CN115181091A - Preparation method of bepotastine - Google Patents
Preparation method of bepotastine Download PDFInfo
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- CN115181091A CN115181091A CN202210709826.XA CN202210709826A CN115181091A CN 115181091 A CN115181091 A CN 115181091A CN 202210709826 A CN202210709826 A CN 202210709826A CN 115181091 A CN115181091 A CN 115181091A
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Abstract
The invention discloses a preparation method of bepotastine, and belongs to the field of medicine manufacturing. The method comprises the following steps: taking (4-chlorphenyl) pyridine-2 ketone as a starting material, and sequentially carrying out asymmetric reduction reaction; hydroxyl conversion and acidolysis reaction; and carrying out substitution and hydrolysis reaction to obtain bepotastine. The synthesis method disclosed by the invention has the advantages that the raw materials are cheap and easy to obtain, an expensive chiral metal catalyst is not needed, and the heavy metal risk of the raw material medicine is reduced. Does not need a chiral resolution step and meets the requirements of ICH guiding principle on the preparation of bulk drugs. During the substitution reaction and the hydrolysis reaction, the alkali reagent is continuously added, the compound VII is used as a transition state and is not treated, the reaction is directly carried out by a one-pot method, the synthetic method is simpler, the side reaction is less, the cost is lower, and the method is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a preparation method of bepotastine.
Background
Bepotastine, a pharmaceutically acceptable salt form of Bepotastine Besilate, is a histamine H1 receptor antagonist developed by association of Tanabe Seiyaku (Tanabe Seiyaku) and Ube Industries (Ube Industries) and first marketed in japan in 2000 under the trade name Talion (tambourine) for the treatment of allergic rhinitis and urticaria, and is approved by FDA in us on 9 months 2009 and marketed, and has a structure shown below,
original manufacturers, namely, japan Tanabe Seiyaku company and Japan Ube Industries company, firstly publish their patent synthesis routes, and JP1998237070, JP2000198784 and WO9829409 disclose 3-step synthesis reaction to prepare bepotastine, namely, a racemate compound is firstly resolved to obtain 4- [4- [ (S) - (4-chlorophenyl) (4-piperidyloxy) methyl ] pyridine, then the 4- [4- [ (S) - (4-chlorophenyl) (4-piperidyloxy) methyl ] pyridine is condensed with ethyl bromobutyrate to obtain bepotastine ethyl ester, and the bepotastine compound is obtained after hydrolysis. The key point of the process synthesis of bepotastine is the formation of chiral diaryl methanol, and the synthesis methods reported in the literature at present mainly comprise an asymmetric reduction carbonyl method and a resolving agent resolving method. The resolution method of the resolving agent is a conventional method adopted by the prior asymmetric synthesis, and has reliable practical feasibility. However, the byproduct of the resolution can not be effectively utilized, and the resolution is not used as a group conversion step according to the ICH guiding principle, which directly causes the defects of prolonged process route, high production cost and the like. In recent years, the asymmetric carbonyl reduction method for producing bepotastine is deeply researched, but most of the catalysts are prepared by complexing chiral phosphine ligands and transition metals, the reaction conditions are harsh, and the API (active pharmaceutical ingredient) increases metal residues, so that the industrial application of the raw material medicines is limited.
Meanwhile, according to the ICH guiding principle, at least 3-step group conversion is required in the synthesis of the bulk drug, and the bepotastine intermediate is difficult to store and study the quality considering that most of the bepotastine intermediate is oily. Therefore, the method has high reference significance for the production of bulk drugs by increasing the group conversion step and reducing the operation step at the same time.
The method has the advantages of simplifying the treatment of the bepotastine intermediate by integrating the prior art and the pharmaceutical guiding principle, optimizing and developing a new method for synthesizing bepotastine, which has high yield, low cost, safety and environmental protection, and has very high social benefit and economic benefit.
Disclosure of Invention
Aiming at the problems in the prior art, the technical problem to be solved by the invention is a preparation method of bepotastine, which has the advantages of simpler synthesis method, less side reaction and the like.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of bepotastine comprises the following steps:
1) Taking the compound II as an initial raw material, and carrying out asymmetric reduction under the catalytic action of (R) -R-CBS-oxazaborolidine to obtain a compound III;
2) Carrying out hydroxyl conversion on the compound III through sulfonation reaction, and then carrying out etherification reaction with N-tert-butyloxycarbonyl-4-hydroxypiperidine to obtain a compound V;
3) Carrying out deprotection and acidolysis on the compound V under an acidic condition to obtain a compound VI;
4) The compound VI and 4-ethyl bromobutyrate are subjected to substitution reaction under the alkaline condition to obtain a compound VII;
5) Continuing the hydrolysis reaction of the compound VII under an alkaline condition without treatment to obtain bepotastine;
the specific reaction formula is as follows:
in step 1), (R) -R-CBS-oxazolylborane is selected from (R) -2-methyl-CBS-oxazolylborane, (R) -2-phenyl-CBS-oxazolylborane, (R) -2-butyl-CBS-oxazolylborane, preferably (R) -2-methyl-CBS-oxazolylborane.
In step 1), the solvent is selected from one of 1, 2-dichloroethane, dichloromethane, toluene and tetrahydrofuran, and tetrahydrofuran is preferred.
In the step 1), the molar ratio of the (R) -2-methyl-CBS-oxazaborolidine to the compound (II) is 1: 10-1: 30, the reaction temperature is-30-20 ℃, and the reaction time is 2-6 h.
In the step 2), the hydroxyl conversion reagent is selected from benzene sulfonyl chloride, p-toluene sulfonyl chloride, methane sulfonyl chloride and trifluoromethane sulfonyl chloride; benzene sulfonyl chloride and p-toluene sulfonyl chloride are preferred.
In the step 2), the solvent is selected from one of 1, 2-dichloroethane, dichloromethane, toluene and tetrahydrofuran, and tetrahydrofuran is preferred.
In the step 2), the molar ratio of the sulfonyl chloride to the compound (III) is 1: 0.8-1: 1, the reaction temperature is-20-40 ℃, and the reaction time is 3-8 h.
In the step 4), the alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and potassium carbonate is preferred.
In step 4), the solvent is selected from one of acetone, tetrahydrofuran, toluene and water, and acetone is preferred.
In the step 4), the molar ratio of the compound VI to the alkaline reagent is 1: 1.5-1: 3.0, the reaction temperature is 20 ℃ to reflux, and the reaction time is 5-12 h.
In step 5), the alkaline reagent is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and potassium hydroxide is preferred.
In step 5), the solvent is selected from one of acetone, tetrahydrofuran, toluene and water, and acetone is preferred.
In the step 5), the molar ratio of the compound VII to the alkaline reagent is 1: 1.5-1: 4.5, the reaction temperature is 0 ℃ to reflux, and the reaction time is 10-24 h.
And 4) after the reaction is completed, directly carrying out the reaction in the step 5) without post-treatment on the reaction solution, namely directly adding a new alkaline reagent, and controlling the temperature to continuously react until the hydrolysis is completed to obtain bepotastine.
In the step 4) and the step 5), the solvent is selected consistently, and the molar ratio of the alkali used in the step 4) to the alkali used in the step 5) is 1: 0.5-1: 3.0.
The preparation method of bepotastine comprises the following steps:
1) Adding (4-chlorphenyl) pyridine-2 ketone, (R) -2-methyl-CBS-oxazole borane and tetrahydrofuran into a reaction bottle, and cooling to 0-5 ℃; dropwise adding 1N BH 3 THF is added, and the reaction is finished for 4 hours; adding water, extracting, concentrating under reduced pressure to remove tetrahydrofuran, extracting with dichloromethane, concentrating organic phase under reduced pressure to dryness, stirring with methanol, and crystallizing to obtain white solidThe compound (R) - (4-chlorophenyl) (pyridin-2-yl) methanol;
2) Adding tosyl chloride, powdered potassium hydroxide and tetrahydrofuran into a reaction bottle, cooling to 0-10 ℃, adding (R) - (4-chlorphenyl) (pyridine-2-yl) methanol, reacting for 2 hours, adding water for quenching, decompressing and concentrating to remove tetrahydrofuran, extracting by dichloromethane, drying by anhydrous sodium sulfate, and concentrating to obtain a compound IV;
adding tetrahydrofuran, DMF and potassium carbonate into a reaction bottle, respectively adding a compound IV and N-tert-butyloxycarbonyl-4-hydroxypiperidine, heating to 40 ℃, and reacting for 8 hours; adding water for quenching, extracting by ethyl acetate, drying, concentrating and drying to obtain a brown oily compound V;
3) Adding a compound V, dichloromethane and trifluoroacetic acid into a reaction bottle, reacting for 3h at 15-25 ℃, quenching the reaction solution by using 2N sodium hydroxide until the pH value is more than 8, separating, drying, and concentrating an organic phase to dryness to obtain a light yellow oily compound VII;
4) Adding a compound VII, acetone and 50% potassium carbonate into a reaction bottle, reacting for 8 hours at 55 ℃, cooling to 20 ℃, adding 0.12mol of potassium hydroxide powder, and reacting for 12 hours at room temperature; adjusting the pH value to 6.5-6.8, and concentrating to remove acetone; the water layer is extracted by dichloromethane, dried, concentrated and dried to obtain the light yellow oily bepotastine.
Has the advantages that: compared with the prior art, the invention has the advantages that:
1) The synthetic method disclosed by the invention has the advantages that the raw materials are cheap and easy to obtain, an expensive chiral metal catalyst is not needed, and the risk of heavy metal in the bulk drugs is reduced.
2) The method does not need a chiral resolution step, only has 4 steps of reaction but comprises 6 steps of group conversion, meets the requirements of ICH guiding principle on the preparation of bulk drugs, and simplifies the production process.
3) In the process of substitution reaction and hydrolysis reaction, an alkali reagent is continuously added, and the compound VII is used as a transition state and is not treated, so that the direct reaction is realized, the synthetic method is simpler, the side reaction is less, the cost is lower, and the method is suitable for large-scale production.
Drawings
FIG. 1 is an HPLC chromatogram of compound III prepared in example 1;
FIG. 2Is of the Compound III prepared in example 1 1 H-NMR spectrum;
FIG. 3 is a photograph of Compound III prepared in example 1 13 C-NMR spectrum;
FIG. 4 is a mass spectrum of compound III prepared in example 1;
FIG. 5 shows Compound V prepared in example 1 1 H-NMR spectrum;
FIG. 6 is a photograph of Compound V prepared in example 1 13 A C-NMR spectrum;
FIG. 7 is a mass spectrum of Compound V prepared in example 1;
FIG. 8 is an HPLC chromatogram of Compound I prepared in example 1.
Detailed Description
The invention is further described with reference to specific examples.
Example 1
A preparation method of bepotastine comprises the following reaction formula:
the preparation process comprises the following steps:
1) Preparation of Compound III
0.1mol of (4-chlorphenyl) pyridine-2 ketone, 0.01mol of (R) -2-methyl-CBS-oxazole borane and 200mL of tetrahydrofuran are added into a reaction bottle, and the temperature is reduced to 0-5 ℃. Dropwise adding 1N BH 3 THF (100mL, 0.1 mol) was added dropwise over 4h. Adding water for quenching, decompressing and concentrating to remove tetrahydrofuran, extracting by dichloromethane, decompressing and concentrating to dryness by organic phase, stirring and crystallizing by 100mL of methanol to obtain 19.6g of off-white solid (R) - (4-chlorphenyl) (pyridine-2-yl) methanol (compound III), the HPLC purity is 99.40%, and the mass yield of the compound II is 90.3%. Wherein the HPLC spectrogram of the compound III is shown in figure 1, 1 the H-NMR spectrum is shown in figure 2, 13 the C-NMR spectrum is shown in FIG. 3, and the mass spectrum is shown in FIG. 4.
2) Preparation of Compound V
Adding 0.1mol of p-toluenesulfonyl chloride, 0.2mol of powdered potassium hydroxide and 100mL of tetrahydrofuran into a reaction bottle, cooling to 0-10 ℃, adding 0.08mol of (R) - (4-chlorophenyl) (pyridine-2-yl) methanol, reacting for 2h, adding water for quenching, decompressing and concentrating to remove tetrahydrofuran, extracting with dichloromethane, drying with anhydrous sodium sulfate, and concentrating to obtain a compound IV.
Tetrahydrofuran 100mL, DMF 10mL and 0.1mol potassium carbonate are added into a reaction bottle, and a compound IV and 0.1mol N-tert-butyloxycarbonyl-4-hydroxypiperidine are respectively added, the temperature is raised to 40 ℃, and the reaction time is 8 hours. Adding water for quenching, extracting by ethyl acetate, drying, concentrating and drying to obtain a brown oily compound V. Wherein of compound V 1 The H-NMR spectrum is shown in FIG. 5, 13 the C-NMR spectrum is shown in FIG. 6, and the mass spectrum is shown in FIG. 7.
3) Preparation of Compound I
Adding the compound V, 200mL of dichloromethane and 0.24mol of trifluoroacetic acid into a reaction bottle, reacting for 3 hours at 15-25 ℃, washing and quenching an organic phase, adjusting the pH value to be more than 8 by using 2N sodium hydroxide in an aqueous phase, separating, drying, and concentrating the organic phase to be dry to obtain 22.2g of a light yellow oily compound VI.
Adding 0.06mol of compound VI, 200mL of acetone, 50% (g/100 mL) of potassium carbonate (0.12 mol) solution and 0.066mol of 4-ethyl bromobutyrate into a reaction bottle, reacting at 55 ℃ for 8h until the compound VI completely reacts, cooling to 20 ℃, adding 0.12mol of potassium hydroxide powder, and reacting at room temperature for 12h. Adjusting the pH value to 6.5-6.8, and concentrating to remove acetone. The aqueous layer was extracted with dichloromethane, dried, concentrated to give 19.2g bepotastine (compound I) as a pale yellow oil with an HPLC purity of 99.92%. The bepotastine is salified by benzenesulfonic acid to obtain 10.6g of bepotastine besilate. The mass yield was 60.2% (for compound III). The HPLC spectrum of the compound I is shown in figure 8.
Example 2
In the preparation method of bepotastine, the compound III is prepared as in example 1; the results are shown in Table 1, with the oxazaborolidine and solvent in Table 1 replacing the oxazaborolidine and solvent in step 1) of example 1 for comparative examples 1-6, respectively.
Table 1: comparison of results of Compound III prepared from different Oxazolylboranes and organic solvent
In the preparation method of bepotastine, the compound III is prepared as in example 1; the reaction conditions in step 1 of example 1 were replaced with those in table 2, comparative examples 7 to 10, respectively, and the results were as follows:
table 2: comparison of results for the preparation of Compound II I under different reaction conditions
Example 3
In the preparation of bepotastine, compound V was prepared as in example 1; comparative examples 11 to 14, respectively, were prepared by substituting the acid chloride and solvent of table 3 for the acid chloride and solvent of step 2 of example 1, and reacting in the same step 3 gave the following results:
table 3: comparison of results for the preparation of Compound V from different acid chlorides and organic solvents
In the preparation of bepotastine, compound V was prepared as in example 1; the reaction conditions in Table 4 were used instead of those in step 2 of example 1, comparative examples 15 to 16, respectively, and the same reaction in step 3 gave the following results:
table 4: comparison of results for the preparation of Compound V under different reaction conditions
Example 4
In the preparation of bepotastine, compound I was prepared as in example 1; wherein, in the step 4), the solvent is selected from one of acetone, tetrahydrofuran, toluene and water, and acetone is preferred. The mol ratio of the compound VI to the alkaline reagent is 1: 1.5-1: 3.0, the reaction temperature is 20 ℃ to reflux, and the reaction time is 5-12 h. The results of the reaction under different conditions are shown in Table 5 below.
Table 5: comparison of results for the preparation of Compound I in different reaction systems
Example 5
In the preparation of bepotastine, compound I was prepared as in example 1; after the reaction in the step 4) is completed, directly carrying out the reaction in the step 5) without post-treatment, namely directly adding a new alkaline reagent, and continuously reacting until the hydrolysis is completed to obtain bepotastine.
In the step 4) and the step 5), the solvent is selected consistently, and the molar ratio of the alkali used in the step 4) to the alkali used in the step 5) is 1: 0.5-1: 3.0.
Table 6: comparison of results for the preparation of Compound I in different reaction systems
| Examples | Step 4 whether or not to post-process | Mass yield to the compound (III) |
| Comparative example 21 | Is that | 40.5～45.5％ |
| Comparative example 22 | Whether or not | 58.5～63.5％ |
Compared with the prior art, the embodiment of the invention does not need an expensive chiral metal catalyst, and reduces the risk of heavy metal in the bulk drug. Does not need a chiral resolution step and meets the requirements of ICH guiding principle on the manufacture of bulk drugs. And meanwhile, the bepotastine is synthesized by continuously adding an alkali reagent in the substitution and hydrolysis reaction through a one-pot method, so that the overall yield can be improved, the process time is shortened, the pollutant emission is reduced, the purity of the obtained product is high, and the product meets the quality standard of the bulk drugs.
The above-described examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the examples, and the examples and features of the examples in the present application may be arbitrarily combined with each other without conflict. Other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principles of the invention are intended to be included within the scope of the invention. In addition, technical details which are not described in detail in the specification belong to the known technology of a person skilled in the art, and therefore the description is not repeated.
Claims (11)
1. The preparation method of bepotastine is characterized by comprising the following steps of:
1) Taking the compound II as an initial raw material, and carrying out asymmetric reduction under the catalytic action of (R) -R-CBS-oxazaborolidine to obtain a compound III;
2) Carrying out hydroxyl conversion on the compound III through sulfonation reaction, and then carrying out etherification reaction with N-tert-butyloxycarbonyl-4-hydroxypiperidine to obtain a compound V;
3) Carrying out deprotection and acidolysis on the compound V under an acidic condition to obtain a compound VI;
4) The compound VI and 4-ethyl bromobutyrate are subjected to substitution reaction under alkaline conditions to obtain a compound VII;
5) Continuing the hydrolysis reaction of the compound VII under an alkaline condition without treatment to obtain bepotastine;
the specific reaction formula is as follows:
2. the method for preparing bepotastine according to claim 1, characterized in that: in step 1), (R) -R-CBS-oxazole borane is selected from (R) -2-methyl-CBS-oxazole borane, (R) -2-phenyl-CBS-oxazole borane, (R) -2-butyl-CBS-oxazole borane; the solvent required for the reaction is selected from 1, 2-dichloroethane, dichloromethane, toluene, tetrahydrofuran.
3. The method for producing bepotastine according to claim 1 or 2, characterized in that: in the step 1), the molar ratio of the (R) -R-CBS-oxazaborolidine to the compound II is 1: 10-1: 30, the reaction temperature is-30-20 ℃, and the reaction time is 2-6 h.
4. The method for producing bepotastine according to claim 1, characterized in that: in the step 2), the reagent for hydroxyl conversion is selected from benzene sulfonyl chloride, p-toluene sulfonyl chloride, methane sulfonyl chloride and trifluoromethane sulfonyl chloride; the solvent required for the reaction is selected from 1, 2-dichloroethane, dichloromethane, toluene, tetrahydrofuran.
5. The method for producing bepotastine according to claim 1 or 4, characterized in that: in the step 2), the molar ratio of the reagent used for hydroxyl conversion to the compound III is 1: 0.8-1: 1, the reaction temperature is-20-40 ℃, and the reaction time is 3-8 h.
6. The method for preparing bepotastine according to claim 1, characterized in that: in the step 4), the alkaline reagent is selected from potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate; the solvent required for the reaction is selected from acetone, tetrahydrofuran, toluene and water.
7. The method for producing bepotastine according to claim 1 or 6, characterized in that: in the step 4), the molar ratio of the compound VI to the alkaline reagent is 1: 1.5-1: 3.0, the reaction temperature is 20 ℃ to reflux, and the reaction time is 5-12 h.
8. The method for preparing bepotastine according to claim 1, characterized in that: in the step 5), the alkaline reagent is selected from potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and the solvent required by the reaction is selected from acetone, tetrahydrofuran, toluene and water.
9. The method for producing bepotastine according to claim 1 or 8, characterized in that: in the step 5), the molar ratio of the compound VII to the alkaline reagent is 1: 1.5-1: 4.5, the reaction temperature is 0 ℃ to reflux, and the reaction time is 10-24 h.
10. The method for preparing bepotastine according to claim 1, characterized in that: in the step 5), after the reaction in the step 4) is completed, directly carrying out the reaction in the step 5) without post-treatment on the reaction solution, namely directly adding an alkaline reagent, and continuously reacting at controlled temperature until the hydrolysis is completed to obtain bepotastine; wherein the molar ratio of the alkali used in the step 4) to the alkali used in the step 5) is 1: 0.5-3.0.
11. The method for producing bepotastine according to claim 1, characterized in that: the method comprises the following steps:
1) Adding (4-chlorphenyl) pyridine-2 ketone, (R) -2-methyl-CBS-oxazole borane and tetrahydrofuran into a reaction bottle, and cooling to 0-5 ℃; dropwise adding 1N BH 3 THF is added, and the reaction is finished for 4 hours; adding water for extraction, concentrating under reduced pressure to remove tetrahydrofuran, extracting with dichloromethane, concentrating organic phase under reduced pressure to dryness, stirring with methanol, and crystallizing to obtain white solid (R) - (4-chlorophenyl) (pyridine-2-yl) methanol;
2) Adding tosyl chloride, powdered potassium hydroxide and tetrahydrofuran into a reaction bottle, cooling to 0-10 ℃, adding (R) - (4-chlorophenyl) (pyridine-2-yl) methanol, reacting for 2 hours, adding water for quenching, concentrating under reduced pressure to remove tetrahydrofuran, extracting with dichloromethane, drying with anhydrous sodium sulfate, and concentrating to obtain a compound IV;
adding tetrahydrofuran, DMF and potassium carbonate into a reaction bottle, respectively adding a compound IV and N-tert-butyloxycarbonyl-4-hydroxypiperidine, heating to 40 ℃, and reacting for 8 hours; adding water for quenching, extracting by ethyl acetate, drying, concentrating and drying to obtain a brown oily compound V;
3) Adding a compound V, dichloromethane and trifluoroacetic acid into a reaction bottle, reacting for 3h at 15-25 ℃, quenching the reaction solution by 2N sodium hydroxide until the pH value is more than 8, separating, drying, and concentrating an organic phase to dryness to obtain a light yellow oily compound VII;
4) Adding a compound VII, acetone and 50% potassium carbonate into a reaction bottle, reacting for 8 hours at 55 ℃, cooling to 20 ℃, adding 0.12mol of potassium hydroxide powder, and reacting for 12 hours at room temperature; adjusting the pH value to 6.5-6.8, and concentrating to remove acetone; the water layer is extracted by dichloromethane, dried, concentrated and dried to obtain the light yellow oily bepotastine.
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