Preparation method of 2-(diphenylmethylene) quinuclidin-3-one

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-(diphenylmethylene) quinuclidin-3-one. According to the invention, 3-quinuclidinone or a salt thereof and diphenyl ketone are used as raw materials and react under the condition of alkali and a solvent to successfully prepare a core intermediate 2-(diphenylmethylene) quinuclidin-3-ketone in a synthesis path of maropitant. The preparation raw materials are cheap and easy to obtain, the reaction only needs one step, the reaction time is short, the operation is simple and efficient, the post-treatment is convenient, the yield is excellent, and the method has an obvious competitive advantage in production cost.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and more specifically relates to a method for preparing 2-(diphenylmethylenyl)quinuclidine-3-one. Background Art

[0002] Maropitant is a quinine NK1 receptor antagonist. It was developed by Pfizer and is the first drug approved for the prevention and treatment of canine motion sickness and acute vomiting. It was approved for marketing in the United States and Europe in 2007 for the treatment and prevention of acute vomiting in dogs. The drug has the advantages of easy absorption, wide distribution, rapid onset, high bioavailability, long duration of action and safety.

[0003] However, in the preparation process of maropitant, a key challenge lies in the selection and optimization of its synthesis route. In particular, 2-(diphenylmethyl)quinuclidine-3-one, as the core intermediate in the synthesis route of maropitant, its synthesis efficiency and cost directly affect the production cost and supply stability of maropitant.

[0004] For example, Chinese patent application CN106977512A discloses a method for preparing maropitant free base, which uses 3-oxoquinuclidine-2-carboxylate as a starting material to prepare 2-(diphenylmethyl)quinuclidine-3-one:

[0005]

[0006] However, the starting material, 3-oxoquinuclidine-2-carboxylate, on which the above-mentioned method for preparing maropitant relies, faces the problem of being difficult to purchase directly from commercial channels, having a high market price, or requiring a series of complex and cumbersome multi-step reactions (CN107721999A, CN110922401A) to be prepared separately. These preparation conditions not only increase the production cost, but also make the entire synthesis process more complicated and time-consuming, thereby limiting the large-scale production and wide application of maropitant.

[0007] Therefore, finding a simpler, more economical and more efficient method for preparing 2-(diphenylmethyl)quinuclidine-3-one is of great significance for optimizing the synthesis route of maropitant and reducing production costs. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the prior art in synthesizing 2-(diphenylformyl)quinuclidine-3-one, namely, expensive raw materials, long routes, complex processes and high costs, and to provide a preparation method of 2-(diphenylformyl)quinuclidine-3-one. The method only requires one step of reaction, is simple and efficient, and is convenient for post-processing, has an excellent yield, and has a significant competitive advantage in production cost.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] The present invention provides a method for preparing 2-(diphenylmethylenyl)quinuclidine-3-one, comprising the following steps: using 3-quinuclidine ketone or its salt shown in formula (I) and diphenyl ketone shown in formula (II) as raw materials, reacting under the conditions of alkali and solvent to prepare 2-(diphenylmethylenyl)quinuclidine-3-one shown in formula (III):

[0011]

[0012] Furthermore, the specific operation of the preparation method is as follows: after mixing 3-quinuclidine ketone or its salt with a solvent, adding a base to mix thoroughly, then adding benzophenone, reacting under stirring conditions, reacting completely, and post-treating to obtain 2-(diphenylmethyl)quinuclidine-3-ketone.

[0013] Furthermore, the specific operation of the preparation method is as follows: 3-quinuclidine ketone or its salt, benzophenone and a solvent are mixed, and then a base is added, and the reaction is carried out under stirring. The reaction is completed, and post-treatment is performed to obtain 2-(diphenylmethyl)quinuclidine-3-one.

[0014] Furthermore, the post-treatment includes cooling, filtering, washing and drying.

[0015] Furthermore, the drying is oven drying.

[0016] Furthermore, the base is an organic base or an inorganic base.

[0017] Preferably, the base is an organic base.

[0018] Preferably, the organic base includes at least one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.

[0019] More preferably, the organic base is selected from one or more of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, and lithium diisopropylamide.

[0020] Preferably, the inorganic base includes one or more of potassium hydroxide, sodium hydroxide and cesium hydroxide.

[0021] Preferably, the solvent includes one or more of diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, tetrahydrofuran, 2-methylfuran, 1,4-dioxane, n-hexane, n-heptane, toluene, benzene, chlorobenzene, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0022] More preferably, the solvent includes one or more of diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, tetrahydrofuran, 2-methylfuran, 1,4-dioxane, toluene, chlorobenzene, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0023] Further, when the raw material is a salt of 3-quinuclidine, the salt of the 3-quinuclidine is generated by reacting 3-quinuclidine with an inorganic acid or an organic acid. During the reaction, the nitrogen atom of 3-quinuclidine combines with the acid to form a salt compound. For example, the structural formula of 3-quinuclidine hydrochloride is as follows:

[0024] Furthermore, the salt of 3-quinuclidinone includes one or more of hydrochloride, sulfate, nitrate, phosphate, hydrobromide, perchlorate, 4-methylbenzenesulfonate, methanesulfonate, formate, acetate, and citrate.

[0025] Furthermore, the organic acid includes one or more of 4-methylbenzenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, and citric acid.

[0026] Furthermore, the inorganic acid includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and perchloric acid.

[0027] Furthermore, the reaction temperature is 0-120°C.

[0028] Preferably, the reaction temperature is 25-120°C.

[0029] More preferably, the reaction temperature is 40-120°C.

[0030] Furthermore, the reaction time is 5 min to 2 h.

[0031] Furthermore, the molar ratio of 3-quinuclidinone or its salt, diphenyl ketone and base is 1:(1-5):(1-5). When the salt of 3-quinuclidinone is used as the raw material, one equivalent of base can be added to remove the salt.

[0032] Preferably, the molar ratio of 3-quinuclidinone or its salt, diphenyl ketone and base is 1:(1-2):(1-2).

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The present invention uses 3-quinuclidine ketone or its salt and diphenyl ketone as raw materials, reacts under the conditions of alkali and solvent, and successfully prepares the core intermediate in the synthesis path of maropitant, 2-(diphenylmethylenyl)quinuclidine-3-one. The preparation raw materials of the above method are cheap and easy to obtain, the reaction only requires one step, the reaction time is short, the operation is simple and efficient, the post-processing is convenient, the yield is excellent, and the production cost has obvious competitive advantages. DETAILED DESCRIPTION

[0035] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0036] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0037] Example 1

[0038] 3-Quinuclidene (2mmol, 250mg, 1.0eq) and solvent ethylene glycol diethyl ether (6mL) were added to a 25mL reaction bottle under a nitrogen atmosphere, stirred and LDA diisopropylamide lithium (2.0eq) was added dropwise at 25°C, stirred for 5 minutes, benzophenone (3mmol, 546mg, 1.5eq) was added, and then the temperature was raised to 100°C and maintained for 5 minutes. A large amount of yellow solid was generated by the reaction, and the reaction of the raw material was monitored to be complete. After cooling, water was added, filtered, the filter cake was collected, washed and dried to obtain 2-(diphenylmethyl)quinuclidene-3-one (529mg, 92%).

[0039] 1 H NMR(500MHz,Chloroform-d)δ7.36–7.30(m,3H),7.28(s,5H),7.12(dq,J=7.2,4.2Hz,2H),3.13–2.99(m,4H) ), 2.53 (p, J = 3.0Hz, 1H), 2.08 (dddt, J = 12.0, 8.8, 5.6, 2.6Hz, 2H), 1.95 (dddd, J = 12.6, 8.9, 5.7, 2.7Hz, 2H). 13 C NMR (126MHz, CDCl3) δ206.07,144.40,141.52,140.12,139.88,130.38,129.16,128.33,128.05,127.90,127.58,48.28,42.13,25.97.

[0040] Example 2

[0041] 3-Quinuclidene (25mmol, 3.13g, 1.0eq) and solvent ethylene glycol diethyl ether (45mL) were added to a 500mL reaction bottle, stirred and LDA diisopropylamide lithium (2.0eq) was added dropwise at 0°C, stirred for 5 minutes, benzophenone (37.5mmol, 6.8g, 1.5eq) was added, and then the system temperature was raised to 100°C and maintained for 10 minutes. A large amount of yellow solid was generated in the system, and the reaction of the raw materials was monitored to be complete. After cooling, water was added, filtered, the filter cake was collected, washed and dried to obtain 2-(diphenylmethylenyl)quinuclidene-3-one (5.4g, 75%).

[0042] Example 3

[0043] 3-Quinuclide hydrochloride (2.5mmol, 404mg, 1.0eq) and solvent ethylene glycol diethyl ether (3.5mL) were added to a 25mL reaction bottle, stirred and LDA (3.0eq) was added dropwise at 25°C, stirred for 5 minutes, benzophenone (3.75mmol, 683mg, 1.5eq) was added, and then the system temperature was raised to 100°C and maintained for 5 minutes. A large amount of yellow solid was generated in the system, and the reaction of the raw material was monitored to be complete. After cooling, water was added, filtered, the filter cake was collected, washed and dried to obtain 2-(diphenylmethyl)quinuclide-3-one (569mg, 79%).

[0044] Embodiments 4 to 13

[0045] Referring to the feeding and process of Example 1, different bases (Table 1) were used to replace the lithium diisopropylamide in Example 1. The other steps and parameters were the same as those in Example 1. The effects on the reaction were as follows:

[0046] Table 1 Synthesis parameters and results of Examples 4 to 13

[0047] Example Alkali Equivalent of base (eq.) Yield (%) Example 4 Lithium Bis(trimethylsilyl)amide 2.0 87 Example 5 Sodium bis(trimethylsilyl)amide 2.0 85 Example 6 Potassium bis(trimethylsilyl)amide 2.0 80 Example 7 Potassium hydroxide 2.0 24 Example 8 Sodium hydroxide 2.0 26 Example 9 Cesium Hydroxide 2.0 33 Example 10 Potassium tert-butoxide 2.0 61 Embodiment 11 Sodium tert-butoxide 2.0 62 Example 12 Lithium diisopropylamide 1.0 68 Embodiment 13 Lithium diisopropylamide 5.0 55

[0048] Examples 4 to 13 show that the reaction can be carried out in different organic bases or inorganic bases and different equivalents to efficiently synthesize 2-(diphenylmethyl)quinuclidine-3-one, and the reaction is better in organic bases.

[0049] Examples 14 to 29

[0050] Referring to the feeding and process of Example 1, the ethylene glycol diethyl ether in Example 1 was replaced with different solvents (Table 2), the reaction temperature was changed, and the other steps and parameters were the same as in Example 1. The effects on the reaction were as follows:

[0051] Table 2 Synthesis parameters and results of Examples 14 to 29

[0052]

[0053]

[0054] Examples 14 to 29 show that the reaction can be carried out in different solvents and temperatures to efficiently synthesize 2-(diphenylmethyl)quinuclidine-3-one, and the reaction is better in ether solvents.

[0055] Embodiments 30 to 33

[0056] Referring to the feeding and process of Example 1, the feeding molar ratio of 3-quinuclidinone, diphenyl ketone and base is shown in Table 3, and the other steps and parameters are the same as those in Example 1, and the effects on the reaction are as follows:

[0057] Table 3 Synthesis parameters and results of Examples 30 to 33

[0058] Example Molar Ratio Yield (%) Embodiment 30 1：1：1 70 Embodiment 31 1：1.2：1.5 84 Embodiment 32 1：2：2 85 Embodiment 33 1：5：5 73

[0059] Examples 30 to 33 show that the reaction can proceed normally under different raw material ratios and 2-(diphenylmethyl)quinuclidine-3-one can be efficiently synthesized.

[0060] Embodiments 34 to 36

[0061] Referring to the feeding and process of Example 3, different 3-quinuclidine ketone salts were used to replace 3-quinuclidine ketone hydrochloride (Table 4), and the other steps and parameters were the same as those in Example 3, which had the following effects on the reaction:

[0062] Table 4 Synthesis parameters and results of Examples 34 to 36

[0063] Example raw material Yield (%) Embodiment 34 3-Quinuclidinone sulfate 70 Embodiment 35 3-Quinuclidinone Nitrate 70 Embodiment 36 3-Quinuclidinone hydrobromide 71

[0064] Examples 34 to 36 show that different salts of 3-quinuclidine ketone can participate in the reaction normally and efficiently synthesize 2-(diphenylmethyl)quinuclidine-3-one.

[0065] Embodiment 37

[0066] 3-Quinuclidene (0.5mmol, 1.0eq), benzophenone (0.75mmol, 1.5eq) and ethylene glycol diethyl ether (1.5mL) were added to a 25mL reaction bottle under nitrogen atmosphere, stirred and LDA diisopropylamide lithium (2.0eq) was added dropwise at 25°C, then the temperature was raised to 100°C and maintained for 2 hours, and the reaction of the raw materials was monitored to be complete. After cooling, water was added, filtered, the filter cake was collected, washed and dried to obtain 2-(diphenylmethyl)quinuclidene-3-one (100mg, 70%).

[0067] Embodiment 38

[0068] 3-Quinuclide hydrochloride (0.5mmol, 1.0eq), benzophenone (0.75mmol, 1.5eq) and ethylene glycol diethyl ether (1.5mL) were added to a 25mL reaction bottle under nitrogen atmosphere, stirred and LDA lithium diisopropylamide (3.0eq) was added dropwise at 25°C, then the temperature was raised to 100°C and maintained for 2 hours, and the reaction of the raw materials was monitored to be complete. After cooling, water was added, filtered, the filter cake was collected, washed and dried to obtain 2-(diphenylmethyl)quinuclide-3-one (97mg, 68%).

[0069] Compared with Example 1, the results of Examples 37 to 38 show that changing the order of adding the raw materials does not affect the efficient synthesis of 2-(diphenylmethyl)quinuclidine-3-one.

[0070] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing 2-(diphenylmethyl)quinuclidine-3-one, characterized in that: The following steps are involved: 3-quinuclidine ketone or its salt represented by formula (I) and diphenyl ketone represented by formula (II) are used as raw materials, and reacted under the conditions of base and solvent to prepare 2-(diphenylmethyl)quinuclidine-3-one represented by formula (III):

2. The preparation method according to claim 1, characterized in that: The base is an organic base or an inorganic base.

3. The preparation method according to claim 2, characterized in that: The organic base includes one or more of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.

4. The preparation method according to claim 2, characterized in that: The inorganic base includes one or more of potassium hydroxide, sodium hydroxide and cesium hydroxide.

5. The preparation method according to claim 1, characterized in that: The solvent includes one or more of diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, tetrahydrofuran, 2-methylfuran, 1,4-dioxane, n-hexane, n-heptane, toluene, benzene, chlorobenzene, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.

6. The preparation method according to claim 1, characterized in that: The reaction temperature is 0-120°C.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the 3-quinuclidinone or its salt, diphenyl ketone and the base is 1:(1-5):(1-5).

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