A process for the preparation of 2-(diphenylalkenyl)quinuclidin-3-ones

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-(diphenylalkenyl)quinuclidin-3-one. The 3-quinuclidinone or a salt thereof and the benzophenone are used as raw materials, and the reaction is carried out under the condition of a base and a solvent, so that the core intermediate 2-(diphenylalkenyl)quinuclidin-3-one in a maropitant synthesis path is successfully prepared. The raw material of the above method is cheap and easy to obtain, the reaction only needs one step, the reaction time is relatively short, the operation is simple, efficient and convenient for post-treatment, the yield is excellent, and the method has obvious competitive advantages in production cost.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology. More specifically, it relates to a method for preparing 2-(diphenylmethylene)quinine-3-one. Background Technology

[0002] Maropitant is a quinine NK1 receptor antagonist, developed by Pfizer, and was 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. This drug has advantages such as easy absorption, wide distribution, rapid onset of action, high bioavailability, long duration of action, and good safety.

[0003] However, a key challenge in the preparation of maloppitan lies in the selection and optimization of its synthetic route. In particular, 2-(diphenylmethylene)quinine-3-one, as the core intermediate in the maloppitan synthetic route, directly affects the production cost and supply stability of maloppitan due to its synthetic efficiency and cost.

[0004] For example, Chinese patent application CN106977512A discloses a method for preparing a free base of maloppitant, which uses 3-oxoquinine ring-2-carboxylic acid ester as a starting material to prepare 2-(diphenylmethylene)quinine ring-3-one:

[0005]

[0006] However, the starting material for the above-mentioned methods of preparing maropitant—3-oxoquinine ring-2-carboxylic acid ester—faces challenges such as difficulty in directly purchasing it from commercial channels, high market prices, or the need for separate preparation through a series of complex and cumbersome multi-step reactions (CN107721999A, CN110922401A). These preparation conditions not only increase production costs but also make the entire synthesis process more complex and time-consuming, thus limiting the large-scale production and widespread application of maropitant.

[0007] Therefore, finding a simpler, more economical, and more efficient method for preparing 2-(diphenylmethylene)quinine-3-one is of great significance for optimizing the synthetic route of maloppitan 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 existing technology for synthesizing 2-(diphenylmethylene)quinine-3-one, which has expensive raw materials, long routes, complex processes and high costs. The present invention provides a method for preparing 2-(diphenylmethylene)quinine-3-one, which requires only one reaction, is simple and efficient and has convenient post-processing, has excellent yield and has a significant competitive advantage in production cost.

[0009] The above-mentioned objective of this invention is achieved through the following technical solution:

[0010] This invention protects a method for preparing 2-(diphenylmethylene)quinine-3-one, comprising the following steps: using 3-quinine-3-one of formula (I) or its salt and diphenyl ketone of formula (II) as raw materials, reacting under alkaline and solvent conditions to prepare 2-(diphenylmethylene)quinine-3-one of formula (III):

[0011]

[0012] Further, the specific operation of the preparation method is as follows: after mixing 3-quininecycloone or its salt with a solvent, add alkali and mix thoroughly, then add benzophenone, react under stirring conditions, and after the reaction is complete, post-treatment is performed to obtain 2-(dibenzoyl)quininecyclo-3-one.

[0013] Further, the specific operation of the preparation method is as follows: 3-quininecycloone or its salt, benzophenone and solvent are mixed, then alkali is added, and the reaction is carried out under stirring. After the reaction is complete, the product is post-treated to obtain 2-(dibenzoyl)quininecyclo-3-one.

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

[0015] Furthermore, the drying process is called baking.

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

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

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

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

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

[0024] Further, the salts of the 3-quinine cycloketone include one or more of the following: 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] Further, the molar ratio of the 3-quininecycloketone or its salt, diphenyl ketone, and base is 1:(1-5):(1-5). When using a salt of 3-quininecycloketone as a raw material, one equivalent of base can be added to remove the salt.

[0032] Preferably, the molar ratio of the 3-quinine cycloketone 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] This invention utilizes 3-quininecycloketone or its salts with diphenyl ketone as raw materials, reacting under alkaline and solvent conditions to successfully prepare 2-(diphenylmethylene)quininecyclo-3-one, a core intermediate in the maropistant synthesis pathway. The method described above uses inexpensive and readily available raw materials, requires only one reaction step, has a short reaction time, is simple and efficient, and offers convenient post-processing, resulting in excellent yields and a significant competitive advantage in production costs. Detailed Implementation

[0035] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field.

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

[0037] Example 1

[0038] Under a nitrogen atmosphere, 3-quininecycloone (2 mmol, 250 mg, 1.0 eq) and ethylene glycol diethyl ether (6 mL) were added to a 25 mL reaction flask. The mixture was stirred, and lithium diisopropylamino (2.0 eq) was added dropwise at 25 °C. After stirring for 5 minutes, benzophenone (3 mmol, 546 mg, 1.5 eq) was added. The temperature was then raised to 100 °C and maintained for 5 minutes. A large amount of yellow solid was produced, and the reaction was monitored until the reaction was complete. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (529 mg, 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-quininecycloone (25 mmol, 3.13 g, 1.0 eq) and ethylene glycol diethyl ether (45 mL) were added to a 500 mL reaction flask. The mixture was stirred, and lithium diisopropylamino (2.0 eq) of LDA was added dropwise at 0 °C. After stirring for 5 minutes, benzophenone (37.5 mmol, 6.8 g, 1.5 eq) was added. The temperature of the system was then raised to 100 °C and maintained for 10 minutes. A large amount of yellow solid was formed in the system, and the reaction was monitored to indicate completion. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (5.4 g, 75%).

[0042] Example 3

[0043] 3-quininecyclohexanone hydrochloride (2.5 mmol, 404 mg, 1.0 eq) and ethylene glycol diethyl ether (3.5 mL) were added to a 25 mL reaction flask. The mixture was stirred, and LDA (3.0 eq) was added dropwise at 25 °C. After stirring for 5 minutes, benzophenone (3.75 mmol, 683 mg, 1.5 eq) was added. The temperature was then raised to 100 °C and maintained for 5 minutes. A large amount of yellow solid was formed, and the reaction was monitored until completion. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (569 mg, 79%).

[0044] Examples 4-13

[0045] Referring to the feeding and process of Example 1, the diisopropylaminolithium in Example 1 was replaced with different bases (Table 1), while other steps and parameters were the same as in Example 1. The effects on the reaction are as follows:

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

[0047] Example alkali Base equivalent (eq.) Yield (%) Example 4 Lithium bis(trimethylsilylamine) 2.0 87 Example 5 Sodium bis(trimethylsilylamino) 2.0 85 Example 6 Ditrimethylsilylaminopotassium 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 Example 11 Sodium tert-butoxide 2.0 62 Example 12 Lithium diisopropylaminodimethylamine 1.0 68 Example 13 Lithium diisopropylaminodimethylamine 5.0 55

[0048] Examples 4-13 show that the reaction can be carried out under different organic or inorganic bases and different equivalences, and the 2-(diphenylmethylene)quinine-3-one can be synthesized efficiently, with the reaction being even better in organic bases.

[0049] Examples 14-29

[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 other steps and parameters were the same as in Example 1. The effects on the reaction are as follows:

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

[0052]

[0053]

[0054] Examples 14–29 demonstrate that the reaction can be carried out in different solvents and temperatures, resulting in the efficient synthesis of 2-(diphenylmethylene)quinine-3-one, with the reaction being even more favorable in ether solvents.

[0055] Examples 30-33

[0056] Referring to the feeding and process of Example 1, the molar ratios of 3-quininecycloone, diphenyl ketone, and base are shown in Table 3. Other steps and parameters are the same as in Example 1, and their effects on the reaction are as follows:

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

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

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

[0060] Examples 34-36

[0061] Referring to the feeding and process of Example 3, except that different 3-quinine cyclic ketone salts were used instead of 3-quinine cyclic ketone hydrochloride (Table 4), and other steps and parameters were the same as in Example 3, the effects on the reaction are as follows:

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

[0063] Example raw material Yield (%) Example 34 3-Quinine Cycloketone Sulfate 70 Example 35 3-Quinine cycloketone nitrate 70 Example 36 3-Quinine-cyclic ketone hydrobromide 71

[0064] Examples 34-36 demonstrate that different salts of 3-quininecycloketones can participate in the reaction normally, enabling the efficient synthesis of 2-(diphenylmethylene)quininecyclo-3-one.

[0065] Example 37

[0066] Under a nitrogen atmosphere, 3-quininecycloone (0.5 mmol, 1.0 eq), benzophenone (0.75 mmol, 1.5 eq), and ethylene glycol diethyl ether (1.5 mL) were added to a 25 mL reaction flask. The mixture was stirred, and lithium diisopropylamino (2.0 eq) of LDA was added dropwise at 25 °C. The temperature was then raised to 100 °C and maintained for 2 hours, monitoring for the completion of the reaction. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (100 mg, 70%).

[0067] Example 38

[0068] Under a nitrogen atmosphere, 0.5 mmol (1.0 eq) of 3-quininecycloketone hydrochloride, 0.75 mmol (1.5 eq) of benzophenone, and 1.5 mL of ethylene glycol diethyl ether solvent were added to a 25 mL reaction flask. The mixture was stirred, and 3.0 eq of lithium diisopropylaminol (LDA) was added dropwise at 25 °C. The temperature was then raised to 100 °C and maintained for 2 hours, monitoring the reaction progress until completion. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 97 mg (68%) of 2-(dibenzoyl)quininecyclo-3-one.

[0069] Compared with Example 1, the results of Examples 37-38 show that changing the order of adding raw materials does not affect the efficient synthesis of 2-(diphenylmethylene)quinine-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 implementation of the present invention. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A process for the preparation of 2-(diphenylalkenyl)quinuclidin-3-one, characterized in that, The method comprises the following steps: 2-(diphenyl methylene) quinuclidine-3-ketone shown in formula (III) is prepared by using 3-quinuclidinone shown in formula (I) or a salt thereof and diphenyl ketone shown in formula (II) as raw materials, and reacting under the condition of a base and a solvent.

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 comprises one or more of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, 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 comprises one or more of potassium hydroxide, sodium hydroxide and cesium hydroxide.

5. The method of claim 1, wherein the step of forming the first and second layers is performed by a process selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The solvent comprises 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, trichloromethane, dichloroethane, N,N-dimethylformamide and N,N-dimethylacetamide.

6. The method of claim 1, wherein the step of forming the first and second layers is performed by a process selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The temperature of the reaction is 0-120 DEG C.

7. The method of claim 1, wherein the step of forming the first and second layers is performed by a process selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The molar ratio of the 3-quinuclidinone or the salt thereof, the diphenyl ketone and the base is 1:(1-5):(1-5).

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