CN112574097A - Preparation method of Ebastine and fumarate thereof - Google Patents
Preparation method of Ebastine and fumarate thereof Download PDFInfo
- Publication number
- CN112574097A CN112574097A CN202011524113.3A CN202011524113A CN112574097A CN 112574097 A CN112574097 A CN 112574097A CN 202011524113 A CN202011524113 A CN 202011524113A CN 112574097 A CN112574097 A CN 112574097A
- Authority
- CN
- China
- Prior art keywords
- solvent
- diphenylmethoxy
- piperidine
- dimethylethyl
- butanone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of Ebastine and fumarate thereof. The preparation method comprises the following steps: 1) mixing 4- (diphenylmethoxy) piperidine, 4' -tert-butyl-4-chlorobutyrophenone, an acid-binding agent and a first solvent for a synthetic reaction, adding a second solvent and water after the reaction is finished, and stirring and layering to obtain an organic layer and an inorganic layer; 2) concentrating the organic layer, adding a third solvent or the third solvent and fumaric acid, filtering and drying to obtain 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone or a fumarate thereof. By applying the technical scheme of the invention, the solvent-free or low-solvent synthesis has the advantages of solvent saving, cost reduction, environmental friendliness and the like.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone and fumarate thereof.
Background
Ebastine (chemical name: 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone) is a long-acting non-sedative second-generation histamine H1 receptor antagonist, has obvious curative effect on allergic rhinitis, small lethargy effect and convenient administration; can be used for treating allergic diseases such as seasonal allergic rhinitis, chronic idiopathic urticaria, eczema, asthma, and skin pruritus; compared with cetirizine, the product has more obvious effect.
The methods for preparing the compound in an industrial production manner, which are disclosed at present, all need to use more solvents, so that the production cost is high, and the environmental pollution is easily caused; in addition, the problems of high yield and high cost exist at the same time.
Disclosure of Invention
The invention aims to provide a preparation method of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone and fumarate thereof, and aims to solve the technical problem that a preparation solvent of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone in the prior art is more in use.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone and a fumarate salt thereof. The preparation method comprises the following steps: 1) mixing 4- (diphenylmethoxy) piperidine, 4' -tert-butyl-4-chlorobutyrophenone, an acid-binding agent and a first solvent for a synthetic reaction, adding a second solvent and water after the reaction is finished, and stirring and layering to obtain an organic layer and an inorganic layer; 2) concentrating the organic layer, adding a third solvent or the third solvent and fumaric acid, filtering and drying to obtain 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone or 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone fumarate; wherein the addition volume of the first solvent is 0-2 times of the mass of 4- (diphenylmethoxy) piperidine, and the unit is mL: g (laboratory) or L: kg (industrial production); the volume of the second solvent is 0-5 times of the mass of 4- (diphenylmethoxy) piperidine, and the unit is mL: g or (laboratory) or L: kg (industrial production); the addition amount of the third solvent is 6-12 times, and the unit is mL: g or (laboratory) or L: kg (industrial production).
Further, the amount of the first solvent added was 1 time the mass of 4- (benzhydryloxy) piperidine.
Further, the first solvent is one or more of toluene, xylene or methyl isobutyl ketone.
Further, the second solvent is one or more of toluene, xylene, ethyl acetate, dichloromethane, methyl tert-butyl ether or methyl isobutyl ketone.
Further, the third solvent is an alcohol solvent, preferably ethanol.
Further, the acid-binding agent is carbonate or bicarbonate.
Further, the acid-binding agent is sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, magnesium carbonate or calcium bicarbonate; sodium bicarbonate is preferred.
Furthermore, the temperature of the synthesis reaction is 100-120 ℃, preferably 110 ℃, and the reaction time is 4-12 hours.
Furthermore, the adding molar weight ratio of the 4- (diphenylmethoxy) piperidine to the 4' -tert-butyl-4-chlorobutyrophenone is 1: 1-1: 2.
Furthermore, the adding molar weight ratio of the 4- (diphenylmethoxy) piperidine to the acid-binding agent is 1: 1-1: 4.
Further, the ratio of the added volume of the third solvent to the mass of the 4- (benzhydryloxy) piperidine in the step 2) is (1: 6) to (1: 12) the unit is mL: g or L: kg, the mass ratio of the added fumaric acid to the 4- (diphenylmethoxy) piperidine is (1: 0.8) - (1: 1.2).
By applying the technical scheme of the invention, the solvent-free or low-solvent synthesis of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone has the advantages of solvent saving, cost reduction, environmental friendliness and the like.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 1;
FIG. 2 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 2;
FIG. 3 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 3;
FIG. 4 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 4;
FIG. 5 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 5;
FIG. 6 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 6;
FIG. 7 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 7;
FIG. 8 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 8;
FIG. 9 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 9; and
FIG. 10 shows a chromatogram of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate prepared in example 10.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
The inventor of the invention finds that 4- (diphenylmethoxy) piperidine and 4' -tert-butyl-4-chlorobutyrophenone can be reacted with high yield under the condition of no solvent or a small amount of solvent, and has great cost advantage.
According to a typical embodiment of the present invention, there is provided a method for preparing 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone and its fumarate salt. The preparation method comprises the following steps: 1) mixing 4- (diphenylmethoxy) piperidine, 4' -tert-butyl-4-chlorobutyrophenone, an acid-binding agent and a first solvent for a synthetic reaction, adding a second solvent and water after the reaction is finished, and stirring and layering to obtain an organic layer and an inorganic layer; 2) concentrating the organic layer to dryness (i.e. volatilizing the solvent to dryness under normal pressure or reduced pressure), adding a third solvent or the third solvent and fumaric acid, filtering and drying to obtain 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone or 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone fumarate; wherein the adding volume of the first solvent is 0-2 times of the mass of 4- (diphenylmethoxy) piperidine, and the unit is mL: g. the volume of the second solvent is 0-5 times of the mass of 4- (diphenylmethoxy) piperidine, and the unit is mL: g; the volume of the third solvent is 6-12 times, and the unit is mL: g. preferably, the first solvent is added in an amount of 1 time the mass of the 4- (benzhydryloxy) piperidine.
Because the synthesis reaction needs to be carried out at a high temperature, such as 100-120 ℃, and the first solvent needs to be a solvent immiscible with water and capable of carrying out reflux water separation operation, it is preferable that the first solvent is one or more of toluene, xylene or methyl isobutyl ketone. When the solvent amount is 0, no solvent is used for refluxing and water diversion, water is completely carried out by boiling evaporation of water, the water removal effect is good when no solvent is added, the reaction effect is slightly poor, wherein the toluene cost is lowest, and the effect is best. The extraction operation requires a water-immiscible solvent in which 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone is well dissolved, preferably the second solvent is one or more of toluene, xylene, ethyl acetate, dichloromethane, methyl tert-butyl ether or methyl isobutyl ketone, where toluene is the lowest cost.
The third solvent has poor solubility for 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, can precipitate solid, and is selected from alcohol solvents such as methanol, ethanol, isopropanol or n-propanol, preferably ethanol, and has low toxicity and is suitable for medicinal use.
According to a typical embodiment of the invention, the acid scavenger is a carbonate or bicarbonate. Preferably, the acid-binding agent is sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, magnesium carbonate or calcium bicarbonate; more preferably sodium bicarbonate.
According to a typical embodiment of the invention, the temperature of the synthesis reaction is 110 ℃ and the reaction time is 4-12 hours. Preferably, the molar weight ratio of the 4- (diphenylmethoxy) piperidine to the 4' -tert-butyl-4-chlorobutyrophenone is 1: 1-1: 2, and the molar weight ratio of the 4- (diphenylmethoxy) piperidine to the acid-binding agent is 1: 1-1: 4.
Preferably, the ratio of the added volume of the third solvent to the mass of the 4- (benzhydryloxy) piperidine in step 2) is (1: 6) to (1: 12) the unit is mL: g or L: kg, the mass ratio of the added fumaric acid to the 4- (diphenylmethoxy) piperidine is (1: 0.8) - (1: 1.2).
The following examples are provided to further illustrate the advantageous effects of the present invention.
Example 1
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 7.9g of sodium bicarbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of raw materials is 96.55%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour for layering, 100ml of ethanol and 4.3g of fumaric acid are added after an organic layer is concentrated and dried, and the mixture is filtered and dried to obtain about 20.0g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 91.3% (a chromatogram of a final product is shown in figure 1, wherein the abscissa is time and the ordinate is absorbance).
Example 2
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone and 7.9g of sodium bicarbonate are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and a sample is taken, wherein the conversion rate of the raw material is 93.25%. After the temperature is reduced to room temperature, 50ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour for layering, 100ml of ethanol and 4.3g of fumaric acid are added after an organic layer is concentrated and dried, and the mixture is filtered and dried to obtain about 19.5g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 89.0 percent (a chromatogram of a final product is shown in figure 2).
Example 3
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 7.9g of sodium bicarbonate and 20ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of raw materials is 90.28%. After the temperature is reduced to room temperature, 30ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour for layering, 100ml of ethanol and 4.3g of fumaric acid are added after an organic layer is concentrated and dried, and about 18.3g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate is obtained after filtration and drying, and the yield is 83.6% (a chromatogram of a final product is shown in figure 3).
Example 4
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 7.9g of sodium bicarbonate and 50ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of the raw material is 79.78%. After the temperature is reduced to room temperature, 60ml of water is added into the reaction bottle, the mixture is stirred for 1 hour for layering, 100ml of ethanol and 4.3g of fumaric acid are added after an organic layer is concentrated and dried, and about 15.7g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate is obtained after filtration and drying, and the yield is 71.7% (a chromatogram of a final product is shown in figure 4).
Example 5
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone and 5.9g of sodium carbonate are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of raw materials is 49.52%. After the temperature is reduced to room temperature, 50ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 9.2g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 42.0 percent (a chromatogram of a final product is shown in figure 5).
Example 6
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 7.8g of potassium carbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of the raw material is 80.03%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 16.1g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 73.5% (a chromatogram of a final product is shown in FIG. 6).
Example 7
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 9.4g of potassium bicarbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred, heated to 110 ℃, kept warm for 8 hours and sampled, and the conversion rate of the raw materials is 50.26%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 10.1g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 46.1% (a chromatogram of a final product is shown in FIG. 7).
Example 8
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 4.1g of lithium carbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the temperature is raised to 110 ℃ by stirring, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of the raw materials is 71.55%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 14.4g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate, wherein the yield is 65.8% (a chromatogram of a final product is shown in FIG. 8).
Example 9
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 4.7g of magnesium carbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of the raw material is 57.81%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 11.2g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate with the yield of 51.1 percent (a chromatogram of a final product is shown in FIG. 9).
Example 10
10.0g of 4- (diphenylmethoxy) piperidine, 11.6g of 4' -tert-butyl-4-chlorobutyrophenone, 15.2g of calcium bicarbonate and 10ml of toluene are respectively added into a 250ml three-necked bottle, the mixture is stirred and heated to 110 ℃, the temperature is kept for 8 hours, and sampling is carried out, wherein the conversion rate of the raw material is 61.59%. After the temperature is reduced to room temperature, 40ml of toluene and 60ml of water are added into a reaction flask, the mixture is stirred for 1 hour and then layered, an organic layer is concentrated and dried, 100ml of ethanol and 4.3g of fumaric acid are added, and the mixture is filtered and dried to obtain about 12.5g of 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidinyl ] -1-butanone fumarate with the yield of 57.1 percent (a chromatogram of a final product is shown in FIG. 10).
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone and fumarate thereof is characterized by comprising the following steps:
1) mixing 4- (diphenylmethoxy) piperidine, 4' -tert-butyl-4-chlorobutyrophenone, an acid-binding agent and a first solvent for a synthetic reaction, adding a second solvent and water after the reaction is finished, and stirring and layering to obtain an organic layer and an inorganic layer;
2) concentrating the organic layer, adding a third solvent or the third solvent and fumaric acid, filtering and drying to obtain 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone or 1- [4- (1, 1-dimethylethyl) phenyl ] -4- [4- (diphenylmethoxy) -1-piperidyl ] -1-butanone fumarate;
wherein the adding volume of the first solvent is 0-2 times of the mass of 4- (benzhydryloxy) piperidine, and the unit is mL: g or L: kg; the volume of the second solvent is 0-5 times of the mass of 4- (benzhydryloxy) piperidine, and the unit is mL: g or L: kg; the volume of the third solvent is 6-12 times, and the unit is mL: g or L: and (kg).
2. The method of claim 1, wherein the first solvent is one or more of toluene, xylene, or methyl isobutyl ketone.
3. The method of claim 1, wherein the second solvent is one or more of toluene, xylene, ethyl acetate, methylene chloride, methyl tert-butyl ether, or methyl isobutyl ketone.
4. The method according to claim 1, wherein the third solvent is an alcohol solvent, preferably ethanol.
5. The method of claim 1, wherein the acid scavenger is a carbonate or bicarbonate.
6. The preparation method according to claim 5, wherein the acid scavenger is sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, magnesium carbonate or calcium bicarbonate; sodium bicarbonate is preferred.
7. The preparation method according to claim 1, wherein the temperature of the synthesis reaction is 100-120 ℃, preferably 110 ℃, and the reaction time is 4-12 hours.
8. The method according to claim 1, wherein the 4- (benzhydryloxy) piperidine and the 4' -tert-butyl-4-chlorobutyrophenone are added in a molar ratio of 1:1 to 1: 2.
9. The preparation method according to claim 1, wherein the molar weight ratio of 4- (benzhydryloxy) piperidine to the acid-binding agent is 1:1 to 1: 4.
10. The method according to claim 1, wherein the ratio of the volume of the third solvent added to the mass of 4- (benzhydryloxy) piperidine in step 2) is (1: 6) to (1: 12) the unit is mL: g or L: kg, the mass ratio of the added fumaric acid to the 4- (diphenylmethoxy) piperidine is (1: 0.8) - (1: 1.2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011524113.3A CN112574097B (en) | 2020-12-21 | 2020-12-21 | Preparation method of Ebastine and fumarate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011524113.3A CN112574097B (en) | 2020-12-21 | 2020-12-21 | Preparation method of Ebastine and fumarate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112574097A true CN112574097A (en) | 2021-03-30 |
| CN112574097B CN112574097B (en) | 2023-01-03 |
Family
ID=75136587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011524113.3A Active CN112574097B (en) | 2020-12-21 | 2020-12-21 | Preparation method of Ebastine and fumarate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112574097B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134124A1 (en) * | 1983-08-05 | 1985-03-13 | Fordonal, S.A. | Piperidine derivatives |
| EP2371817A1 (en) * | 2010-04-01 | 2011-10-05 | Arevipharma GmbH | Process for the preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone and acid addition salts thereof |
| CN102558083A (en) * | 2010-12-22 | 2012-07-11 | 上海药明康德新药开发有限公司 | Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound |
| CN103864624A (en) * | 2014-03-05 | 2014-06-18 | 湖北大学 | Simple method for efficiently preparing secondary amine through alkali catalyzed N-alkylation |
| CN109265439A (en) * | 2018-10-31 | 2019-01-25 | 西北大学 | A kind of 1-(2- pyridyl group) indoline derivative object no-solvent synthesis process |
| CN109593058A (en) * | 2019-01-23 | 2019-04-09 | 江苏联环药业股份有限公司 | A kind of preparation method of Ebastine |
| CN109694335A (en) * | 2017-10-23 | 2019-04-30 | 西华大学 | The non-solvent preparation of disubstituted para orientation nitration derivative |
-
2020
- 2020-12-21 CN CN202011524113.3A patent/CN112574097B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134124A1 (en) * | 1983-08-05 | 1985-03-13 | Fordonal, S.A. | Piperidine derivatives |
| EP2371817A1 (en) * | 2010-04-01 | 2011-10-05 | Arevipharma GmbH | Process for the preparation of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone and acid addition salts thereof |
| CN102558083A (en) * | 2010-12-22 | 2012-07-11 | 上海药明康德新药开发有限公司 | Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound |
| CN103864624A (en) * | 2014-03-05 | 2014-06-18 | 湖北大学 | Simple method for efficiently preparing secondary amine through alkali catalyzed N-alkylation |
| CN109694335A (en) * | 2017-10-23 | 2019-04-30 | 西华大学 | The non-solvent preparation of disubstituted para orientation nitration derivative |
| CN109265439A (en) * | 2018-10-31 | 2019-01-25 | 西北大学 | A kind of 1-(2- pyridyl group) indoline derivative object no-solvent synthesis process |
| CN109593058A (en) * | 2019-01-23 | 2019-04-09 | 江苏联环药业股份有限公司 | A kind of preparation method of Ebastine |
Non-Patent Citations (5)
| Title |
|---|
| YEWEI YANGET AL.: "PIPERIDINE NUCLEOPHILIC SUBSTITUTION WITHOUT SOLVENT: AN EFFICIENT SYNTHESIS OF RALOXIFENE", 《SYNTHETIC COMMUNICATIONS》 * |
| 刘宏民等: "《药物合成技巧与策略》", 31 December 2016, 河南科学技术出版社 * |
| 宋正恩等: "无溶剂室温研磨固相反应合成4-吗啉基香豆素", 《中兽医医药杂志》 * |
| 杨小斌等: "N-烷基化反应的研究进展", 《化学通报》 * |
| 毛志杰等: "6-苯并三氮唑取代的7-去氮嘌呤类似物的无溶剂合成", 《许昌学院学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112574097B (en) | 2023-01-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1174970C (en) | Method of preparing 3-haloalkyl-1H-pyrazoles | |
| CN101386605B (en) | Febustat novel crystal and preparation method thereof | |
| EP3395813B1 (en) | Voriconazole intermediate and voriconazole synthesis method | |
| WO2012081031A1 (en) | Process for preparing tetrabenazine | |
| CN101410374A (en) | Synthesis and preparations of intermediates and polymorphs thereof useful for the preparation of donepezil hydrochloride | |
| CN112645869A (en) | Preparation method of chlorpheniramine maleate intermediate | |
| CN112574097B (en) | Preparation method of Ebastine and fumarate thereof | |
| CN102344407A (en) | 3-droperidol derivative and preparation method thereof | |
| CN101293877A (en) | Method for preparing thiazolidinedione derivatives | |
| CN105153169B (en) | A kind of synthetic method of epinastine hydrochloride | |
| JP3152941B2 (en) | Spirocyclic dopamine receptor subtype ligand | |
| CN101037445A (en) | Imidazo [2,1-b]-1,3,4-thiadiazole derivatives having potential biological activity and synthesizing method thereof | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN108484451A (en) | A kind of method that one kettle way prepares 1,2- alkamine compounds | |
| CN1629142A (en) | Piperazine-bridged tacrine binary derivatives and synthesis method thereof | |
| CN101747261B (en) | Method for preparing 4-[4-(1-piperidinyl) pyridine-2-O]-cis-2-butene-1-ol | |
| CN105294703A (en) | Synthetic method for 3,7,10-trioxo-2,4,6,8,9,11-hexa aza(3,3,3)propellane | |
| CN111484455A (en) | Synthetic method of 2-chloro-5-fluoro-6-methylpyrimidine | |
| WO2004099183A1 (en) | Novel polymorphs of pantoprazole sodium | |
| CN112430205B (en) | Preparation method of arylpyrrole compound | |
| CN104829483B (en) | A kind of preparation method of Propacetamol Hydrochloride A crystal formation | |
| WO2005016937A1 (en) | A SYNTHETIC METHOD FOR 6-CHLORO-4-HYDROXY-2-METHYL-2H-THIENO (2,3-e)-1,2-THIAZINE1, 1-DIOXIDE-3-CARBOXYLATE | |
| CN113999242B (en) | 3-fluoro-benzofuro [3,2-b ] pyridine compound and synthesis method thereof | |
| CN113773327B (en) | Preparation method of pyrazolopyrimidinyltriazole ring compound | |
| CN102558138A (en) | Preparation method for 2-halogenated phenyl-2-(2-thiophene diethylamino) acetic ester and salt thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |