CN113461598A - Process for producing piperidinol compound - Google Patents
Process for producing piperidinol compound Download PDFInfo
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- CN113461598A CN113461598A CN202110859202.1A CN202110859202A CN113461598A CN 113461598 A CN113461598 A CN 113461598A CN 202110859202 A CN202110859202 A CN 202110859202A CN 113461598 A CN113461598 A CN 113461598A
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- 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
- C07D211/42—Oxygen atoms attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
Disclosed is a method for preparing a piperidinol compound selected from the group consisting of (R) -1-benzyl-3-piperidinol; 1-benzyl-3-piperidone is used as a reaction raw material, and LiAlH is used4And a chiral reagent formed by the chiral ligand is used as a reducing agent to carry out reduction reaction. The main product of the preparation method is (R) -1-benzyl-3-piperidinol, and the yield and the ee value of the main product are higher.
Description
Technical Field
The invention belongs to the technical field of preparation of medical intermediates; in particular to a preparation method of a piperidinol compound.
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.
In the synthetic route of 1-benzyl-3-piperidinol, a process route is as follows: taking 3-hydroxypyridine as a raw material, and firstly carrying out quaternization reaction to obtain 3-hydroxypyridine quaternary ammonium salt; the latter is further reduced to obtain 1-benzyl-3-piperidinol. 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.
The inventors found that, similarly to other synthetic routes, a process route of reduction of 3-hydroxypyridine or a derivative thereof is often used, and such a reduction route is easy to obtain a high yield, but the reaction stereoselectivity is not high, a reaction product having (R) -1-benzyl-3-piperidinol as a main product is not easy to obtain, and the ee value is not high.
Therefore, in view of the drawbacks of the prior art, a method for preparing a piperidinol compound is needed.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a method for producing a piperidinol compound.
In order to achieve the purpose, the invention adopts the following technical scheme: a method for producing a piperidinol compound selected from the group consisting of (R) -1-benzyl-3-piperidinol; it is characterized in that 1-benzyl-3-piperidone is used as a reaction raw material, and LiAlH is used4And a chiral reagent formed by the chiral ligand is used as a reducing agent to carry out reduction reaction.
The preparation method of the invention is characterized in that the chiral ligand is chiral amino alcohol.
The preparation method of the invention is characterized in that the chiral ligand is selected from (1R,2R) -2- (dimethylamino) cyclohexanol.
The preparation method of the invention, wherein the LiAlH4The molar ratio of the chiral ligand to the chiral ligand is 1: (1.6-2.4).
Preferably, LiAlH4The molar ratio of the chiral ligand to the chiral ligand is 1: (1.8-2.2).
The preparation method of the invention, wherein the LiAlH4The molar ratio of the 1-benzyl-3-piperidone to the 1-benzyl-3-piperidone is 1: (0.75-0.9).
Preferably, LiAlH4The molar ratio of the chiral ligand to the chiral ligand is 1: (0.8-0.85).
The preparation method provided by the invention is characterized in that the reaction temperature of the reduction reaction is 0-20 ℃; the reaction time is 6-72 h.
Preferably, the reaction temperature of the reduction reaction is 0-10 ℃; the reaction time is 18-48 h.
According to the preparation method, after the reaction is finished, a dilute hydrochloric acid solution is added for standing.
The preparation method further comprises ethyl acetate extraction and anhydrous Na2SO4Drying and distilling off the solvent.
The preparation method according to the present invention further comprises the step of isolating the crude product using a silica gel G thin layer chromatography plate.
According to the preparation method, the developing solvent is a mixed solvent of n-hexane and ethyl acetate with the volume ratio of (2-4): 1.
Preferably, the developing solvent is a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 3: 1.
Compared with the prior art, the preparation method has higher yield and ee value of the main product.
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
In the dry fourIntroducing N into a flask211.4mg (0.3mmol) of LiAlH4Adding the solution of (5%) into 85.9mg (0.6mmol) of chiral ligand (1R,2R) -2- (dimethylamino) cyclohexanol in tetrahydrofuran (20mL) dropwise, and stirring at 5 deg.C for 1 h; then 47.3mg (0.25mmol) of 1-benzyl-3-piperidone is added, and the reaction is carried out for 24 hours under the condition of 5 ℃; then 5mL of 1mol/L hydrochloric acid solution is added, and the mixture is kept stand for 15 min; extracting with ethyl acetate for 3 times, each time 20 mL; followed by anhydrous Na2SO4Drying, filtering, and evaporating the solvent to obtain a crude product; separating the crude product by using a silica gel G thin-layer chromatography plate, wherein a developing agent is a mixed solvent of n-hexane and ethyl acetate with the volume ratio of 3:1, and obtaining the product, mainly (R) -1-benzyl-3-piperidinol.
Example 2
Introducing N into a dry four-neck flask211.4mg (0.3mmol) of LiAlH4Is added into a tetrahydrofuran (10mL) solution of 78.8mg (0.55mmol) of chiral ligand (1R,2R) -2- (dimethylamino) cyclohexanol (20mL), and is stirred for 2h at the temperature of 0 ℃; then 47.3mg (0.25mmol) of 1-benzyl-3-piperidone is added, and the reaction is carried out for 48 hours under the condition of 0 ℃; then 5mL of 1mol/L hydrochloric acid solution is added, and the mixture is kept stand for 15 min; extracting with ethyl acetate for 3 times, each time 20 mL; followed by anhydrous Na2SO4Drying, filtering, and evaporating the solvent to obtain a crude product; separating the crude product by using a silica gel G thin-layer chromatography plate, wherein a developing agent is a mixed solvent of n-hexane and ethyl acetate with the volume ratio of 3:1, and obtaining the product, mainly (R) -1-benzyl-3-piperidinol.
Example 3
Introducing N into a dry four-neck flask211.4mg (0.3mmol) of LiAlH4Is added into 93.1mg (0.65mmol) of chiral ligand (1R,2R) -2- (dimethylamino) cyclohexanol in tetrahydrofuran (20mL) dropwise, and stirred for 0.5h at 10 ℃; then 47.3mg (0.25mmol) of 1-benzyl-3-piperidone is added, and the reaction is carried out for 18 hours under the condition of 10 ℃; then 5mL of 1mol/L hydrochloric acid solution is added, and the mixture is kept stand for 15 min; extracting with ethyl acetate for 3 times, each time 20 mL; followed by anhydrous Na2SO4Drying, filtering, and evaporating the solvent to obtain a crude product; the crude product was isolated using silica gel G thin layer chromatography plateThe developing solvent is a mixed solvent of n-hexane and ethyl acetate with the volume ratio of 3:1 to obtain a product, mainly (R) -1-benzyl-3-piperidinol.
Comparative example 1
The same conditions as in example 1 were followed, except that the chiral ligand (1R,2R) -2- (dimethylamino) cyclohexanol was added in an amount of 0.3 mmol.
Comparative example 2
The same conditions as in example 1 were followed, except that the chiral ligand (1R,2R) -2- (dimethylamino) cyclohexanol was added in an amount of 0.9 mmol.
The yields (%) of the products of examples and comparative examples were calculated and the ee values were determined on a liquid chromatograph using a japanese xylonite CHIRALCEL OD-H chiral liquid chromatography column. See table 1 for results.
TABLE 1
| Yield (%) | ee value (%) | |
| Example 1 | 84.9 | 76.1 |
| Comparative example 1 | 49.3 | 53.7 |
| Comparative example 2 | 62.5 | 42.6 |
As can be seen from Table 1, the process of example 1 of the present application has higher yield and ee value of the main product than those of comparative examples 1-2.
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. A method for producing a piperidinol compound selected from the group consisting of (R) -1-benzyl-3-piperidinol; it is characterized in that 1-benzyl-3-piperidone is used as a reaction raw material, and LiAlH is used4And a chiral reagent formed by the chiral ligand is used as a reducing agent to carry out reduction reaction.
2. The method of claim 1, wherein the chiral ligand is a chiral amino alcohol.
3. The process according to claim 2, wherein the chiral ligand is selected from (1R,2R) -2- (dimethylamino) cyclohexanol.
4. The method according to claim 1, wherein LiAlH4The molar ratio of the chiral ligand to the chiral ligand is 1: (1.6-2.4).
5. The method according to claim 1, wherein LiAlH4The molar ratio of the 1-benzyl-3-piperidone to the 1-benzyl-3-piperidone is 1: (0.75-0.9).
6. The production method according to claim 1, wherein the reaction temperature of the reduction reaction is 0 to 20 ℃; the reaction time is 6-72 h.
7. The method according to claim 1, wherein the diluted hydrochloric acid solution is added after the reaction is completed and left to stand.
8. The method of claim 1, further comprising ethyl acetate extraction, anhydrous Na2SO4Drying and distilling off the solvent.
9. The method according to claim 8, further comprising a step of isolating the crude product using a silica gel G thin layer chromatography plate.
10. The preparation method according to claim 9, wherein the developing solvent is a mixed solvent of n-hexane/ethyl acetate in a volume ratio of (2-4): 1.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035652A1 (en) * | 2001-10-26 | 2003-05-01 | Merck Generics [Uk] Limited | A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES |
| EP3115358A1 (en) * | 2014-03-04 | 2017-01-11 | ABA Chemicals Corporation | Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine |
| CN106520855A (en) * | 2016-11-10 | 2017-03-22 | 中国科学院成都生物研究所 | Method for preparing stereoscopic complementary N-heterocycle alcohol compounds by conducting biological catalysis through carbonyl reductase |
| CN109320515A (en) * | 2018-11-22 | 2019-02-12 | 常州大学 | A kind of method of asymmetric synthesis of Capromorelin chiral intermediate |
-
2021
- 2021-07-28 CN CN202110859202.1A patent/CN113461598B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035652A1 (en) * | 2001-10-26 | 2003-05-01 | Merck Generics [Uk] Limited | A PROCESS FOR PREPARING ENANTIOMERICALLY PURE α-PHENYL-α-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YL)-ACETIC ACID DERIVATIVES |
| EP3115358A1 (en) * | 2014-03-04 | 2017-01-11 | ABA Chemicals Corporation | Method of preparation and chiral inversion of chiral-1-t-butoxycarbonyl-3-hydroxy piperidine |
| CN106520855A (en) * | 2016-11-10 | 2017-03-22 | 中国科学院成都生物研究所 | Method for preparing stereoscopic complementary N-heterocycle alcohol compounds by conducting biological catalysis through carbonyl reductase |
| CN109320515A (en) * | 2018-11-22 | 2019-02-12 | 常州大学 | A kind of method of asymmetric synthesis of Capromorelin chiral intermediate |
Non-Patent Citations (4)
| Title |
|---|
| CHAO LI，等: "Stereo-complementary bioreduction of saturated N-heterocyclic ketones", 《PROCESS BIOCHEMISTRY》 * |
| YADU B. TEWARI，等: "A thermodynamic study of ketoreductase-catalyzed reactions 5. Reduction of substituted ketones in n-hexane", 《J. CHEM. THERMODYNAMICS》 * |
| 李阳等: "催化合成2,2,6,6-四甲基-4-氨基哌啶", 《化学工业与工程》 * |
| 王多禄，等: "常压催化氢化合成2, 2, 6, 6-四甲基-4-哌啶醇的研究", 《化学工业与工程》 * |
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