CN112110916B - Process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane - Google Patents
Process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane Download PDFInfo
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- CN112110916B CN112110916B CN202011012908.6A CN202011012908A CN112110916B CN 112110916 B CN112110916 B CN 112110916B CN 202011012908 A CN202011012908 A CN 202011012908A CN 112110916 B CN112110916 B CN 112110916B
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- AFYZAHZKOFBVLE-UONOGXRCSA-N (4as,7as)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine Chemical compound C([C@H]1NCCC[C@H]1C1)N1CC1=CC=CC=C1 AFYZAHZKOFBVLE-UONOGXRCSA-N 0.000 title claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 90
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 54
- 239000003054 catalyst Substances 0.000 claims abstract description 47
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 46
- 239000007787 solid Substances 0.000 claims abstract description 41
- 238000007598 dipping method Methods 0.000 claims abstract description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 29
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- BFXAWOHHDUIALU-UHFFFAOYSA-M sodium;hydron;difluoride Chemical compound F.[F-].[Na+] BFXAWOHHDUIALU-UHFFFAOYSA-M 0.000 claims abstract description 10
- 150000002500 ions Chemical class 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 26
- AFYZAHZKOFBVLE-KGLIPLIRSA-N (4ar,7ar)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine Chemical compound C([C@@H]1NCCC[C@@H]1C1)N1CC1=CC=CC=C1 AFYZAHZKOFBVLE-KGLIPLIRSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- QQSGKBJPQJJHOR-UHFFFAOYSA-N 6-benzyl-1,2,3,4-tetrahydropyrrolo[3,4-b]pyridine Chemical compound C(C1=CC=CC=C1)N1C=C2NCCCC2=C1 QQSGKBJPQJJHOR-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- NPFLDCSXDJEZNN-UHFFFAOYSA-N 4,5-dichloro-2-phenyl-1h-imidazole;1,3-dioxolane Chemical compound C1COCO1.N1C(Cl)=C(Cl)N=C1C1=CC=CC=C1 NPFLDCSXDJEZNN-UHFFFAOYSA-N 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 abstract description 17
- 235000007164 Oryza sativa Nutrition 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 235000009566 rice Nutrition 0.000 abstract description 5
- 240000007594 Oryza sativa Species 0.000 abstract 1
- 239000000047 product Substances 0.000 description 20
- 239000003814 drug Substances 0.000 description 6
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 6
- 229960003702 moxifloxacin Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 241000209094 Oryza Species 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 229940124307 fluoroquinolone Drugs 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000007809 chemical reaction catalyst Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- -1 platinum ions Chemical class 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RRBLNPCNHNHAFW-NWDGAFQWSA-N (4as,7ar)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C([C@@H]1NCCC[C@@H]1C1=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-NWDGAFQWSA-N 0.000 description 1
- AFYZAHZKOFBVLE-UHFFFAOYSA-N 6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine Chemical class C1C2CCCNC2CN1CC1=CC=CC=C1 AFYZAHZKOFBVLE-UHFFFAOYSA-N 0.000 description 1
- JJFNYKMZELJLBL-UHFFFAOYSA-N 6-benzyl-1,2,3,4-tetrahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C(NCCC2)=C2C(=O)N1CC1=CC=CC=C1 JJFNYKMZELJLBL-UHFFFAOYSA-N 0.000 description 1
- JIMFXOQAQLUDKB-UHFFFAOYSA-N 7a-benzyl-1,2,3,4,4a,5,6,7-octahydropyrrolo[3,4-b]pyridine Chemical compound C1NCC(CCCN2)C12CC1=CC=CC=C1 JIMFXOQAQLUDKB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010011509 Crystalluria Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/42—Platinum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J33/00—Protection of catalysts, e.g. by coating
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/0201—Impregnation
- B01J37/0203—Impregnation the impregnation liquid containing organic compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/0201—Impregnation
- B01J37/0207—Pretreatment of the support
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention provides a process for the preparation of racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, comprising the steps of: step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution; step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 30-40 parts of chloroplatinic acid and 1-5 parts of rice furoic acid in parts by weight; step S3: dehydrogenation reaction of piperidine ring; step S4: and (3) high-pressure hydrogenation reaction. The invention provides a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high selectivity, high catalytic efficiency and high product purity.
Description
Technical Field
The invention relates to the field of preparation of medical intermediates, in particular to a preparation process of racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
Background
Moxifloxacin is a novel fluoroquinolone drug, the chemical structure of the moxifloxacin is obviously different from other fluoroquinolone drugs, methoxy is introduced into the 8-position carbon atom of a quinolone mother nucleus, and benzyl-2, 8-diazabicyclo [4,3,0] nonane is introduced into the 7-position carbon atom of the quinolone mother nucleus, so that the gram-positive aerobic bacteria resistance of the moxifloxacin drug is enhanced, obvious phototoxicity is not generated, the solubility of moxifloxacin drug is increased, and the risk of formation of crystalluria is reduced. The presence of these substituents provides the drug with a broad spectrum of antimicrobial activity and has been used as a chemotherapeutic agent for humans and animals, and is effective in treating infections caused by a variety of bacteria.
(S, S) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is a key intermediate for synthesizing a new generation of fluoroquinolone medicaments, moxifloxacin, a nonane mother liquor for synthesizing (S, S) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane usually contains a chiral by-product (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is unstable and is not beneficial for the subsequent synthesis of moxifloxacin, so that the racemic cis product obtained by racemizing (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane needs to be obtained and then used as a raw material for resolution to generate (R, r) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is subjected to reduction reaction to generate the target product (S, S) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
The present invention of the Chinese patent publication No. CN101429199B discloses a method for preparing racemic cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane in two steps, which comprises the first step of catalyzing the dehydrogenation of (1R,6S) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane using manganese dioxide as a catalyst, the second step is to catalyze 6-benzyl-5, 7-dioxo-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine to carry out hydrogenation reaction under high pressure by adopting a palladium-carbon catalyst, and finally prepare the 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane racemate. However, in the first step, manganese dioxide as a catalyst has the problems of low catalytic efficiency and low reaction selectivity, and the purity of the product is influenced.
Therefore, there is a need to develop a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high selectivity, high catalytic efficiency and high product purity.
Disclosure of Invention
The invention aims to provide a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high selectivity, high catalytic efficiency and high product purity.
The technical purpose of the invention is realized by the following technical scheme:
a process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 30-40 parts of chloroplatinic acid and 1-5 parts of rice furoic acid in parts by weight;
step S3: dehydrogenation reaction of piperidine ring: subjecting (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, which is subjected to optical resolution, to a piperidine ring dehydrogenation reaction with a platinum dehydrogenation catalyst;
step S4: high-pressure hydrogenation reaction: and (3) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst under reaction conditions to obtain the target product, namely the racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
As a further configuration of the present invention, the ratio of the weight of the platinum dehydrogenation catalyst of step S2 to the weight of (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 0.1:1 to 2: 1.
As a further configuration of the present invention, the dipping solution in the step S2 further comprises 1-3 parts of dichlorophenyl imidazole dioxolan.
As a further configuration of the present invention, the amount of platinum loaded on the solid support in the step S2 is 0.1% to 5% by weight of the solid support.
As a further configuration of the present invention, the solid support of step S1 is one of silica, porous alumina and silica alumina gel.
As a further setting of the invention, the reaction temperature in the step S2 piperidine ring dehydrogenation reaction is 130-140 ℃, and the reaction time is 3-5 h.
As a further configuration of the present invention, the reaction conditions in the high-pressure hydrogenation reaction of step S3 are: the reaction temperature is 80-110 ℃, the hydrogen pressure is 5-10MPa, and the reaction time is 5-8 h.
As a further configuration of the present invention, the solvent of step S3 is tetrahydrofuran or dioxane.
As a further configuration of the present invention, the solvent of step S4 is tetrahydrofuran or dioxane.
The invention has the beneficial effects that:
1. according to the invention, the platinum dehydrogenation catalyst is adopted in the piperidine ring dehydrogenation reaction in the first step, the selectivity of the platinum dehydrogenation catalyst is high, the catalytic reaction speed is high, the conversion rate of the reaction can be effectively improved, the purity of the product is improved, the platinum dehydrogenation catalyst in the first step can be used as the catalyst for high-pressure hydrogenation in the second step after treatment, the type of the reaction catalyst is effectively the same, the using amount of the catalyst is saved, the catalyst can be recycled, the utilization rate of the reaction catalyst is improved, and the production cost is effectively reduced.
2. The solid carrier of the platinum dehydrogenation catalyst is firstly subjected to sodium hydroxide or sodium bifluoride in the coarsening solution to form countless uniformly and densely distributed micropores on the surface of the carrier, and the coarsening solution reacts with the functional groups of the solid carrier to break the functional group bonds in the solid carrier to ensure that the micropores are provided with negative charges, so that the difficulty of anchoring subsequent platinum ions on the solid carrier is reduced, more platinum ions are attached to the unit area of the solid carrier, the catalytic efficiency of the platinum dehydrogenation catalyst is effectively improved, the selectivity and the full degree of reaction are also improved, and the purity of the product is improved.
3. According to the invention, when the platinum dehydrogenation catalyst is prepared, the rice bran acid and the dichlorophenyl imidazole dioxolane are added into the impregnation liquid, and the reaction is deepened along with the reaction degree, so that a byproduct piperidine derivative with high carbon content is easily generated, and the carbon deposition of the platinum dehydrogenation catalyst is caused.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
First, an embodiment
Example 1
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a silicon dioxide solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 30 parts by weight of chloroplatinic acid, 1 part by weight of rice bran acid and 1 part by weight of dichlorophenyl imidazole dioxolane, and the loading amount on the solid carrier is 0.1 percent of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 130 ℃ in an environment of tetrahydrofuran or dioxane solvent for 3h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 0.1: 1;
step S4: high-pressure hydrogenation reaction: and (3) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5 hours in an environment with the reaction temperature of 80 ℃, the hydrogen pressure of 5MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 93.4% and the product purity is 99.4%.
Example 2
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a porous alumina solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 40 parts by weight of chloroplatinic acid, 5 parts by weight of furoic acid and 3 parts by weight of dichlorophenyl imidazole dioxolane, and the loading amount on the solid carrier is 5% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 140 ℃ in an environment of tetrahydrofuran or dioxane solvent for 5h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 2: 1;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5-8h at the reaction temperature of 110 ℃, the hydrogen pressure of 10MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 96.2% and the product purity is 99.8%.
Example 3
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a silica-alumina gel solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 35 parts by weight of chloroplatinic acid, 3 parts by weight of furoic acid and 2 parts by weight of dichlorophenyl imidazole dioxolane, and the loading amount on the solid carrier is 2% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ in the environment of tetrahydrofuran or dioxane as a solvent for 4h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 1: 1;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5-8h at the reaction temperature of 100 ℃, the hydrogen pressure of 8MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 95.3% and the product purity is 99.7%.
Example 4
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a silicon dioxide solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 35 parts by weight of chloroplatinic acid and 2 parts by weight of dichlorophenyl imidazole dioxolane, and the loading amount on the solid carrier is 2% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ in the environment of tetrahydrofuran or dioxane as a solvent for 4h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 1: 1;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5-8h at the reaction temperature of 100 ℃, the hydrogen pressure of 8MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 91.1% and the product purity is 95.2%.
Example 5
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a silicon dioxide solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 35 parts by weight of chloroplatinic acid and 3 parts by weight of rice bran acid, and the loading amount on the solid carrier is 2% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ in the environment of tetrahydrofuran or dioxane as a solvent for 4h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 1: 1;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5-8h at the reaction temperature of 100 ℃, the hydrogen pressure of 8MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 90.6% and the product purity is 92.6%.
Example 6
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening liquid to prepare an attached carrier, wherein the coarsening liquid is a sodium hydroxide solution or a sodium bifluoride solution;
step S2: preparation of platinum dehydrogenation catalyst: loading noble metal platinum on a silicon dioxide solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the dipping solution comprises 35 parts by weight of chloroplatinic acid, and the loading amount on the solid carrier is 2% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ in the environment of tetrahydrofuran or dioxane as a solvent for 4h, wherein the weight part ratio of the platinum dehydrogenation catalyst to the (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 1: 1;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst for 5-8h at the reaction temperature of 100 ℃, the hydrogen pressure of 8MPa and the solvent of tetrahydrofuran or dioxane to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 87.5% and the product purity is 90.1%.
The principles and embodiments of the present invention are explained herein using specific examples, which are set forth only to help understand the method and its core ideas of the present invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (5)
1. A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, characterised in that it comprises the steps of:
step S1: preparing an attachment carrier: immersing a solid carrier into a coarsening solution to prepare an attached carrier, wherein the coarsening solution is a sodium hydroxide solution or a sodium bifluoride solution, and the solid carrier is one of silicon dioxide, porous alumina and silica-alumina gel;
step S2: preparation of platinum dehydrogenation catalyst: the method comprises the steps of loading noble metal platinum on a solid carrier by dipping in a dipping solution containing noble metal ions by adopting a dipping method to prepare a platinum dehydrogenation catalyst, wherein the dipping solution comprises 30-40 parts of chloroplatinic acid, 1-5 parts of furoic acid and 1-3 parts of dichlorophenyl imidazole dioxolane by weight, the weight part ratio of the platinum dehydrogenation catalyst to (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 0.1:1-2:1, and the loading amount of platinum on the solid carrier is 0.1-5% of the weight of the solid carrier;
step S3: dehydrogenation reaction of piperidine ring: performing piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst in a solvent environment;
step S4: high-pressure hydrogenation reaction: and (2) carrying out high-pressure hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S3) and a palladium hydrogenation catalyst under reaction conditions in a solvent environment to obtain a target product, namely, the racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
2. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the reaction temperature in the step S3 piperidine ring dehydrogenation reaction is 130 ℃ to 140 ℃ and the reaction time is 3 to 5 hours.
3. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the reaction conditions in the high pressure hydrogenation of step S4 are: the reaction temperature is 80-110 ℃, the hydrogen pressure is 5-10MPa, and the reaction time is 5-8 h.
4. The process for preparing racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent of step S3 is tetrahydrofuran or dioxane.
5. The process for preparing racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent of step S4 is tetrahydrofuran or dioxane.
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Denomination of invention: Preparation process of racemic cis 8-benzyl-2,8-diazabicyclo [4,3,0] nonane Granted publication date: 20220114 Pledgee: Agricultural Bank of China Limited Shayang County Branch Pledgor: SHAYANG QINJIANG CHEMICAL Co.,Ltd. Registration number: Y2024980002499 |
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