CN114835639B - Preparation method of nevirapine intermediate - Google Patents
Preparation method of nevirapine intermediate Download PDFInfo
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- CN114835639B CN114835639B CN202210600480.XA CN202210600480A CN114835639B CN 114835639 B CN114835639 B CN 114835639B CN 202210600480 A CN202210600480 A CN 202210600480A CN 114835639 B CN114835639 B CN 114835639B
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- methylpyridine
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- chloro
- amino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 title abstract description 18
- 229960000689 nevirapine Drugs 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 239000003054 catalyst Substances 0.000 claims abstract description 45
- CMJNIYUZFQWYCK-UHFFFAOYSA-N 2,6-dichloro-4-methyl-3-nitropyridine Chemical compound CC1=CC(Cl)=NC(Cl)=C1[N+]([O-])=O CMJNIYUZFQWYCK-UHFFFAOYSA-N 0.000 claims abstract description 38
- UOBCYTOUXLAABU-UHFFFAOYSA-N 2-chloro-4-methylpyridin-3-amine Chemical compound CC1=CC=NC(Cl)=C1N UOBCYTOUXLAABU-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229910004298 SiO 2 Inorganic materials 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 20
- 229910002787 Ru-Ni Inorganic materials 0.000 claims abstract description 18
- 229910002793 Ru–Ni Inorganic materials 0.000 claims abstract description 18
- GTHRJKYVJZJPCF-UHFFFAOYSA-N 2,6-dichloro-4-methylpyridine Chemical compound CC1=CC(Cl)=NC(Cl)=C1 GTHRJKYVJZJPCF-UHFFFAOYSA-N 0.000 claims abstract description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 13
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 230000009467 reduction Effects 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 5
- 239000002184 metal Substances 0.000 claims abstract description 5
- 238000006396 nitration reaction Methods 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 229910052759 nickel Inorganic materials 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 8
- 229910021641 deionized water Inorganic materials 0.000 claims description 8
- 238000011068 loading method Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052707 ruthenium Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000000227 grinding Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 230000009849 deactivation Effects 0.000 abstract description 2
- 238000006298 dechlorination reaction Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000011049 filling Methods 0.000 description 5
- 230000001502 supplementing effect Effects 0.000 description 5
- 230000007547 defect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JHARVUVBTAAPLA-UHFFFAOYSA-N 2-chloro-4-methyl-3-nitropyridine Chemical compound CC1=CC=NC(Cl)=C1[N+]([O-])=O JHARVUVBTAAPLA-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- 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
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/89—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with noble metals
- B01J23/892—Nickel and noble metals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of nevirapine, which takes 2, 6-dichloro-4-methylpyridine as a raw material, and obtains the 2, 6-dichloro-3-nitro-4-methylpyridine through nitration reaction in mixed acid consisting of concentrated sulfuric acid and nitric acid; organic solvent is used as reaction solvent, and Pd-Ru-Ni/SiO is carried out in the presence of acid-binding agent 2 Under the action of a catalyst, the 2, 6-dichloro-3-nitro-4-methylpyridine is subjected to selective hydrodechlorination and nitro reduction by a one-pot method to obtain the 2-chloro-3-amino-4-methylpyridine. The invention adopts SiO 2 The supported Pd-Ru-Ni multi-metal catalyst can well avoid the deactivation of the catalyst under the condition of chlorine and has the characteristic of selective dechlorination and nitro reduction; the catalyst is used for catalyzing 2, 6-dichloro-3-nitro-4-methylpyridine to prepare 2-chloro-3-amino-4-methylpyridine, and has high raw material conversion rate and good product selectivity.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to a preparation method of a nevirapine intermediate, and in particular relates to a preparation method of a nevirapine intermediate 2-chloro-3-amino-4-methylpyridine.
Background
Nevirapine is developed by Berlinger Engelsemium, germany, is marketed in the United states in 1996, belongs to a non-nucleoside reverse transcriptase inhibitor, and is an anti-AIDS drug capable of effectively inhibiting human immunodeficiency virus (HIV-1). Compared with other anti-AIDS medicines, nevirapine has strong antiviral effect, long half-life, high bioavailability, good tolerance, less adverse reaction and low cost.
2-chloro-3-amino-4-methylpyridine is a key intermediate of nevirapine, and the preparation method mainly comprises the following steps:
method one, patent US5200522A, US5668287A, US5686618A, discloses: the method for synthesizing 2-chloro-3-amino-4-methylpyridine by using acetoacetic ester and cyanoacetamide as raw materials has the defects of low yield, more waste water and the like.
The second method is to synthesize 2-chloro-3-amino-4-methylpyridine by using ethyl cyanoacetate and crotonaldehyde as raw materials, and has long route, low yield and no industrialization prospect.
The fourth method and the patent US5654429A disclose a method for preparing 2-chloro-3-amino-4-methylpyridine by taking 2-chloro-3-aminopyridine and methyl sulfide as raw materials, and the method has the advantages of complex reaction process, high separation difficulty, high cost, low yield and no industrialization prospect.
Method three, patent CN102898361a discloses: 4-methylpyridine is used as a raw material, nitration reaction is carried out in trifluoroacetic anhydride, and then 2-chloro-3-amino-4-methylpyridine is obtained through the steps of nitro migration, reduction, chlorination and the like.
In addition, the preparation methods of 2-chloro-3-amino-4-methylpyridine disclosed in WO0043364A1, WO0043365A1 and US2002052507A1 have the problems of long reaction route, low yield and the like.
Disclosure of Invention
Aiming at the defects of the process, the invention provides a preparation method of 2, 6-dichloro-4-methylpyridine, which has the advantages of short reaction route, high yield and easy separation of target products.
The invention aims at realizing the following technical scheme:
a preparation method of nevirapine intermediate 2-chloro-3-amino-4-methylpyridine comprises the following synthetic route:
the method takes 2, 6-dichloro-4-methylpyridine as a raw material, and 2, 6-dichloro-3-nitro-4-methylpyridine is obtained through nitration reaction in mixed acid consisting of concentrated sulfuric acid and nitric acid; organic solvent is used as reaction solvent, and Pd-Ru-Ni/SiO is carried out in the presence of acid-binding agent 2 Under the action of a catalyst, the 2, 6-dichloro-3-nitro-4-methylpyridine is subjected to selective hydrodechlorination and nitro reduction by a one-pot method to obtain the 2-chloro-3-amino-4-methylpyridine.
Specifically, the method comprises the following steps:
stirring and mixing 2, 6-dichloro-4-methylpyridine and concentrated sulfuric acid under ice bath conditions, slowly dropwise adding concentrated nitric acid, controlling the dropwise adding speed in the dropwise adding process, maintaining the temperature to be not more than 10 ℃, after dropwise adding, maintaining the temperature to be not more than 10 ℃, stirring for 30-40 min, heating to 60-80 ℃, preserving heat for reaction, and performing central control reaction until the raw materials react; cooling the reaction solution to normal temperature, slowly adding the reaction solution into ice water, fully stirring, filtering, washing a filter cake with water, and drying to obtain 2, 6-dichloro-3-nitro-4-methylpyridine;
step (2), mixing 2, 6-dichloro-3-nitro-4-methylpyridine with an acid binding agent and an organic solvent, and adding Pd-Ru-Ni/SiO 2 The catalyst is replaced by nitrogen, heated to 60-80 ℃, and stirred to react under the pressure of hydrogen of 2-4 MPa to obtain the 2-chloro-3-amino-4-methylpyridine.
In the step (1), the mass ratio of the concentrated sulfuric acid to the 2, 6-dichloro-4-methylpyridine is 2:1-10:1, preferably 4:1-6:1.
The mass fraction of the concentrated sulfuric acid is 98%.
By HNO 3 Meter, the nitric acid andthe molar ratio of the 2, 6-dichloro-4-methylpyridine to the catalyst is 1:1-3:1, preferably 1.5:1-2:1.
The mass fraction of the nitric acid is 80-90%.
In the step (2), the organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran or toluene, preferably ethanol or tetrahydrofuran. The mass ratio of the organic solvent to the 2, 6-dichloro-3-nitro-4-methylpyridine is 5:1-10:1, preferably 4:1-8:1.
The acid binding agent is one of sodium carbonate, sodium hydroxide, pyridine or triethylamine, preferably pyridine or triethylamine. The molar weight of the acid binding agent and the 2, 6-dichloro-3-nitro-4-methylpyridine is 1:1-1.5:1.
The 2, 6-dichloro-3-nitro-4-methylpyridine and Pd-Ru-Ni/SiO 2 The mass ratio of the catalyst is 1:0.02-1:0.15, preferably 1:0.04-1:0.11, and more preferably 1:0.08-1:0.11.
The Pd-Ru-Ni/SiO 2 Catalyst of SiO 2 As a carrier, simple substances of nickel, ruthenium and palladium are taken as active components, and the loading capacity of nickel (namely per 100g SiO 2 The mass of Pd supported) is 10-30%, and the load of ruthenium (i.e., per 100g SiO) 2 The mass of the supported ruthenium) is 1 to 10%, and the palladium loading (i.e., per 100g SiO) 2 The mass of the supported Ni) is 0.1 to 1%.
The Pd-Ru-Ni/SiO 2 The catalyst is prepared by the following method which comprises the following steps:
step (a), siO 2 Pretreatment: siO (SiO) 2 Roasting at 500 deg.c for 6 hr, cooling to room temperature, grinding, sieving to obtain 100-150 mesh SiO 2 ；
Step (b), pre-treating SiO 2 Mixing with deionized water, and heating to 60-80 ℃; pdCl is respectively controlled according to the loading amounts of Pd, ru and Ni in the catalyst 2 Aqueous solution, ruCl 3 Aqueous solution, ni (NO) 3 ) 2 ·6H 2 The dosage of the O aqueous solution is 0.5 to 2 hours, and Pd is dripped simultaneously 2+ PdCl with mass concentration of 1-10 g/L 2 Aqueous solution, ru 3+ RuCl with mass concentration of 0.5-2.0 g/L 3 Aqueous solution、Ni 2+ Ni (NO) with mass concentration of 10-50 g/L 3 ) 2 ·6H 2 O aqueous solution is added dropwise at the same time, stirring is carried out for 2-8 h at the temperature of 60-80 ℃, then NaOH solution is adopted to adjust the pH value to 8-9, stirring is continued for 4-8 h, filtering is carried out, filter cakes are washed by deionized water until the filtrate is neutral, drying is carried out at 110 ℃, roasting is carried out for 4-6 h in an air atmosphere at 450-550 ℃, and reduction is carried out for 6-8 h in a hydrogen atmosphere at 350-450 ℃ to obtain Pd-Ru-Ni/SiO 2 A catalyst.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts SiO 2 The supported Pd-Ru-Ni multi-metal catalyst changes the binding energy of three metals through high-temperature treatment of the metals, so that the interaction is enhanced, an alloy is formed, the poisoning resistance of the catalyst is obviously enhanced, the deactivation of the catalyst under the condition of chlorine exposure can be well avoided, and the catalyst has the characteristics of selective dechlorination and nitro reduction; compared with the traditional Pd/C catalyst, the Pd-Ru-Ni/SiO of the invention 2 The catalyst has the advantages of low Pd loading, good stability and repeated application for a plurality of times; the catalyst is used for catalyzing 2, 6-dichloro-3-nitro-4-methylpyridine to prepare 2-chloro-3-amino-4-methylpyridine, and has high raw material conversion rate and good product selectivity.
Compared with the prior art, the invention not only can reduce the production cost, but also overcomes the defects of more three wastes and low product yield of the traditional method, and has better industrial application value.
Detailed Description
The technical scheme of the invention is further described through the specific embodiments.
Example 1
0.5％Pd-1.5％Ru-25％Ni/SiO 2 The preparation method of the catalyst comprises the following steps:
step (1), siO 2 Pretreatment: siO (SiO) 2 Roasting at 500 deg.c for 6 hr, cooling to room temperature, grinding and sieving SiO of 100-150 mesh size 2 Standby;
step (2), 100g deionized water and 10g pretreated SiO are added into a reactor 2 Stirring, heating to 80 ℃, taking 50mL Pd 2+ The concentration isPdCl 1g/L 2 Aqueous solution, 100mL Ru 3+ RuCl with concentration of 1.5g/L 3 Aqueous solution, 100mL Ni 2+ Ni (NO) at a concentration of 25g/L 3 ) 2 ·6H 2 O aqueous solution, simultaneously dropwise adding three solutions, respectively controlling the dropwise adding speed, after the dropwise adding is completed within 2 hours, keeping the temperature at 60 ℃, continuously stirring for 4 hours, then dropwise adding NaOH solution to adjust the pH to 8-9, continuously stirring for 4 hours, filtering, washing a filter cake with deionized water until the filtrate is neutral, drying at 110 ℃, roasting at 550 ℃ in air atmosphere for 6 hours, reducing at 350 ℃ in hydrogen atmosphere for 8 hours, and obtaining 0.5% Pd-1.5% Ru-25% Ni/SiO 2 A catalyst.
Example 2
Under ice bath condition (0-5 ℃), adding 16.5g (purity 98.0%,0.1 mol) of 2, 6-dichloro-4-methylpyridine and 66g (mass fraction 98%) of concentrated sulfuric acid into a four-mouth bottle, stirring for 30min, slowly dropwise adding 11.8g (mass fraction 80%,0.15 mol) of concentrated nitric acid, controlling dropwise adding speed, maintaining the temperature at not more than 10 ℃, continuously maintaining the temperature at not more than 10 ℃ after dropwise adding is completed, stirring for 30min, heating to 60 ℃, preserving heat for reaction, and performing central control reaction until the raw material reaction is completed. The reaction solution was cooled to room temperature, the reaction solution was slowly added to 150g of ice water, stirred sufficiently, filtered, the filter cake was washed with water, and vacuum-dried at 40℃to give 20.2g (purity 95.1%) of 2, 6-dichloro-3-nitro-4-methylpyridine, with a yield of 93.0%.
20.2g (purity: 95.1%,0.093 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of absolute ethanol and 10.2g (purity: 99%,0.1 mol) of triethylamine were mixed, 2, 6-dichloro-3-nitro-4-methylpyridine was dissolved in ethanol, placed in a 250mL autoclave, and 2g of the catalyst (0.5% Pd-1.5% Ru-25% Ni/SiO) obtained in example 1 was added 2 ) Filling nitrogen for three times, pressurizing to 3MPa, heating to 80 ℃ for reaction, continuously supplementing hydrogen in the reaction process, maintaining the pressure of the hydrogen at 2.5-3.2 MPa, preserving the temperature at 80 ℃ for reaction for 10 hours, and ending the reaction; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of the 2, 6-dichloro-3-nitro-4-methylpyridine to be 93.4 percent and the selectivity of the 2-chloro-3-amino-4-methylpyridine to be 90.2 percent.
Example 3
20.2g (purity: 95.1%,0.093 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of tetrahydrofuran and 8.0g (purity: 99%,0.1 mol) of pyridine were mixed, 2, 6-dichloro-3-nitro-4-methylpyridine was dissolved in tetrahydrofuran, placed in a 250mL autoclave, and 2g of the catalyst (0.5% Pd-1.5% Ru-25% Ni/SiO) obtained in example 1 was added 2 ) Filling nitrogen for three times, pressurizing to 3MPa, heating to 80 ℃ for reaction, continuously supplementing hydrogen in the reaction process, maintaining the pressure of the hydrogen at 2.5-3.2 MPa, preserving the temperature at 80 ℃ for reaction for 10 hours, and ending the reaction; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of 2, 6-dichloro-3-nitro-4-methylpyridine to be 94.4%, wherein the selectivity of 2-chloro-3-amino-4-methylpyridine to be 90.8%.
Example 4
Under ice bath condition (0-5 ℃), adding 33.1g (purity 98.0%,0.2 mol) of 2, 6-dichloro-4-methylpyridine and 132g (mass fraction 98%) of concentrated sulfuric acid into a four-mouth bottle, stirring for 25min, slowly dropwise adding 21.1g (mass fraction 90%,0.3 mol) of concentrated nitric acid, controlling dropwise adding acceleration, maintaining the temperature at not more than 10 ℃, continuously maintaining the temperature at not more than 10 ℃ after dropwise adding is completed, stirring for 30min, heating to 60 ℃, preserving heat for reaction, and performing central control reaction until the raw material reaction is completed. The reaction solution is cooled to normal temperature, the reaction solution is slowly added into 300g of ice water, fully stirred, filtered, the filter cake is washed by water, and vacuum drying is carried out at 40 ℃ to obtain 40.0g (purity 96.1%) of 2-chloro-3-nitro-4-methylpyridine, and the yield is 92.8%.
Example 5
0.7％Pd-2.0％Ru-30％Ni/SiO 2 The preparation method of the catalyst comprises the following steps:
step (1), siO 2 Pretreatment: siO (SiO) 2 Roasting at 500 deg.c for 6 hr, cooling to room temperature, grinding and sieving SiO of 100-150 mesh size 2 Standby;
step (2), 100g deionized water and 10g pretreated SiO are added into a reactor 2 Stirring, heating to 80 ℃, taking 70mL Pd 2+ PdCl with concentration of 1g/L 2 Aqueous solution, 100mL Ru 3+ RuCl with concentration of 2.0g/L 3 Aqueous solution, 100mL Ni 2+ Ni (NO) at a concentration of 30g/L 3 ) 2 ·6H 2 O aqueous solution, simultaneously dropwise adding three solutions, respectively controlling the dropwise adding speed, after the dropwise adding is completed within 2 hours, keeping the temperature at 60 ℃, continuously stirring for 4 hours, then dropwise adding NaOH solution to adjust the pH to 8-9, continuously stirring for 4 hours, filtering, washing a filter cake with deionized water until the filtrate is neutral, drying at 110 ℃, roasting at 550 ℃ in air atmosphere for 6 hours, reducing at 350 ℃ in hydrogen atmosphere for 8 hours, and obtaining 0.7% Pd-2.0% Ru-30% Ni/SiO 2 A catalyst.
Example 6
Under ice bath condition (0-5 ℃), adding 33.0g (purity 98.0%,0.2 mol) of 2, 6-dichloro-4-methylpyridine and 140g (mass fraction 98%) of concentrated sulfuric acid into a four-mouth bottle, stirring for 30min, slowly dropwise adding 23.6g (mass fraction 80%,0.3 mol) of concentrated nitric acid, controlling dropwise acceleration, maintaining the temperature at not more than 10 ℃, continuously maintaining the temperature at not more than 10 ℃ after dropwise adding, stirring for 30min, heating to 60 ℃, preserving heat for reaction, and performing central control reaction until the raw material reaction is completed. The reaction solution was cooled to room temperature, the reaction solution was slowly added to 300g of ice water, stirred well, filtered, and after washing the filter cake with water, it was dried under vacuum at 40℃to give 40.5g (96.2%) of 2-chloro-3-nitro-4-methylpyridine, with a yield of 94.1%.
21.5g (96.2%, 0.1 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of ethanol and 10.2g (99%, 0.1 mol) of triethylamine were mixed, 2, 6-dichloro-3-nitro-4-methylpyridine was dissolved in ethanol, placed in a 250mL autoclave, and 2g of the catalyst (0.7% Pd-2.0% Ru-30% Ni/SiO) obtained in example 5 was added 2 ) Filling nitrogen for three times, pressurizing to 3MPa, heating to 80 ℃ for reaction, continuously supplementing hydrogen in the reaction process, maintaining the pressure of the hydrogen at 2.5-3.2 MPa, preserving the temperature at 80 ℃ for reaction for 10 hours, and ending the reaction; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of the 2, 6-dichloro-3-nitro-4-methylpyridine to be 95.9%, and the selectivity of the 2-chloro-3-amino-4-methylpyridine to be 91.9%.
Example 7
21.5g (purity: 96.2%,0.1 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of ethanol and 10.2g (purity: 99%,0.1 mol) of triethylamine were mixed to dissolve 2, 6-dichloro-3-nitro-4-methylpyridine inEthanol was placed in a 250mL autoclave, and 2g of the catalyst recovered in example 6 (0.7% Pd-2.0% Ru-30% Ni/SiO) 2 ) Filling nitrogen for three times, pressurizing to 3MPa, heating to 80 ℃ for reaction, continuously supplementing hydrogen in the reaction process, maintaining the pressure of the hydrogen at 2.5-3.2 MPa, preserving the temperature at 80 ℃ for reaction for 10 hours, and ending the reaction; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of the 2, 6-dichloro-3-nitro-4-methylpyridine to be 95.6 percent and the selectivity of the 2-chloro-3-amino-4-methylpyridine to be 91.3 percent.
Example 8
21.5g (purity 96.2%,0.1 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of ethanol and 10.2g (purity 99%,0.1 mol) of triethylamine were mixed, 2, 6-dichloro-3-nitro-4-methylpyridine was dissolved in ethanol, placed in a 250mL autoclave, and 2g of the catalyst recovered in example 7 (0.7% Pd-2.0% Ru-30% Ni/SiO) was added 2 ) Filling nitrogen for three times, pressurizing to 3MPa, heating to 80 ℃ for reaction, continuously supplementing hydrogen in the reaction process, maintaining the pressure of the hydrogen at 2.5-3.2 MPa, preserving the temperature at 80 ℃ for reaction for 10 hours, and ending the reaction; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of 2, 6-dichloro-3-nitro-4-methylpyridine to be 94.9%, and the selectivity of 2-chloro-3-amino-4-methylpyridine to be 91.5%.
Comparative example 1
21.5g (purity 96.2 percent, 0.1 mol) of 2, 6-dichloro-3-nitro-4-methylpyridine, 100g of ethanol and 10.2g (purity 99 percent, 0.1 mol) of triethylamine are mixed, so that the 2, 6-dichloro-3-nitro-4-methylpyridine is dissolved in the ethanol, the mixture is placed in a 250mL autoclave, 2g of Pd/C catalyst (Pd content 5 percent) is added, nitrogen is filled for three times for replacement, the mixture is pressurized to 3MPa, the temperature is raised to 80 ℃ for reaction, hydrogen is continuously fed in the reaction process, the hydrogen pressure is maintained between 2.5 and 3.2MPa, the reaction is carried out at 80 ℃ for 10 hours, and the reaction is finished; cooling, decompressing, filtering out a catalyst, sampling filtrate, quantitatively analyzing by HPLC, and calculating to obtain the conversion rate of the 2, 6-dichloro-3-nitro-4-methylpyridine to be 96.8 percent and the selectivity of the 2-chloro-3-amino-4-methylpyridine to be 45.8 percent.
Claims (12)
1. A preparation method of 2-chloro-3-amino-4-methylpyridine is characterized by comprising the following steps: the synthetic route is as follows:
comprising the following steps: 2, 6-dichloro-4-methylpyridine is taken as a raw material, and 2, 6-dichloro-3-nitro-4-methylpyridine is obtained through nitration reaction in mixed acid consisting of concentrated sulfuric acid and nitric acid; organic solvent is used as reaction solvent, and Pd-Ru-Ni/SiO is carried out in the presence of acid-binding agent 2 Under the action of a catalyst, 2, 6-dichloro-3-nitro-4-methylpyridine reacts in a one-pot method to obtain 2-chloro-3-amino-4-methylpyridine;
the 2, 6-dichloro-3-nitro-4-methylpyridine and Pd-Ru-Ni/SiO 2 The mass ratio of the catalyst is 1:0.02-1:0.15;
the Pd-Ru-Ni/SiO 2 The catalyst is prepared by the following method which comprises the following steps:
step (a), siO 2 Pretreatment: siO (SiO) 2 Roasting at 500 deg.c for 6 hr, cooling to room temperature, grinding, sieving to obtain 100-150 mesh SiO 2 ；
Step (b), pre-treating SiO 2 Mixing with deionized water, and heating to 60-80 ℃; pdCl is respectively controlled according to the loading amounts of Pd, ru and Ni in the catalyst 2 Aqueous solution, ruCl 3 Aqueous solution, ni (NO) 3 ) 2 ·6H 2 The dosage of the O aqueous solution is 0.5 to 2 hours, and Pd is dripped simultaneously 2+ PdCl with mass concentration of 1-10 g/L 2 Aqueous solution, ru 3+ RuCl with mass concentration of 0.5-2.0 g/L 3 Aqueous solution, ni 2+ Ni (NO) with mass concentration of 10-50 g/L 3 ) 2 ·6H 2 O aqueous solution is added dropwise at the same time, stirring is carried out for 2-8 h at the temperature of 60-80 ℃, naOH solution is adopted to adjust the pH value to 8-9, stirring is continued for 4-8 h, filtering is carried out, filter cakes are washed by deionized water until the filtrate is neutral, drying is carried out at the temperature of 110 ℃, roasting is carried out for 4-6 h in an air atmosphere at the temperature of 450-550 ℃, and reduction is carried out for 6-8 h in a hydrogen atmosphere at the temperature of 350-450 ℃ to obtain Pd-Ru-Ni/SiO 2 A catalyst.
2. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1, wherein: the method comprises the following steps:
stirring and mixing 2, 6-dichloro-4-methylpyridine and concentrated sulfuric acid under ice bath conditions, dropwise adding concentrated nitric acid, maintaining the temperature at not more than 10 ℃ in the dropwise adding process, maintaining the temperature at not more than 10 ℃ after dropwise adding, stirring for 30-40 min, and heating to 60-80 ℃ for heat preservation reaction; cooling the reaction solution to normal temperature, adding the reaction solution into ice water, stirring, filtering, washing a filter cake with water, and drying to obtain 2, 6-dichloro-3-nitro-4-methylpyridine;
step (2), mixing 2, 6-dichloro-3-nitro-4-methylpyridine with an acid binding agent and an organic solvent, and adding Pd-Ru-Ni/SiO 2 The catalyst is replaced by nitrogen, heated to 60-80 ℃, and stirred to react under the pressure of hydrogen of 2-4 MPa to obtain the 2-chloro-3-amino-4-methylpyridine.
3. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1 or 2, characterized by: the mass ratio of the concentrated sulfuric acid to the 2, 6-dichloro-4-methylpyridine is 2:1-10:1; by HNO 3 The molar ratio of the nitric acid to the 2, 6-dichloro-4-methylpyridine is 1:1-3:1.
4. A process for the preparation of 2-chloro-3-amino-4-methylpyridine according to claim 3, wherein: the mass ratio of the concentrated sulfuric acid to the 2, 6-dichloro-4-methylpyridine is 4:1-6:1; by HNO 3 The molar ratio of the nitric acid to the 2, 6-dichloro-4-methylpyridine is 1.5:1-2:1.
5. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1 or 2, characterized by: the mass fraction of the concentrated sulfuric acid is 98%; the mass fraction of the nitric acid is 80-90%.
6. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1 or 2, characterized by: the organic solvent is one of methanol, ethanol, isopropanol, tetrahydrofuran or toluene.
7. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 6, wherein: the organic solvent is ethanol or tetrahydrofuran.
8. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1 or 2, characterized by: the acid binding agent is one of sodium carbonate, sodium hydroxide, pyridine or triethylamine; the molar weight of the acid binding agent and the 2, 6-dichloro-3-nitro-4-methylpyridine is 1:1-1.5:1.
9. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 8, wherein: the acid binding agent is pyridine or triethylamine.
10. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1, wherein: the 2, 6-dichloro-3-nitro-4-methylpyridine and Pd-Ru-Ni/SiO 2 The mass ratio of the catalyst is 1:0.04-1:0.11.
11. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 10, wherein: the 2, 6-dichloro-3-nitro-4-methylpyridine and Pd-Ru-Ni/SiO 2 The mass ratio of the catalyst is 1:0.08-1:0.11.
12. The method for producing 2-chloro-3-amino-4-methylpyridine according to claim 1 or 2, characterized by: the Pd-Ru-Ni/SiO 2 Catalyst of SiO 2 The catalyst is a carrier, and is prepared from nickel, ruthenium and palladium metal simple substances as active components, wherein the loading of nickel is 10-30%, the loading of ruthenium is 1-10%, and the loading of palladium is 0.1-1%.
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| WO2002062761A1 (en) * | 2001-02-07 | 2002-08-15 | Abbott Laboratories | Aminal diones as potassium channel openers |
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| CN102898361A (en) * | 2012-10-08 | 2013-01-30 | 鲁东大学 | Method for preparing 2-chlorine-3-amino-4-picoline |
| CN102952133A (en) * | 2012-11-28 | 2013-03-06 | 康普药业股份有限公司 | Method for preparing nevirapine |
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