The invention provides a method for synthesizing a key intermediate of pilocarpine. The method uses 2,2-dimethyl-1,3-dioxane-5-one as a starting material, synthesizes 4-ethyl-5-oxy-2,5-dihydrofuran-3-acetic acid through Horner-Wadsworth-Emmons olefination, hydrolysis, oxidation, Wittig reaction, hydrolysis, oxidation and the like, and then synthesizes the final product according to the steps in the document "Concise Synthesis of Both Enantiomers of Pilocarpine".

Description

Technical Field

[0001] The invention belongs to the technical fields of organic synthetic chemistry and medicinal chemistry, and relates to the synthesis of pilocarpine, and in particular to a method for synthesizing a key intermediate of pilocarpine, which has a relatively simple starting raw material structure, greatly improved yield, avoids environmental pollution, is relatively economical, environmentally friendly, and has simple post-processing. Background Art

[0002] Pilocarpine (also known as pilocarpine) is a natural alkaloid with a wide range of biological activities. It was originally isolated from Pilocarpus jaborandi. Its main function is to stimulate acetylcholine receptors, thereby increasing the secretion of saliva and sweat, dilating the pupils and lowering intraocular pressure. In addition to being used to treat eye diseases such as glaucoma and dry eyes, pilocarpine is also used to treat a variety of other diseases. For example, patients with dry mouth may use an oral preparation of pilocarpine (Salagen) to stimulate salivary gland secretion. Pilocarpine is also used to treat neurological and respiratory diseases such as epilepsy and asthma. In addition, pilocarpine is also widely used in research as a compound that can stimulate neurotransmission.

[0003] The activity of pilocarpine is primarily due to its stimulation of acetylcholine receptors. It can increase saliva and sweat secretion by stimulating the M1 and M3 acetylcholine receptors, while it can decrease heart rate by stimulating the M2 acetylcholine receptor. Furthermore, pilocarpine can dilate the pupil and lower intraocular pressure, primarily through stimulation of the M3 acetylcholine receptor.

[0004] Currently, all pilocarpine on the market is extracted from plants. Since the natural content of the product is extremely low (0.12%-0.8%), it is far from meeting the demand as the application volume continues to expand. Therefore, it is of great significance to develop a chemical synthesis process for this product.

[0005] The journal Molecules 2021, 26, 3676 published a paper entitled "Concise Synthesis of Both Enantiomers of Pilocarpine" written by Theresa Schmidt et al., which introduced Figure 2The synthesis method of pilocarpine is shown. The main problem of this route is that Int-1 needs to undergo a photochemical reaction, the reaction conversion rate is low, the selectivity is poor, it is difficult to purify, and it is not easy to scale up the production. The synthesis of Int-2 and Int-2-1 requires a large amount of phosphorus pentoxide, which pollutes the environment. The synthesis of Int-3 requires metallic sodium, which has a high production risk and a low conversion rate. Among them, the main intermediate Int-4 is the key intermediate of the current route. The reaction time from Int-3 to Int-4 in this route is too long (2 days) and is difficult to control. If the time is greater than 48 hours, more than 4% of by-products will be produced. Summary of the Invention

[0006] In order to solve the defects of the current key intermediate synthesis route of pilocarpine, Int-1 needs to be subjected to a photochemical reaction, has a low reaction conversion rate, poor selectivity, is difficult to purify, and is not easy to scale up for production, and the synthesis of Int-3 requires sodium metal, has a high production risk and a low conversion rate, the present invention provides a key intermediate synthesis method of pilocarpine, which uses 2,2-dimethyl-1,3-dioxane-5-one as a starting material, and synthesizes 4-ethyl-5-oxy-2,5-dihydrofuran-3-acetic acid (( Figure 1 , (5)), and then synthesize the final product according to the steps in the literature "Concise Synthesis of Both Enantiomers of Pilocarpine".

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The present invention provides a method for synthesizing a key intermediate of pilocarpine, which comprises the following steps:

[0009] (a) The substance represented by formula (2) is oxidized with pyridine sulfur trioxide to obtain the compound represented by formula (3);

[0010] (b) the compound represented by formula (3) is subjected to a Wittig reaction to obtain a compound represented by formula (4);

[0011] (c) the compound represented by formula (4) is hydrolyzed and oxidized to obtain the compound represented by formula (5);

[0012] Among them, the compound represented by formula (2):

[0013]

[0014] The compound represented by formula (3):

[0015]

[0016] The compound represented by formula (4):

[0017]

[0018] The compound represented by formula (5):

[0019]

[0020] As a preferred embodiment of the present invention, step a) is specifically as follows: dissolving the substance represented by formula (2) in a solvent, adding N,N-diisopropylethylamine dropwise, cooling to -30°C, adding pyridine sulfur trioxide, reacting at -30 to 5°C until the reaction is complete, adding the reaction solution dropwise to water, extracting with ethyl acetate, washing with saturated sodium bicarbonate solution, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and dehydrating under reduced pressure to obtain the compound represented by formula (3); the amount of N,N-diisopropylethylamine used is 1.5 to 3.0 equivalents, and the amount of pyridine sulfur trioxide used is 1.5 to 3.0 equivalents.

[0021] As a preferred embodiment of the present invention, step (b) is specifically as follows: using tetrahydrofuran as a solvent, adding potassium tert-butoxide, cooling to -10°C, adding (methoxymethyl)triphenylphosphonium chloride, maintaining stirring at 0-10°C for 1 hour, adding the compound represented by formula (3), heating to 20-25°C and stirring to complete the reaction; dropping the reaction solution into an aqueous ammonium chloride solution, extracting with ethyl acetate, washing once with saturated brine, drying with anhydrous sodium sulfate, filtering, decompressing and drying in a 50°C water bath, and then distilling under vacuum at 50-120 Pa and a temperature of 90-100°C to obtain the compound represented by formula (4); the amount of potassium tert-butoxide is 1.0-3.0 equivalents.

[0022] As a preferred embodiment of the present invention, the amount of (methoxymethyl)triphenylphosphonium chloride used is 1.0 to 2.0 equivalents.

[0023] As a preferred embodiment of the present invention, in step (b), the reaction temperature is 0-25°C.

[0024] As a preferred embodiment of the present invention, step (c) is specifically as follows: using acetonitrile and water as solvents, adding 37% hydrochloric acid, adding iodobenzene, raising the temperature to 50°C, passing oxygen, adding dropwise the compound represented by formula (4), and then completing the reaction at 50-55°C; desolventizing, the solution is salted, impurities are extracted and washed, the aqueous phase is acidified to pH = 1 with hydrochloric acid, extracted with TBME, the organic phase is dried over anhydrous sodium sulfate, filtered, and desolventized to obtain the compound represented by (5).

[0025] As a preferred embodiment of the present invention, in step (c), the amount of hydrochloric acid used is 1.1 to 1.6 equivalents.

[0026] As a preferred embodiment of the present invention, in step (c), the amount of iodobenzene used is 0.1-0.3W.

[0027] As a preferred embodiment of the present invention, in step (c), sodium carbonate is used to adjust the pH to form salt.

[0028] As a preferred embodiment of the present invention, in step (c), the impurities are extracted and washed with dichloromethane.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1) The starting materials of the present invention have a relatively simple structure and are easily available in commercial quantities.

[0031] 2) The present invention avoids the existing synthesis routes. Int-1 requires a photochemical reaction, which has low reaction conversion rate, poor selectivity, difficulty in purification, and difficulty in scale-up production; the synthesis of Int-3 requires metallic sodium, which has high production risks and low conversion rate.

[0032] 3) Compared with other existing technologies, the product yield is greatly improved. The total yield of compound (5) synthesized by the route of the present invention is 54.6%, while the total yield of compound (5) synthesized by the existing technology is 41.3%, which is a significant improvement. The route of the present invention is simple to operate and easy to control.

[0033] 4) The present invention also avoids the problem of environmental pollution caused by the use of a large amount of phosphorus pentoxide, and is a relatively economical, environmentally friendly, simple post-processing, and convenient technical route for scaled-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is the synthesis route diagram of the present invention.

[0035] Figure 2 This is the existing synthetic route.

[0036] Figure 3 This is the NMR spectrum of compound (+-(11)). DETAILED DESCRIPTION

[0037] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0038] The present invention uses 2,2-dimethyl-1,3-dioxane-5-one as a starting material, and synthesizes 4-ethyl-5-oxy-2,5-dihydrofuran-3-acetic acid (( Figure 1 , (5)), and then synthesize the final product according to the steps in the literature "Concise Synthesis of Both Enantiomers of Pilocarpine".

[0039] The specific steps of the present invention are:

[0040] 1. The compound represented by formula (2) was synthesized according to the reference "Stereoselective Synthesis of the Stereomeric PilopylAlcohols" (By: Reimann, Eberhard; et al, Monatshefte fuer Chemie (2002), 133(10), 1285-1290).

[0041] 2. The substance represented by formula (2) is dissolved in a solvent, N,N-diisopropylethylamine is added dropwise, the temperature is lowered to -30°C, pyridine sulfur trioxide is added, and the reaction is carried out at -30 to 5°C until the reaction is completed. The reaction solution is added dropwise to water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the compound represented by formula (3);

[0042] 3. Add potassium tert-butoxide to tetrahydrofuran as the solvent, cool to -10°C, add (methoxymethyl)triphenylphosphonium chloride, maintain stirring at 0-10°C for 1 hour, add the compound represented by formula (3), raise the temperature to 20-25°C, and stir to complete the reaction. The reaction solution is dropped into an aqueous ammonium chloride solution, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dehydrated in a 50°C water bath under reduced pressure. Then, distill under vacuum at 50-120 Pa and a temperature of 90-100°C to obtain the compound represented by formula (4).

[0043] 4. Add 37% hydrochloric acid and iodobenzene to acetonitrile and water as solvents, raise the temperature to 50°C, introduce oxygen, and dropwise add the compound represented by formula (4). The reaction is then completed at 50-55°C. Remove the solvent under reduced pressure, form a salt with aqueous sodium carbonate solution, and wash out impurities with DCM. The aqueous phase is then acidified to pH = 1 with hydrochloric acid and extracted with TBME. The organic phase is dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure to obtain the compound represented by (5).

[0044] 5. The final product was synthesized according to the steps in the literature "Concise Synthesis of Both Enantiomers of Pilocarpine" to give the compound shown in (11).

[0045] Example 1

[0046] See also Figure 1 , Synthesis compound of 2-(2,2-dimethyl-[1,3]dioxane-5-ethylidene)-butyric acid methyl ester (1):

[0047] Under nitrogen protection, 150 mL of tetrahydrofuran was put into a 250 mL three-necked flask, stirred, 4.5 g (0.117 mol, 1.5 eq) of 60% sodium hydrogen phosphate was added, 27.4 g (0.115 mol, 1.5 eq) of 2-(diethyl phosphonate)-methyl butyrate was added dropwise at 20-25 ° C, and stirred at 20-25 ° C for 1 hour, 10 g (0.077 mol, 1.0 eq) of 2,2-dimethyl-1,3-dioxane-5-one was added dropwise. The reaction mixture was stirred at 20-25°C for 2 hours. The reaction was completed by GC detection. The reaction solution was added dropwise to 160 mL of 10% ammonium chloride aqueous solution, desolvated under reduced pressure in a 50°C water bath, extracted with 2 x 100 mL of ethyl acetate, dried over 10 g of anhydrous sodium sulfate, filtered, and dehydrated under reduced pressure in a 50°C water bath. The product was purified by column chromatography (n-heptane:ethyl acetate=17:3) to obtain 13.7 g of colorless liquid compound (1), with a yield of 83.0% and a purity of 96.5%.

[0048] Example 2

[0049] See also Figure 1 , Synthetic compound of 3-ethyl-4-hydroxymethyl-2(5H)-furanone (2):

[0050] 2-(2,2-Dimethyl-[1,3]dioxane-5-ethylidene)-butyric acid methyl ester (10 g, 0.0467 mol, 1.0 eq) was placed in a 250 mL three-necked flask, 100 mL (10 V) of ethanol was added, 0.42 g (0.796 mmol, 0.017 eq) of 2N hydrochloric acid was added, and the mixture was stirred at 20-23° C. for 4 hours. After GC detection, the reaction was complete. 50 mL of saturated brine was added, 0.15 g of triethylamine was added, and the mixture was placed in a 50° C. water bath and vacuum desolventized. The mixture was extracted with 3×100 mL of dichloromethane, dried over 15 g of anhydrous sodium sulfate, and filtered. The filtrate was placed in a 40° C. water bath and vacuum desolventized to obtain 6.5 g of compound (2), with a yield of 98.0% and a purity of 97.1%.

[0051] Example 3

[0052] See also Figure 1, Synthesis Compound of 4-ethyl-5-oxo-2,5-dihydrofuran-3-carbaldehyde (3):

[0053] To a 250 mL reaction flask, add 6.4 g (0.045 mol, 1.0 eq) of 3-ethyl-4-hydroxymethyl-2(5H)-furanone, 38.4 mL (6 V) of dichloromethane, and 38.4 mL (6 V) of DMSO. Replace the atmosphere with nitrogen and cool to -10-5°C. Add 14.4 g (0.111 mol, 2.5 eq) of N,N-diisopropylethylamine dropwise, controlling the temperature at -10-5°C. After complete addition, cool to -30°C and add 17.9 g (0.112 mol, 2.5 eq) of pyridine sulfur trioxide, controlling the temperature at -20-30°C. After complete addition, maintain the reaction at -5-5°C for 1 hour. Sample the reaction mixture for completion by GC. The reaction solution was added dropwise to 50 mL of water at 0-10°C, the dropping temperature was controlled at 0-10°C, 100 mL of ethyl acetate was added, the mixture was stirred and separated, and then extracted once with 50 mL of ethyl acetate. The organic phases were combined, washed once with 50 mL of saturated sodium bicarbonate solution, washed once with 50 mL of saturated brine, dried over 10 g of anhydrous sodium sulfate, filtered, and dried under reduced pressure in a 50°C water bath to obtain 6.03 g of compound (3) with a yield of 95.6% and a purity of 95.7%.

[0054] Example 4

[0055] See also Figure 1 , Synthesis compound of 4-ethyl-5-oxo-2,5-dihydrofuran-3-vinyl methyl ether (4):

[0056] Under nitrogen protection, 60 mL (10V) of tetrahydrofuran was added to a 250 mL reaction bottle, 7.2 g (0.064 mol, 1.5 eq) of potassium tert-butoxide was added, the temperature was lowered to -10 ° C, 17.2 g (0.05 mol, 1.2 eq) of (methoxymethyl) triphenylphosphonium chloride was added in batches, and the temperature was kept at 0-10 ° C and stirred for 1 hour. 6.0 g (0.043 mol, 1.0 eq) of 4-ethyl-5-oxy-2,5-dihydrofuran-3-carbaldehyde was added. After the addition was complete, the temperature was raised to 20-25 ° C and stirred for 3 hours. The reaction was completed by GC sampling. The reaction solution was added dropwise to a solution of 7 g of ammonium chloride and 40 mL of water at 0-10°C, and extracted with 2 x 50 mL of ethyl acetate. The organic phase was washed once with 50 mL of saturated brine, dried over 10 g of anhydrous sodium sulfate, filtered, and dried under reduced pressure in a 50°C water bath. The product was then distilled under vacuum at 50-120 Pa and a temperature of 90-100°C to obtain 6.1 g of compound (4) with a yield of 84.7% and a purity of 96.3%.

[0057] Example 5

[0058] See also Figure 1, Synthesis compound of 4-ethyl-5-oxo-2,5-dihydrofuran-3-acetic acid (5):

[0059] To a 250 mL reaction flask, 30 mL (5 V) of acetonitrile, 30 mL (5 V) of water, 5 g (0.051 mol, 1.4 eq) of 37% hydrochloric acid, and 0.12 g (0.2 W) of iodobenzene were added. The temperature was raised to 50° C., oxygen was introduced (70 mL / min), and a solution of 6.0 g (0.036 mol, 1.0 eq) of 4-ethyl-5-oxygen-2,5-dihydrofuran-3-vinyl methyl ether and 30 mL of acetonitrile was added dropwise over 53 minutes. After the addition was complete, the reaction was stirred at 50-55° C. for 5 hours, and the reaction was completed by GC sampling. The mixture was removed by decompression in a 50°C water bath, and a solution prepared by mixing 10 g of sodium carbonate and 50 mL of water was added dropwise. The pH was measured to be 9, and impurities were washed with 3×50 mL of DCM. The aqueous phase was acidified to pH=1 with 19 g of 37% hydrochloric acid, and extracted with 3×50 mL of TBME. The organic phase was dried over 10 g of anhydrous sodium sulfate, filtered, and removed by decompression in a 50°C water bath to obtain 5.03 g of compound (5) with a yield of 82.9% and a purity of 97.6%.

[0060] Example 6

[0061] See also Figure 1 , Synthesis compound of 4-ethyl-5-oxo-2,5-dihydrofuran-3-hexyl acetate (6):

[0062] To a 250 mL reaction flask, 5.0 g (0.029 mol, 1.0 eq) of 4-ethyl-5-oxo-2,5-dihydrofuran-3-acetic acid and 100 mL of n-hexanol (0.81 mol, 27.9 eq) were added, and the mixture was stirred. 10 mL of thionyl chloride (0.05 mol, 1.7 eq) was added dropwise. The mixture was heated and refluxed for 15 hours. The reaction was sampled and detected by GC. The mixture was desolvated in a 50°C water bath, a 50-60°C water bath, and a vacuum pressure of 50-100 Pa. The distilled residue was added dropwise to a solution of 7 g of sodium carbonate and 50 mL of water, and extracted with TBME 3×50 mL. The organic phase was dried over 10 g of anhydrous sodium sulfate, filtered, and desolvated in a 50°C water bath under reduced pressure to obtain 7.16 g of compound (6), with a yield of 97.1% and a purity of 97.2%.

[0063] Example 7

[0064] See also Figure 1 , (±)-[(3RS, 4SR)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid hexyl ester] (±-(7)):

[0065] To a 300 mL autoclave, 7.1 g (0.028 mol, 1.0 eq) of 4-ethyl-5-oxo-2,5-dihydrofuran-3-acetic acid hexyl ester, 107 mL of tetrahydrofuran (15 V), and 2.9 g of 5% Rh / Al2O3 (0.4 W) were added. The atmosphere was replaced with nitrogen and filled with hydrogen to 3.0 MPa. The mixture was stirred and heated to 70°C for 72 hours. The reaction was then sampled and tested for completion by GC. The mixture was cooled to 25°C and filtered. The filtrate was washed with water at 50°C and then desolvated under reduced pressure to obtain 7.13 g of compound ±-(7), with a yield of 99.4% and a purity of 97.0%.

[0066] Example 8

[0067] See also Figure 1 , (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid hexyl ester (+-(7))

[0068] In a pH automatic stabilizer, (±)-[(3RS, 4SR)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid hexyl ester (4.0 g, 15.6 mmol) and 260 mL of purified water were added, Lipase PS "Amano" (7.6 g) was added at 25°C, (87 mL, 0.1 N NaOH) was added dropwise, and the reaction system was kept at pH = 7 for 48 hours. The pH was then adjusted to 6.5 with 5% dilute hydrochloric acid, and the mixture was extracted with TBME (3×300 mL). The organic phase was dried over anhydrous sodium sulfate (30 g), desolvated under reduced pressure, and the residual liquid after desolvation was separated by column to obtain compound +-(7) (1.86 g, 46.5%).

[0069] Example 9

[0070] See also Figure 1 , (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid] compound (+-(8)):

[0071] In a pH automatic stabilizer, (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid hexyl ester (3.3 g, 12.9 mmol) and 150 mL of purified water were added, maintained at 25°C, and (130 mL, 0.1 N NaOH) was added dropwise to maintain the pH of the reaction system at 7 for 8 hours. The pH was then adjusted to 6.5 with 5% dilute hydrochloric acid, and the mixture was extracted with TBME (3×200 mL). The organic phase was dried over anhydrous sodium sulfate (20 g), desolvated under reduced pressure, and the residual liquid after desolvation was separated by column to obtain compound +-(8) (2.12 g, 95.6%).

[0072] Example 10

[0073] See also Figure 1, (+)-2-[(3S,4R)-4-ethyl-5-oxo-tetrahydrofuran-3-N-methoxy-N-methylacetamide synthetic compound (+-(9)):

[0074] To a 250 mL reaction bottle, add (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetic acid (2.1 g, 12 mmol), add 100 mL of ethyl acetate, cool to 0 ° C, add N-methylmorpholine (1.4 mL, 12.9 mmol, dissolved in 20 mL of ethyl acetate) dropwise, then add isobutyl chloroformate (1.6 mL, 12.2 mmol, dissolved in 3 mL of ethyl acetate) dropwise, stir for 15 minutes, add N, O-dimethylhydroxylamine salt The mixture was stirred at 0 ° C for 30 minutes, then stirred at 23 ° C for 24 hours, washed once with 5 mL of water, once with 5 mL of 10% citric acid aqueous solution, and once with 10 mL of saturated brine. It was dried over 5 g of anhydrous sodium sulfate and desolvated under reduced pressure. The residue after desolvation was separated by column to obtain compound +- (9) (2.23 g, 85.2%).

[0075] Example 11

[0076] See also Figure 1 , (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetaldehyde] (+-(10)):

[0077] To a 250 mL reaction bottle, (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-N-methoxy-N-methylacetamide (2.2 g, 10.2 mmol) was added, and 200 mL of tetrahydrofuran was added. The temperature was lowered to -45°C, and lithium aluminum hydride (0.47 g, 12.4 mmol) was added. The temperature was then raised to 20°C and stirred for 1 hour. The reaction solution was added dropwise to 20 mL of 10% aqueous ammonium chloride solution, desolvated, and extracted with TBME (4×100 mL). The organic phase was dried over 10 g of anhydrous sodium sulfate, filtered, and desolvated in a 40°C water bath under reduced pressure. The residue after desolvation was separated by column to obtain compound +-(10) (1.51 g, 94.6%).

[0078] Example 12

[0079] See also Figure 1 , Synthetic Compound of (+)-pilocarpine [(+)-1] (+-(11)):

[0080] To a 250 mL reaction bottle, (+)-2-[(3S, 4R)-4-ethyl-5-oxo-tetrahydrofuran-3-acetaldehyde (1.5 g, 9.6 mmol) was added, and powdered anhydrous potassium carbonate (4.0 g, 28.9 mmol) was added to DCM150 mL and DME150 mL. Methylamine DME solution (5 mL, 11.5 mmol) was added dropwise at 20°C, and then stirred at 20-25°C for 3 hours, and the mixture was desorbed under reduced pressure. The mixture was dissolved in water, DCM (25 mL) was added, and the solvent was removed under reduced pressure. p-Toluenesulfonylmethyl isocyanide (4.14 g, 21.2 mmol) and triethylamine (6.8 mL, 48.9 mmol) were added. The mixture was stirred at 20-25°C for 120 hours. The mixture was removed under reduced pressure in a 50°C water bath. The residue was separated by column to obtain a colorless liquid compound +-(11) (1.1 g, 55.0%) with a purity of 99.6% and an ee value of 99.1%. The sample NMR spectrum is shown in Figure 2. Figure 3 .

[0081] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a key intermediate of pilocarpine, characterized in that: The synthesis method comprises the following steps: (a) The substance represented by formula (2) is oxidized with pyridine sulfur trioxide to obtain the compound represented by formula (3); (b) the compound represented by formula (3) is subjected to a Wittig reaction to obtain a compound represented by formula (4); (c) the compound represented by formula (4) is hydrolyzed and oxidized to obtain the compound represented by formula (5); Among them, the compound represented by formula (2): The compound represented by formula (3): The compound represented by formula (4): The compound represented by formula (5):

2. The method for synthesizing a key intermediate of pilocarpine according to claim 1, wherein: Step (a) is specifically as follows: dissolving the substance represented by formula (2) in a solvent, adding N,N-diisopropylethylamine dropwise, cooling to -30°C, adding pyridine sulfur trioxide, reacting at -30 to 5°C until the reaction is completed, adding the reaction solution dropwise to water, extracting with ethyl acetate, washing with saturated sodium bicarbonate solution, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and dehydrating under reduced pressure to obtain the compound represented by formula (3); the amount of N,N-diisopropylethylamine used is 1.5 to 3.0 equivalents, and the amount of pyridine sulfur trioxide used is 1.5 to 3.0 equivalents.

3. The method for synthesizing a key intermediate of pilocarpine according to claim 1, wherein: The step (b) specifically comprises: using tetrahydrofuran as a solvent, adding potassium tert-butoxide, cooling to -10°C, adding (methoxymethyl)triphenylphosphonium chloride, maintaining stirring at 0-10°C for 1 hour, adding the compound represented by formula (3), heating to 20-25°C and stirring to complete the reaction; dropping the reaction solution into an aqueous ammonium chloride solution, extracting with ethyl acetate, washing once with saturated brine, drying with anhydrous sodium sulfate, filtering, decompressing and drying in a 50°C water bath, and then distilling under vacuum at 50-120 Pa and a temperature of 90-100°C to obtain the compound represented by formula (4); the amount of potassium tert-butoxide used is 1.0-3.0 equivalents.

4. The method for synthesizing a key intermediate of pilocarpine according to claim 3, wherein: The amount of (methoxymethyl)triphenylphosphonium chloride used is 1.0 to 2.0 equivalents.

5. The method for synthesizing a key intermediate of pilocarpine according to claim 1, wherein: In step (b), the reaction temperature is 0-25°C.

6. The method for synthesizing a key intermediate of pilocarpine according to claim 1, wherein: Step (c) is specifically as follows: using acetonitrile and water as solvents, adding 37% hydrochloric acid, adding iodobenzene, raising the temperature to 50°C, passing oxygen, adding dropwise the compound represented by formula (4), and then completing the reaction at 50-55°C; desolventizing, the solution is salted, impurities are extracted and washed, the aqueous phase is acidified to pH = 1 with hydrochloric acid, extracted with TBME, the organic phase is dried over anhydrous sodium sulfate, filtered, and desolventized to obtain the compound represented by (5).

7. The method for synthesizing a key intermediate of pilocarpine according to claim 6, wherein: In step (c), the amount of hydrochloric acid used is 1.1 to 1.6 equivalents.

8. The method for synthesizing a key intermediate of pilocarpine according to claim 6, wherein: In step (c), the amount of iodobenzene used is 0.1-0.3W.

9. The method for synthesizing a key intermediate of pilocarpine according to claim 6, wherein: In step (c), sodium carbonate is used to adjust the pH to form salt.

10. The method for synthesizing a key intermediate of pilocarpine according to claim 6, characterized in that: In step (c), the impurities are extracted and washed with dichloromethane.

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