CN111778297A - Improved synthesis method of 1-benzyl-3-piperidinol intermediate - Google Patents
Improved synthesis method of 1-benzyl-3-piperidinol intermediate Download PDFInfo
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Abstract
The invention discloses an improved synthesis method of a 1-benzyl-3-piperidinol intermediate, which is characterized in that 4-bromobutanal is used as a raw material to perform cyano group transfer reaction with a racemic hydrocyanic acid donor under the action of an R-amygdalol nitrilase catalyst without carrier immobilization, so as to obtain the 1-benzyl-3-piperidinol intermediate. The 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 a 1-benzyl-3-piperidinol intermediate.
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 synthesis route of 1-benzyl-3-piperidinol mainly comprises the following steps:
firstly, 3-hydroxypyridine is used as a raw material, and is subjected to hydrogenation reaction under a high-pressure condition to obtain 3-hydroxypiperidine; the latter is further reacted with benzyl chloride or benzyl bromide to give 1-benzyl-3-piperidinol. For example, U.S. Pat. No. 2802007A discloses the use of noble metals such as rhodium, palladium or platinum as catalysts for catalytic hydrogenation reactions. However, the above synthesis process has high requirements for equipment, severe reaction conditions and high operational risk, and is not suitable for continuous production.
Secondly, 3-hydroxypyridine is used as a raw material, and quaternary ammonium salt of the 3-hydroxypyridine is obtained through quaternization; the latter is further reduced to obtain 1-benzyl-3-piperidinol. For example, chinese patent application CN101817779A discloses a synthesis process for catalytic reduction of 3-hydroxypyridine quaternary ammonium salt using a new nickel-based catalyst supported by diatomite under moderate hydrogen pressure (3-5 atm). The synthesis process effectively reduces the hydrogenation pressure and improves the product purity; however, the stereoselectivity of this synthesis process is not high and the product is actually a racemic mixture of (R) -1-benzyl-3-piperidinol and (S) -1-benzyl-3-piperidinol.
Thirdly, using gamma-azido methyl-gamma-butyrolactone as a raw material, firstly carrying out catalytic ring expansion reaction on palladium carbon under a high pressure condition, and reducing by lithium aluminum hydride or borane-tetrahydrofuran to obtain 3-hydroxypiperidine; the latter is further reacted with benzyl chloride or benzyl bromide to give 1-benzyl-3-piperidinol. For example, Thom pson C.M. et al, using the above-described scheme, have obtained analogues of the piperidine structure. However, this process route also suffers from similar disadvantages as the first process route; moreover, the stereoselectivity of the obtained product is likewise not high.
Fourthly, taking benzyl tetrahydrofurfuryl amine as a raw material, firstly using halogen acid to salify and open a ring, and then closing the ring to obtain 1-benzyl-3-piperidinol; or taking tetrahydrofurfuryl amine as a raw material, salifying by using halogen acid, and then reacting with benzyl chloride or benzyl bromide under the action of alkali to obtain the 1-benzyl-3-piperidinol. Examples of the former are described in Japanese patent application JP Kokai Hei 5-168493A; examples of the latter are found in chinese patent application CN 106432059 a. However, the starting materials for this route are not readily available; in addition, the conversion and stereoselectivity of the reaction are low.
Fifthly, 4-bromobutanal is taken as a raw material, hydrocyanic acid is firstly used for carrying out cyano group transfer reaction under the action of R-amygdalonitrile enzyme, and (R) -1-hydroxy-4-bromo-1-butyronitrile is obtained. 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%).
Therefore, in view of the drawbacks of the prior art, there is a need to find an improved synthesis method of 1-benzyl-3-piperidinol intermediate.
Disclosure of Invention
In view of the above problems, the present invention aims to provide an improved synthesis method of 1-benzyl-3-piperidinol intermediate. The intermediate synthesis method has the advantages of high stereoselectivity and high yield.
In order to achieve the purpose, on one hand, the invention adopts the following technical scheme: : an improved synthesis method of 1-benzyl-3-piperidinol intermediate is characterized in that 4-bromobutanal is used as a raw material, and the raw material and racemic hydrocyanic acid donor perform cyano group transfer reaction under the action of R-amygdalol nitrilase catalyst to obtain 1-benzyl-3-piperidinol intermediate, namely (R) -1-hydroxy-4-bromo-1-butyronitrile; it is characterized in that the R-almond oxynitrilase catalyst is selected from R-almond oxynitrilase immobilized without a carrier.
The synthesis according to the invention, wherein the hydrocyanic acid donor 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 to the 4-bromobutanal is (1.2-1.8): 1.
preferably, the molar ratio of the hydrocyanic acid donor to 4-bromobutanal is (1.4-1.6): 1.
in a specific embodiment, the molar ratio of hydrocyanic acid donor to 4-bromobutanal is 1.5: 1.
the synthesis method of the invention comprises the following steps of: adding the R-amygdalonitrile enzyme crude product water solution into the tert-butanol water solution, slowly stirring the mixed solution at 0-10 ℃ to fully generate precipitate, and standing for 0.5-3 h; then adding glutaraldehyde 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, and drying to obtain the carrier-free immobilized R-amygdalonitrile enzyme.
The synthesis method of the invention is characterized in that the concentration of the R-amygdaloronitrile crude product aqueous solution is 50-150 g/L.
Preferably, the concentration of the R-amygdaloronitrile enzyme crude water solution is 75-125 g/L.
In a specific embodiment, the concentration of the crude R-amygdalonitrile enzyme aqueous solution is 100 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).
The synthesis method provided by the invention is characterized in that the concentration of the tertiary butanol aqueous solution is 80-100% (v/v).
Preferably, the concentration of the tert-butanol aqueous solution is 85-95% (v/v).
In a specific embodiment, the concentration of the aqueous solution of t-butanol is 90% (v/v).
The synthesis method of the invention comprises the following steps of (1.2-2.0) mixing glutaraldehyde and the crude product of R-amygdalonitrile enzyme by weight: 1.
preferably, the weight ratio of glutaraldehyde to the crude product of R-amygdalonitrile enzyme is (1.4-1.8): 1.
in a specific embodiment, the weight ratio of glutaraldehyde to the 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 is 0-10 ℃, and the reaction time is 12-48 h.
Preferably, the reaction temperature of the fixation reaction is 2-6 ℃, and the reaction time is 18-36 h.
In a specific embodiment, the reaction temperature of the immobilization 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 is 4-5.
Preferably, the pH value of the citric acid buffer is 4.2-4.8.
In a specific embodiment, the pH of the citrate buffer is 4.5.
The synthesis method provided by the invention is characterized in that the dosage ratio of the R-amygdalol nitrilase immobilized without a carrier to the 4-bromobutanal is (15-25): 1 g/mol.
Preferably, the dosage ratio of the R-amygdalonitrile enzyme immobilized without carrier to the 4-bromobutanal is (18-22): 1 g/mol.
In a specific embodiment, the amount ratio of the non-carrier immobilized R-amygdaloronidase to 4-bromobutanal is 20: 1 g/mol.
The synthesis method of the invention is characterized in that the solvent system of the cyano transfer reaction is (10-16): diisopropyl ether of 1 and citric acid buffer at pH 4-5.
Preferably, the solvent system of the cyano transfer reaction is (11-15) by volume: diisopropyl ether of 1 and citric acid buffer at pH 4.2-4.8.
In one embodiment, the solvent system for the cyano transfer reaction is a solvent system having a volume ratio of 12: diisopropyl ether at 1 and citric acid buffer at pH 4.5.
The synthesis method of the invention, wherein the temperature of the cyano transfer reaction is 5-15 ℃; the reaction time is 6-72 h.
Preferably, the temperature of the cyano transfer reaction is 8-12 ℃; the reaction time is 12-36 h.
In a specific embodiment, the temperature of the cyanogroup transfer reaction is 10 ℃; the reaction time was 24 h.
The synthesis method of the invention further comprises the steps of filtration, washing and flash column chromatography purification after the cyano transfer reaction.
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: ethyl acetate volume ratio 7: 2: 1 as eluent.
Compared with the prior art, the improved synthesis method of the 1-benzyl-3-piperidinol intermediate is provided by the invention. The intermediate synthesis method has the advantages of high stereoselectivity and high yield.
Without wishing to be bound by any theory, the carrier-free immobilized R-amygdaloronidase and hydrocyanic acid donor in the process of the invention play a key role in achieving the above-mentioned technical effects simultaneously.
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
(1) Preparation of carrier-free immobilized R-almond oxynitrilase
Adding 100mL of R-amygdalonitrile enzyme crude water solution with the concentration of 100g/L into 200mL of tert-butyl alcohol water solution (with the concentration of 90% (v/v)), slowly stirring the mixed solution at 4 ℃ to fully generate precipitate, and standing for 1 h; then adding the R-amygdalonitrile enzyme crude product in a weight ratio of 1.6: 1, carrying out a fixing reaction on the precipitate by glutaraldehyde; the reaction temperature is 4 ℃, and the reaction time is 24 hours; washing the precipitate with citric acid buffer solution with pH of 4.5, centrifuging, washing the precipitate with acetonitrile, ethyl acetate and diethyl ether, and drying to obtain the carrier-free immobilized R-amygdalonitrile enzyme.
(2) Improved synthesis method of 1-benzyl-3-piperidinol intermediate
200mg of the aforementioned R-amygdalonitrile enzyme immobilized without a carrier 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 uniformly. Adding 10m mol of 4-bromobutanal and 15m mol of racemic 2-hydroxy-2-methylhexanitrile into the mixture to carry out 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: ethyl acetate volume ratio 7: 2: 1 as eluent, and purifying by flash column chromatography. 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 CH IRALCEL OD-H chiral liquid chromatography column. See table 1 for results.
Comparative example 1
Replacing the R-almond oxynitrilase immobilized without a carrier with 200mg of a crude product of the R-almond oxynitrilase; the other conditions were the same as in example 1.
Comparative example 2
Replacing the tert-butanol aqueous solution with 200mL of ethylene glycol dimethyl ether; the other conditions were the same as in example 1.
Comparative example 3
Replacing 2-hydroxy-2-methylhexanitrile with 15m mol of hydrocyanic acid; the other conditions were the same as in example 1.
TABLE 1
The results show that the improved synthesis of 1-benzyl-3-piperidinol intermediate of example 1 of the present invention not only provides higher stereoselectivity, but also higher yield, as compared to comparative examples 1-3.
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 a 1-benzyl-3-piperidinol intermediate is characterized in that 4-bromobutanal is used as a raw material, and the raw material and a racemic hydrocyanic acid donor perform a cyano group transfer reaction under the action of an R-amygdalol nitrilase catalyst to obtain a 1-benzyl-3-piperidinol intermediate, namely (R) -1-hydroxy-4-bromo-1-butyronitrile; it is characterized in that the R-almond oxynitrilase catalyst is selected from R-almond oxynitrilase immobilized without a carrier.
2. The synthetic method according to claim 1, wherein the hydrocyanic acid donor 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 is (1.2-1.8): 1.
3. the synthetic method according to claim 1 or 2, wherein the non-carrier immobilized R-amygdalonitrile enzyme is prepared according to the following method: adding the R-amygdalonitrile enzyme crude product water solution into the tert-butanol water solution, slowly stirring the mixed solution at 0-10 ℃ to fully generate precipitate, and standing for 0.5-3 h; then adding glutaraldehyde 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, and drying to obtain the carrier-free immobilized R-amygdalonitrile enzyme.
4. The synthesis method according to claim 3, wherein the concentration of the crude R-amygdaloronitrile enzyme aqueous solution is 50-150 g/L; and/or the concentration of the tertiary butanol aqueous solution is 80-100% (v/v).
5. The synthetic method of claim 3, wherein the weight ratio of glutaraldehyde to the crude R-amygdalonitrile enzyme is (1.2-2.0): 1.
6. the synthesis method according to claim 3, wherein the reaction temperature of the immobilization reaction is 0-10 ℃ and the reaction time is 12-48 h.
7. The synthetic method according to claim 1 or 2, wherein the amount ratio of the non-carrier immobilized R-amygdaloronidase to 4-bromobutanal is (15-25): 1 g/mol.
8. The synthesis method according to claim 1 or 2, wherein the solvent system of the cyano transfer reaction is (10-16): diisopropyl ether of 1 and citric acid buffer at pH 4-5.
9. The synthesis method according to claim 1 or 2, wherein the temperature of the cyanotransfer reaction is 5-15 ℃; the reaction time is 6-72 h.
10. The synthesis of claim 1 or 2, further comprising filtration, washing and flash column chromatography purification steps after the cyano transfer reaction.
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Cited By (2)
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| CN113264868A (en) * | 2021-05-31 | 2021-08-17 | 山东华素制药有限公司 | Improved synthesis method of 1-benzyl-3-piperidinol |
| CN113265392A (en) * | 2021-05-31 | 2021-08-17 | 山东华素制药有限公司 | Cyano-group transfer catalyst and preparation method thereof |
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| CN113264868A (en) * | 2021-05-31 | 2021-08-17 | 山东华素制药有限公司 | Improved synthesis method of 1-benzyl-3-piperidinol |
| CN113265392A (en) * | 2021-05-31 | 2021-08-17 | 山东华素制药有限公司 | Cyano-group transfer catalyst and preparation method thereof |
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