Preparation method of pilocarpine and its intermediate compound

Abstract

The present invention relates to a method for preparing pilocarpine and an intermediate compound thereof. Specifically, the present invention relates to key intermediate compounds of formula I and formula II for preparing pilocarpine and methods for preparing the same. One method is to use malic acid as a raw material, sequentially react with alcohol or sulfate, react with ethane halide, etc. to obtain a compound of formula II, and finally react with a halogenating agent to obtain a compound of formula I; another method is to use n-butyraldehyde as a raw material, sequentially react with a condensation reaction, an oxidation reaction, an esterification reaction, and a sulfonylation reaction to obtain a compound of formula II, and finally react with a halogenating agent to obtain a compound of formula I. The preparation method of the present invention has the advantages of mild reaction conditions, simple reaction process, high total yield of the target product and high purity, and is therefore very suitable for industrial production.

Description

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 the intermediates. Background Art

[0002] Glaucoma is an eye disease in which the intraocular pressure increases intermittently or continuously. Continuous high intraocular pressure can cause damage to various tissues and visual functions of the eyeball. If not treated in time, the visual field can be completely lost and blindness may occur.

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

[0004]

[0005] Pilocarpine can be used to treat primary glaucoma, including open-angle and closed-angle glaucoma. Compared with physostigmine, pilocarpine has a mild and short-lived effect, and its aqueous solution is more stable. It can also be used for salivary gland hypofunction, and its oral tablet SALAGEN can relieve dry mouth. In addition, it can also be used for symptomatic treatment of miosis during cataract intraocular lens implantation surgery and atropine drug poisoning. Currently, medicinal pilocarpine is isolated and extracted from plants, but with the increasing requirements for environmental protection, extraction from plants has become increasingly difficult. Therefore, if it can be obtained through chemical synthesis, higher social and economic benefits will be achieved.

[0006] The chemical synthesis of pilocarpine has always been a hot topic of research. The early literature Tetrahedron, 1972, 28, 967-972 and patents JP03161481 and US 5182198 reported its synthesis route. This route uses furfural as a raw material and splits homopilopic acid ester by enzyme. However, homopilopic acid ester is easily isomerized by hydrolysis of the 2-ethyl group under alkaline conditions, and it is necessary to obtain (+)-homopilopic acid by enzymatic reaction. This method has a long route and uses dangerous materials such as sodium metal and precious metal rhodium. In addition, this route uses expensive enzyme hydrolysis splitting, and the splitting yield is low. All of these bring great inconvenience to industrial production.

[0007]

[0008] The chemical properties of pilocarpine free base are unstable. Under alkaline conditions, the 2-ethyl group is easily isomerized to thermodynamically stable isopilocarpine.

[0009]

[0010] The literature Helvetica Chimica Acta, 1972, vol. 55, p. 1053–1062 attempts to synthesize racemic pilosinine with diethyl succinate through steps such as Stobbe condensation, and then obtain the desired (+)-pilocarpine through chiral resolution. In order to stereoselectively introduce the cis-2-ethyl group, it is necessary to undergo 2-acetylation, hydrogenation reduction, dehydration, and hydrogenation to obtain a 75 / 25 mixture of pilocarpine and isopilocarpine, and then recrystallize and purify using a salt formation method to obtain pure pilocarpine. The resolution efficiency of the intermediate pilosinine in this method is extremely low; and the introduction of the 2-ethyl group requires the use of metal platinum, and the stereoselectivity is not high, making subsequent separation and purification very difficult.

[0011]

[0012] The subsequent document Tetrahedron Letters. Vol. 33. No. 18.. 2441-2450. 1992 attempted to improve the synthesis of the intermediate pilosinine by using Even's asymmetric alkylation reaction. However, the yield of the asymmetric alkylation step of this method was only 50%, and the reaction cycle of the reduction apoactylation was too long, making it difficult to industrialize.

[0013]

[0014] The document J.AM.CHEM.SOC.2002,124,8198-8199 reports that butynoic acid cis-butenediol monoester can be efficiently and enantioselectively obtained under the catalysis of metal rhodium and chiral phosphine ligands to obtain dehydrohomopilopic aldehyde (4R)-(Z)-dehydrohomopilopic aldehyde, which is then catalytically hydrogenated to obtain homopilopilopic aldehyde, and then undergoes a [3+2] cycloaddition elimination reaction with p-methylsulfonylmethyl isonitrile and methylamine to obtain pilocarpine. However, this method not only requires the use of 5% noble metal rhodium, but also has poor stereoselectivity of the homopilopilopic aldehyde obtained by hydrogenation, and the reaction cycle of the last step of introducing a diazole heterocycle is too long, which is not suitable for industrial production.

[0015]

[0016] Literature Tetrahedron 65, 2009, 8283–8296, using diethyl malonate as a raw material, alkylated with 2-bromo-1,1-dimethoxyethane in the presence of sodium ethoxide, reduced with lithium aluminum hydride to obtain a diol intermediate, then enzymatically esterified to obtain a chiral monoalcohol, Dess-Martin oxidation to obtain the corresponding aldehyde, then added with vinyl magnesium bromide to obtain a chiral diol, and cyclized with carbonyl diimidazole to obtain a 1,3-dioxane-2-one intermediate, which reacted in the presence of metal palladium and carbon monoxide to obtain a chiral acetal lactone. Then, after deprotection, it reacted with p-methylsulfonylmethyl isonitrile and methylamine to undergo a [3+2] cycloaddition elimination reaction, catalytic hydrogenation, etc. to obtain pilocarpine nitrate. This route has a long reaction step, the intermediates are all oily, and each step is difficult to purify. It also involves biological enzymes and two steps of precious metal palladium and platinum catalytic reactions, which are costly.

[0017]

[0018] The literature Journal of Organic Chemistry, 1993, vol. 58, #5, p. 1159-1166 and patent WO9221675 reported a method for preparing pilocarpine hydrochloride, which uses L-aspartic acid as a starting material, protects the amino group with a bulky protecting agent (9-bromo-9-phenylfluorene (PhFIBr)), stereoselectively alkylates, deprotects, diazotizes, brominates, esterifies, and then undergoes a Zn(Ag)-mediated Reformatsky reaction to obtain a trisubstituted lactone intermediate, wherein the ratio of the α-configuration / β-configuration of the methyl formate at the 4-position on the lactone ring of the intermediate is about 9 / 1. Subsequently, pilocarpine is finally obtained by hydrogenolysis, selective reduction of the carboxyl group by LiBH4, and lactonization. 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 9-bromo-9-phenylfluorene (PhFIBr) reagent, 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 there are safety hazards in industrial production. These shortcomings severely limit the industrial production of this route.

[0019]

[0020] Therefore, how to prepare the compound of formula I simply and efficiently becomes the key to solving the industrial production of pilocarpine. Summary of the invention

[0021] The present invention overcomes the disadvantages of the methods in the prior art, provides intermediate compounds of formula II and formula I for preparing pilocarpine and their preparation methods, and also provides a method for preparing pilocarpine using the intermediate compounds. The method of the present invention has the advantages of mild reaction conditions, simple reaction process, high total yield of target products and high purity, and is particularly suitable for industrial production.

[0022] definition:

[0023] 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.

[0024] 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 mono- or poly-halogenated groups in which one or more same or different halogens replace one or more hydrogens in the group.

[0025] The term "alkyl" as used herein refers to a straight or branched 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, neopentyl), n-hexyl, 2-methylpentyl, and the like.

[0026] 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 appreciated by those skilled in the art that when there are 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 and the like.

[0027] 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.

[0028] “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.

[0029] "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 may be phenyl or naphthyl.

[0030] "Arylalkyl" 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, for example benzyl.

[0031] "Aralkoxy" refers to an alkoxy group as defined above substituted with an aryl group as defined above, for example, benzyloxy.

[0032] "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, for example acetyl or benzoyl group.

[0033] "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 ethanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a p-chlorobenzenesulfonyl group, a p-nitrobenzenesulfonyl group or a m-dinitrobenzenesulfonyl group.

[0034] 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 groups are 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, hydroxyl 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 Benzenesulfonyl group substituted by alkyl, halogen or nitro.

[0035] In a first aspect, the present invention provides an intermediate compound of formula II for synthesizing pilocarpine:

[0036]

[0037] 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 with 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

[0038] 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 substituted with 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,

[0039] 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.

[0040] In a preferred embodiment, R3 is selected from methanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-nitrosulfonyl or m-dinitrosulfonyl.

[0041] In a second aspect, the present invention provides a method for preparing a compound of formula II, comprising the following steps:

[0042]

[0043] wherein R1, R2 and R3 are as defined in the first aspect above, X is Cl, Br or I,

[0044] Step 1: Compound V and R y -OH alcohol or with a sulfate to obtain a compound of formula IV, wherein R y As defined above for R1 and R2 in the first aspect;

[0045] Step 2: Under basic conditions, reacting the compound of formula IV with a halogenated hydrocarbon CH3CH2X to obtain a compound of formula III;

[0046] Step 3: Under basic conditions, the compound of formula III is reacted with a sulfonylating agent to obtain a compound of formula II.

[0047] In one embodiment, the sulfate in step 1 is selected from dimethyl sulfate, diethyl sulfate, diisopropyl sulfate or dipropyl sulfate.

[0048] 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.

[0049] 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, phenethylamine and benzylamine.

[0050] In one embodiment, the sulfonylating agent in step 3 is XS(O)2-R x , where R x As defined in the first aspect above, X is Cl, Br or I. 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.

[0051] 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 a monoacyl chloride is prepared, an alcohol or phenol is added to obtain a monoesterified compound of formula IV, and then the acyl chloride is repeated again, and different alcohol or phenol reagents are added to obtain a compound of formula IV with R1≠R2.

[0052] Dissolve the compound of formula IV in an organic solvent, control the reaction temperature at -80 to -20°C, add 1.0 to 1.2 equivalents of base, and keep warm for 30 minutes after the addition is complete. Then add an equivalent of halogenated hydrocarbon CH3CH2X until the reaction is complete. After conventional quenching, extraction, stratification, and concentration, obtain the compound of formula III.

[0053] The compound of formula II is prepared by a conventional reaction in an organic solvent under basic conditions.

[0054] In a third aspect, the present invention provides another method for preparing a compound of formula II, comprising the following steps:

[0055]

[0056] Step 4: n-butyraldehyde and compound IX undergo condensation reaction under the action of a catalyst to obtain a compound of formula VIII;

[0057] Step 5: The compound of formula VIII is subjected to oxidation reaction to obtain the compound of formula VII;

[0058] Step 6: The compound of formula VII is subjected to an esterification reaction to obtain the compound of formula VI;

[0059] Step 7: Sulfonylation reaction of the compound of formula VI to obtain the compound of formula II;

[0060] wherein R1, R2 and R3 are as defined above in the first aspect.

[0061] In one embodiment, the catalyst in step 4 is:

[0062]

[0063] 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

[0064] In the above method, the catalyst preparation method used can be prepared according to the reference The Journal of Organic Chemistry, 2002, 67, 22, 7769-7773.

[0065] In one embodiment, step 4 is to react n-butyraldehyde with the compound of formula II in an aqueous organic solvent to undergo an asymmetric aldol condensation reaction to selectively generate a compound of formula VIII, and the product is directly added with an oxidant to carry out the reaction in step 5 without separation and purification. The aqueous organic solvent refers to any one of tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or a mixed solvent of any proportion of the combination thereof and water. The amount of the catalyst used is 1.0 to 20% equivalent, and the reaction temperature is 0 to 35°C.

[0066] In one embodiment, the oxidant used in step 5 is selected from any one of hydrogen peroxide, tert-butyl hydroperoxide, sodium hypochlorite, sodium chlorite, sodium chlorate, or a combination thereof.

[0067] In one embodiment, in step 6, under acidic conditions, the compound of formula VII is subjected to an esterification reaction 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.

[0068] 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, N-methylpyrrolidone.

[0069] In a fourth aspect, the present invention provides a method for preparing a compound of formula I,

[0070]

[0071] The method comprises: reacting a compound of formula II with a halogenating agent to obtain a compound of formula I

[0072]

[0073] wherein R1, R2 and R3 are as defined above in the first aspect, and X is Cl, Br or I.

[0074] 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.

[0075] In a fifth aspect, the present invention provides a method for preparing pilocarpine, characterized in that it comprises the following steps:

[0076]

[0077] Step 8: reacting the compound of formula II with a halogenating agent to obtain a compound of formula I;

[0078] Step 9: reacting the compound of formula I with 1-methylimidazole-5-carbaldehyde to obtain a compound of formula IX;

[0079] Step 10: The compound of formula IX is treated with a reducing agent to obtain a compound of formula X;

[0080] Step 11: Compound X is treated with another reducing agent to obtain pilocarpine;

[0081] wherein R1, R2 and R3 are as defined above in the first aspect, and X is Cl, Br or I.

[0082] In one embodiment, the halogenating agent described in step 8 is as described above in the fourth aspect.

[0083] In one embodiment, in step 9, the compound of formula I is subjected to Reformatsky condensation and lactonization reaction 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.

[0084] In one embodiment, the reducing agent described in step 10 is a reducing agent for catalytic hydrogenation or reduction catalysis, and 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.

[0085] 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.

[0086] 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.

[0087] In a preferred embodiment, the present invention provides a compound of formula II selected from the following compounds:

[0088]

[0089] In a sixth aspect, the present invention provides a compound of formula I:

[0090]

[0091] wherein R1 and R2 are as described above in the first aspect, X is Cl, Br or I,

[0092] Provided that the following are not included: 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.

[0093] In one embodiment, the compound of formula I does not include the following four compounds:

[0094]

[0095] 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, isopropanol, or a mixture of two or more thereof.

[0096] In the above method, there is no particular limitation on the reaction temperature, which is within the conventional reaction temperature range.

[0097] In the above method, conventional quenching reaction refers to adding an aqueous solution, an ammonium chloride solution, an aqueous hydrochloric acid solution, an aqueous phosphoric acid solution, etc. into the reaction solution to terminate the reaction or destroy the reaction system. DETAILED DESCRIPTION

[0098] Abbreviations and other explanations used:

[0099] LiHMDS refers to lithium hexamethyldisilazide.

[0100] NaHMDS refers to sodium hexamethyldisilazane.

[0101] LDA refers to lithium diisopropylamide.

[0102] NCS refers to N-chlorosuccinimide.

[0103] NBS refers to N-bromosuccinimide.

[0104] 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 only to enable a better understanding of the present invention, and is not intended to limit the scope of the present invention in any way.

[0105] Unless otherwise specified, 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 detected by high performance liquid chromatography, and the target product was confirmed by the consistency of the HPLC retention value with the standard.

[0106] Example 1: Preparation of a compound of formula IV (wherein R1 and R2 are methyl (Me))

[0107]

[0108] Under nitrogen protection, add 100g L-malic acid and 200g methanol to a 500mL reaction bottle, stir to dissolve, cool to 0-10°C, add 180g thionyl chloride dropwise, and stir at room temperature overnight. After the reaction is completed, add solid sodium bicarbonate to adjust the system to neutrality, concentrate to dryness under reduced pressure, add 1000mL of dichloromethane and 300mL of water, stand for stratification, wash the organic layer twice with 100g×2 water, and concentrate the organic layer to obtain 120g of oily matter with a yield of 99%.

[0109] 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).

[0110] Example 2: Preparation of a compound of formula III (wherein R1 and R2 are methyl (Me))

[0111]

[0112] To a 1000mL reaction bottle, 40g of the compound of formula IV prepared in Example 1 and 400mL of tetrahydrofuran were added, stirred to dissolve, cooled to -70-80°C, 543mL of 1M LiHMDS tetrahydrofuran solution was added dropwise, and stirring was continued at -70-80°C for 1 hour. Then 29.6mL of iodoethane was added dropwise, and the mixture was warmed to 0-5°C and kept for reaction for 20h. After the insulation was completed, the mixture was cooled to -70-80°C, and ammonium chloride solution was added for quenching. 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. Ethyl acetate 500mL×2 was added for extraction, and the organic layer was added with anhydrous Na2SO4 for drying, filtered, and concentrated under reduced pressure to obtain 45g of an oily substance with a yield of 96%.

[0113] 1 H 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).

[0114] Example 3: Preparation of the compound of formula II (wherein R1 and R2 are methyl (Me), R3 is p-nitrobenzenesulfonyl (Ns))

[0115]

[0116] 18 g of the compound of formula III prepared in Example 2 was dissolved in 200 mL of dichloromethane, and 14 mL of Et3N and 1 g of DMAP were added in sequence. 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 was completed, the mixture was stirred at 0-5°C for 2-3 h, and then stirred at room temperature for 3 h. 1N HCl 50 mL×2 was added for washing, washed with water, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to dryness, and 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%.

[0117] 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).

[0118] Example 4: Preparation of a compound of formula I (wherein R1 and R2 are methyl (Me), and X is bromine)

[0119]

[0120] 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, the temperature was raised to 40-45° C., and the reaction was stirred for 6 h. 350 mL of water and 70 mL of methyl tert-butyl ether were added, and 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 with anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain 17.7 g of an oily substance with a yield of 94% and a purity of 95%. 1 H 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).

[0121] Example 5: Preparation of the compound of formula IV (wherein R1 and R2 are ethyl (Et))

[0122]

[0123] Under nitrogen protection, add 100g L-malic acid and 200g ethanol to a 500mL reaction bottle, stir to dissolve, cool to 0-10°C, add 180g thionyl chloride dropwise, and stir at room temperature overnight. After the reaction is completed, add solid sodium bicarbonate to adjust the system to neutrality, concentrate to dryness under reduced pressure, add 1000mL of dichloromethane and 300mL of water, stand for stratification, wash the organic layer twice with 100g×2 water, and concentrate the organic layer to obtain 140.3g of oily matter with a yield of 99%.

[0124] Example 6: Preparation of the compound of formula III (wherein R1 and R2 are ethyl (Et))

[0125]

[0126] To a 1000mL reaction bottle, 56.7g of the compound of formula IV prepared in Example 5 and 400mL of tetrahydrofuran were added, stirred to dissolve, cooled to -70~-80°C, 543mL of 1M LiHMDS tetrahydrofuran solution was added dropwise, and stirring was continued at -70~-80°C for 1 hour. Then 29.6mL of iodoethane was added dropwise, and the mixture was warmed to 0-5°C and kept for reaction for 20h. After the insulation was completed, the mixture was cooled to -70~-80°C, and ammonium chloride solution was added for quenching. 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. Ethyl acetate 500mL×2 was added for extraction, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 62.5g of an oil with a yield of 96%.

[0127] Example 7: Preparation of the compound of formula II (wherein R1 and R2 are ethyl (Et), and R3 is p-nitrobenzenesulfonyl)

[0128]

[0129] 20.6 g of the compound of formula III prepared in Example 6 was dissolved in 250 mL of dichloromethane, and 14 mL of Et3N and 1 g of DMAP were added in sequence. 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 was completed, the mixture was stirred at 0-5°C for 2-3 h, and then stirred at room temperature for 3 h. 1N HCl 50 mL×2 was added for washing, washed with water, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to dryness, and 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%.

[0130] Example 8: Preparation of a compound of formula I (wherein R1 and R2 are ethyl (CH2CH3), and X is bromine)

[0131]

[0132] 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., the mixture was stirred and reacted 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 for extraction, the organic layers were combined, washed once with water, dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain 58 g of an oily substance with a yield of 90% and a purity of 96%.

[0133] Example 9: Preparation of the compound of formula IV (wherein R1 and R2 are isopropyl)

[0134]

[0135] Under nitrogen protection, add 100g L-malic acid and 200g isopropanol to a 500mL reaction bottle, stir to dissolve, cool to 0-10°C, add 180g thionyl chloride dropwise, and stir at room temperature overnight. After the reaction is completed, add solid sodium bicarbonate to adjust the system to neutrality, concentrate to dryness under reduced pressure, add 1000mL of dichloromethane and 300mL of water, stand for stratification, wash the organic layer twice with 100g×2 water, and concentrate the organic layer to obtain 163g of oily matter with a yield of 100%.

[0136] 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.

[0137] Example 10: Preparation of pilocarpine hydrochloride

[0138]

[0139] 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 0.9 M Me2AlCl solution was added dropwise at room temperature. After the addition was completed, 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 completed, 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 50% MeOH aqueous solution was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 20 min, filtered through diatomaceous earth, and the filter cake was washed with 1200 mL MeOH and 500 mL 10% hydrochloric acid / MeOH mixed solution in turn. The filtrate was evaporated to dryness under reduced pressure, and the residue was added with 2500 mL 1.0 M H3PO3 solution, extracted twice with methyl tert-butyl ether, added ethyl acetate to the aqueous layer, and neutralized with solid Na2CO3, filtered with diatomaceous earth, 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.

[0140] The oily substance in 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 mixture was filtered and the filtrate was concentrated to obtain 84.7 g of X oily substance.

[0141] The oily substance in the previous step was dissolved in 2000 mL of isopropanol, cooled to -5 to 0°C, and 38 g of lithium borohydride was slowly added in batches. After the addition was completed, the mixture was stirred at -5 to 0°C for 1 hour. After the insulation was completed, 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. Ethanol was added, and 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%.

[0142] Example 11: Preparation of compounds of formula VIII (wherein R2 = Me):

[0143]

[0144] 2L acetonitrile and 100mL water were added to a 5L reaction bottle, followed by 200g of n-butyraldehyde, 250g of methyl glyoxylate and 100g of catalyst, and stirred overnight at room temperature. After TLC showed that the reaction was complete, acetonitrile was spin-dried, 500mL of methyl tert-butyl ether was added, and the mixture was stirred and layered. The aqueous layer was extracted with 500mL of methyl tert-butyl ether, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 444.5g of a light yellow oil of formula VIII-1, with a yield of 100%, and the reaction was directly carried out in the next step.

[0145] Example 12: Preparation of compounds of formula VIII (wherein R2 = isopropyl):

[0146]

[0147] 2L acetonitrile and 100mL water were added to a 5L reaction flask, followed by 200g of n-butyraldehyde, 260g of isopropyl glyoxylate and 100g of catalyst, and the mixture was stirred overnight at room temperature. After TLC showed that the reaction was complete, acetonitrile was spin-dried, 500mL of methyl tert-butyl ether was added, and the mixture was stirred for stratification. The aqueous layer was extracted with 500mL of methyl tert-butyl ether, and the organic phases were combined, washed with saturated common salt water, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 522.1g of a light yellow oily substance with a yield of 100%, which was directly reacted in the next step.

[0148] Example 13: Preparation of compounds of formula VII (wherein R2 = Me):

[0149]

[0150] Add 125.0g of sodium dihydrogen phosphate aqueous solution to the product of Example 11, and add 650g of 30% hydrogen peroxide and 750mL of 25% sodium chlorite aqueous solution dropwise in an ice bath, and stir at room temperature for 1-2 hours. After the heat preservation is completed, add sodium bisulfite aqueous solution dropwise in an ice bath until the aqueous solution does not turn blue when tested with potassium iodide paper. Concentrate under reduced pressure to evaporate the acetonitrile, and after concentration, add liquid alkali dropwise in an ice bath until the pH value of the water layer is 8-9, extract impurities twice with dichloromethane, discard the organic layer, add refined hydrochloric acid dropwise to the water layer until the pH value of the water layer is 1-2, and then extract with dichloromethane three times, combine the organic phases, and concentrate under reduced pressure to obtain 452.3g of the compound of formula VII, with a yield of 92.5%.

[0151] Example 14: Preparation of compounds of formula VI (wherein R1 and R2 are Me):

[0152]

[0153] 200.0 g of the compound of Example 13 was dissolved in 600 g of methanol, and 60 g of concentrated sulfuric acid was added dropwise at room temperature. After the addition was completed, the temperature was raised to 50-60° C. to react overnight. After TLC showed that the raw materials had reacted completely, the temperature of the reaction system was lowered to room temperature, 70 g of triethylamine was added dropwise at room temperature, and the mixture was distilled under reduced pressure. The mixture was extracted twice with dichloromethane, and 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%.

[0154] Example 15: Preparation of a compound of formula II (wherein R1 and R2 are Me, and R3 is tosyl)

[0155]

[0156] Dissolve 216.0 g of the compound of Example 14 in 1000 g of dichloromethane, add 100 g of triethylamine and 10 g of DMAP, and then dropwise add 700 g of a dichloromethane solution containing 217.0 g of tosyl chloride under ice bath. After the dropwise addition is completed, react under ice bath for 3-4 hours. After TLC shows that the raw material has reacted completely, dropwise add 500 mL of 1 M hydrochloric acid aqueous solution, stir to separate layers, extract the water layer with 200 mL of dichloromethane, combine the organic phases, wash with 500 mL of 20% sodium bicarbonate aqueous solution, wash with 500 mL of water, concentrate under reduced pressure, and steam twice with n-heptane. 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. Then, 1000 mL of n-heptane was added dropwise at 40.0-50.0°C. After the addition was completed, the mixture was slowly cooled to room temperature, stirred at room temperature for 3-4 hours, filtered, and washed once with 200 mL of n-heptane. 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 a HPLC purity of 98.5%.

[0157] The specific implementation schemes and examples described above further describe the purpose, technical solutions and beneficial effects of the present invention in detail. It should be understood that the specific implementation schemes and examples described above are only examples 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 should be included in the protection scope of the present application.

Claims

1. A method for preparing a compound of formula II, comprising the following steps: Step 4: n-butyraldehyde and the compound of formula IX undergo condensation reaction in the presence of 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; Wherein R3 is -S(O)2-R x , and R x It is C 1-8 Alkyl or C 6-10 Aryl, the C 6-10 The aryl group is optionally substituted with 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, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy-substituted benzyl or halogen-substituted benzyl.

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

3. The method according to claim 1 or 2, 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.

4. The method according to claim 3, wherein: R4 and R5 are each independently selected from phenyl.

5. The method according to claim 1, 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.

6. The method according to claim 1 or 2, wherein the sulfonylating agent used in step 7 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.

7. A method for preparing a compound of formula I, The method includes: Step 4: n-butyraldehyde and the compound of formula IX undergo condensation reaction in the presence of 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; as well as Step 8: Reaction of the compound of formula II with a halogenating agent to obtain a compound of formula I Wherein R3 is -S(O)2-R x , and R x It is C 1-8 Alkyl or C 6-10 Aryl, the C 6-10 The aryl group is optionally substituted with one or more selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkyl, halogen and nitro substituents, R1 and R2 may be the same or different and are independently selected from C 1-8 Alkyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 alkoxy-substituted benzyl or halogen-substituted benzyl; and X is Cl, Br or I.

8. The method according to claim 7, wherein R3 is selected from methanesulfonyl, ethylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl or m-dinitrobenzenesulfonyl.

9. The method according to claim 7 or 8, wherein the halogenating agent in step 8 is selected from 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.

10. A method for preparing pilocarpine, comprising the following steps: Step 4: n-butyraldehyde and the compound of formula IX undergo condensation reaction in the presence of 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; 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: The compound of formula IX is treated with a reducing agent to obtain a compound of formula X; Step 11: Compound X is treated with another reducing agent to obtain pilocarpine; Wherein R3 is -S(O)2-R x , and R x It is C 1-8 Alkyl or C 6-10 Aryl, the C 6-10 Aryl is optionally substituted with 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, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 alkoxy-substituted benzyl or halogen-substituted benzyl; and X is Cl, Br or I.

11. The method according to claim 10, wherein R3 is selected from methanesulfonyl, ethylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-nitrobenzenesulfonyl or m-dinitrobenzenesulfonyl.

12. The method according to claim 10 or 11, 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.

13. The method according to claim 10 or 11, 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.

14. The method according to claim 10 or 11, further comprising reacting pilocarpine with an acid to prepare a salt thereof.

15. The method according to claim 10 or 11, further comprising reacting pilocarpine with an acid to prepare a hydrochloride or a nitrate thereof.

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