A compound and a method for preparing the same

Abstract

The application discloses a compound, which has the following general structural formula: formula (I); in the formula (I), R1 is hydrogen or a hydrocarbon group; R2 is an ether group or a sulfide group; wherein, R3 is an alkylene group, R4 is hydrogen or an alkyl group, and R5 is an alkyl group. The application develops a new synthetic route of the compound, and the route uses microwave reaction, so that the reaction time is shorter, the yield and purity of the prepared compound (such as denaverine hydrochloride) are higher, and the method is a very good new method.

Description

Technical Field

[0001] This invention relates to the technical field of compound synthesis, and specifically to a compound and its preparation method. Background Technology

[0002] This invention relates to novel benzoic acid derivatives, which are neuromuscular antispasmodics with additional analgesic activity.

[0003] To date, the only known benzoic acid derivative reported is denaverine hydrochloride. In the veterinary field, denaverine hydrochloride injection was first applied for marketing approval in Germany on April 26, 2017, under the brand name Sensiblex. Denaverine has a relaxant effect on smooth muscle. It relaxes the uterus before parturition and increases the elasticity of the soft birth canal. In addition, denaverine also has surface anesthetic and anticonvulsant effects, as well as mild sedative and antipyretic effects, and is currently marketed in more than 20 countries in the European Union. In the human field, denaverine has been successfully used for more than 25 years to treat smooth muscle spasms of the gastrointestinal and genitourinary tracts, as well as obstetric conditions.

[0004] Regarding the production of denaveline, Chinese patent CN 113061095A discloses a method for synthesizing denaveline hydrochloride:

[0005]

[0006] First, the raw material 2,2-diphenyl-2-hydroxyacetic acid is reacted with acyl chloride, and then 2-ethylbutanol and a base are added to react and obtain the intermediate 2-(2-ethylbutoxy)-2,2-diphenylacetic acid. Then, a base and N,N-dimethylaminochloroethane hydrochloride are added to the intermediate to react and finally hydrogen chloride gas is passed through. After a period of time, the mixture is concentrated, ethyl acetate is added, and the mixture is filtered to obtain denavirine hydrochloride.

[0007] Chinese patent CN 113979873 A discloses a method for preparing denaveline hydrochloride: the method uses 2,2-diphenyl-2-hydroxyacetic acid as a raw material, adds thionyl chloride reagent, and reacts the carboxyl group in the 2,2-diphenyl-2-hydroxyacetic acid molecule to form acyl chloride in one step, and benzyl alcohol to form benzyl chloride; then, under certain conditions, dimethylaminoethanol is added and reacts with acyl chloride to obtain ester, and then 2-ethylbutanol is added and the reaction conditions are controlled to react with benzyl chloride to obtain denaveline hydrochloride.

[0008]

[0009] European patent EP0537608 discloses a method for preparing denaveline hydrochloride, which uses 2,2-diphenyl-2-hydroxyacetic acid as a raw material, adds dimethylaminochloroethane hydrochloride to react and obtain an esterification product of 2,2-diphenyl-2-hydroxyacetic acid and dimethylaminochloroethane, then adds thionyl chloride to carry out a chlorination reaction, and then reacts with 2-ethylbutanol at high temperature to obtain denaveline hydrochloride.

[0010]

[0011] However, the three existing routes all utilize chlorine atoms on acyl chlorides, which easily lead to side reactions and byproducts. This negatively impacts the impurities and yield of the final product, denaveline hydrochloride, and the overall reaction time is quite long. Therefore, there is a need to develop a production method for denaveline hydrochloride that offers high efficiency and good preparation results. Summary of the Invention

[0012] The purpose of this invention is to overcome the deficiencies in existing technologies and provide a compound and its preparation method. This invention develops a novel process for preparing benzoic acid derivatives (including denavitine). This route utilizes a microwave reaction, which not only shortens the reaction time but also results in higher yields and purity of the prepared compounds (such as denavitine hydrochloride), making it a highly effective new method. The novel route developed in this invention uses a microwave reactor, completing the reaction in just a few minutes. Compared to existing technologies, the overall time is shorter, and the prepared products exhibit higher purity and yield.

[0013] To achieve the above objectives, the technical solution of the present invention is as follows:

[0014] The first aspect of the present invention is to provide a compound having the following general structural formula:

[0015]

[0016] In formula (I), R1 is a hydrogen or hydrocarbon group;

[0017] R2 is Ether group or thioether group; wherein R3 is alkylene, R4 is hydrogen or alkyl; and R5 is alkyl.

[0018] In a preferred embodiment, in formula (I), R1 is hydrogen or an alkyl group; preferably, R1 is hydrogen or a C1-C8 alkyl group; more preferably, R1 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

[0019] As a preferred implementation method,

[0020] R2 is The group is a C2-C8 ether group or a C2-C8 thioether group; wherein R3 is a C1-C6 alkylene group, R4 is hydrogen or a C1-C6 alkyl group, and R5 is a C1-C6 alkyl group;

[0021] Preferably,

[0022] R2 is Its structure includes:

[0023]

[0024] And / or,

[0025] R2 is a C2-C8 ether group, and its structure includes:

[0026] And / or,

[0027] R2 is a C2-C8 thioether group, and its structure includes:

[0028]

[0029] A second aspect of the present invention is to provide a method for preparing a compound as described in the first aspect of the present invention, comprising the following steps:

[0030] (1) R2-OH and After mixing, acid is added and mixed evenly, then microwave reaction is carried out, followed by post-processing to obtain intermediate I;

[0031] (2) Mix intermediate I, solvent, R1-X, base and catalyst evenly, then carry out microwave reaction, and post-process to obtain the compound;

[0032] The structural formula of intermediate I is as follows:

[0033]

[0034] R2 corresponds to the same R2 described in the first aspect of the present invention;

[0035] Wherein, R6 is a hydroxyl group or a halogen, preferably a chlorine atom;

[0036] R1 in R1-X corresponds to the same R1 described in the first aspect of the present invention; X is a halogen.

[0037] Microwave reaction principle: When a solution is irradiated with microwaves, polar molecules in the solution absorb microwave energy. Simultaneously, these energy-absorbing polar molecules transfer energy to other molecules through collisions, thus raising the liquid temperature. Because every polar molecule in the liquid simultaneously transfers and absorbs energy, the reaction proceeds rapidly. Since microwave reactions are intermolecular reactions, the entire reaction is very fast; reactions that would normally take a long time can be completed in just a few minutes using microwaves. However, some solvents cannot undergo microwave reactions, such as non-polar solvents like dichloromethane, toluene, and chloroform. The route described in this paper solves the problems of long reaction times and long reaction routes.

[0038] As a preferred embodiment, in step (1),

[0039] R2-OH and The molar ratio is 100 to 1:1;

[0040] The acid added was concentrated sulfuric acid.

[0041] As a preferred embodiment, in step (1),

[0042] The volume ratio of R2-OH to the added acid is 10 to 1:1; and / or,

[0043] The microwave reaction time is 2-10 minutes.

[0044] In a preferred embodiment, in step (2),

[0045] The solvent is at least one of DMSO, NMP, and DMF; and / or,

[0046] R1-X is selected from at least one of 2-ethylbromobutane, 2-ethylchlorobutane, and 2-ethyliodobutane; and / or,

[0047] The base is selected from triethylamine; and / or,

[0048] The catalyst is selected from at least one of DMAP and 4-dimethylaminopyridine.

[0049] In a preferred embodiment, in step (2),

[0050] The molar ratio of solvent to intermediate I is 100 to 1:1; and / or,

[0051] The molar ratio of intermediate I to R1-X is 1:1.05-10.

[0052] In a preferred embodiment, in step (2),

[0053] The molar ratio of intermediate I to base is 1:1.05-5; and / or,

[0054] The molar ratio of catalyst to intermediate I is 0.1-10:100.

[0055] In a preferred embodiment, in step (2),

[0056] The microwave reaction time is 3–10 minutes; and / or,

[0057] Microwave reaction power range: 200W-1000W.

[0058] As a preferred embodiment, in step (1),

[0059] Post-processing method: Add water to the reactants, then extract with an extractant, dry, and concentrate to obtain intermediate I;

[0060] Preferably, the extractant is dichloromethane, and the drying agent is anhydrous sodium sulfate.

[0061] In a preferred embodiment, in step (2),

[0062] Post-processing method: Water is added to the reactants, then extracted with an extractant, and concentrated acid is added to precipitate the solid, yielding the compound hydrochloride.

[0063] Preferably, the extractant is dichloromethane, and the concentrated acid is at least one of concentrated hydrochloric acid and concentrated sulfuric acid.

[0064] The present invention relates to benzoic acid derivatives, which are neuromuscular antispasmodics with additional analgesic activity, used to treat smooth muscle spasms of the gastrointestinal and genitourinary tracts, as well as obstetric conditions.

[0065] The complete reaction process of a compound of the present invention (such as denavirine hydrochloride) is as follows:

[0066]

[0067] Compared with the prior art, the present invention has at least the following advantages:

[0068] This invention opens up a new reaction route, which has the advantages of short route, short reaction time, high yield, easy processing, short time consumption and low cost. Attached Figure Description

[0069] Figure 1 This is the HPLC chromatogram of denaveline hydrochloride from Example 1 of the present invention;

[0070] Figure 2 This is the LC-MS spectrum of denaveline hydrochloride from Example 1 of the present invention. Detailed Implementation

[0071] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0072] The microwave reactor used in the embodiments and comparative examples of this invention is model WBFY-201.

[0073] Example 1

[0074]

[0075] Add 19.5 g (219 mmol) of dimethylaminoethanol and 5.0 g (21.9 mmol) of 2,2-diphenyl-2-hydroxyacetic acid to a dry 100 ml single-necked reaction flask. Stir until dissolved, then add 5 drops of concentrated sulfuric acid. After the addition is complete, place the flask in a microwave reactor, set the power to 500 W, turn on the stirrer, and microwave the reaction. Stop the reaction after 2 minutes, remove the flask, pour it into 100 ml of water, extract three times with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to dryness; yield 6.1 g of intermediate I, with a yield of 93.8%.

[0076] Add 30 ml of DMSO to 6.1 g (20 mmol) of intermediate I, then add 16.6 g (100 mmol) of 2-ethylbutane, 3.0 g (30 mmol) of triethylamine, and 0.1 ml (1 mmol) of DMAP (4-dimethylaminopyridine). Stir to dissolve, and react in a microwave reactor at 500 W for 3 minutes. Remove the mixture, pour it into 120 ml of water, extract with dichloromethane, and add concentrated hydrochloric acid to precipitate 6.3 g of denavirine hydrochloride (purity: 99.6%), yield: 96.9%.

[0077] Example 2

[0078]

[0079] 20.6 g (0.2 mol) of dimethylaminopropanol and 11.4 g (0.02 mmol) of 2,2-diphenyl-2-hydroxyacetic acid (compound 1) were added to a dry 100 ml single-necked reaction flask. The mixture was stirred until dissolved, and 5 drops of concentrated sulfuric acid were added. After the addition was complete, the flask was placed in a microwave reactor, the power was set to 500 W, and the stirring was turned on to carry out the microwave reaction. The reaction was stopped after 3 minutes, and the mixture was poured into 300 ml of water. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 13.35 g of product compound 2, with a yield of 81.65%.

[0080] Add 30 ml of DMSO to 10.0 g (0.03 mol) of compound 2, then add 9.84 g (0.06 mmol) of 2-ethylbutane and 6.06 g (0.06 mol) of triethylamine, and 0.1 ml (1 mmol) of DMAP (4-dimethylaminopyridine). Stir to dissolve, and react in a microwave reactor at 500 W for 3 minutes. Remove the mixture, pour it into 300 ml of water, extract with dichloromethane, and add concentrated hydrochloric acid to precipitate 9.8 g of compound 3 (purity: 98.9%, yield: 75.4%).

[0081] The compound prepared in Example 2 of this invention is used for treating smooth muscle spasms of the gastrointestinal tract and urogenital tract, as well as in obstetrics and gynecology.

[0082] The NMR test data are as follows: HNMR (400MHZ, CDCl3) δ=7.32-7.42(m,10H), 4.71(b,2H), 3.16(t,4H), 2.41(s,6H), 1.30-1.40(m,5H), 0.78-0.80(t,6H).

[0083] Example 3

[0084]

[0085] Add 9.2 g (0.1 mol) of dimethylthioethanol to a dry 100 ml single-necked reaction flask, then add 2.28 g (0.01 mmol) of 2,2-diphenyl-2-hydroxyacetic acid (compound A), stir until dissolved, add 3 drops of concentrated sulfuric acid, and after the addition is complete, place the flask in a microwave reactor, set the power to 500 W, turn on the stirrer, and carry out the microwave reaction. After 3 minutes, stop the reaction, remove the flask, pour it into 150 ml of water, extract three times with dichloromethane, dry with anhydrous sodium sulfate, and concentrate to dryness; yield 2.5 g of product compound B, yield 82.7%.

[0086] 2.5 g (8.2 mmol) of compound B was added to 15 ml of DMF, followed by 2.7 g (16.4 mmol) of 2-ethylbutane, 1.6 g (16.4 mol) of triethylamine, and 0.05 ml (0.5 mmol) of DMAP (4-dimethylaminopyridine). The mixture was stirred to dissolve the solid, and then reacted in a microwave reactor at 500 W for 3 minutes. The mixture was then removed, poured into 100 ml of water, and the solid precipitated. The solid was then crystallized with ethyl acetate to give 2.3 g of compound C with a purity of 98% and a yield of 79.3%.

[0087] The NMR test data are as follows: HNMR (400MHZ, CDCl3) δ=7.32-7.42(m,10H), 4.70(b,2H), 3.16(t,4H), 2.96(t,2H), 2.19(s,3H), 1.30-1.40(m,3H), 0.78-0.80(t,6H).

[0088] The compound prepared in Example 3 of this invention is used for treating smooth muscle spasms of the gastrointestinal tract and urogenital tract, as well as in obstetrics and gynecology.

[0089] The above embodiments are merely illustrative examples and are not intended to limit the implementation. 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 list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing a compound, characterized in that, Includes the following steps: (1) R2-OH and After mixing, acid is added and mixed evenly, then microwave reaction is carried out, followed by post-processing to obtain intermediate I; (2) Intermediate I, solvent, R1-X, base and catalyst are mixed evenly, and then microwave reaction is carried out. After post-treatment, the compound is obtained. The solvent is at least one of DMSO, NMP and DMF. The base is selected from triethylamine. The catalyst is selected from 4-dimethylaminopyridine. The structural formula of intermediate I is as follows: R2 is selected from: or, R2 is selected from: In this context, R6 represents a hydroxyl group or a halogen. In R1-X, R1 is hydrogen or a C1-C8 alkyl group; X is a halogen. The compound has the following general structural formula: In equation (I), R1 corresponds to R1 in R1-X, and R2 corresponds to R2 in intermediate I.

2. The method for preparing the compound according to claim 1, characterized in that: In step (1), R2-OH and The molar ratio is 100 to 1:1; The acid added was concentrated sulfuric acid.

3. The method for preparing the compound according to claim 1, characterized in that: In step (1), The volume ratio of R2-OH to the added acid is 10 to 1:1; The microwave reaction time is 2-10 minutes.

4. The method for preparing the compound according to claim 1, characterized in that: In step (2), R1-X is selected from at least one of 2-ethylbromobutane, 2-ethylchlorobutane, and 2-ethyliodobutane.

5. The method for preparing the compound according to claim 1, characterized in that: In step (2), The molar ratio of solvent to intermediate I is 100 to 1:1; The molar ratio of intermediate I to R1-X is 1:1.05-10.

6. The method for preparing the compound according to claim 1, characterized in that: In step (2), The molar ratio of intermediate I to base is 1:1.05-5; The molar ratio of catalyst to intermediate I is 0.1-10:

100.

7. The method for preparing the compound according to claim 1, characterized in that: In step (2), The microwave reaction time is 3 to 10 minutes; Microwave reaction power range: 200W-1000W.

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