Pillocarpine intermediate compounds and methods for preparing them
A novel method for synthesizing pyrocarpine intermediate through a series of reactions addresses the inefficiencies of current pilocarpine synthesis, achieving high purity and yield suitable for industrial production.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- ZHEJIANG AUSUN PHARMACEUTICAL CO LTD
- Filing Date
- 2024-04-11
- Publication Date
- 2026-04-14
AI Technical Summary
Current methods for synthesizing pilocarpine are lengthy, utilize hazardous or expensive materials, and have low yields, making them inconvenient for industrial production.
A method involving a series of reactions using specific halogenating, oxidizing, and azidation agents, followed by reduction and oxidative desulfurization steps, to produce a novel pyrocarpine intermediate with high purity and yield, suitable for industrial production.
The method achieves a high overall yield of up to 99.9% purity, making it suitable for industrial production of pilocarpine.
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Abstract
Description
Technical Field
[0001] The present disclosure relates to the field of pharmaceutical chemistry. More particularly, the present disclosure relates to intermediate compounds for synthesizing pilocarpine and methods for preparing such intermediate compounds.
Background Art
[0002] Glaucoma is an eye disease in which intraocular pressure intermittently or continuously increases. Persistent ocular hypertension can damage various tissues of the eye and visual functions. There is a possibility of complete loss of the visual field and blindness if treatment is not timely.
[0003] Pilocarpine is an alkaloid extracted from the leaves of Pilocarpus jaborandi Holmes and Pilocarpus microphyllus Stapf of the genus Pilocarpus, and has the effect of mimicking acetylcholine.
[0004]
Chemical Formula
[0005] Pilocarpine is useful in the treatment of primary glaucoma such as open-angle glaucoma and closed-angle glaucoma. Compared with physostigmine, pilocarpine has a mild and short-lived effect, and its aqueous solution is more stable. Pilocarpine can also be used for hypofunction of the salivary gland, and its oral tablet SALAGEN can relieve dry mouth. Furthermore, pilocarpine can also be used for pupillary constriction during cataract intraocular lens implantation and symptomatic treatment of atropine drug poisoning. Currently, pharmaceutical pilocarpine is isolated and extracted from plants. However, with the increasing requirements for environmental protection, extraction from plants is becoming increasingly difficult. Furthermore, when obtaining pilocarpine by chemical synthesis, there are still many difficulties in currently known methods.
[0006] From the literature Tetrahedron, 1972, 28, 967-972, and patent applications JP03161481 and US 5182198, it is clear that current methods for synthesizing pilocarpine involve lengthy pathways, utilize hazardous or expensive materials such as metallic sodium and the noble metal rhodium, and employ two enzymatic hydrolysis processes. However, the enzymes are expensive, require large quantities, and yields low resolutions; all of these are highly inconvenient for industrial production and significantly increase the cost of industrial production.
[0007] [ka]
[0008] Therefore, a simple and efficient method for preparing pilocarpine became key to solving the problem of industrial production of pilocarpine. [Overview of the Initiative] [Problems that the invention aims to solve]
[0009] The object of this disclosure is to overcome the shortcomings of the prior art and to provide a method for preparing a novel pyrocarpine intermediate, namely the compound of formula I, and its use in the preparation of pyrocarpine. This method has advantages such as mild reaction conditions, a simple reaction process, convenient operation, high overall yield of the target product, and a purity of up to 99.9% of the target product, making it particularly suitable for industrial production. [Means for solving the problem]
[0010] In a first aspect, the present disclosure relates to a method for preparing a compound of formula V, Step 1: The compound of formula II is reacted with a halogenating reagent, and then hydrolyzed to obtain the compound of formula III. Step 2: A step of reacting the compound of formula III with an oxidizing agent to obtain the compound of formula IV, Step 3: The step of reacting the compound of formula IV with an azide reagent to obtain the compound of formula V.
[0011] [ka]
[0012] (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) This provides a method that includes this.
[0013] In one embodiment, the halogenating reagent in step 1 is selected from one of chlorine, NCS, trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin, lithium chloride, sodium chloride, potassium chloride, tetrabutylammonium chloride, bromine, NBS, 1,3-dibromo-5,5-dimethylhydantoin, tribromoisocyanuric acid, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, iodine, 1,3-diiodo-5,5-dimethylhydantoin, lithium iodide, sodium iodide, potassium iodide, and tetrabutylammonium iodide, or from a combination of two or more of the above halogenating reagents.
[0014] In one embodiment, the reaction solvent in step 1 is selected from one of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, and acetone, or from a combination of two or more of the above reaction solvents.
[0015] In one embodiment, the oxidizing agent in step 2 is selected from one of Dess Martin periodinane, hydrogen peroxide, Jones reagent, PCC, PDC, and Swahn reagent, or a combination of two or more of the above oxidizing agents.
[0016] In one embodiment, the azidation reagent in step 3 is selected from one of sodium azide, trimethylsilyl azide, diphenylphosphoryl azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidinium azide, and ethyl azidoacetate, or a combination of two or more of the above azidation reagents.
[0017] In one embodiment, the reaction solvents in steps 2 and 3 are selected from one of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, and acetone, or a combination of two or more of the above reaction solvents.
[0018] In a second aspect, the present disclosure provides a method for preparing a compound of formula I, comprising: Step 4: subjecting a compound of formula V and a reducing agent to a reduction reaction to obtain a compound of formula VI; Step 5: reacting the compound of formula VI with methyl isothiocyanate to obtain a compound of formula VII or a salt thereof; Step 6: subjecting the compound of formula VII to oxidative desulfurization to obtain a compound of formula I.
[0019]
Chemical formula
[0020] (where R is H or ethyl) A method including the above steps is provided. In one embodiment, the reduction reaction in step 4 is a catalytic hydrogenation-reduction reaction or a reduction reaction using a reducing agent, in which a combination of catalyst and reducing agent is used, the catalyst being selected from Ni, Pd / C, Pt / C, PtO2, barium sulfate-supported palladium or any combination thereof, and the reducing agent being selected from hydrogen, ammonium chloride, formic acid, ammonium formate or any combination thereof; the reducing agent used in the reduction reaction using a reducing agent is selected from one of sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, Red-Al and lithium aluminum hydride, or a combination of two or more of the above reducing agents.
[0021] In one embodiment, the salt in step 5 is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, or nitrate. In one embodiment, the oxidizing agent in step 6 is selected from hydrogen peroxide, Jones reagent, or sodium nitrite.
[0022] In one embodiment, the reaction solvent in steps 4, 5, and 6 is selected from one or more combinations thereof from methanol, ethanol, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, and acetone.
[0023] In a third aspect, the disclosure provides a method for preparing pilocarpine or its hydrochloride or nitrate. For compounds of formula I where R is ethyl (referred to as compounds of formula I'), this method includes the step of forming a salt of the compound of formula I' and crystallizing it to obtain the hydrochloride or nitrate of pilocarpine.
[0024] [ka]
[0025] In one embodiment, hydrochloric acid or pyrocarpine nitrate is obtained by dissolving the compound of formula I' in an alcohol reagent and recrystallizing it after adding hydrochloric acid or nitric acid. The alcohol solvent is selected from, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, or any combination thereof.
[0026] For compounds of formula I where R is H (referred to as compounds of formula I''), this method includes the step of reacting the compound of formula I'' with the halogenating reagent CH3CH2X to obtain a compound of formula I' where R is ethyl, and then forming a salt and crystallizing the compound of formula I' to obtain the hydrochloride or nitrate of pilocarpine.
[0027] [ka]
[0028] In certain embodiments, the compound of formula I'' is dissolved in an organic solvent, and a strong base is added at -10 to 5°C. After the addition is complete, the mixture is stirred for 0.5 to 1.5 hours while maintaining this temperature. Ethyl bromide is then added dropwise, and the reactants are heated to 15 to 25°C and stirred for 2.0 to 3.0 hours. The reaction is quenched by adding a solution of hydrochloric acid or ammonium chloride, washed, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the compound of formula I'.
[0029] The organic solvent is selected from, for example, toluene, acetonitrile, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, and 1,4-dioxane.
[0030] The strong base is selected from, for example, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or LDA. The methods described in the first, second, and third embodiments of this application may be combined as needed. For example, the present disclosure provides a method for preparing a compound of formula I, Step 1: The compound of formula II is reacted with a halogenating reagent, and then hydrolyzed to obtain the compound of formula III. Step 2: A step of reacting the compound of formula III with an oxidizing agent to obtain the compound of formula IV, Step 3: A step of reacting the compound of formula IV with an azide reagent to obtain the compound of formula V, Step 4: A step of subjecting the compound of formula V and a reducing agent to a reduction reaction to obtain the compound of formula VI, Step 5: A step of reacting the compound of formula VI with methyl isothiocyanate to obtain the compound of formula VII or a salt thereof, Step 6: The step of subjecting the compound of formula VII to oxidative desulfurization to obtain the compound of formula I.
[0031] [ka]
[0032] (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) This relates to a method that includes the above, with the reaction conditions for each step being as described above.
[0033] In a preferred embodiment, the method further includes a step of preparing a pilocarpine hydrochloride or nitrate as described in a third embodiment of this application. In a fourth aspect, the present disclosure relates to formula V
[0034] [ka]
[0035] (In the formula, R is either H or ethyl) The present invention provides compounds or salts thereof. This disclosure also relates to Formula IV
[0036] [ka]
[0037] (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) A compound or salt thereof, The present invention provides compounds, excluding, however, compounds of the following formula IV in which R is H and X is Cl or Br, or R is ethyl and X is Cl.
[0038] [ka]
[0039] This disclosure also provides the following compounds:
[0040] [ka] [Brief explanation of the drawing]
[0041] [Figure 1] This figure shows the HPLC test results of pilocarpine hydrochloride obtained in Example 8. [Modes for carrying out the invention]
[0042] Abbreviations and other explanations used in this specification: NBS refers to N-bromosuccinimide. PCC refers to pyridinium chlorochromate.
[0043] PDC refers to pyridinium dichromate. DMSO refers to dimethyl sulfoxide. DMF refers to N,N-dimethylformamide.
[0044] LDA refers to lithium diisopropylamide. The organic solvent used is not particularly limited, as long as it is capable of dissolving the starting compound. Preferably, the organic solvent used may be selected from one or more of the following: toluene, hexane, n-heptane, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, dichloromethane, acetone, methanol, ethanol, and isopropanol.
[0045] In the above method, the reaction temperature is not particularly limited and falls within the range of conventional reaction conditions. In the method described above, conventional quenching of a reaction refers to adding aqueous solutions, ammonium chloride solutions, hydrochloric acid solutions, phosphoric acid solutions, etc., to the reaction solution to stop the reaction or interfere with the reaction system.
[0046] In the above method, the conventional extraction process refers to a process of dissolving reaction products in an organic solvent or in an aqueous phase to separate them from other substances in the reaction system or to remove impurities.
[0047] The compound of formula II is prepared by referring to the methods described in Org. Biomol. Chem., 2017, 15, 3728-3735, CN108929289 and Organic Letters, 2011, 13, 1, 118-121 or similar methods.
[0048] The methods of this disclosure are further illustrated by the following embodiments. Naturally, the following embodiments are provided solely for the purpose of enabling a better understanding of the invention and are not intended to limit the scope of the invention in any way.
[0049] Unless otherwise specified, the raw materials and reagents used in the examples of the present invention were commercially available or obtained by known methods, their purity and chiral values were measured by high-performance liquid chromatography, and the identification of the target product was confirmed by the agreement of the HPLC retention values of the standard substance.
[0050] Example 1 Preparation of compounds of formula III (where R is ethyl)
[0051] [ka]
[0052] 39 g of compound II, 53.5 g of NBS, 450 mL of acetonitrile, and 150 mL of water were added to a four-necked flask and stirred at 25°C for 12 hours. After monitoring the completion of the reaction by TLC, the reaction solution was concentrated under reduced pressure. 100 mL of water was added to the concentrate and extracted with 3 × 100 mL of methyl tert-butyl ether. The organic layers were washed once with water and evaporated to dryness to obtain 45.0 g of oily substance in 70.8% yield, which was used directly in the next step without purification.
[0053] Example 2 Preparation of compounds of formula IV (where R is ethyl)
[0054] [ka]
[0055] 27.0 g of compound III, 58.4 g of Dess-Martin periodinane, and 350 mL of dichloromethane were added to a four-necked flask and stirred at 25°C for 8 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding 200 mL of saturated NaHSO3 solution. The mixture was extracted and the layers were separated. The organic layer was washed twice with NaHCO3 solution and once with brine. After evaporation to dryness, 23.6 g of a pale yellow oily substance was obtained in 88.0% yield by column chromatography.
[0056] 1H NMR (400 MHz, CDCl3) δ 4.53 (dd, J = 9.3, 7.5 Hz, 1H), 3.87 (s, 2H), 3.79 (dd, J = 9.3, 7.5 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.86 - 2.77 (m, 1H), 2.75 - 2.65 (m, 1H), 2.22 - 2.15 (m, 1H), 1.74 - 1.68 (m, 2H), 1.01 (t, J = 6.3 Hz, 3H). Example 3 Preparation of compounds of formula V (where R is ethyl)
[0057] [ka]
[0058] Under nitrogen protection, 21.6 g of compound IV and 200 mL of acetone were added to a four-necked flask, and 8.4 g of NaN3 solid was added in several portions. The mixture was stirred at 25°C for 13 hours. After monitoring the completion of the reaction by TLC, 200 mL of water and 200 mL of ethyl acetate were added. The mixture was extracted, and the layers were separated. The organic layer was washed three times with water and evaporated to dryness to obtain 16.7 g of oily substance in 91.5% yield. This was used directly in the next step without purification.
[0059] 1 H NMR (400 MHz, CDCl3) δ 4.47 (dd, J = 9.3, 7.5 Hz, 1H), 3.93 (s, 2H), 3.72 (dd, J = 9.4, 7.5 Hz, 1H), 2.80 (dd, J = 17.7, 4.1 Hz, 1H), 2.68 - 2.50 (m, 2H), 2.12 (dt, J = 8.5, 6.1 Hz, 1H), 1.70 - 1.50 (m, 2H), 0.93 (t, J = 6.4 Hz, 3H). Example 4 Preparation of compounds of formula VI (where R is ethyl)
[0060] [ka]
[0061] 14.7 g of compound V, 12 mL of concentrated hydrochloric acid, 150 mL of methanol, and 1.5 g of 10% palladium / carbon were placed in a hydrogenation reactor and purged three times with hydrogen. The reaction mixture was stirred at 25°C for 6 hours under a hydrogen pressure of 1 kg. After monitoring the completion of the reaction by TLC, the reaction mixture was filtered and evaporated to dryness to obtain 15.2 g of crude product in 99.0% yield. This product was used directly in the next step without purification.
[0062] Example 5 Preparation of compounds of formula VII (where R is ethyl)
[0063] [ka]
[0064] 15.0 g of compound VI, 9.8 g of potassium carbonate, 16.3 g of methyl isothiocyanate, and 150 mL of 70% tetrahydrofuran (105 mL of tetrahydrofuran and 45 mL of water) were added to a four-necked flask and stirred at 25°C for 14 hours. After monitoring the completion of the reaction by TLC, the reaction product was extracted with 5 × 80 mL of dichloromethane. The organic layers were combined and evaporated to dryness to obtain 10.7 g of solid in 65.9% yield. This solid was used directly in the next step without purification.
[0065] Example 6 Preparation of compounds of formula I (where R is ethyl)
[0066] [ka]
[0067] 10.0 g of compound VII, 180 mL of water, and 20 mL of nitric acid were added to a four-necked flask, and 4.0 g of solid sodium nitrite was added under ice water. After maintaining this temperature for 0.5 hours, the reaction mixture was heated to 25°C for 3 hours. After monitoring the completion of the reaction by TLC, impurities were extracted with 2 × 80 mL of dichloromethane, and the organic layer was discarded. The aqueous layer was adjusted to pH 7-8 using aqueous ammonia and extracted with 4 × 100 mL of dichloromethane. The dichloromethane layer was combined and evaporated to dryness, and 7.49 g of liquid was obtained by column chromatography in yield 86.4% with ee = 27.2%.
[0068] 1 H NMR (500 MHz, d-DMSO) δ 9.12 (s, 1H), 7.59 (s, 1H), 4.41 (t, J = 8.2 Hz, 1H), 3.90 (t, J = 8.4 Hz, 1H), 3.80 (s, 3H), 2.99 (dd, J = 15.8, 5.1 Hz, 1H), 2.85 (dd, J = 15.9, 9.5 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.46 (dt, J = 8.9, 6.0 Hz, 1H), 1.66 - 1.57 (m, 2H), 0.93 (t, J = 7.4Hz, 3H). Example 7 Preparation of compounds of formula I (where R is ethyl)
[0069] [ka]
[0070] 1.8 g of compound I' was dissolved in 100 mL of anhydrous tetrahydrofuran, and 6 mL of LDA (2.0 M) was added dropwise in an ice bath. After the addition was complete, the reaction mixture was stirred at this temperature for 0.5 hours, and then 1.5 g of ethyl bromide was added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 2-3 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding saturated ammonium chloride solution in an ice bath, and 30 mL of ethyl acetate was added. Impurities were extracted twice. The organic phases were combined and washed with saturated brine, evaporated to dryness, and 1.5 g of the liquid was obtained by column chromatography in yield 79.4% and ee=25.6%.
[0071] Example 8 Preparation of hydrochloride compounds (where R is ethyl)
[0072] [ka]
[0073] 6.0 g of compound I (ee=27.2%), 50 mL of isopropanol, and 5 mL of concentrated hydrochloric acid were added to a four-necked flask. The reaction mixture was heated to 45-50°C and stirred at this temperature for 1-2 hours. The reaction mixture was concentrated under reduced pressure to obtain crude pilocarpine hydrochloride. Next, 30 mL of isopropanol was added, and the mixture was heated to 65-75°C and stirred at this temperature for 0.5-1.0 hours. The mixture was then slowly cooled to room temperature, filtered, and the filter cake was washed with 10 mL of isopropanol and dried to obtain 3.0 g of white pilocarpine hydrochloride.
[0074] 3.0 g of the above product was added to 30 mL of isopropanol for a second recrystallization, and after drying, 2.6 g of pilocarpine hydrochloride was obtained in an overall yield of 43.1% and ee = 99.9% (as shown in Figure 1).
[0075] 1H NMR (500 MHz, DMSO) δ 9.21 (d, J = 0.9 Hz, 1H), 7.62 (d, J = 0.9 Hz, 1H), 4.27 (dd, J = 9.1, 5.8 Hz, 1H), 3.98 (dt, J = 14.2, 7.1 Hz, 1H), 3.82 (s, 3H), 3.07 - 2.94 (m, 1H), 2.80 (dd, J = 15.4, 7.0 Hz, 2H), 2.56 (dd, J = 16.0, 11.2 Hz, 1H), 1.68 (dp, J = 14.7, 7.4 Hz, 1H), 1.58 - 1.47 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H). The specific embodiments and examples described above further illustrate in detail the object, technical solution, and beneficial effects of the present invention. Naturally, the specific embodiments and examples described above are for illustrative purposes only and are not intended to limit the scope of the disclosure of this application. Any modifications, equivalents, improvements, etc., made within the spirit and principles of the present invention shall be included within the scope of the disclosure of this application.
Claims
1. A method for preparing a compound of formula V, Step 1: The compound of formula II is reacted with a halogenating reagent, and then hydrolyzed to obtain the compound of formula III. Step 2: A step of reacting the compound of formula III with an oxidizing agent to obtain the compound of formula IV, Step 3: A step of reacting the compound of formula IV with an azide reagent to obtain the compound of formula V. 【Chemistry 1】 (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) The above method, including.
2. The method according to claim 1, wherein the halogenating reagent in step 1 is selected from one of chlorine, NCS, trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin, lithium chloride, tetrabutylammonium chloride, bromine, NBS, 1,3-dibromo-5,5-dimethylhydantoin, tribromoisocyanuric acid, lithium bromide, tetrabutylammonium bromide, iodine, 1,3-diiodo-5,5-dimethylhydantoin, lithium iodide, sodium iodide, potassium iodide, and tetrabutylammonium iodide, or from a combination of two or more of the above halogenating reagents.
3. The method according to claim 1, wherein the oxidizing agent in step 2 is selected from one of Dess Martin periodinane, hydrogen peroxide, Jones reagent, PCC, PDC, and Swahn reagent, or a combination of two or more of the above oxidizing agents.
4. The method according to claim 1, wherein the azidine reagent in step 3 is selected from one of sodium azide, azidotrimethylsilane, diphenylphosphoryl azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidinium azide, and ethyl azide, or from a combination of two or more of the above azidine reagents.
5. A method for preparing the compound of formula I, Step 4: A step of subjecting the compound of formula V and a reducing agent to a reduction reaction to obtain the compound of formula VI, Step 5: A step of reacting the compound of formula VI with methyl isothiocyanate to obtain the compound of formula VII or a salt thereof, Step 6: The step of subjecting the compound of formula VII to oxidative desulfurization to obtain the compound of formula I. 【Chemistry 2】 (In the formula, R is H or ethyl) The above method, including.
6. The reduction reaction in step 4 is either a catalytic hydrogenation-reduction reaction or a reduction reaction using a reducing agent. In the catalytic hydrogenation-reduction reaction, a combination of catalyst and reducing agent is used, and the catalysts are Ni, Pd / C, Pt / C, and PtO. ２ The method according to claim 5, wherein the reducing agent is selected from barium sulfate-supported palladium or any combination thereof, and the reducing agent is selected from hydrogen, ammonium chloride, formic acid, ammonium formate or any combination thereof; the reducing agent used in the reduction reaction using the reducing agent is selected from one of sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, Red-Al and lithium aluminum hydride, or a combination of two or more of the above reducing agents.
7. The method according to claim 5, wherein the salt in step 5 is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, or nitrate.
8. The method according to claim 5, wherein the oxidizing agent in step 6 is selected from hydrogen peroxide, Jones reagent, or sodium nitrite.
9. When R is ethyl, the compound is referred to as the compound of formula I', and the method further involves forming a salt of the compound of formula I' and crystallizing it to obtain the hydrochloride or nitrate of pilocarpine. 【Transformation 3】 The method according to claim 5, including the method described in claim 5.
10. When R is H, the compound is called formula I'', and the method further involves halogenating the compound of formula I'' with the reagent CH ３ CH ２ The process involves reacting with X, followed by salt formation and crystallization to obtain pilocarpine hydrochloride or nitrate. 【Chemistry 4】 (In the formula, X is a halogen selected from Cl, Br, or I.) The method according to claim 5, including the method described in claim 5.
11. The method according to claim 9 or 10, wherein salt formation and crystallization are carried out using hydrochloric acid or nitric acid in an alcohol solvent, for example, one of methanol, ethanol, n-propanol, isopropanol, n-butanol, or any combination thereof.
12. Step 1: The compound of formula II is reacted with a halogenating reagent, and then hydrolyzed to obtain the compound of formula III. Step 2: A step of reacting the compound of formula III with an oxidizing agent to obtain the compound of formula IV, Step 3: A step of reacting the compound of formula IV with an azide reagent to obtain the compound of formula V, Step 4: A step of subjecting the compound of formula V and a reducing agent to a reduction reaction to obtain the compound of formula VI, Step 5: A step of reacting the compound of formula VI with methyl isothiocyanate to obtain the compound of formula VII or a salt thereof, Step 6: The step of subjecting the compound of formula VII to oxidative desulfurization to obtain the compound of formula I. 【Transformation 5】 (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) The reaction conditions for steps 1 to 3 are as described in any one of claims 1 to 4. The method according to any one of claims 5 to 11.
13. Formula V 【Transformation 6】 (In the formula, R is H or ethyl) A compound or salt thereof.
14. Formula IV 【Transformation 7】 (In the formula, R is H or ethyl, and X is a halogen selected from Cl, Br, or I.) A compound or salt thereof, However, compounds of formula IV in which R is H and X is Cl or Br, or compounds of formula IV in which R is ethyl and X is Cl are excluded, the above compounds or salts thereof. 【Request Item 15】 【Chemistry 8】 A compound or a salt thereof, selected from the following.