CN115010652A - Synthesis process of piperidine derivative intermediate - Google Patents
Synthesis process of piperidine derivative intermediate Download PDFInfo
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- CN115010652A CN115010652A CN202210823094.7A CN202210823094A CN115010652A CN 115010652 A CN115010652 A CN 115010652A CN 202210823094 A CN202210823094 A CN 202210823094A CN 115010652 A CN115010652 A CN 115010652A
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- benzyl
- palladium
- methylpiperidine
- methylbenzoyl
- oxy
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 150000003053 piperidines Chemical class 0.000 title claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 74
- 239000003054 catalyst Substances 0.000 claims abstract description 44
- OVQAJYCAXPHYNV-NSHDSACASA-N (3s)-1-benzyl-3-methylpiperidin-4-one Chemical compound C1CC(=O)[C@@H](C)CN1CC1=CC=CC=C1 OVQAJYCAXPHYNV-NSHDSACASA-N 0.000 claims abstract description 43
- 238000002360 preparation method Methods 0.000 claims abstract description 40
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 33
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 32
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 238000003756 stirring Methods 0.000 claims abstract description 21
- -1 (4-methylbenzoyl) oxy Chemical group 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 19
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000005406 washing Methods 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- OVQAJYCAXPHYNV-UHFFFAOYSA-N 1-benzyl-3-methylpiperidin-4-one Chemical compound C1CC(=O)C(C)CN1CC1=CC=CC=C1 OVQAJYCAXPHYNV-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- FOTRUJUPLHRVNU-QNBGGDODSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid;hydrate Chemical compound O.C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 FOTRUJUPLHRVNU-QNBGGDODSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VWSBNWIPICCWAM-QMMMGPOBSA-N tert-butyl (3s)-3-methyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCC1=O VWSBNWIPICCWAM-QMMMGPOBSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- VWSBNWIPICCWAM-UHFFFAOYSA-N tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCC1=O VWSBNWIPICCWAM-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SXDQRQUWNQKZBL-UHFFFAOYSA-N butanedioic acid;hydrate Chemical compound O.OC(=O)CCC(O)=O SXDQRQUWNQKZBL-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The application relates to the technical field of organic synthesis, and particularly discloses a synthesis process of a piperidine derivative intermediate, which comprises the following steps: preparation of (S) -1-benzyl-3-methylpiperidine-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate; preparing (S) -1-benzyl-3-methylpiperidine-4-one; preparing a palladium-carbon catalyst: dissolving palladium nitrate in water to obtain a palladium nitrate solution; adding activated carbon into water, then adding a palladium nitrate solution, uniformly stirring, filtering and drying to obtain a mixture; reducing the mixture, hydrolyzing, washing and drying to obtain a palladium-carbon catalyst; dissolving (S) -1-benzyl-3-methylpiperidine-4-one, adding di-tert-butyl dicarbonate and palladium-carbon catalyst, reacting, filtering, concentrating, adding n-heptane, cooling, crystallizing and drying to obtain the product.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis process of a piperidine derivative intermediate.
Background
The piperidine derivative is an important pharmacodynamic group in the field of medicinal chemistry, wherein the 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester is a key intermediate for synthesizing a plurality of medicaments, the 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester is divided into an S type and an R type, and the S type 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester has better pharmacological activity. However, the synthesis process of the commonly used S-type tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate is complicated in steps, the purity of the prepared product is low, and the cost is high if the production is carried out on a large scale.
Disclosure of Invention
In order to improve the purity of the prepared product, the application provides a synthesis process of a piperidine derivative intermediate.
The synthesis process of the piperidine derivative intermediate provided by the application adopts the following technical scheme:
a synthesis process of a piperidine derivative intermediate comprises the following steps:
preparation of (S) -1-benzyl-3-methylpiperidin-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate: uniformly mixing 1-benzyl-3-methylpiperidine-4-one and an organic solvent A, heating, adding (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate, reacting under a heating condition to obtain a mixture A, filtering, washing and drying to obtain (S) -1-benzyl-3-methylpiperidine-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate;
preparation of (S) -1-benzyl-3-methylpiperidine-4-one: uniformly mixing (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate and dichloromethane, adding purified water, stirring, separating an organic layer, concentrating in vacuum, and crystallizing to obtain (S) -1-benzyl-3-methylpiperidine-4-one;
preparing a palladium-carbon catalyst: dissolving palladium nitrate in water to obtain a palladium nitrate solution; adding activated carbon into water, then adding a palladium nitrate solution, uniformly stirring, filtering and drying to obtain a mixture; reducing the mixture, hydrolyzing, washing and drying to obtain a palladium-carbon catalyst;
preparation of tert-butyl (S) -3-methyl-4-oxopiperidine-1-carboxylate: mixing (S) -1-benzyl-3-methylpiperidine-4-one with an organic solvent B, stirring until the mixture is completely dissolved, adding di-tert-butyl dicarbonate and a palladium-carbon catalyst, stirring uniformly, reacting, filtering, concentrating filter residue in vacuum, adding n-heptane, cooling, crystallizing and drying to obtain the product.
By adopting the technical scheme, the active carbon is added into water firstly, then the palladium nitrate solution is added, the mixture is obtained by uniformly stirring, and then the mixture is reduced, hydrolyzed, washed and dried, so that the palladium in the palladium nitrate is loaded on the active carbon to prepare the palladium-carbon catalyst; the palladium catalyst in the palladium-carbon catalyst has good palladium catalytic effect, so that the (S) -1-benzyl-3-methylpiperidine-4-one and di-tert-butyl dicarbonate fully react, and the activated carbon in the palladium-carbon catalyst can adsorb some impurities, thereby improving the purity of the prepared (S) -3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester product.
In a specific implementation scheme, in the step of preparing the palladium-carbon catalyst, activated carbon is firstly added into nitric acid to be soaked for 1.5-2.5 hours, filtration is carried out, filter residue is dried to obtain pretreated activated carbon, the pretreated activated carbon is added into water, then palladium nitrate solution is added, the mixture is uniformly stirred, filtered and dried to obtain a mixture.
By adopting the technical scheme, the activated carbon is treated by nitric acid to remove impurities in the adsorption holes of the activated carbon, so that the adsorption effect of the activated carbon is improved, and the purity of the prepared (S) -3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester product is further improved.
In a specific possible embodiment, in the step of preparing the palladium on carbon catalyst, the weight ratio of the palladium nitrate to the activated carbon is 1: (5-15).
By adopting the technical scheme, the proportion of the palladium nitrate and the activated carbon is further optimized, so that the catalytic effect of the palladium-carbon catalyst is improved.
In a specific embodiment, the weight ratio of the 1-benzyl-3-methylpiperidin-4-one and the (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is 1: (2-2.5).
By adopting the technical scheme, the proportion of the 1-benzyl-3-methylpiperidine-4-one and the (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is further limited in the application, so that the 1-benzyl-3-methylpiperidine-4-one and the (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate are fully reacted, the generation of byproducts is reduced, and the purity of the product is improved.
In a specific possible embodiment, the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to dichloromethane is 1: (5.5-7.5).
By adopting the technical scheme, the proportion of the (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to the dichloromethane is further limited in the application, so that the (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate and the dichloromethane are fully reacted, the generation of byproducts is reduced, and the purity of the product is improved.
In a specific embodiment, the weight ratio of the (S) -1-benzyl-3-methylpiperidine-4-one, the di-tert-butyl dicarbonate and the palladium-carbon catalyst is 1: (1-2): (0.02-0.08).
By adopting the technical scheme, the proportion of the (S) -1-benzyl-3-methylpiperidine-4-one, the di-tert-butyl dicarbonate and the palladium-carbon catalyst is further limited in the application, so that the (S) -1-benzyl-3-methylpiperidine-4-one and the di-tert-butyl dicarbonate are fully reacted, the generation of byproducts is reduced, and the purity of the product is improved.
In a specific embodiment, the organic solvent a comprises one or more of ethanol, acetone, acetonitrile, ethyl acetate, dichloromethane.
In a specific embodiment, the organic solvent B comprises one or more of ethanol, ethyl acetate, tetrahydrofuran.
In summary, the present application includes at least one of the following beneficial technical effects:
1. adding activated carbon into water, then adding a palladium nitrate solution, uniformly stirring to obtain a mixture, and then reducing, hydrolyzing, washing and drying to load palladium in palladium nitrate on the activated carbon to obtain a palladium-carbon catalyst; the palladium catalyst in the palladium-carbon catalyst has a good palladium catalytic effect, so that the (S) -1-benzyl-3-methylpiperidine-4-one and di-tert-butyl dicarbonate fully react, and activated carbon in the palladium-carbon catalyst can adsorb impurities, thereby improving the purity of the prepared (S) -3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester product;
2. according to the method, the activated carbon is treated by nitric acid, impurities in the activated carbon adsorption holes are removed, and the adsorption effect of the activated carbon is improved, so that the purity of the prepared (S) -3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester product is further improved;
3. the proportion of 1-benzyl-3-methylpiperidine-4-one and (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is further defined in the application, so that 1-benzyl-3-methylpiperidine-4-one and (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate are fully reacted, the generation of byproducts is reduced, and the purity of the product is improved.
Detailed Description
The present application will be described in further detail with reference to examples.
All the starting materials in the examples are commercially available.
Preparation example
Preparation example 1
Dissolving palladium nitrate in water to obtain a palladium nitrate solution; adding activated carbon into water, then adding a palladium nitrate solution, uniformly stirring for 2 hours at room temperature, filtering, and drying filter residues to obtain a mixture; reducing the mixture by formaldehyde, formic acid and hydrazine hydrate, hydrolyzing the mixture by sodium hydroxide to obtain a precipitate, washing the precipitate, and drying to obtain a palladium-carbon catalyst; wherein the weight ratio of the palladium nitrate to the activated carbon is 1: 2.
preparation example 2
The difference between the preparation example 2 and the preparation example 1 is that activated carbon is firstly added into nitric acid to be soaked for 2 hours, the filtration is carried out, and filter residue is dried to obtain pretreated activated carbon; adding activated carbon into water, then adding a palladium nitrate solution, stirring uniformly, then stirring at a constant speed for 2 hours at room temperature, filtering, and drying filter residues to obtain a mixture, wherein the rest steps are consistent with those of preparation example 1.
Preparation example 3
The difference between preparation 3 and preparation 2 is that the weight ratio of palladium nitrate to activated carbon is 1: 5, the remaining steps correspond to preparation 2.
Preparation example 4
Preparation 4 differs from preparation 2 in that the weight ratio of palladium nitrate to activated carbon is 1: the remaining steps correspond to preparation 2.
Preparation example 5
Preparation example 5 differs from preparation example 2 in that the weight ratio of palladium nitrate to activated carbon was 1: 15, the remaining steps correspond to preparation 2.
Preparation example 6
Preparation example 6 differs from preparation example 2 in that the weight ratio of palladium nitrate to activated carbon was 1: 18, the remaining steps correspond to preparation 2.
Examples
Example 1
Example 1 provides a process for the synthesis of a piperidine derivative intermediate.
A synthesis process of a piperidine derivative intermediate comprises the following steps:
preparation of (S) -1-benzyl-3-methylpiperidin-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate: uniformly mixing 1-benzyl-3-methylpiperidine-4-one and an organic solvent A, heating to 40 ℃ to completely dissolve 1-benzyl-3-methylpiperidine-4-one, adding (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate, stirring for 12 hours at 40 ℃ to obtain a mixture A, filtering, washing filter residue with the organic solvent A, and then drying in vacuum at 40 ℃ to obtain (S) -1-benzyl-3-methylpiperidine-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate; wherein the organic solvent A is acetonitrile, and the weight ratio of the 1-benzyl-3-methylpiperidine-4-one to the acetonitrile is 1: 6; the weight ratio of 1-benzyl-3-methylpiperidin-4-one to (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is 1: 2;
preparation of (S) -1-benzyl-3-methylpiperidine-4-one: uniformly mixing (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate and dichloromethane, adding purified water, uniformly stirring to obtain a mixed solution, adding ammonium hydroxide to adjust the pH value of the mixed solution to 10, layering the mixed solution, separating an organic layer, adding water into the organic layer, stirring, separating the organic layer again, concentrating the organic layer at 40 ℃ in vacuum, adding n-heptane, cooling to 0 ℃ for crystallization, and drying the crystals at room temperature in vacuum to obtain (S) -1-benzyl-3-methylpiperidine-4-one; wherein the weight ratio of (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to dichloromethane is 1: 5.5;
preparation of tert-butyl (S) -3-methyl-4-oxopiperidine-1-carboxylate: mixing (S) -1-benzyl-3-methylpiperidine-4-one with an organic solvent B, stirring until the (S) -1-benzyl-3-methylpiperidine-4-one is completely dissolved, adding di-tert-butyl dicarbonate and a palladium-carbon catalyst, uniformly stirring, stirring for 24 hours at 25 ℃ and under the hydrogen pressure of 50psi, filtering out the palladium-carbon catalyst, then carrying out vacuum concentration at 40 ℃, then adding n-heptane into the concentrate, then cooling to 0 ℃, crystallizing, and carrying out vacuum drying on the crystal at room temperature to obtain a product; wherein the weight ratio of (S) -1-benzyl-3-methylpiperidine-4-one, di-tert-butyl dicarbonate and palladium carbon catalyst is 1: 1: 0.02; the organic solvent B is ethyl acetate.
As shown in Table 1, examples 1-6 differ in the choice of palladium on carbon catalyst.
| Sample (I) | Selection of palladium-carbon catalyst |
| Example 1 | Preparation example 1 |
| Example 2 | Preparation example 2 |
| Example 3 | Preparation example 3 |
| Example 4 | Preparation example 4 |
| Example 5 | Preparation example 5 |
| Example 6 | Preparation example 6 |
Example 7
Example 7 differs from example 4 in that the weight ratio of 1-benzyl-3-methylpiperidin-4-one and (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is 1: 2.3, the remaining steps correspond to example 4.
Example 8
Example 8 differs from example 4 in that the weight ratio of 1-benzyl-3-methylpiperidin-4-one and (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is 1: 2.5, the remaining steps correspond to example 4.
Example 9
Example 9 differs from example 7 in that the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to dichloromethane was 1: 6.5, the remaining steps correspond to example 7.
Example 10
Example 10 differs from example 7 in that the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to dichloromethane was 1: 7.5, the remaining steps correspond to example 7.
Example 11
Example 11 differs from example 9 in that the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one, di-tert-butyl dicarbonate and palladium on carbon catalyst is 1: 1.5: 0.05, the rest of the procedure corresponds to example 9.
Example 12
Example 12 differs from example 9 in that the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one, di-tert-butyl dicarbonate and palladium on carbon catalyst is 1: 2: 0.08 and the rest of the procedure corresponds to example 9.
Comparative example
Comparative example 1
Comparative example 1 differs from example 1 in that the palladium on carbon catalyst is replaced with an equal amount of palladium hydroxide and the remaining procedure is identical to example 1.
Comparative example 2
Comparative example 2 differs from example 1 in that the palladium on carbon catalyst is replaced with an equal amount of a dirhodium catalyst and the remaining procedure is identical to example 1.
Purity of performance testing test: the product of each example was weighed as a and the product was checked for the weight of tert-butyl (S) -3-methyl-4-oxopiperidine-1-carboxylate as B and the purity (B/a) × 100%.
TABLE 2 results of the product Performance test
| Sample(s) | Purity (%) |
| Example 1 | 78.1 |
| Example 2 | 80.2 |
| Example 3 | 81.9 |
| Example 4 | 82.4 |
| Example 5 | 82.0 |
| Example 6 | 80.6 |
| Example 7 | 83.6 |
| Example 8 | 83.1 |
| Example 9 | 84.8 |
| Example 10 | 84.2 |
| Example 11 | 85.7 |
| Example 12 | 84.9 |
| Comparative example 1 | 73.5 |
| Comparative example 2 | 72.1 |
By combining the example 1, the comparative example 1 and the comparative example 2, the purity of the product in the example 1 is the highest, and it can be seen that when (S) -3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester is synthesized, a palladium carbon catalyst is selected, the palladium catalytic effect in the palladium carbon catalyst is better, so that (S) -1-benzyl-3-methylpiperidine-4-one and di-tert-butyl dicarbonate fully react, and the activated carbon in the palladium carbon catalyst adsorbs impurities, thereby improving the purity of the product.
By combining the embodiment 1 and the embodiment 2, the purity of the product in the embodiment 2 is higher, and it can be seen that when the palladium-carbon catalyst is prepared, the nitric acid is firstly utilized to pretreat the activated carbon, so that impurities in the activated carbon adsorption holes are removed, and the adsorption effect of the activated carbon is improved, thereby further improving the purity of the product.
By combining the example 2 and the examples 3 to 6, the purity of the product in the examples 3 to 5 is higher, and it can be seen that when preparing the palladium-carbon catalyst, the ratio of the palladium nitrate to the activated carbon is controlled to be 1: (5-15), the prepared palladium-carbon catalyst has better catalytic effect.
In combination with example 4, example 7 and example 8, the product of example 7 had the highest purity, and it can be seen that when (S) -1-benzyl-3-methylpiperidin-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate was synthesized, when the weight ratio of 1-benzyl-3-methylpiperidin-4-one and (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate hydrate was 1: in the case of (2-2.5), the amount of (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate used was increased, and the purity of the obtained product tended to increase and then decrease.
In combination with example 7, example 9 and example 10, the product of example 9 had the highest purity, and it can be seen that when (S) -1-benzyl-3-methylpiperidin-4-one was synthesized, (S) -1-benzyl-3-methylpiperidin-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate and dichloromethane were present in a weight ratio of 1: (5.5-7.5), the purity of the product tends to increase and decrease with increasing amount of methylene chloride.
Combining example 9, example 11 and example 12, the purity of the product in example 11 is the highest, and it can be seen that when (S) -3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester is synthesized, when the weight ratio of (S) -1-benzyl-3-methylpiperidine-4-one, di-tert-butyl dicarbonate and palladium on charcoal catalyst is 1: (1-2): (0.02 to 0.08), the amount of di-tert-butyl dicarbonate used is increased, and the amount of catalyst used is increased, so that the purity of the resulting product tends to increase first and then decrease.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (8)
1. A synthesis process of a piperidine derivative intermediate is characterized by comprising the following steps: the method comprises the following steps:
preparation of (S) -1-benzyl-3-methylpiperidin-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate: uniformly mixing 1-benzyl-3-methylpiperidine-4-one and an organic solvent A, heating, adding (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate, reacting under a heating condition to obtain a mixture A, filtering, washing and drying to obtain (S) -1-benzyl-3-methylpiperidine-4-one (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate;
preparation of (S) -1-benzyl-3-methylpiperidin-4-one: uniformly mixing (S) -1-benzyl-3-methylpiperidine-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate and dichloromethane, adding purified water, stirring, separating an organic layer, concentrating in vacuum, and crystallizing to obtain (S) -1-benzyl-3-methylpiperidine-4-one;
preparation of palladium-carbon catalyst: dissolving palladium nitrate in water to obtain a palladium nitrate solution; adding activated carbon into water, then adding a palladium nitrate solution, uniformly stirring, filtering and drying to obtain a mixture; reducing the mixture, hydrolyzing, washing and drying to obtain a palladium-carbon catalyst;
preparation of tert-butyl (S) -3-methyl-4-oxopiperidine-1-carboxylate: mixing (S) -1-benzyl-3-methylpiperidine-4-one with an organic solvent B, stirring until the mixture is completely dissolved, adding di-tert-butyl dicarbonate and a palladium-carbon catalyst, stirring uniformly, reacting, filtering, concentrating filter residue in vacuum, adding n-heptane, cooling, crystallizing and drying to obtain the product.
2. The process of claim 1, wherein the intermediate comprises: in the preparation step of the palladium-carbon catalyst, firstly adding activated carbon into nitric acid to be soaked for 1.5-2.5h, filtering, drying filter residues to obtain pretreated activated carbon, adding the pretreated activated carbon into water, then adding a palladium nitrate solution, uniformly stirring, filtering and drying to obtain a mixture.
3. The process of claim 1, wherein the intermediate comprises: in the step of preparing the palladium-carbon catalyst, the weight ratio of the palladium nitrate to the activated carbon is 1: (5-15).
4. The process of claim 1, wherein the intermediate comprises: the weight ratio of the 1-benzyl-3-methylpiperidin-4-one to the (2R,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate is 1: (2-2.5).
5. The process of claim 4, wherein the intermediate comprises: the weight ratio of (S) -1-benzyl-3-methylpiperidin-4-one (2S,3R) -2, 3-bis ((4-methylbenzoyl) oxy) succinate to dichloromethane is 1: (5.5-7.5).
6. The process of claim 5, wherein the intermediate comprises: the weight ratio of the (S) -1-benzyl-3-methylpiperidine-4-one, the di-tert-butyl dicarbonate and the palladium-carbon catalyst is 1: (1-2): (0.02-0.08).
7. The process of claim 1, wherein the intermediate comprises: the organic solvent A comprises one or more of ethanol, acetone, acetonitrile, ethyl acetate and dichloromethane.
8. The process of claim 1, wherein the intermediate comprises: the organic solvent B comprises one or more of ethanol, ethyl acetate and tetrahydrofuran.
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| CN101433839A (en) * | 2008-12-19 | 2009-05-20 | 长沙荣星贵金属有限公司 | Method for preparing palladium carbon catalyst of high activity |
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| CN111587240A (en) * | 2017-12-11 | 2020-08-25 | 怡诺安有限公司 | Intermediate of optically active piperidine derivative and process for producing the same |
| CN114213316A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of intermediate of optically active piperidine derivative |
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