Preparation method of pilocarpine and intermediate compound thereof

Abstract

The invention relates to a preparation method of pilocarpine and an intermediate compound of pilocarpine. Specifically, the invention relates to key intermediates of formula (I) and formula (II) compounds for preparing pilocarpine and a preparation method of the key intermediates. According to one method, malic acid is used as a raw material and sequentially reacts with alcohol or sulfate, reacts with halogenated ethane and the like to obtain a compound shown in a formula (II), and finally reacts with a halogenating reagent to obtain a compound shown in a formula (I). According to the other method, n-butyraldehyde is used as a raw material and is subjected to a condensation reaction, an oxidation reaction, an esterification reaction and a sulfonylation reaction in sequence to obtain a compound shown in the formula (II), and finally the compound shown in the formula (I) is obtained after the compound reacts with a halogenation reagent. The preparation method disclosed by the invention has the advantages of mild reaction conditions, simple reaction process, high total yield of target products, high purity and the like, so that the preparation method is very suitable for industrial production.

Description

Preparation method of pilocarpine and its intermediate compound Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and more particularly to compounds serving as intermediates for synthesizing pilocarpine and methods for preparing these intermediates. Background Art

[0002] Glaucoma is an eye disease characterized by intermittent or persistent increases in intraocular pressure. Sustained high intraocular pressure can damage various eye structures and visual function. If left untreated, it can lead to complete loss of vision and even blindness.

[0003] Pilocarpine, also known as pilocarpine, is an alkaloid extracted from the leaves of Pilocarpus microphyllus Stapf and Pilocarpus microphyllus Stapf, which has the effect of simulating acetylcholine.

[0004] Pilocarpine can be used to treat primary glaucoma, including both open-angle and angle-closure glaucoma. Compared to physostigmine, pilocarpine has a milder, shorter-lived effect and a more stable aqueous solution. It is also used for salivary gland hypofunction, and its oral tablet, SALAGEN, can relieve dry mouth. It can also be used for miosis during cataract surgery and for the symptomatic treatment of atropine-related drug poisoning. Currently, medicinal pilocarpine is isolated and extracted from plants. However, with increasing environmental protection requirements, plant extraction is becoming increasingly difficult. Therefore, if it can be obtained through chemical synthesis, it will have higher social and economic benefits.

[0005] The chemical synthesis of pilocarpine has long been a hot topic of research. Early publications such as Tetrahedron, 1972, 28, 967-972, and patents JP03161481 and US Pat. No. 5,182,198 reported synthetic routes. This route uses furfural as a raw material and employs enzymatic resolution to produce homopilopic acid ester. However, homopilopic acid ester readily undergoes isomerization during hydrolysis of the 2-ethyl group under alkaline conditions, necessitating further enzymatic reaction to yield (+)-homopilopic acid. This method is lengthy and involves the use of hazardous materials such as sodium and precious rhodium. Furthermore, this route utilizes expensive enzymatic hydrolysis and resolution, resulting in low resolution yields. These factors significantly hinder industrial production.

[0006] The chemical properties of pilocarpine free base are unstable, and the 2-ethyl group is easily isomerized to thermodynamically stable isopilocarpine under alkaline conditions.

[0007] Helvetica Chimica Acta, 1972, vol. 55, pp. 1053-1062, attempts to synthesize racemic pilosinine using diethyl succinate via a Stobbe condensation and other steps, followed by chiral resolution to obtain the desired (+)-pilocarpine. To stereoselectively introduce the cis-2-ethyl group, a 75 / 25 mixture of pilocarpine and isopilocarpine is obtained through 2-acetylation, hydrogenation reduction, dehydration, and hydrogenation. This mixture is then purified by recrystallization using a salt formation method to obtain pure pilocarpine. This method results in extremely low resolution efficiency for the intermediate pilosinine. Furthermore, the introduction of the 2-ethyl group requires the use of platinum, resulting in low stereoselectivity and making subsequent separation and purification extremely difficult.

[0008] The subsequent literature Tetrahedron Letters. Vol. 33. No. 18.. 2441-2450. 1992 attempted to improve the synthesis of the intermediate pilosinine using Even's asymmetric alkylation reaction. However, the yield of the asymmetric alkylation step was only 50%, and the reduction reaction cycle was too long, making it difficult to industrialize.

[0009] J. AM. CHEM. SOC. 2002, 124, 8198-8199 reports that butynoic acid cis-butenediol monoester can be efficiently and enantioselectively converted to dehydrohomopilopic aldehyde (4R)-(Z)-dehydrohomopilopic aldehyde under the catalysis of rhodium metal and a chiral phosphine ligand. Homopilopic aldehyde is then catalytically hydrogenated to obtain homopilopic aldehyde, which then undergoes a [3+2] cycloaddition elimination reaction with p-methylsulfonylmethyl isocyanide and methylamine to obtain pilocarpine. However, this method not only requires the use of 5% noble metal rhodium, but also suffers from poor stereoselectivity of the homopilopic aldehyde obtained by hydrogenation. Furthermore, the final step of introducing a diazole heterocycle takes a very long reaction time, making it unsuitable for industrial production.

[0010] Reference Tetrahedron 65, 2009, 8283-8296 uses diethyl malonate as a starting material. It undergoes alkylation with 2-bromo-1,1-dimethoxyethane in the presence of sodium ethoxide, followed by lithium aluminum hydride reduction to yield a diol intermediate. This is followed by enzymatic esterification to yield a chiral monoalcohol, followed by Dess-Martin oxidation to the corresponding aldehyde. This aldehyde is then reacted with vinylmagnesium bromide to yield a chiral diol, which is then cyclized with carbonyldiimidazole to yield a 1,3-dioxane-2-one intermediate. This intermediate reacts in the presence of palladium and carbon monoxide to yield a chiral acetal lactone. This acetal is then deprotected, undergoes a [3+2] cycloaddition elimination reaction with p-methylsulfonylmethyl isocyanide and methylamine, and undergoes catalytic hydrogenation to yield pilocarpine nitrate. This route involves a long reaction process, and the intermediates are all oily, making purification difficult at each step. Furthermore, the cost is high due to the involvement of enzymes and two precious metal palladium and platinum catalytic reactions.

[0011] The Journal of Organic Chemistry, 1993, vol. 58, #5, pp. 1159-1166, and patent WO9221675 report a method for preparing pilocarpine hydrochloride. This method, starting from L-aspartic acid, involves protecting the amino group with a bulky protecting reagent (9-bromo-9-phenylfluorene (PhFIBr)), stereoselective alkylation, deprotection, diazotization, bromination, esterification, and then a Zn(Ag)-mediated Reformatsky reaction to yield a trisubstituted lactone intermediate. The 4-position methyl formate on the lactone ring has an α / β configuration ratio of approximately 9:1. Subsequently, hydrogenolysis, selective reduction of the carboxyl group by LiBH4, and lactonization are performed to yield pilocarpine. However, the reaction steps for preparing the compound (2S,3R)-2-bromo-3-ethylsuccinate of formula I are lengthy, the amino protection of the raw material aspartic acid requires the expensive reagent 9-bromo-9-phenylfluorene (PhFIBr), and the introduction of the protecting group requires the use of the environmentally unfriendly reagent Pb(NO3)2; in addition, the protecting group has a large molecular weight and poor atom economy; and the Reformatsky reaction for introducing the imidazole heterocycle requires the use of Zn(Ag) azide, but the preparation process of Zn(Ag) azide is cumbersome and poses safety risks in industrial production. These shortcomings severely limit the industrial production of this route.

[0012] Therefore, how to prepare the compound of formula I simply and efficiently becomes the key to solving the industrial production of pilocarpine.

[0013] Summary of the Invention

[0014] The present invention overcomes the shortcomings of prior art methods and provides intermediate compounds of Formula II and Formula I for preparing pilocarpine, as well as methods for preparing them. It also provides a method for preparing pilocarpine using these intermediates. The method of the present invention has the advantages of mild reaction conditions, a simple reaction process, and a high overall yield and high purity of the target product, making it particularly suitable for industrial production.

[0015] definition:

[0016] To interpret this specification, the following definitions will apply, and wherever appropriate, terms used in the singular may also include the plural, and vice versa. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0017] As used herein, the term "halogen" or "halo" refers to F, Cl, Br or I. Furthermore, the term "halogen-substituted" group is intended to include monohalogenated or polyhalogenated groups in which one or more same or different halogens replace one or more hydrogens in the group.

[0018] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-8 The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), n-hexyl, 2-methylpentyl and the like.

[0019] The term "halogenated C 1-8 "Alkyl" refers to the C 1-8 Alkyl, wherein one or more (e.g., 1, 2, 3, 4, 5, or 6) hydrogen atoms are replaced by halogen. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. 1-8 Examples of "alkyl" include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CF(CF3)2, etc.

[0020] The term "alkoxy" alone or in combination with other groups means a group R y -O-, where R y is an alkyl group as described above. For example, "C 1-8 "Alkoxy" means a group R y-O-, where R y is C as mentioned above 1-8 alkyl.

[0021] “C 3-8 "Cycloalkyl" refers to a cyclic saturated hydrocarbon group containing 3 to 8 ring carbon atoms, examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclobutyl, etc.

[0022] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring composed of carbon atoms and hydrogen atoms. 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms. For example, an aryl group can be a phenyl group or a naphthyl group.

[0023] "Aralkyl" refers to an alkyl group as described above substituted with an aryl group as described above, preferably C 6-10 Aryl-C 1-8 Alkyl groups, such as benzyl.

[0024] "Aralkoxy" refers to an alkoxy group as defined above substituted with an aryl group as defined above, for example, benzyloxy.

[0025] "Acyl" refers to the group -CO-R x , where R x is an alkyl, cycloalkyl, aryl or aralkyl group as described above, for example an alkanoyl or aralkanoyl group, such as acetyl or benzoyl.

[0026] "Sulfonyl" refers to -S(O)2-R x , where R x is an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group as described above, for example, a methanesulfonyl group, an ethylsulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a p-chlorobenzenesulfonyl group, a p-nitrobenzenesulfonyl group or a m-dinitrobenzenesulfonyl group.

[0027] The aryl groups described above, whether as aryl groups themselves or as part of other groups such as aralkyl, aralkyloxy, acyl or sulfonyl groups, may be optionally substituted with one or more substituents. When the aryl group is substituted, the substituents are selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogen, hydroxy and nitro, more preferably methyl, ethyl, methoxy, ethoxy, halogen or nitro. For example, substituted benzenesulfonyl can be a phenyl ring having one or more selected from C 1-8 Alkyl, halogenated C 1-8 phenylsulfonyl group substituted by alkyl, halogen or nitro.

[0028] In a first aspect, the present invention provides an intermediate compound of formula II for synthesizing pilocarpine:

[0029] Wherein, R3 is -S(O)2-R x , and R x It is C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 6-10 Aryl-C 1-8 Alkyl, each of which is optionally substituted by one or more selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 substituted with alkyl, halogen and nitro substituents, and

[0030] R1 and R2 may be the same or different and are independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 6-10 Aryl-C 1-8 Alkyl, wherein the C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Each alkyl group is optionally replaced by one or more C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogen, hydroxy and nitro substitutions,

[0031] Preferably, R1 and R2 are each independently selected from C 1-8 Alkyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy-substituted benzyl or halogen-substituted benzyl.

[0032] In a preferred embodiment, R3 is selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl or m-dinitrobenzenesulfonyl.

[0033] In a second aspect, the present invention provides a method for preparing a compound of formula II, comprising the following steps:

[0034] wherein R1, R2 and R3 are as defined above in the first aspect, X is Cl, Br or I,

[0035] Step 1: Compound V and R y-OH alcohol or with sulfate to obtain a compound of formula IV, wherein R y As defined above for R1 and R2 in the first aspect;

[0036] Step 2: Under basic conditions, reacting the compound of formula IV with a halogenated hydrocarbon CH3CH2X to obtain a compound of formula III;

[0037] Step 3: Under basic conditions, the compound of formula III is reacted with a sulfonylating agent to obtain a compound of formula II.

[0038] In one embodiment, the sulfate ester in step 1 is selected from dimethyl sulfate, diethyl sulfate, diisopropyl sulfate or dipropyl sulfate.

[0039] In one embodiment, the basic condition in step 2 is achieved by adding one or more reagents selected from LiHMDS, NaHMDS, LDA, n-butyllithium, tert-butyllithium, and NaH.

[0040] In one embodiment, the basic conditions in step 3 are achieved by adding one or more reagents selected from methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, tert-butylamine, n-pentylamine, isopentylamine, tert-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine and benzylamine.

[0041] In one embodiment, the sulfonylating agent in step 3 is XS(O)2-R x , where R x As defined in claim 1, X is Cl, Br or I, and preferably, the sulfonylating agent is selected from methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-nitrosulfonyl chloride or m-dinitrosulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl bromide, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-chlorobenzenesulfonyl bromide, p-nitrosulfonyl bromide or m-dinitrosulfonyl bromide.

[0042] Generally, in an organic solvent at a suitable temperature, a compound of formula V is reacted with an equivalent or excess amount of an acyl chloride to prepare an acyl chloride of the compound of formula V, and then an alcohol or phenol is added to react to prepare a compound of formula IV with R1 = R2. When preparing a monoacyl chloride, an alcohol or phenol is added to obtain a monoesterified compound of formula IV, and the acyl chloride reaction is then repeated with the addition of a different alcohol or phenol reagent to obtain a compound of formula IV with R1 ≠ R2.

[0043] Dissolve the compound of formula IV in an organic solvent and control the reaction temperature to -80 to -20°C. Add 1.0-1.2 equivalents of a base dropwise. After complete addition, incubate for 30 minutes. Then, add an equivalent of a halogenated hydrocarbon (CH3CH2X) until the reaction is complete. After conventional quenching, extraction, separation, and concentration, obtain the compound of formula III.

[0044] The compound of formula II is prepared by conventional reaction in an organic solvent under basic conditions.

[0045] In a third aspect, the present invention provides another method for preparing a compound of formula II, comprising the following steps:

[0046] Step 4: n-Butyraldehyde and compound IX undergo condensation reaction under the action of a catalyst to obtain a compound of formula VIII;

[0047] Step 5: The compound of formula VIII is subjected to oxidation reaction to obtain the compound of formula VII;

[0048] Step 6: The compound of formula VII is subjected to an esterification reaction to obtain the compound of formula VI;

[0049] Step 7: Sulfonylation reaction of the compound of formula VI to obtain the compound of formula II;

[0050] wherein R1, R2 and R3 are as defined above in the first aspect.

[0051] In one embodiment, the catalyst of step 4 is:

[0052] Wherein, R4 and R5 are each independently selected from C 6-10 Aryl, C 1-8 Alkyl substituted C 6-10 Aryl and halogen substituted C 6-10 In a preferred embodiment, the catalyst is

[0053] In the above method, the catalyst used can be prepared according to the method described in the reference The Journal of Organic Chemistry, 2002, 67, 22, 7769-7773.

[0054] In one embodiment, step 4 involves an asymmetric aldol condensation reaction between n-butyraldehyde and the compound of formula II in an aqueous organic solvent to selectively produce the compound of formula VIII. This product is directly added to an oxidant without isolation or purification to proceed to step 5. The aqueous organic solvent is any one of tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or a mixture thereof with water in any proportion. The catalyst is used in an amount of 1.0 to 20% equivalent, and the reaction temperature is 0 to 35°C.

[0055] In one embodiment, the oxidant used in step 5 is selected from any one of hydrogen peroxide, tert-butyl hydroperoxide, sodium hypochlorite, sodium chlorite, and sodium chlorate, or a combination thereof.

[0056] In one embodiment, in step 6, under acidic conditions, the compound of formula VII is esterified with R1OH to prepare the compound of formula VI. The acidic conditions are sulfuric acid, hydrochloric acid, hydrobromic acid or phosphoric acid. The R1 is as defined above and is selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, C 1-8 Alkyl substituted C 6-10 Aryl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy substituted benzyl or halogen substituted benzyl; preferably, R1 is selected from C 1-8 Alkyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy-substituted benzyl or halogen-substituted benzyl.

[0057] In one embodiment, in step 7, the compound of formula VI is reacted with a sulfonylating agent to produce a compound of formula II, wherein the sulfonylating agent and the R3 group are as described above. The reaction solvent is an aprotic organic solvent, including toluene, acetonitrile, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0058] In a fourth aspect, the present invention provides a method for preparing a compound of formula I,

[0059] The method comprises: reacting a compound of formula II with a halogenating agent to obtain a compound of formula I

[0060] wherein R1, R2 and R3 are as defined above in the first aspect, and X is Cl, Br or I.

[0061] In one embodiment, the halogenating agent is selected from the group consisting of chlorine, NCS, trichloroisocyanuric acid, dichlorohydantoin, lithium chloride, sodium chloride, potassium chloride, tetrabutylammonium chloride, bromine, NBS, dibromohydantoin, tribromoisocyanuric acid, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, iodine, diiodohydantoin, lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide, or a combination of two or more halogenating agents.

[0062] In a fifth aspect, the present invention provides a method for preparing pilocarpine, characterized in that it comprises the following steps:

[0063] Step 8: reacting the compound of formula II with a halogenating agent to obtain a compound of formula I;

[0064] Step 9: reacting the compound of formula I with 1-methylimidazole-5-carbaldehyde to obtain a compound of formula IX;

[0065] Step 10: Compound IX is treated with a reducing agent to obtain compound X;

[0066] Step 11: Compound X is treated with another reducing agent to obtain pilocarpine;

[0067] wherein R1, R2 and R3 are as defined above in the first aspect, and X is Cl, Br or I.

[0068] In one embodiment, the halogenating agent described in step 8 is as described above in the fourth aspect.

[0069] In one embodiment, in step 9, the compound of formula I is subjected to Reformatsky condensation and lactonization with 1-methylimidazole-5-carboxaldehyde in the presence of zinc powder, dialkylaluminum chloride, and cuprous bromide in an aprotic organic solvent to obtain a compound of formula IX. The aprotic organic solvent is as described above.

[0070] In one embodiment, the reducing agent in step 10 is a reducing agent for catalytic hydrogenation or reduction catalysis. The reducing agent for catalytic hydrogenation is selected from Ni, Pd / C, Pt / C, PtO2 / C and hydrogen, ammonium chloride, and ammonium nitrate. The reducing agent for reduction catalysis is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum, and lithium aluminum hydride.

[0071] In one embodiment, the another reducing agent in step 11 is selected from any one of sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum, lithium aluminum hydride, or any combination thereof.

[0072] In one embodiment, the method further comprises reacting pilocarpine with an acid to prepare a salt thereof, such as a hydrochloride or nitrate salt thereof.

[0073] In a preferred embodiment, the present invention provides a compound of formula II selected from the group consisting of:

[0074] In a sixth aspect, the present invention provides a compound of formula I:

[0075] wherein R1 and R2 are as described above in the first aspect, X is Cl, Br or I,

[0076] Provided that the following are excluded: when X is Br, R1 and R2 are both Me, or R1 is Me and R2 is Et or tert-butyl; or when X is I, R1 is Me and R2 is Et.

[0077] In one embodiment, the compounds of formula I do not include the following four compounds:

[0078] In the above method, there is no particular limitation on the organic solvent used, as long as it can dissolve the starting material compound and does not participate in the reaction. Preferably, the organic solvent used can be selected from toluene, hexane, n-heptane, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, dichloromethane, acetone, methanol, ethanol, isopropyl alcohol, or a mixture of two or more thereof.

[0079] In the above method, there is no particular limitation on the reaction temperature, which is within the conventional reaction temperature range.

[0080] In the above method, conventional quenching reaction refers to adding an aqueous solution, ammonium chloride solution, hydrochloric acid aqueous solution, phosphoric acid aqueous solution, etc. to the reaction solution to terminate the reaction or destroy the reaction system. DETAILED DESCRIPTION

[0081] Abbreviations and other explanations used:

[0082] LiHMDS refers to lithium hexamethyldisilazide.

[0083] NaHMDS refers to sodium hexamethyldisilazane.

[0084] LDA refers to lithium diisopropylamide.

[0085] NCS refers to N-chlorosuccinimide.

[0086] NBS refers to N-bromosuccinimide.

[0087] The method of the present invention will be further described below by way of examples. It should be understood that the purpose of providing the following examples is merely to enable a better understanding of the present invention, and is not intended to limit the scope of the present invention in any way.

[0088] Unless otherwise stated, the raw materials and reagents used in the examples of the present invention were purchased commercially or obtained by known methods. The purity and chirality were determined by high performance liquid chromatography. The identity of the target product was confirmed by its consistency with the HPLC retention value of the standard.

[0089] Example 1: Preparation of a compound of formula IV (wherein R1 and R2 are methyl (Me))

[0090] Under nitrogen, 100 g of L-malic acid and 200 g of methanol were added to a 500 mL reaction flask, stirred to dissolve, and the temperature was lowered to 0-10°C. 180 g of thionyl chloride was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction, solid sodium bicarbonate was added to neutralize the system, and the mixture was concentrated to dryness under reduced pressure. 1000 mL of dichloromethane and 300 mL of water were added, and the mixture was allowed to stand to separate. The organic layer was washed twice with 100 g of water. The organic layer was concentrated to dryness to obtain 120 g of an oily substance with a yield of 99%.

[0091] 1 H NMR (500MHz, CDCl3) δ4.53 (dd, J = 6.1, 4.2Hz, 1H), 3.80 (s, 3H), 3.61 (s, 3H), 2.92-2.88 (m, 1H), 2.83-2.75 (m, 1H).

[0092] Example 2: Preparation of a compound of formula III (wherein R1 and R2 are methyl (Me))

[0093] To a 1000mL reaction flask, 40g of the compound of formula IV prepared in Example 1 and 400mL of tetrahydrofuran were added, stirred and dissolved, and the temperature was lowered to -70-80°C. 543mL of 1M LiHMDS tetrahydrofuran solution was added dropwise, and after the dropwise addition, stirring was continued at -70-80°C for 1 hour. 29.6mL of iodoethane was then added dropwise, and the reaction was warmed to 0-5°C for 20h. After the insulation was completed, the temperature was lowered to -70-80°C, and ammonium chloride solution was added to quench the mixture. After the quenching was completed, the mixture was warmed to room temperature, hydrochloric acid was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. 500mL×2 of ethyl acetate was added for extraction, and the organic layer was added anhydrous Na2SO4 and dried, filtered, and concentrated under reduced pressure to give 45g of an oily substance with a yield of 96%.

[0094] 1H NMR (500MHz, CDCl3) δ4.30 (d, J = 5.0Hz, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 2.82 -2.77(m,1H),1.90-1.85(m,1H),1.75-1.70(m,1H),1.01(t,J=7.2Hz,3H).

[0095] Example 3: Preparation of a compound of formula II (wherein R1 and R2 are methyl (Me), and R3 is p-nitrobenzenesulfonyl (Ns))

[0096] 18 g of the compound of formula III prepared in Example 2 above was dissolved in 200 mL of dichloromethane, and 14 mL of Et3N and 1 g of DMAP were added sequentially. The mixture was cooled in an ice bath, and a DCM solution of p-nitrobenzenesulfonyl chloride (NsCl) (22 g of NsCl + 100 mL of dichloromethane) was added dropwise. After the addition, the mixture was stirred at 0-5°C for 2-3 h, then at room temperature for 3 h. The mixture was washed with 1N HCl (50 mL x 2), washed with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. Ethyl acetate / hexane was added for crystallization to obtain 29.1 g of an off-white solid with a yield of 81.7% and a purity of 99%.

[0097] 1 H NMR(500MHz,DMSO)δ8.49-8.30(m,2H),8.18-8.04(m,2H),5.16(d,J=6.2Hz,1H),3.72(s,3H),3.6 3(s,3H),2.94(dt,J=8.1,6.2Hz,1H),1.82-1.71(m,1H),1.60-1.51(m,1H),0.96(t,J=7.4Hz,3H).

[0098] Example 4: Preparation of a compound of formula I (wherein R1 and R2 are methyl (Me), and X is bromine)

[0099] 28.6 g of the raw material prepared according to the method of Example 3 was dissolved in 335 mL of DMF, 33.3 g of lithium bromide was added, and the temperature was raised to 40-45° C. and stirred for 6 h. 350 mL of water and 70 mL of methyl tert-butyl ether were added. The mixture was allowed to stand for stratification. 70 mL of methyl tert-butyl ether was added to the aqueous layer for extraction. The organic layers were combined, washed once with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain 17.7 g of an oil with a yield of 94% and a purity of 95%. 1H NMR (500MHz, DMSO) δ4.63 (dd, J=24.1, 9.7Hz, 1H), 3.73 (dd, J=21.0, 6.3Hz, 3H), 3.65 (d, J=17. 2Hz,3H),3.03-2.93(m,1H),1.93-1.71(m,1H),1.65-1.46(m,1H),0.86(dt,J=9.5,7.5Hz,3H).

[0100] Example 5: Preparation of a compound of formula IV wherein R1 and R2 are ethyl (Et)

[0101] Under nitrogen, 100 g of L-malic acid and 200 g of ethanol were added to a 500 mL reaction flask, stirred to dissolve, and the temperature was lowered to 0-10°C. 180 g of thionyl chloride was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction, solid sodium bicarbonate was added to neutralize the mixture, and the mixture was concentrated to dryness under reduced pressure. 1000 mL of dichloromethane and 300 mL of water were added, and the mixture was allowed to stand to separate. The organic layer was washed twice with 100 g of water. The organic layer was concentrated to dryness to give 140.3 g of an oily substance with a yield of 99%.

[0102] Example 6: Preparation of the compound of formula III (wherein R1 and R2 are ethyl (Et))

[0103] To a 1000mL reaction flask, 56.7g of the compound of formula IV prepared in Example 5 and 400mL of tetrahydrofuran were added, stirred and dissolved, and the temperature was lowered to -70 to -80°C. 543mL of 1M LiHMDS tetrahydrofuran solution was added dropwise. After the dropwise addition, stirring was continued at -70 to -80°C for 1 hour. 29.6mL of iodine was then added dropwise. After the dropwise addition, the temperature was raised to 0-5°C and the reaction was incubated for 20h. After the incubation was completed, the temperature was lowered to -70 to -80°C, and ammonium chloride solution was added to quench the mixture. After the quenching was completed, the mixture was warmed to room temperature, hydrochloric acid was added to adjust the pH to 5-6, and the mixture was concentrated under reduced pressure. 500mL of ethyl acetate was added and extracted, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 62.5g of an oil with a yield of 96%.

[0104] Example 7: Preparation of the compound of formula II (wherein R1 and R2 are ethyl (Et), and R3 is p-nitrobenzenesulfonyl)

[0105] 20.6 g of the compound of formula III prepared in Example 6 above was dissolved in 250 mL of dichloromethane, and 14 mL of Et3N and 1 g of DMAP were added sequentially. The mixture was cooled in an ice bath, and a DCM solution of NsCl (22 g of NsCl + 100 mL of dichloromethane) was added dropwise. After the addition, the mixture was stirred at 0-5°C for 2-3 h, then at room temperature for 3 h. The mixture was washed with 1N HCl 50 mL×2, washed with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. Ethyl acetate / hexane was added for crystallization to obtain 31.2 g of an off-white solid with a yield of 81.9% and a purity of 99%.

[0106] Example 8: Preparation of a compound of formula I (wherein R1 and R2 are ethyl (CH2CH3), and X is bromine)

[0107] 92.5 g of the product prepared according to the method of Example 7 was dissolved in 1000 mL of DMF, 100 g of lithium bromide was added, the temperature was raised to 40-45° C. and the mixture was stirred for 6 h. 1000 mL of water and 200 mL of methyl tert-butyl ether were added, the mixture was allowed to stand for stratification, 200 mL of methyl tert-butyl ether was added to the aqueous layer, and the mixture was extracted. The organic layers were combined, washed once with water, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain 58 g of an oily product with a yield of 90% and a purity of 96%.

[0108] Example 9: Preparation of the compound of formula IV (wherein R1 and R2 are isopropyl)

[0109] Under nitrogen, 100 g of L-malic acid and 200 g of isopropanol were added to a 500 mL reaction flask, stirred to dissolve, and the temperature was lowered to 0-10°C. 180 g of thionyl chloride was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction, solid sodium bicarbonate was added to neutralize the mixture, and the mixture was concentrated to dryness under reduced pressure. 1000 mL of dichloromethane and 300 mL of water were added, and the mixture was allowed to stand to separate. The organic layer was washed twice with 100 g of water. The organic layer was concentrated to dryness to obtain 163 g of an oily substance with a yield of 100%.

[0110] According to the method similar to the above example, the compound of formula II wherein R1 and R2 are isopropyl and R3 is p-nitrobenzenesulfonyl is prepared, and then the compound of formula I wherein R1 and R2 are isopropyl and X is bromine is obtained.

[0111] Example 10: Preparation of Pilocarpine Hydrochloride

[0112] Under nitrogen protection, 32.1 g zinc powder, 6.5 g CuBr and 800 mL THF were added to a 1000 mL reaction bottle, and 430 mL of 0.9 M Me2AlCl solution was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 20 min, cooled to -5 to -10 ° C, and 800 mL of a THF solution of a compound of formula I (87.9 g) in which R1 and R2 are methyl and X is bromine and 1-methylimidazole-5-carboxaldehyde (35.9 g) was added dropwise. After the addition was complete, the mixture was stirred at -10 ° C to -8 ° C for 2 h, stirred at room temperature for 30 min, cooled to -5 to -10 ° C, and 500 mL of a 50% MeOH aqueous solution was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 20 min, filtered through celite, and the filter cake was washed with 1200 mL MeOH and 500 mL of a 10% hydrochloric acid / MeOH mixture in sequence. The filtrate was evaporated to dryness under reduced pressure, and the residue was added with 2500 mL of 1.0 M The H3PO3 solution was extracted twice with methyl tert-butyl ether, ethyl acetate was added to the aqueous layer, and the solution was neutralized with solid Na2CO3. The solution was filtered through celite, the filtrate was separated, the aqueous layer was extracted twice with ethyl acetate, the extracts were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated to dryness to obtain 84.5 g of IX oil.

[0113] The oily product from the previous step was dissolved in 500 mL of methanol, 10 g of palladium / carbon was added, and the reaction was carried out for 20 hours while maintaining a certain hydrogen pressure. The product was filtered and the filtrate was concentrated to obtain 84.7 g of oily product X.

[0114] The oily substance from the previous step was dissolved in 2000 mL of isopropanol, cooled to -5-0°C, and 38 g of lithium borohydride was slowly added in batches. After the addition was completed, the mixture was stirred at -5-0°C for 1 hour. After the temperature was maintained at -5-0°C, the mixture was transferred to room temperature for reaction for 20 hours. After the reaction was completed, hydrochloric acid was added dropwise to quench the system, and the mixture was concentrated under reduced pressure. Ammonia water was added until the system was alkaline, and 500 mL of dichloromethane was added twice for extraction. The organic layers were combined and concentrated under reduced pressure, and ethanol was added. Hydrochloric acid was added dropwise until the system was acidic. The mixture was concentrated under reduced pressure to dryness, and ethanol and acetone were added for crystallization to obtain 60 g of pilocarpine hydrochloride with a total yield of 70.8% and a purity of 99.4%.

[0115] Example 11: Preparation of compounds of formula VIII (wherein R2 = Me):

[0116] 2L acetonitrile and 100mL water were added to a 5L reaction flask, followed by 200g of n-butyraldehyde, 250g of methyl glyoxylate and 100g of catalyst, and the mixture was stirred overnight at room temperature. After TLC showed complete reaction, acetonitrile was spin-dried, 500mL of methyl tert-butyl ether was added, and the mixture was stirred and separated. The aqueous layer was extracted with 500mL of methyl tert-butyl ether, and the organic phases were combined, washed with saturated common salt, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 444.5g of a light yellow oil of formula VIII-1 in a yield of 100%, which was directly reacted in the next step.

[0117] Example 12: Preparation of compounds of formula VIII (wherein R2 = isopropyl):

[0118] 2L acetonitrile and 100mL water are added to the reaction flask of 5L, then 200g of n-butyraldehyde, 260g of isopropyl glyoxylate and 100g of catalyst are added, and stirring is spent the night at room temperature. After TLC shows that the reaction is complete, acetonitrile is spin-dried, 500mL of methyl tert-butyl ether is added, and layering is stirred. The aqueous layer is extracted with 500mL of methyl tert-butyl ether, and the organic phase is merged. Saturated common salt is washed, and anhydrous sodium sulfate is dried, and filtered, and is spin-dried to obtain 522.1g of light yellow oil. Yield 100%, directly enters next step reaction.

[0119] Example 13: Preparation of compounds of formula VII (wherein R2 = Me):

[0120] To the product of Example 11, 125.0 g of sodium dihydrogen phosphate aqueous solution was added, followed by dropwise addition of 650 g of 30% hydrogen peroxide and 750 mL of 25% sodium chlorite aqueous solution under an ice bath. After the additions were complete, the mixture was stirred at room temperature for 1-2 hours. After the incubation period, sodium bisulfite aqueous solution was added dropwise under an ice bath until the solution did not turn blue when tested with potassium iodide paper. The mixture was concentrated under reduced pressure to remove the acetonitrile. After concentration, liquid caustic soda was added dropwise under an ice bath until the pH of the aqueous layer reached 8-9. Impurities were extracted twice with dichloromethane. The organic layer was discarded, and purified hydrochloric acid was added dropwise to the aqueous layer until the pH of the aqueous layer reached 1-2. The mixture was then extracted three times with dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 452.3 g of the compound of formula VII, with a yield of 92.5%.

[0121] Example 14: Preparation of a compound of formula VI (wherein R1 and R2 are Me):

[0122] 200.0 g of the compound from Example 13 was dissolved in 600 g of methanol. 60 g of concentrated sulfuric acid was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50-60°C and the reaction was allowed to proceed overnight. After TLC indicated complete reaction of the starting materials, the reaction system was cooled to room temperature. 70 g of triethylamine was added dropwise at room temperature and the mixture was evaporated under reduced pressure. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 216.0 g of the compound of Formula VI. Yield: 100%.

[0123] Example 15: Preparation of a compound of formula II (wherein R1 and R2 are Me, and R3 is tosyl)

[0124] 216.0 g of the compound from Example 14 was dissolved in 1000 g of dichloromethane. 100 g of triethylamine and 10 g of DMAP were added, followed by a 700 g solution of 217.0 g of tosyl chloride in dichloromethane added dropwise under ice-cooling. After the addition was complete, the mixture was allowed to react under ice-cooling for 3-4 hours. After TLC indicated complete reaction of the starting material, 500 mL of 1 M aqueous hydrochloric acid was added dropwise. The layers were stirred and separated. The aqueous layer was extracted with 200 mL of dichloromethane. The organic phases were combined, washed with 500 mL of 20% aqueous sodium bicarbonate solution and 500 mL of water, concentrated under reduced pressure, and then jacketed with n-heptane twice. The crude product was dissolved in 300 mL of ethyl acetate and the temperature was raised to 40.0-50.0°C to dissolve it clearly. Then, 1000 mL of n-heptane was added dropwise at 40.0-50.0°C. After the addition was complete, the mixture was slowly cooled to room temperature and stirred at room temperature for 3-4 hours. The mixture was filtered, washed once with 200 mL of n-heptane, and the solid was dried to obtain 365.9 g of a compound of formula II (wherein R1 and R2 are Me, and R3 is tosyl), with a yield of 93.6% and an HPLC purity of 98.5%.

[0125] The specific embodiments and examples described above further illustrate the objectives, technical solutions, and beneficial effects of the present invention. It should be understood that the specific embodiments and examples described above are merely illustrative of the present invention and are not intended to limit the scope of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present application.

Claims

1. Compound of formula II: in, R3 is -S(O)2-R x , and R x It is C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 6-10 Aryl-C 1-8 Alkyl, each of which is optionally substituted by one or more selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 substituted with alkyl, halogen and nitro substituents, and R1 and R2 may be the same or different and are independently selected from C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, or C 6-10 Aryl-C 1-8 Alkyl, wherein the C 1-8 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or C 6-10 Aryl-C 1-8 Each alkyl group is optionally replaced by one or more C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, halogen, hydroxy and nitro substitutions, Preferably, R1 and R2 are each independently selected from C 1-8 Alkyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy-substituted benzyl or halogen-substituted benzyl.

2. The compound according to claim 1, wherein R3 is selected from methylsulfonyl, ethylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl or m-dinitrobenzenesulfonyl.

3. A method for preparing a compound of formula II as claimed in claim 1, comprising the following steps: wherein R1, R2 and R3 are as defined in claim 1 or 2, Step 1: Compound V and R y -OH alcohol or with sulfate to obtain a compound of formula IV, wherein R y As defined in R1 and R2 of claim 1; Step 2: Under basic conditions, reacting the compound of formula IV with a halogenated hydrocarbon CH3CH2X to obtain a compound of formula III, wherein X is Cl, Br or I; Step 3: Under basic conditions, the compound of formula III is reacted with a sulfonylating agent to obtain a compound of formula II.

4. The method according to claim 3, wherein the sulfuric acid ester described in step 1 is selected from dimethyl sulfate, diethyl sulfate, diisopropyl sulfate or dipropyl sulfate.

5. The method according to claim 3, wherein the alkaline condition in step 2 is selected from one or more of LiHMDS, NaHMDS, LDA, n-butyllithium, tert-butyllithium, and NaH.

6. The method according to claim 3, wherein the alkaline conditions in step 3 are selected from the group consisting of adding one or more of methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, tert-butylamine, n-pentylamine, isopentylamine, tert-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine, and benzylamine.

7. The method according to claim 3, wherein the sulfonylating agent in step 3 is XS(O)2-R x , where R x As defined in claim 1, X is Cl, Br or I, and preferably, the sulfonylating agent is selected from methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or m-dinitrobenzenesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl bromide, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-chlorobenzenesulfonyl bromide, p-nitrobenzenesulfonyl bromide or m-dinitrobenzenesulfonyl bromide.

8. A method for preparing a compound of formula II as claimed in claim 1, comprising the following steps: wherein R1, R2 and R3 are as defined in claim 1 or 2, Step 4: n-Butyraldehyde and the compound of Formula IX undergo condensation reaction under a catalyst to obtain a compound of Formula VIII; Step 5: The compound of formula VIII is subjected to oxidation reaction to obtain the compound of formula VII; Step 6: The compound of formula VII undergoes an esterification reaction with R1-OH to obtain the compound of formula VI; Step 7: The compound of formula VI is subjected to sulfonylation reaction to obtain the compound of formula II.

9. The method according to claim 8, wherein the catalyst described in step 4 is: in, R4 and R5 are each independently selected from C 6-10 Aryl, C 1-8 Alkyl substituted C 6-10 Aryl and halogen substituted C 6-10 Aryl, preferably phenyl.

10. The method according to claim 8, wherein the sulfonylating agent used in step 7 is XS(O)2-R x , where R x As defined in claim 1, X is Cl, Br or I, and preferably, the sulfonylating agent is selected from methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or m-dinitrobenzenesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl bromide, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-chlorobenzenesulfonyl bromide, p-nitrobenzenesulfonyl bromide or m-dinitrobenzenesulfonyl bromide.

11. A method for preparing a compound of formula I, The method includes: The compound of formula II is reacted with a halogenating agent to obtain a compound of formula I wherein R1, R2 and R3 are as defined in claim 1 or 2, and X is Cl, Br or I.

12. The method according to claim 11, wherein the halogenating agent is selected from the group consisting of chlorine, NCS, trichloroisocyanuric acid, dichlorohydantoin, lithium chloride, sodium chloride, potassium chloride, tetrabutylammonium chloride, bromine, NBS, dibromohydantoin, tribromoisocyanuric acid, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, iodine, diiodohydantoin, lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide, or a combination of two or more of these halogenating agents.

13. A method for preparing pilocarpine, comprising the following steps: Step 8: reacting the compound of formula II with a halogenating agent to obtain a compound of formula I; Step 9: reacting the compound of formula I with 1-methylimidazole-5-carbaldehyde to obtain a compound of formula IX; Step 10: Compound IX is treated with a reducing agent to obtain compound X; Step 11: Compound X is treated with another reducing agent to obtain pilocarpine. wherein R1, R2 and R3 are as defined in claim 1, and X is Cl, Br or I.

14. The method according to claim 13, wherein the reducing agent in step 10 is a reducing agent for catalytic hydrogenation or reduction catalysis, wherein the reducing agent for catalytic hydrogenation is selected from Ni, Pd / C, Pt / C, PtO2 / C and hydrogen, ammonium chloride, formic acid and ammonium formate, or a combination of two or more thereof, and the reducing agent for reduction catalysis is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum and lithium aluminum hydride, or a combination of two or more thereof.

15. The method according to claim 13, wherein the another reducing agent in step 11 is selected from sodium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum, lithium aluminum hydride, or a combination of two or more thereof.

16. The method according to claim 13, further comprising reacting pilocarpine with an acid to prepare a salt thereof, such as a hydrochloride or a nitrate.

17. The method according to any one of claims 13 to 16, wherein the method further comprises steps 1 to 3: in, Steps 1-3 are as defined in any one of claims 3-7, and R1, R2 and R3 are as defined in claim 1 or 2.

18. The method according to any one of claims 13 to 16, wherein the method further comprises steps 4 to 7: in, Steps 4 to 7 are as defined in any one of claims 8 to 10, and R1, R2 and R3 are as defined in claim 1 or 2.

19. A compound of formula II according to claim 1, which is selected from the following compounds:

20. Compounds of formula I: R1 and R2 are as described in claim 1, X is Cl, Br or I, Provided that the following are excluded: when X is Br, R1 and R2 are both Me, or R1 is Me and R2 is Et or tert-butyl; or when X is I, R1 is Me and R2 is Et.

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