CN113264868A - Improved synthesis method of 1-benzyl-3-piperidinol - Google Patents
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Abstract
Discloses an improved synthesis method of 1-benzyl-3-piperidinol, which comprises the following steps: coprecipitation of mixed solution of R-almond oxynitrilase crude product and polyethyleneimine; adding oxidized dextran for immobilization reaction; washing and drying to obtain a cyano-group transfer catalyst; carrying out cyano transfer reaction under the action of a catalyst to obtain (R) -1-hydroxy-4-bromo-1-butyronitrile; then reacting with benzyl halide, distilling under reduced pressure, and purifying by chromatography to obtain (R) -1-benzyl-3-piperidinol. The improved synthesis method has the advantages of high stereoselectivity and high yield.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical raw materials, and particularly relates to a synthesis method of a medical intermediate; more particularly, relates to an improved synthesis method of 1-benzyl-3-piperidinol.
Background
1-benzyl-3-piperidinol is a key intermediate of Benidipine (Benidipine), which can be obtained from it by a one-step esterification reaction. Benidipine has the effects of reducing blood pressure, resisting angina and protecting kidney, and has certain influence on bone metabolism. Benidipine is a second generation dihydropyridine calcium antagonist drug, has stronger action effect than nifedipine and amlodipine, and has good protective function on blood vessels. In the synthesis process, the intermediate 1-benzyl-3-piperidinol is (R) -1-benzyl-3-piperidinol.
The synthetic route for 1-benzyl-3-piperidinol involves several process routes. One of the two is to use 4-bromobutanal as a raw material, and firstly carry out cyano group transfer reaction by using hydrocyanic acid under the action of R-amygdalonitrile enzyme to obtain (R) -1-hydroxy-4-bromo-1-butyronitrile. The latter is subjected to cyano reduction reaction under borane-tetrahydrofuran reduction condition, and then subjected to nucleophilic reaction under alkaline condition to obtain the analogue of piperidine structure. The stereoselectivity of the cyanotransfer reaction in this route is high (ee 90%), but the yield is not high (about 40%).
Chinese patent application CN111778297A discloses an improved synthesis method of 1-benzyl-3-piperidinol intermediate, which comprises the step of carrying out cyano transfer reaction on 4-bromobutanal serving as a raw material and racemic hydrocyanic acid donor under the action of an unsupported fixed R-amygdalonitrile enzyme catalyst to obtain the 1-benzyl-3-piperidinol intermediate. The synthesis method has the advantages of high stereoselectivity and high yield.
However, there is some loss of active sites during the preparation of the cyanotransfer catalyst, resulting in stereoselectivity and yield still having room for improvement.
Therefore, in view of the above-mentioned drawbacks of the prior art, there is a need to find an improved synthesis method for 1-benzyl-3-piperidinol.
Disclosure of Invention
In view of the above problems, the present invention aims to provide an improved synthesis method of 1-benzyl-3-piperidinol. The improved synthesis method not only has higher stereoselectivity, but also has higher yield.
In order to achieve the purpose, the invention adopts the following technical scheme: an improved synthesis method of 1-benzyl-3-piperidinol, which comprises the following steps:
(1) coprecipitating the mixed solution of the R-almond oxynitrilase crude product and the polyethyleneimine at 0-10 ℃, and standing for 0.5-3 h; then adding oxidized dextran to carry out a fixing reaction on the precipitate; washing the precipitate with citric acid buffer solution, centrifuging, washing the precipitate with acetonitrile, ethyl acetate and diethyl ether respectively, and drying to obtain a cyano group transfer catalyst;
(2) taking 4-bromobutanal as a raw material, and carrying out a cyano transfer reaction with a racemic hydrocyanic acid donor under the action of a cyano transfer catalyst to obtain a 1-benzyl-3-piperidinol intermediate, namely (R) -1-hydroxy-4-bromo-1-butyronitrile;
(3) (R) -1-hydroxy-4-bromo-1-butanenitrile and BH3THF reaction, reduced pressure distillation, adding inorganic base, extracting with organic solvent, filtering, and reduced pressure distillation; adding inorganic base and benzyl halide to react; extracting with organic solvent, drying, filtering, distilling under reduced pressure, and collecting 101-104 deg.C fraction; the fraction was purified by flash column chromatography to finally obtain (R) -1-benzyl-3-piperidinol.
According to the synthesis method, in the mixed liquid in the step (1), the concentration of the R-amygdaloronidase crude product is 60-130 g/L.
Preferably, in the mixed solution in the step (1), the concentration of the R-amygdaloronidase crude product is 70-120 g/L.
In a specific embodiment, the concentration of the crude product of R-amygdaloronidase in the mixture of step (1) is 95 g/L.
In the invention, the R-almond oxynitrilase crude product is prepared by crushing bitter almonds and degreasing the crushed bitter almonds by ethyl acetate. This method is well known to those skilled in the art. In a subsequent embodiment of the invention, the preparation is carried out according to the method of Liu forest et al (journal of catalysis, 2001, 22(1), P67).
According to the synthesis method, the concentration of polyethyleneimine in the mixed solution in the step (1) is 7-12 g/L.
Preferably, the concentration of polyethyleneimine in the mixed solution in the step (1) is 9-10 g/L.
In a specific embodiment, the mixed solution in the step (1) has a polyethyleneimine concentration of 9.5 g/L.
The synthesis method of the invention comprises the step of determining the average molecular weight Mn of polyethyleneimine, which is 5000-25000 dalton, by GPC (gel permeation chromatography).
Preferably, the polyethyleneimine has an average molecular weight Mn of 8000-.
In a particular embodiment, the polyethyleneimine has an average molecular weight Mn of 10000 dalton.
The synthetic method of the invention is characterized in that the structural formula of the polyethyleneimine is as follows:
the synthesis method comprises the step of (1) coprecipitating, wherein a precipitant used in the step of (1) coprecipitation is tert-butanol aqueous solution, and the concentration of the precipitant is 80-100% (v/v).
Preferably, the concentration of the tertiary butanol aqueous solution in the step (1) is 85-95% (v/v).
In a specific embodiment, the concentration of the tertiary butanol aqueous solution of step (1) is 90% (v/v).
According to the synthesis method, the volume ratio of the mixed solution to the tertiary butanol aqueous solution is 1: (1.5-2.5).
Preferably, the volume ratio of the mixed solution to the tertiary butanol aqueous solution is 1: (1.8-2.2).
In a specific embodiment, the volume ratio of the mixed solution to the tertiary butanol aqueous solution is 1: 2.
the synthesis method of the invention, wherein the oxidized glucan obtained in the step (1) is obtained by the following method: according to the following steps of 1: (1.8-2.8) reacting dextran with average molecular weight Mw of 100000-400000 dalton with sodium periodate under stirring for 60-240 min; dialyzing with water as medium, and freeze drying the dialysate.
Preferably, according to 1: (2-2.6) reacting dextran with average molecular weight Mw of 200000-300000 dalton with sodium periodate for 90-180min under stirring; dialyzing with water as medium, and freeze drying the dialysate.
In a specific embodiment, the ratio of 1: 2.33 weight ratio, dextran with average molecular weight Mw 250000 dalton is reacted with sodium periodate for 120min with stirring; dialyzing with water as medium for 2d, and freeze drying the dialysate.
The synthesis method provided by the invention is characterized in that the weight ratio of the oxidized glucan in the step (1) to the R-amygdalonitrile enzyme crude product is (1.2-2): 1.
preferably, the weight ratio of the oxidized dextran to the R-amygdalonitrile enzyme crude product is (1.4-1.8): 1.
in a specific embodiment, the weight ratio of oxidized dextran to crude R-amygdalonitrile enzyme is 1.6: 1.
the synthesis method provided by the invention is characterized in that the reaction temperature of the fixation reaction in the step (1) is 0-10 ℃, and the reaction time is 6-48 h.
Preferably, the reaction temperature of the fixation reaction in the step (1) is 2-8 ℃, and the reaction time is 12-36 h.
In a specific embodiment, the reaction temperature of the step (1) fixing reaction is 4 ℃, and the reaction time is 24 h.
The synthesis method of the invention, wherein the pH value of the citric acid buffer solution in the step (1) is 4-5.
Preferably, the pH value of the citric acid buffer solution in the step (1) is 4.2-4.8.
In a specific embodiment, the pH of the citric acid buffer of step (1) is 4.5.
The synthesis method according to the invention, wherein the hydrocyanic acid donor of step (2) is selected from compounds of formula I,
wherein m is an integer of 0 to 5.
Preferably, m is an integer of 1 to 4.
In a specific embodiment, m is 2.
In another specific embodiment, m is 3.
The synthesis method provided by the invention is characterized in that the molar ratio of the hydrocyanic acid donor in the step (2) to the 4-bromobutanal is (1.2-1.8): 1.
preferably, the molar ratio of the hydrocyanic acid donor to 4-bromobutanal in step (2) is (1.4-1.6): 1.
in a specific embodiment, the molar ratio of hydrocyanic acid donor to 4-bromobutanal in step (2) is 1.5: 1.
the synthesis method disclosed by the invention is characterized in that the dosage ratio of the cyano transfer catalyst and the 4-bromobutanal in the step (2) is (15-25): 1 g/mol.
Preferably, the dosage ratio of the cyano-group transfer catalyst to the 4-bromobutanal in the step (2) is (18-22): 1 g/mol.
In one embodiment, the ratio of the amount of cyano transfer catalyst to 4-bromobutanal used in step (2) is 20: 1 g/mol.
The synthetic method of the invention, wherein the solvent system of the cyano transfer reaction of the step (2) is diisopropyl ether with the volume ratio of (10-16):1 and citric acid buffer solution with the pH value of 4-5.
Preferably, the solvent system of the cyano transfer reaction of the step (2) is diisopropyl ether and citric acid buffer solution with pH value of 4.2-4.8 in a volume ratio of (11-15): 1.
In a specific embodiment, the solvent system for the cyano transfer reaction of step (2) is diisopropyl ether and citric acid buffer solution with pH 4.5 in a volume ratio of 12: 1.
The synthesis method of the invention, wherein the temperature of the cyano-group transfer reaction in the step (2) is 5-15 ℃; the reaction time is 6-72 h.
Preferably, the temperature of the cyano-group transfer reaction of the step (2) is 8-12 ℃; the reaction time is 12-36 h.
In a specific embodiment, the temperature of the cyanogroup transfer reaction of step (2) is 10 ℃; the reaction time was 24 h.
The synthesis method of the invention further comprises the steps of filtering, washing and flash column chromatography purification after the cyano transfer reaction in the step (2).
Advantageously, the washing is carried out 1 to 3 times with dichloromethane; the flash column chromatography purification adopts a silica gel column and adopts petroleum ether: dichloromethane: and a mixed solvent with the volume ratio of ethyl acetate being 7:2:1 is used as an eluent.
The synthesis method of the invention is characterized in that (R) -1-hydroxy-4-bromo-1-butyronitrile obtained in the step (3) is reacted with BH3The molar ratio of (1) to (2-10).
Preferably, said step (3) (R) -1-hydroxy-4-bromo-1-butanenitrile and BH3The molar ratio of (1) to (4-8).
In one embodiment, the (R) -1-hydroxy-4-bromo-1-butanenitrile of step (3) is reacted with BH3Is 1: 5.74.
The synthesis method provided by the invention is characterized in that the molar ratio of the (R) -1-hydroxy-4-bromo-1-butyronitrile to the benzyl halide in the step (3) is (0.9-1.1): (1.1-0.9).
Preferably, the molar ratio of (R) -1-hydroxy-4-bromo-1-butanenitrile to benzyl halide of step (3) is (0.95-1.05): (1.05-0.95).
In a specific embodiment, the molar ratio of (R) -1-hydroxy-4-bromo-1-butanenitrile to benzyl halide of step (3) is 1: 1.
the synthesis method of the invention, wherein the flash column chromatography purification of the step (3) adopts silica gel column and adopts petroleum ether: and (3) using a mixed solvent with the volume ratio of ethyl acetate being 7:3 as an eluent.
Compared with the prior art, the improved synthesis method of the 1-benzyl-3-piperidinol has the advantages of higher stereoselectivity and higher yield.
Detailed Description
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and/or methods described and claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for.
Unless otherwise indicated, parts are parts by weight, temperatures are in degrees Celsius or at ambient temperature, and pressures are at or near atmospheric. There are many variations and combinations of reaction conditions (e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges) and conditions that can be used to optimize the purity and yield of the product obtained by the process. Only reasonable routine experimentation will be required to optimize such process conditions.
Example 1
Preparation of a cyano transfer catalyst
To 100mL of a 100g/L aqueous solution of the crude product of R-amygdalonitrile enzyme was added 5mL of a 200g/L PEI (Mn: 10000 Dalton; gel permeation chromatography GPC measurement) solution, and the mixture was stirred for 15min to obtain a mixed solution. Then, the mixture was added to 200mL of an aqueous solution of t-butanol (concentration: 90% (v/v)), and the mixture was stirred slowly at 4 ℃ to sufficiently precipitate, and allowed to stand for 1 hour.
1.8g of dextran (Mw 250000 Dalton) was dissolved in 50mL of water, 4.2g of sodium periodate was added, and the reaction was stirred at room temperature for 120 min. And putting the reaction mixture into a dialysis bag, and dialyzing for 2d by taking water as a medium. And (4) freeze-drying the dialyzate to obtain the oxidized glucan.
Then adding oxidized glucan with the weight ratio of 1.6:1 to the R-amygdalonitrile enzyme crude product to carry out a fixation reaction on the precipitate; the reaction temperature is 4 ℃ and the reaction time is 24 h. Washing the precipitate with citric acid buffer solution with pH value of 4.5, centrifuging, washing the precipitate with acetonitrile, ethyl acetate and ether, and drying to obtain the cyano group transfer catalyst.
Transfer reaction of cyano group
200mg of the cyanotransfer catalyst was added to 52mL of a solvent system (diisopropyl ether at a volume ratio of 12:1 and citric acid buffer pH 4.5) and stirred well. Adding 10mmol of 4-bromobutanal and 15mmol of racemic 2-hydroxy-2-methylhexanitrile into the mixture to perform a cyano group transfer reaction; the reaction temperature is 10 ℃; the reaction time was 24 h. After the cyano transfer reaction, filtration and washing with dichloromethane 2 times; and using a silica gel column and mixing with a petroleum ether: dichloromethane: and (3) carrying out flash column chromatography purification by using a mixed solvent of ethyl acetate with the volume ratio of 7:2:1 as an eluent. Finally obtaining the 1-benzyl-3-piperidinol intermediate, namely (R) -1-hydroxy-4-bromo-1-butyronitrile. The yield (%) of the synthesis was calculated and the ee value was determined on a liquid chromatograph using a japanese xylonite CHIRALCEL OD-H chiral liquid chromatography column. See table 1 for results.
Comparative example 1
No 5mL of 200g/L PEI solution (Mn 10000 Dalton; gel permeation chromatography GPC determination) was added; the other conditions were the same as in example 1.
Comparative example 1'
Replacing oxidized dextran with glutaraldehyde; the other conditions were the same as in example 1.
TABLE 1
| Yield (%) | ee(％) | |
| Example 1 | 91 | 97 |
| Comparative example 1 | 89 | 86 |
| Comparative example 1' | 83 | 92 |
Example 2
Improved synthesis method of 1-benzyl-3-piperidinol
8.7mmol of (R) -1-hydroxy-4-bromo-1-butanenitrile from example 1 are added to 200mL of anhydrous THF at 0 ℃; then 50mL of 1mol/L BH is added dropwise3THF solution. After the dropwise addition, the temperature is raised to room temperature, and the reaction is carried out for 8 hours under the stirring condition. Then, 50mL of a 6mol/L hydrochloric acid solution was added, and THF was removed by distillation under the reduced pressure. The remaining solution was adjusted to alkaline pH by addition of NaOH. The solution was extracted 3 times with 50mL of dichloromethane. The combined organic phases were collected, filtered and distilled under reduced pressure until dichloromethane was almost completely distilled off. Adding 8.7mmol sodium carbonate and a small amount of water, cooling to 0 ℃, and dropwise adding 8.7mmol benzyl bromide; and stirring and reacting for 12 hours after the dropwise addition. The solution was extracted 3 times with 50mL of dichloromethane. The combined organic phases were collected and dried over anhydrous sodium sulfate; filtering, distilling under reduced pressure, and collecting the fractions at 101-104 ℃. Silica gel column and petroleum ether: and (3) carrying out flash column chromatography purification by using a mixed solvent with ethyl acetate volume ratio of 7:3 as an eluent. Finally, colorless oily liquid (R) -1-benzyl-3-piperidinol is obtained. Ms (esi) M/z 192.3(M + 1).
The yield (%) of the synthesis was calculated and the ee value was determined on a liquid chromatograph using a japanese xylonite CHIRALCEL OD-H chiral liquid chromatography column. See table 2 for results.
Comparative example 2
(R) -1-hydroxy-4-bromo-1-butanenitrile from example 1 was replaced with (R) -1-hydroxy-4-bromo-1-butanenitrile from comparative example 1.
Comparative example 2'
(R) -1-hydroxy-4-bromo-1-butanenitrile from example 1 was replaced with (R) -1-hydroxy-4-bromo-1-butanenitrile from comparative example 1'.
TABLE 2
| Yield (%) | ee(％) | |
| Example 2 | 72 | 93 |
| Comparative example 2 | 49 | 82 |
| Comparative example 2' | 63 | 85 |
The results show that the synthesis method of 1-benzyl-3-piperidinol of example 2 of the present invention not only provides higher stereoselectivity, but also provides higher yield, compared to the comparative examples.
It should be understood that the detailed description of the invention is merely illustrative of the spirit and principles of the invention and is not intended to limit the scope of the invention. Furthermore, it should be understood that various changes, substitutions, deletions, modifications or adjustments may be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents are also within the scope of the invention as defined in the appended claims.
Claims (10)
1. An improved synthesis method of 1-benzyl-3-piperidinol, which comprises the following steps:
(1) coprecipitating the mixed solution of the R-almond oxynitrilase crude product and the polyethyleneimine at 0-10 ℃, and standing for 0.5-3 h; then adding oxidized dextran to carry out a fixing reaction on the precipitate; washing the precipitate with citric acid buffer solution, centrifuging, washing the precipitate with acetonitrile, ethyl acetate and diethyl ether respectively, and drying to obtain a cyano group transfer catalyst;
(2) taking 4-bromobutanal as a raw material, and carrying out a cyano transfer reaction with a racemic hydrocyanic acid donor under the action of a cyano transfer catalyst to obtain a 1-benzyl-3-piperidinol intermediate, namely (R) -1-hydroxy-4-bromo-1-butyronitrile;
(3) (R) -1-hydroxy-4-bromo-1-butanenitrile and BH3THF reaction, reduced pressure distillation, adding inorganic base, extracting with organic solvent, filtering, and reduced pressure distillation; adding inorganic base and benzyl halide to react; extracting with organic solvent, drying, filtering, distilling under reduced pressure, and collecting 101-104 deg.C fraction; the fraction was purified by flash column chromatography to finally obtain (R) -1-benzyl-3-piperidinol.
2. The preparation method according to claim 1, wherein the concentration of the crude product of R-amygdalonitrile enzyme in the mixed solution of step (1) is 60-130 g/L; and/or the concentration of the polyethyleneimine is 7-12 g/L; and/or the polyethyleneimine has an average molecular weight Mn of 5000-; and/or the structural formula of the polyethyleneimine is shown as follows:
3. the preparation method according to claim 1, wherein the precipitant in the step (1) is an aqueous solution of t-butanol at a concentration of 80-100% (v/v); and/or the volume ratio of the mixed solution to the tertiary butanol aqueous solution is 1: (1.5-2.5).
4. The method of claim 1, wherein the oxidized dextran of step (1) is obtained by: according to the following steps of 1: (1.8-2.8) reacting dextran with average molecular weight Mw of 100000-400000 dalton with sodium periodate under stirring for 60-240 min; dialyzing with water as medium, and freeze-drying the dialysate; and/or the weight ratio of the oxidized dextran in the step (1) to the crude product of the R-amygdalonitrile enzyme is (1.2-2): 1.
5. the preparation method of claim 1, wherein the reaction temperature of the step (1) fixing reaction is 0-10 ℃ and the reaction time is 6-48 h.
6. The synthetic method according to claim 1, wherein the hydrocyanic acid donor of step (2) is selected from compounds of formula I,
wherein m is an integer of 0 to 5; and/or the molar ratio of the hydrocyanic acid donor to the 4-bromobutanal in the step (2) is (1.2-1.8): 1; and/or the dosage ratio of the cyano-group transfer catalyst to the 4-bromobutanal is (15-25): 1 g/mol.
7. The synthesis method according to claim 1, wherein the temperature of the cyano-group transfer reaction of the step (2) is 5-15 ℃; the reaction time is 6-72 h.
8. The synthesis method according to claim 1, wherein the cyano transfer reaction of step (2) is further followed by filtration, washing and flash column chromatography purification steps; preferably, the first and second electrodes are formed of a metal,
washing for 1-3 times by adopting dichloromethane; the flash column chromatography purification adopts a silica gel column and adopts petroleum ether: dichloromethane: and a mixed solvent with the volume ratio of ethyl acetate being 7:2:1 is used as an eluent.
9. The synthesis method according to claim 1, wherein the (R) -1-hydroxy-4-bromo-1-butanenitrile of step (3) is reacted with BH3The molar ratio of (1), (2-10); and/or the presence of a gas in the gas,
(R) -1-hydroxy-4-bromo-1-butanenitrile and benzyl halide in a molar ratio of (0.9-1.1): (1.1-0.9).
10. The synthesis method according to claim 1, wherein the flash column chromatography purification of step (3) is performed with silica gel column and petroleum ether: and (3) using a mixed solvent with the volume ratio of ethyl acetate being 7:3 as an eluent.
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