CN116143687A - Preparation method of (R) -3-aminopiperidine dihydrochloride - Google Patents
Preparation method of (R) -3-aminopiperidine dihydrochloride Download PDFInfo
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- CN116143687A CN116143687A CN202310226205.0A CN202310226205A CN116143687A CN 116143687 A CN116143687 A CN 116143687A CN 202310226205 A CN202310226205 A CN 202310226205A CN 116143687 A CN116143687 A CN 116143687A
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- aminopiperidine dihydrochloride
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- aminopiperidine
- sodium
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- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 5
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 5
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 229960003966 nicotinamide Drugs 0.000 abstract description 4
- 235000005152 nicotinamide Nutrition 0.000 abstract description 4
- 239000011570 nicotinamide Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 4
- -1 lithium aluminum hydride Chemical compound 0.000 description 3
- PEUGKEHLRUVPAN-RXMQYKEDSA-N (3r)-piperidin-3-amine Chemical compound N[C@@H]1CCCNC1 PEUGKEHLRUVPAN-RXMQYKEDSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- 229930182847 D-glutamic acid Natural products 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QONUZQBHASYEAL-GFCCVEGCSA-N benzyl n-[(2r)-1,5-dihydroxypentan-2-yl]carbamate Chemical compound OCCC[C@H](CO)NC(=O)OCC1=CC=CC=C1 QONUZQBHASYEAL-GFCCVEGCSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 229960002397 linagliptin Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- ZUEUGHANSCCAJC-NUBCRITNSA-N methyl (2r)-2,5-diaminopentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)CCCN ZUEUGHANSCCAJC-NUBCRITNSA-N 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001308 synthesis method 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
- C07D211/06—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
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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 invention discloses a preparation method of (R) -3-aminopiperidine dihydrochloride, belonging to the field of drug intermediate synthesis. The method takes 3-pyridine carboxamide as a raw material to synthesize (R) -3-aminopiperidine dihydrochloride through salifying, reducing, huffman degradation, chiral resolution, hydrodebenzyl and salifying. The invention provides a preparation method of (R) -3-aminopiperidine dihydrochloride, which has the advantages of easily available and cheap raw materials, controllable reaction process, simple operation and good product purity.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of (R) -3-aminopiperidine dihydrochloride.
Background
A process for the preparation of (R) -3-aminopiperidine dihydrochloride of formula (i): c (C) 5 H 14 Cl 2 N 2 Molecular weight: 173.08, CAS:334618-23-4, the chemical structural formula is shown as follows:
the (R) -3-aminopiperidine dihydrochloride is an important intermediate of high-added-value medicines and chemical engineering thereof, and mainly synthesizes the important intermediates of the dipeptidyl enzyme IV antidiabetic medicines alogliptin, linagliptin and trogliptin, and three synthesis methods exist at present.
Route one (university of Nanchang, 2014,36 (002): 129-132.): the (R) -2- ((carbobenzoxy) amino) -1, 5-pentanediol is taken as a raw material, and the (R) -3-aminopiperidine is prepared through three steps of reactions of esterification, cyclization and catalytic hydrogenation, and the synthetic route is as follows.
In the method, the raw materials are expensive, enterprises which are not supplied on a large scale are not involved, racemization is easy to occur in the process of forming rings, the difficulty of forming rings is high, the pressure required by catalytic hydrogenation reaction is high, and the reaction is not easy to complete.
Route two (Bioorganic & Medicinal Chemistry,2006,14 (7): 2131-2150): d-ornithine hydrochloride is taken as a raw material, is acylated by thionyl chloride and then is esterified with methanol to generate D-ornithine methyl ester hydrochloride, then an intermediate (R) -3-aminopiperidine-2-ketone hydrochloride is generated by strong-base anion exchange resin, and then carbonyl of (R) -3-aminopiperidine-2-ketone lactam is reduced by lithium aluminum hydride to be methylene, so that the (R) -3-aminopiperidine is obtained, and the synthetic route is as follows.
The ornithine used in the alternative method is not easy to obtain, has high price, contains more impurities in the ring closing reaction, has lower yield, reduces the carbonyl of the lactam into methylene to use lithium aluminum hydride, and is not easy to industrialize.
Route three (Liu Chaoyong) (R) -3-aminopiperidine dihydrochloride synthesis process modification [ D ]. University of eastern chemical, 2011.): d-glutamic acid is used as an initial raw material, and is subjected to 9 steps of reactions such as carboxyl esterification, amido Cbz protection, ester group reduction and the like to obtain (R) -3-aminopiperidine dihydrochloride, wherein the synthetic route is as follows.
The route is tedious, three times of protecting groups are needed, three times of protecting groups are removed, the reaction steps are increased, the yield is reduced, and the total yield is low and the cost is high.
Disclosure of Invention
The invention provides a preparation method of (R) -3-aminopiperidine dihydrochloride aiming at the defects in the prior art.
The method takes 3-pyridine carboxamide as a raw material to synthesize (R) -3-aminopiperidine dihydrochloride through salifying, reducing, huffman degradation, chiral resolution, hydrodebenzyl and salifying, and the specific synthetic route is as follows.
S1: adding 3-pyridine formamide and benzyl chloride or benzyl bromide into a reaction bottle, adding a solvent, and heating to react to obtain an intermediate 1; the solvent in the step is one or more of acetonitrile, 1, 4-dioxane, DMF, ethylene glycol, ethanol and isopropanol, preferably acetonitrile; the reaction temperature is 80-120 ℃.
S2: adding the intermediate 1 into a solvent, adding alkali, and adding a reducing agent for reduction to obtain an intermediate 2; the solvent in the step is one of water, methanol, ethanol and acetonitrile, and preferably water; the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate, preferably sodium hydroxide; the reducing agent is one of sodium borohydride and potassium borohydride, and the molar ratio of the reducing agent to the intermediate 1 is 1.0:2.0-4.0.
S3: dissolving the intermediate 2 in a solution of sodium hypochlorite or sodium hypobromite, and heating to react to obtain an intermediate 3; the molar concentration of sodium hypochlorite or sodium hypobromite in this step is 10-30%, preferably 20%; the reaction temperature is 70-85 ℃.
S4: adding the intermediate 3 into a solvent, adding a resolving agent for the first time, heating to dissolve, cooling to crystallize, and filtering; adding the solid into a solvent, adding a resolving agent for the second time for resolution, heating for dissolution, cooling for crystallization, filtering, and freeing to obtain an intermediate 4; the resolving agent in the step is one of L-tartaric acid, L-dibenzoyl tartaric acid, L-mandelic acid and L-camphorsulfonic acid, preferably L-dibenzoyl tartaric acid and L-mandelic acid; the molar ratio of the resolving agent added for the first time to the intermediate 3 is 1:1.5, the molar ratio of the resolving agent to the intermediate 3 added for the second time is 1: the resolution solvent is one of n-butanol, DMF, DMAC, acetonitrile and DMSO, preferably DMF and n-butanol.
S5: adding a solvent into the intermediate 4, removing benzyl under the action of a catalyst, and then adding concentrated hydrochloric acid to obtain (R) -3-aminopiperidine dihydrochloride; the catalyst in the step is Pd/C; the solvent is one of methanol, ethanol and isopropanol, preferably ethanol.
The invention has the beneficial effects that:
(1) The raw material 3-pyridine formamide belongs to bulk chemicals, and is cheap and easy to obtain;
(2) The chiral resolution reagent is used, racemization in the reaction process is avoided, and the chiral resolution effect is good;
(3) The preparation process of the invention avoids the use of strong lithium aluminum tetrahydroide reducer and reaction conditions such as ultralow temperature, high pressure and the like, has mild reaction conditions, does not need to carry out the processes of protecting group loading and protecting group removing for many times, and improves the atom utilization rate.
Detailed Description
Example 1:
preparation of intermediate 1: to a 3L reaction flask was added 3-pyridinecarboxamide (200 g,1 eq), benzyl chloride (230 g,1.1 eq) and acetonitrile (400 g), and the mixture was heated to 80℃for 3h, cooled to room temperature, cooled to 5-10℃and solid was precipitated. The mixture was filtered, and the filter cake was washed with acetonitrile (200 g) and dried in vacuo to give intermediate 1 (387 g, 95% yield).
Preparation of intermediate 2: to a 3L reaction flask was added intermediate 1 (250 g,1 eq), stirring was started, water (750 g) was added, ph=9 was adjusted by adding sodium hydroxide, sodium borohydride (85 g,2.2 eq) was added in portions, the process temperature did not exceed 60 ℃, the addition was completed, the temperature was raised to 85 ℃ for 3 hours, the reaction was cooled to room temperature, ethyl acetate (350 g+150 g) was added for extraction, the organic phases were combined, dried, concentrated to give crude intermediate 2, ethanol (600 g) was added for recrystallization to give white solid (190.6 g, yield 87%).
Preparation of intermediate 3: intermediate 2 (227 g,1.5 mol) was dissolved in acetonitrile (1L), cooled to 0 ℃, 20% sodium hypochlorite solution (744 ml,2.0 mol) was added dropwise, stirred for half an hour, and the ice bath was removed. Heating to 80 ℃, and preserving heat for reaction for 1.5 hours. Cooled to room temperature, extracted with ethyl acetate (1000 ml+500 ml), the organic phases were combined, dried and concentrated in vacuo to give crude intermediate 3, which was distilled under reduced pressure to give intermediate 3 as a pure product (242.6 g, yield 85%).
Preparation of intermediate 4: n-butanol (1.5L), intermediate 3 (190 g,1.0 mol) and L-dibenzoyl tartaric acid (537 g,1.5 eq) were added to a 5L three-necked flask, the temperature was raised to 95℃and the reaction was stirred for 2 hours, the system was completely dissolved, the temperature was lowered to 0-5℃and stirred for 5 hours, and a white solid was obtained by filtration. The solid was added to n-butanol (1.5L), L-dibenzoyltartaric acid (178 g,0.5 eq) was added, the temperature was raised to 100℃for 3 hours, the temperature was lowered to 5-10℃and stirred overnight, and the mixture was filtered and dried to give a white solid.
The above white solid was dissolved in water (500 mL) with stirring, ph=9 to 10 was adjusted with sodium hydroxide (1 mol/L), stirred at room temperature for 2 hours, extracted with methylene chloride (250 ml+250 mL), the organic phase was washed with 200ml×2 water, the organic phase was dried, and concentrated to give a colorless oil, intermediate 4 (83.6 g, ee value 99.5%, yield 88%, calculated as theoretical 95 g).
Preparation of (R) -3-aminopiperidine dihydrochloride: intermediate 4 (190 g,1 eq) was added to a 5L autoclave, ethanol (1L) was added, 9.5g of 10% palladium on carbon (water content 58%, model D10H5A, new materials, inc. Of shanxi, rayleigh) was added, nitrogen was replaced three times, hydrogen was replaced three times, the pressure of the reaction system was maintained at 0.3MPa, the temperature was slowly raised to 65 ℃ for 2.5 hours, palladium on carbon was recovered by filtration after the reaction, concentrated hydrochloric acid (175 ml,12mol/L,2.1 eq) was added dropwise to the filtrate, stirring was carried out at room temperature overnight, and a white solid was obtained by filtration, namely (R) -3-aminopiperidine dihydrochloride (145 g, yield 84%, chemical purity 99.1%, ee value 99.6%).
Example 2:
preparation of intermediate 1: to a 3L reaction flask was added 3-pyridinecarboxamide (200 g,1 eq), benzyl bromide (311 g,1.1 eq) and isopropanol (400 g) were added, and the reaction was continued at 80℃for 3h, cooled to room temperature and continued to 5-10℃until a solid was precipitated. The mixture was filtered, and the filter cake was washed with isopropyl alcohol (200 g) and dried in vacuo to give intermediate 1 (358 g, yield 90%).
Preparation of intermediate 2: to a 3L reaction flask, add intermediate 1 (250 g,1 eq), start stirring, add methanol (750 g), add potassium carbonate 18g, add sodium borohydride (116 g,3.0 eq) in portions, the process temperature does not exceed 60 ℃, after addition, heat to 85 ℃ to react for 3 hours, cool to room temperature, concentrate the solvent, add water (1L) stirring, extract with ethyl acetate (350g+150 g), combine the organic phases, dry, concentrate to obtain intermediate 2 crude, add ethanol (600 g) to recrystallise to obtain a white solid (77.4 g, yield 87%).
Preparation of intermediate 3: intermediate 2 (227 g,1.5 mol) was dissolved in acetonitrile (1L), cooled to 0 ℃, and 30% sodium hypobromite solution (793 ml,2.0 mol) was added dropwise, stirred for half an hour, and the ice bath was removed. Heating to 80 ℃, and preserving heat for reaction for 1.5 hours. Cooled to room temperature, extracted with ethyl acetate (1000 ml+500 ml), the organic phases were combined, dried and concentrated in vacuo to give crude intermediate 3, which was distilled under reduced pressure to give pure intermediate 3 (228.3 g, 80% yield).
Preparation of intermediate 4: DMF (1.5L), intermediate 3 (190 g,1.0 mol) and L-mandelic acid (228 g,1.5 eq) were added to a 5L three-necked flask, the temperature was raised to 95℃and the reaction was stirred for 2 hours, the system was completely dissolved, the temperature was lowered to 0-5℃and the reaction was stirred for 5 hours, and the mixture was filtered to obtain a white solid. The solid was added to DMF (1.5L), L-mandelic acid (76 g,0.5 eq) was added, the temperature was raised to 100℃and kept for 3 hours, the temperature was lowered to 5-10℃and stirred overnight, and the white solid was obtained by filtration and drying.
The above white solid was dissolved in water (500 mL) with stirring, ph=9 to 10 was adjusted with sodium hydroxide (1 mol/L), stirred at room temperature for 2 hours, extracted with methylene chloride (250 ml+250 mL), the organic phase was washed with 200ml×2 water, the organic phase was dried, and concentrated to give a colorless oil, intermediate 4 (83.6 g, ee value 99.5%, yield 88%, calculated as theoretical 95 g).
Preparation of (R) -3-aminopiperidine dihydrochloride: intermediate 4 (190 g,1 eq) was added to a 5L autoclave, isopropanol (1L) was added, 9.5g of 10% palladium on carbon (water content 58%, model D10H5A, available from new materials, inc. Of shanxi rayleigh) was added, nitrogen was replaced three times, hydrogen was replaced three times, the pressure of the reaction system was maintained at 0.3MPa, the temperature was slowly raised to 65 ℃ for 2.5 hours, palladium on carbon was recovered by filtration after the reaction, concentrated hydrochloric acid (175 ml,12mol/L,2.1 eq) was added dropwise to the filtrate, stirred overnight at room temperature, and a white solid was obtained by filtration, namely (R) -3-aminopiperidine dihydrochloride (140 g, yield 84%, chemical purity 99.0%, ee value 99.3%).
While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.
Claims (6)
1. A preparation method of (R) -3-aminopiperidine dihydrochloride is characterized by comprising the following synthetic routes:
s1: adding 3-pyridine formamide and benzyl chloride or benzyl bromide into a reaction bottle, adding a solvent, and heating to react to obtain an intermediate 1;
s2: adding the intermediate 1 into a solvent, adding alkali, and adding a reducing agent for reduction to obtain an intermediate 2;
s3: dissolving the intermediate 2 in a solution of sodium hypochlorite or sodium hypobromite, and heating to react to obtain an intermediate 3;
s4: adding the intermediate 3 into a solvent, adding a resolving agent for the first time, heating to dissolve, cooling to crystallize, and filtering; adding the solid into a solvent, adding a resolving agent for the second time for resolution, heating for dissolution, cooling for crystallization, filtering, and freeing to obtain an intermediate 4;
s5: the intermediate 4 is added with a solvent, benzyl is removed under the action of a catalyst, and then concentrated hydrochloric acid is added to obtain (R) -3-aminopiperidine dihydrochloride.
2. (R) -3-aminopiperidine dihydrochloride according to claim 1, wherein the solvent in step S1 is one or more of acetonitrile, 1, 4-dioxane, DMF, ethylene glycol, ethanol, isopropanol; the reaction temperature is 80-120 ℃.
3. The (R) -3-aminopiperidine dihydrochloride according to claim 1, wherein the solvent in step S2 is one of water, methanol, ethanol, acetonitrile; the alkali is one of sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate; the reducing agent is one of sodium borohydride and potassium borohydride, and the molar ratio of the reducing agent to the intermediate 1 is 1.0:2.0-4.0.
4. (R) -3-aminopiperidine dihydrochloride according to claim 1, characterised in that the molar concentration of sodium hypochlorite or sodium hypobromite in step S3 is 10-30% and the reaction temperature is 70-85 ℃.
5. The (R) -3-aminopiperidine dihydrochloride according to claim 1, wherein the resolving agent in step S4 is one of L-tartaric acid, L-dibenzoyltartaric acid, L-mandelic acid, L-camphorsulfonic acid; the molar ratio of the resolving agent added for the first time to the intermediate 3 is 1:1.5, the molar ratio of the resolving agent to the intermediate 3 added for the second time is 1:0.5 the resolution solvent is one of n-butanol, MDF, DMAC, acetonitrile and DMSO.
6. The (R) -3-aminopiperidine dihydrochloride according to claim 1, wherein the catalyst in step S5 is Pd/C and the solvent is one of methanol, ethanol and isopropanol.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100105917A1 (en) * | 2007-02-19 | 2010-04-29 | Kaneka Corporation | Method for producing optically active 3-aminopiperidine or salt thereof |
| US20130172562A1 (en) * | 2010-06-17 | 2013-07-04 | Dr. Reddy's Laboratories, Inc. | Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride |
| CN103319399A (en) * | 2013-05-29 | 2013-09-25 | 威海迪素制药有限公司 | Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride |
| CN104387315A (en) * | 2013-11-12 | 2015-03-04 | 药源药物化学（上海）有限公司 | Compound I and (R)-3-aminopiperidine hydrochloride II, preparation method and application in Linagliptin synthesis |
| CN115557882A (en) * | 2022-11-03 | 2023-01-03 | 苏州艾缇克药物化学有限公司 | Preparation method of (R) -1-Boc-3-aminopiperidine |
-
2023
- 2023-03-10 CN CN202310226205.0A patent/CN116143687A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100105917A1 (en) * | 2007-02-19 | 2010-04-29 | Kaneka Corporation | Method for producing optically active 3-aminopiperidine or salt thereof |
| US20130172562A1 (en) * | 2010-06-17 | 2013-07-04 | Dr. Reddy's Laboratories, Inc. | Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride |
| CN103319399A (en) * | 2013-05-29 | 2013-09-25 | 威海迪素制药有限公司 | Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride |
| CN104387315A (en) * | 2013-11-12 | 2015-03-04 | 药源药物化学（上海）有限公司 | Compound I and (R)-3-aminopiperidine hydrochloride II, preparation method and application in Linagliptin synthesis |
| CN115557882A (en) * | 2022-11-03 | 2023-01-03 | 苏州艾缇克药物化学有限公司 | Preparation method of (R) -1-Boc-3-aminopiperidine |
Non-Patent Citations (5)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119552110A (en) * | 2024-11-29 | 2025-03-04 | 浙江工业大学 | A kind of synthetic method of 4-tert-butylpiperidine hydrochloride |
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