CN107987028B - A kind of preparation method for treating type II diabetes pharmaceutical intermediate - Google Patents
A kind of preparation method for treating type II diabetes pharmaceutical intermediate Download PDFInfo
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- CN107987028B CN107987028B CN201711371093.9A CN201711371093A CN107987028B CN 107987028 B CN107987028 B CN 107987028B CN 201711371093 A CN201711371093 A CN 201711371093A CN 107987028 B CN107987028 B CN 107987028B
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- Prior art keywords
- ammonium metatungstate
- methyluracil
- catalyst
- nitroso
- palladium metal
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title abstract description 5
- 239000012450 pharmaceutical intermediate Substances 0.000 title abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 70
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 229910052751 metal Inorganic materials 0.000 claims abstract description 27
- 239000002184 metal Substances 0.000 claims abstract description 27
- AHOWVSJPUQTRNN-UHFFFAOYSA-N 6-amino-1-methyl-5-nitrosopyrimidine-2,4-dione Chemical compound CN1C(N)=C(N=O)C(=O)NC1=O AHOWVSJPUQTRNN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052581 Si3N4 Inorganic materials 0.000 claims abstract description 17
- 230000009467 reduction Effects 0.000 claims abstract description 17
- VNQDUDYVRUASAA-UHFFFAOYSA-N CC=1C(NC(NC1)=O)=O.NC=1C=CC=C(C1N)C=CC1=CC=CC=C1 Chemical compound CC=1C(NC(NC1)=O)=O.NC=1C=CC=C(C1N)C=CC1=CC=CC=C1 VNQDUDYVRUASAA-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims abstract description 7
- 238000001556 precipitation Methods 0.000 claims abstract description 6
- 150000002940 palladium Chemical class 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 15
- 239000005543 nano-size silicon particle Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 239000000758 substrate Substances 0.000 claims description 10
- 238000006555 catalytic reaction Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 101150003085 Pdcl gene Proteins 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims 1
- 239000010937 tungsten Substances 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 23
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 abstract description 10
- 229910052763 palladium Inorganic materials 0.000 abstract description 8
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 238000003889 chemical engineering Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 8
- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Inorganic materials O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 8
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 229910052593 corundum Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229910001845 yogo sapphire Inorganic materials 0.000 description 5
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000002832 nitroso derivatives Chemical class 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011946 reduction process Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JTVBCXIVJCAUBK-UHFFFAOYSA-N 1-methyl-5-nitropyrimidine-2,4-dione Chemical compound CN1C=C([N+]([O-])=O)C(=O)NC1=O JTVBCXIVJCAUBK-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- DNIDAYOSPDNUKP-UHFFFAOYSA-N 3-(2-phenylethenyl)benzene-1,2-diamine Chemical compound NC1=CC=CC(C=CC=2C=CC=CC=2)=C1N DNIDAYOSPDNUKP-UHFFFAOYSA-N 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- JWEOEZZCZCCPJL-UHFFFAOYSA-N 4-methylquinazoline Chemical compound C1=CC=C2C(C)=NC=NC2=C1 JWEOEZZCZCCPJL-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 230000003820 β-cell dysfunction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- 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
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/24—Nitrogen 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
- B01J37/03—Precipitation; Co-precipitation
- B01J37/031—Precipitation
- B01J37/035—Precipitation on carriers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to technical field of chemistry and chemical engineering, and in particular to a kind of preparation method for treating type II diabetes pharmaceutical intermediate.The present invention is with PdCl2.2H2O and ammonium metatungstate are presoma, using silicon nitride as catalyst carrier, have prepared a kind of palladium metal catalyst that novel ammonium metatungstate is modified using deposition-precipitation；The catalyst can be used for being catalyzed 6- amino -5- nitroso -1- methyluracil reduction preparation 5,6- diaminostilbene-methyluracil, selectivity and high conversion rate, green non-pollution；Material can be added at one time simultaneously, avoid the shortcomings that traditional sodium dithionite reduction system is added portionwise to high operation requirements.
Description
Technical field
The invention belongs to technical field of chemistry and chemical engineering, and in particular to a kind of preparation for treating type II diabetes pharmaceutical intermediate
Method.
Background technique
The entitled 8- [(3 of Li Gelieting chemistryR) -3- amino piperidine -1- base] -7- (2- butynyl) -3,7- dihydro -3- first
Base -1- [(4- methylquinazolin -2- base) methyl] -1HPurine -2,6- diketone, structural formula such as (1) formula:
(1)
Li Gelieting is German Boehringer Ingelheim company research and development for treating the dipeptidyl peptidase-IV of diabetes B
(DPP-IV) inhibitor, in May, 2011 are approved by the FDA in the United States listing.The insulin that may act on during type-2 diabetes mellitus supports
Anti- and pancreatic islet alpha, β cell dysfunction, it slows down the drop of glucagon-like-peptide-1 (GLP-1) by inhibiting DPP-IV activity
Solution, to play blood sugar reducing function.This product is the first DPP-IV inhibitor mainly drained with non-kidney removing approach-with bile,
Have the characteristics that high activity, selectivity, long-term effect and orally active, good market prospect.
There are a key intermediate 5,6- diaminostilbene-methyluracil, the intermediates in Li Gelieting synthesis process
It is made by 6- amino -5- nitroso -1- methyluracil by reduction reaction, reaction equation is as shown in Scheme1:
The preparation method of initial document report like derivatives is mostly nitroso compound in sodium dithionite/ammonium hydroxide
Reaction reduction prepares corresponding amino-compound, such as document 1(Eur. J. Med. Chem.(1990 in solution) 25,653-
658:Structure-activityrelationshipsinaseriesofxanthinede rivatives:
Withantibronchoconstrictoryandbronchodilatoryactivities) diisobutyl -4 1,3- reported,
The preparation method of 5- diamino uracil, the document control reaction temperature by the way of sodium dithionite is added portionwise；
So far sodium dithionite is added portionwise in alkaline solution still and is the mainstream synthetic method of such compound, such as document 2(China
Medical industry magazine, 2016,47(1): the synthesis of 4-7, Li Gelieting), the document changes compared with early literatures report method without larger
Into still as reducing agent and being added portionwise using sodium dithionite.
Sodium dithionite is known as sodium hydrosulfite, is a kind of white sand shape crystallization or pale yellow powder chemical article, fusing point 300
DEG C (decomposition) 250 DEG C of ignition temperature, does not dissolve in ethyl alcohol, is dissolved in sodium hydroxide solution, meets water kickback occurs and simultaneously burn.?
General runaway reaction in order to prevent generates hot-spot and causes to release harmful oxysulfide in reduction reaction, by hydrosulfurous acid
Sodium is added portionwise, more demanding to operating；And it is caused in waste water in nitroso compound reduction process mostly using ammonium hydroxide as solvent
Ammonia-nitrogen content is high.
So developing a kind of clean Catalytic processes to prepare Li Gelieting key intermediate 5,6- diaminostilbene-methyl urine
Pyrimidine has great importance.
Summary of the invention
The purpose of the present invention is overcoming existing sodium dithionite system, a kind of novel, clean catalysis is provided
6- amino -5- nitroso -1- methyluracil reduction preparation 5,6- diaminostilbene-methyluracil method, the present invention with
PdCl2.2H2O and ammonium metatungstate are that presoma using silicon nitride as catalyst carrier has prepared one kind using deposition-precipitation
The modified palladium metal catalyst of novel ammonium metatungstate；It is phonetic that the catalyst can be used for being catalyzed 6- amino -5- nitroso -1- methyl urine
Pyridine reduction preparation 5,6- diaminostilbene-methyluracil, selectivity and high conversion rate, green non-pollution；Material can be primary simultaneously
Property be added, avoid the shortcomings that traditional sodium dithionite reduction system is added portionwise to high operation requirements.
According to an aspect of the present invention, the present invention provides a kind of preparations of the modified palladium metal catalyst of ammonium metatungstate
Method, comprising the following steps:
1) nano-silicon nitride is added in aqueous solution ultrasonic disperse at room temperature, PdCl is then added2.2H2O and metatungstic acid
Ammonium stirs to obtain the first mixed liquor；
2) the first mixed liquor is warming up to 50 DEG C, and ammonia spirit is added dropwise, and adjusts pH to 9.5-10.5, insulated and stirred 3-5h
Obtain the second mixed liquor；
3) it filters, filter cake 80-100 DEG C of drying under nitrogen atmosphere, before then calcining 2h obtains catalyst at 110-400 DEG C
Body；
4) catalyst precarsor is restored to obtain in atmosphere of hydrogen in 200-500 DEG C to the modified palladium metal catalysis of ammonium metatungstate
Agent.
The present invention can be by adjusting PdCl2.2H2The additional amount of O and ammonium metatungstate exists to adjust two kinds of elements of Pd and W
Load capacity in carrier silicon nitride, by adjusting PdCl2.2H2O adjusts the element ratio in catalyst with ammonium metatungstate additional amount,
To adjust the catalytic performance of catalyst；Preferably, PdCl in step 1)2.2H2The sum of O and ammonium metatungstate weight are nano silicon nitride
The 2-10wt% of silicon weight, PdCl2.2H2The mole dosage of O and ammonium metatungstate ratio is 1:0.2-0.8；More it is selected as in step 1)
PdCl2.2H2The sum of O and ammonium metatungstate weight are the 6wt%, PdCl of nano-silicon nitride weight2.2H2Mole of O and ammonium metatungstate
Amount ratio is 1:0.4；
Preferably, catalyst precarsor is obtained ammonium metatungstate in 350-380 DEG C of reductase 12 h in atmosphere of hydrogen and is modified by step 4)
Palladium metal catalyst.It is restored at a temperature of test discovery is different, obtained catalyst morphology difference is larger, is embodied in and urges
Specific surface area, Kong Rong and the aperture of agent etc. are different, to influence catalyst catalytic performance.
According to another aspect of the present invention, the present invention provides a kind of use of the modified palladium metal catalyst of ammonium metatungstate
On the way, the modified palladium metal catalyst of ammonium metatungstate is used to be catalyzed 6- amino -5- nitroso -1- methyl in the presence of hydrogen and solvent
Uracil reduction preparation 5,6- diaminostilbene-methyluracil.
Preferably, the purposes of the modified palladium metal catalyst of the ammonium metatungstate, is catalyzed 6- in the presence of hydrogen and solvent
Amino -5- nitroso -1- methyluracil reduction preparation 5,6- diaminostilbene-methyluracil；Specific steps are as follows:
1) the modified palladium metal catalyst of ammonium metatungstate, substrate 6- amino -5- nitroso -1- methyluracil are added to
Solvent stirs evenly in hydrogenation reaction kettle；
2) air three times, then adjusts hydrogenation reaction kettle temperature to 15-65 DEG C, is passed through hydrogen in nitrogen displacement hydrogenation reaction kettle
Solid/liquid/gas reactions, HPLC detect 0.5% or less 6- amino -5- nitroso -1- methyluracil residue and stop reaction；
3) it filters, filters out catalyst, collection filtrate is warming up to 50-60 DEG C and obtains post-treatment solution；
4) anti-solvent is added dropwise into post-treatment solution, stops being added dropwise when occurring muddy, keeps the temperature growing the grain 2h, then proceed to drip
Add anti-solvent to there is no being cooled to 10-30 DEG C when crystal precipitation, filters, dries to obtain 5,6- diaminostilbene-methyluracil.
Preferably, the modified palladium metal catalyst inventory of ammonium metatungstate is 6- amino -5- nitroso -1- first in step 1)
The 0.2%wt-15%wt of base uracil weight, is more selected as 3%wt-5%wt；
Preferably, the solvent is one of methanol, ethyl alcohol, isopropanol, ethyl acetate or tetrahydrofuran；It is described anti-molten
Agent is n-hexane, normal heptane or water；More being selected as the solvent is isopropanol, and the anti-solvent is water；
Preferably, the pressure for being passed through hydrogen reaction is 0.1-2.0MPa, preferably 0.2-0.5MPa；
Compared with prior art, the present invention has the advantage that
1) present invention has prepared a kind of palladium metal catalyst of novel ammonium metatungstate modification by deposition-precipitation to replace
Generation traditional sodium dithionite system, can once feed, easy to operate；
2) catalyst catalytic performance prepared by the present invention is high, the selection compared with traditional Pd/C catalyst, to product
Property is higher, avoids the generation of side reaction；
3) present invention uses nano-silicon nitride as carrier, using ammonium metatungstate as modifying agent, with traditional Al2O3、TiO2、
ZrO2It is compared with absorbent charcoal carrier, the catalytic performance that catalyst is made is higher；
4) catalyst recoverable prepared by the present invention, low in cost, safety and environmental protection.
Specific embodiment
In order to make the objectives, technical solutions and advantages of the present invention clearer, With reference to embodiment, to this
Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the invention.
Nano-silicon nitride is from Beijing Deco Dao Jin Science and Technology Ltd., model DK-Si3N4- 001, partial size is
20nm, specific surface area 59.6m2The white amorphous particle of/g.
Embodiment 1
Prepare the modified palladium metal catalyst of ammonium metatungstate, comprising the following steps:
1) 20g nano-silicon nitride is added to ultrasonic disperse in 200ml aqueous solution at room temperature, be then added
1.2gPdCl2.2H2Two kinds of mixtures of O and ammonium metatungstate (PdCl in mixture2.2H2O and ammonium metatungstate molar ratio are 1:0.4)
Stir to obtain the first mixed liquor；
2) the first mixed liquor is warming up to 50 DEG C, and ammonia spirit is added dropwise, and adjusts pH to 9.5-10.5, insulated and stirred 3-
5h obtains the second mixed liquor；
3) it filters, then filter cake 80-100 DEG C of drying under nitrogen atmosphere calcines 2h at 200-240 DEG C and obtain catalyst
Precursor；
4) catalyst precarsor the modified palladium metal of ammonium metatungstate is obtained in 350-380 DEG C of reductase 12 h in atmosphere of hydrogen to urge
Agent.
Using ASPS2020 type BET specific surface area analyzer, operation temperature is 150 DEG C, vacuum outgas 3h, measures bimetallic
The specific surface area and Kong Rong of catalyst, the results are shown in Table 1.
The catalyst and carrier nano-silicon nitride specific surface area and hole that table 1 is prepared hold comparison
| Specific surface area m2/g | Hole holds cm3/g | |
| Carrier nano-silicon nitride | 59.6 | 0.37 |
| Embodiment 1 prepares catalyst | 58.3 | 0.36 |
The above result shows that the palladium metal catalyst phase that the present invention is modified by the ammonium metatungstate that deposition-precipitation is prepared
Its specific surface area of carrier nano-silicon nitride itself and hole are held substantially without influence, carrier Large ratio surface can be played to greatest extent
Product is to provide the possibility of efficient catalytic to catalyst.
Embodiment 2
Using the preparation method of embodiment 1, respectively with nanoscale Al2O3、TiO2Or ZrO2Nano silicon nitride is replaced for carrier
Silicon (but each carrier addition weight and nano-silicon nitride weight are consistent) prepares the modified palladium of the ammonium metatungstate of different carriers
Metallic catalyst, respectively as Cat/Al2O3、Cat/TiO2Or Cat/ZrO2；
Using 6- amino -5- nitroso -1- methyluracil as substrate, carried out using the catalyst of above-mentioned different carriers preparation
Catalytic performance assessment, concrete operation step are as follows: take different catalysts 0.5g, substrate 6- amino -5- nitroso -1- methyl urine respectively
Pyrimidine 10g is placed in 100ml ethyl alcohol, is passed through hydrogen and is carried out hydrogenation reaction under room temperature normal pressure, HPLC detects the reaction solution after 2h
Situation, the results are shown in Table 2:
2 different carriers of table prepare the catalytic effect of catalyst
| Catalyst | Conversion ratio/% | Selectivity/% |
| It is prepared by embodiment 1 | 90.2 | 97.3 |
| Cat/Al2O3 | 99.1 | 68.1 |
| Cat/TiO2 | 69.2 | 45.1 |
| Cat/ZrO2 | 23.1 | 78.3 |
| Pd/C (the palladium load capacity of 5%wt) | >99.9 | 62.1 |
| 1 preparation of embodiment-NW | 89.1 | 69.2 |
Note: 1) Pd/C is commercially available conventional palladium carbon catalyst, and wherein the load capacity of palladium is 5%wt；
2) 1 preparation of embodiment-NW refers to that the catalyst is not added with metatungstic acid compared with catalyst prepared by embodiment 1
Ammonium, remaining and material, material amounts in embodiment 1 and preparation method thereof are completely the same.
3) conversion ratio refers to: the method that HPLC uses area percentage to calculate, and the remaining substrate 6- amino -5- of 100%- is sub-
The area percentage of nitro -1- methyluracil；
4) selectivity, which refers to, generates 5,6- diaminostilbene-methyluracil molal quantity/6- amino -5- nitroso -1- first
The reaction molal quantity X100% of base uracil, because carbonyl, cyclic olefinic bond, nitroso may be reduced in reduction process.
Test result shows the catalyst 6- amino -5- nitroso -1- methyluracil of nano-silicon nitride preparation also
It is primary in the reaction of 5,6- diaminostilbene-methyluracil, selectivity and conversion ratio are above other carrier (Al2O3、
TiO2、ZrO2) or routine Pd/C catalyst；And test proves that the modification of ammonium metatungstate greatly strengthens the selectivity of catalyst.
Embodiment 3
In catalyst preparation process it is different at a temperature of restore, obtained catalyst morphology difference is larger, is embodied in
Specific surface area, Kong Rong and the aperture of catalyst etc. are different, to influence catalyst catalytic performance；The present invention is in system research early period
Influence (the reaction condition are as follows: take different reduction respectively of reduction temperature in catalyst preparation process step 4) to catalysis reaction
Catalyst 0.5g, the substrate 6- amino -5- nitroso -1- methyluracil 10g that temperature obtains are placed in 100ml ethyl alcohol, are passed through
Hydrogen carries out hydrogenation reaction under room temperature normal pressure, and HPLC detects the reaction solution situation after 2h), as a result as shown in table 3 below:
The different reduction temperatures of table 3 prepare the catalytic performance of catalyst
| Reduction temperature/DEG C | Conversion ratio/% | Selectivity/% |
| Room temperature | 45.7 | 95.2 |
| 80-100 | 69.8 | 96.4 |
| 100-200 | 73.7 | 96.6 |
| 200-300 | 85.2 | 97.1 |
| 310-350 | 89.3 | 97.3 |
| 350-400 | 92.1 | 97.1 |
| 410-450 | 89.1 | 95.2 |
| 460-500 | 93.1 | 88.1 |
| 510-550 | 97.2 | 76.3 |
Note: room temperature refers to 20-30 DEG C；It is tested every 10 DEG C for 100-200 DEG C in table, measurement is urged at this temperature
Agent is catalyzed the conversion ratio and selectivity of reaction, and the conversion ratio and selectivity that count in table are the average value under the temperature section.
The above result shows that its catalytic performance of the catalyst of the reduction acquisition at 350 DEG C or so is excellent.
Embodiment 4
For the conversion ratio for further increasing reaction, 5 are generated to catalysis 6- amino -5- nitroso -1- methyluracil reduction,
6- diaminostilbene-methyluracil reaction system is optimized, in addition to obtaining high separation yield to post-reaction treatment
Also it is optimized, step after optimization are as follows:
1) by the modified palladium metal catalyst (preparation of embodiment 1) of 0.4g ammonium metatungstate, substrate 6- amino -5- nitroso -
1- methyluracil 10.0g is added in 80ml isopropanol to stir evenly in hydrogenation reaction kettle；
2) air three times, then adjusts hydrogenation reaction kettle temperature to 55 DEG C, is passed through hydrogen in nitrogen displacement hydrogenation reaction kettle
It reacts (Hydrogen Vapor Pressure 0.3MPa), progress HPLC detection is extracted reaction solution after reaction 2h, and (HPLC testing result is conversion ratio
99.6%, 98.3%) selectivity, stops stirring, removal Hydrogen Vapor Pressure is cooled to room temperature；
3) it filters, filters out catalyst, collection filtrate is warming up to 50-60 DEG C and obtains post-treatment solution；
4) purified water is added dropwise into post-treatment solution, stops being added dropwise when occurring muddy, keeps the temperature growing the grain 2h, then proceed to
It drips and adds water to when being precipitated there is no crystal (total instillation 45ml water occurs that 10ml has been added dropwise when muddiness, subsequent that 35ml has been added dropwise)
10 DEG C are cooled to, filters, dry to obtain light yellow 5,6- diaminostilbene-methyluracil (weight yield 92.3%, HPLC detection
99.4%) purity is.
Embodiment 5
It carries out catalyst after catalyst recycling after reacting embodiment 4 to apply, again according to the preparation work in embodiment 4
Sequence is reacted, the results showed that catalysis reaction substantially without influence (reaction 2h after HPLC detect its reaction solution conversion ratio be 99.5%,
Selectivity is 98.1%；But postprocessing working procedures are not carried out, have only carried out reaction test).
Embodiment 6
In order to expand the catalytic performance of catalyst of the present invention, applicant further studies the catalyst to different substrates
Catalytic effect, concrete operation step are as follows: ammonium metatungstate prepared by Example 1 modified palladium metal catalyst 50mg, 1.0g are set
In 10ml ethyl alcohol, it is passed through hydrogen and carries out hydrogenation reaction under room temperature normal pressure, HPLC detects the reaction solution situation after 2h, as a result such as
Shown in table 4:
Catalytic performance of the modified palladium metal catalyst of 4 ammonium metatungstate of table to different substrates
| Substrate | Product | Conversion ratio/% | Selectivity/% |
| The close pyridine of 1,3- dimethyl -5- nitroso -6- semicarbazides | 5,6- diaminostilbene, 3- FU dimethyl | 98.3 | 99.7 |
| Parachloroacetophenone | Acetophenone | 92.1 | 94.2 |
| 4- bromoanisole | Methyl phenyl ethers anisole | 45.1 | 85.2 |
The above result shows that the palladium metal catalyst that ammonium metatungstate prepared by the present invention is modified has preferable catalytic effect,
It cannot be only used for catalysis reduction and prepare other nitroso compounds, it can also be used to selective catalysis aryl dehalogenate, but to some
The aromatic compound conversion ratio of electron rich group is low.
Although embodiments of the present invention are described in detail, it should be understood that, without departing from of the invention
In the case where spirit and scope, embodiments of the present invention can be made with various changes, replacement and change.
Claims (8)
1. a kind of preparation method of the modified palladium metal catalyst of ammonium metatungstate, comprising the following steps:
1) nano-silicon nitride is added in aqueous solution ultrasonic disperse at room temperature, PdCl is then added2.2H2O and ammonium metatungstate stir
Mix to obtain the first mixed liquor；
2) the first mixed liquor is warming up to 50 DEG C, is added dropwise ammonia spirit, adjusts pH to 9.5-10.5, and insulated and stirred 3-5h obtains the
Two mixed liquors；
3) it filters, then filter cake 80-100 DEG C of drying under nitrogen atmosphere calcines 2h at 110-400 DEG C and obtain catalyst precarsor；
4) catalyst precarsor is restored to obtain in atmosphere of hydrogen in 200-500 DEG C to the modified palladium metal catalyst of ammonium metatungstate；
PdCl in step 1)2.2H2The sum of O and ammonium metatungstate weight are the 6wt%, PdCl of nano-silicon nitride weight2.2H2O and inclined tungsten
The mole dosage ratio of sour ammonium is 1:0.4.
2. preparation method according to claim 1, it is characterised in that: step 4) by catalyst precarsor in atmosphere of hydrogen in
350-380 DEG C of reductase 12 h obtains the modified palladium metal catalyst of ammonium metatungstate.
3. a kind of purposes of the modified palladium metal catalyst of ammonium metatungstate described in claim 1, which is characterized in that in hydrogen and molten
The modified palladium metal catalyst of ammonium metatungstate is for being catalyzed 6- amino -5- nitroso -1- methyluracil reduction system in the presence of agent
Standby 5,6- diaminostilbene-methyluracil.
4. purposes according to claim 3, it is characterised in that: the modified porpezite of ammonium metatungstate in the presence of hydrogen and solvent
Metal catalyst is for being catalyzed 6- amino -5- nitroso -1- methyluracil reduction preparation 5,6- diaminostilbene-methyluracil；
Specific steps are as follows:
1) the modified palladium metal catalyst of ammonium metatungstate, substrate 6- amino -5- nitroso -1- methyluracil are added to molten
Agent stirs evenly in hydrogenation reaction kettle；
2) air three times, then adjusts hydrogenation reaction kettle temperature to 15-65 DEG C, is passed through hydrogen in nitrogen displacement hydrogenation reaction kettle
Reaction, HPLC detect 0.5% or less 6- amino -5- nitroso -1- methyluracil residue and stop reaction；
3) it filters, filters out catalyst, collection filtrate is warming up to 50-60 DEG C and obtains post-treatment solution；
4) anti-solvent is added dropwise into post-treatment solution, stops being added dropwise when occurring muddy, keeps the temperature growing the grain 2h, then proceed to be added dropwise
Anti-solvent filters to there is no being cooled to 10-30 DEG C when crystal precipitation, dries to obtain standby 5,6- diaminostilbene-methyluracil.
5. purposes according to claim 4, it is characterised in that: the modified palladium metal catalysis of ammonium metatungstate in the step 1)
Agent inventory is the 0.2%wt-15%wt of 6- amino -5- nitroso -1- methyluracil weight.
6. purposes according to claim 5, it is characterised in that: the modified palladium metal catalysis of ammonium metatungstate in the step 1)
Agent inventory is the 3%wt -5%wt of 6- amino -5- nitroso -1- methyluracil weight.
7. purposes according to claim 4, it is characterised in that: the solvent is methanol, ethyl alcohol, isopropanol, ethyl acetate
Or tetrahydrofuran；The anti-solvent is n-hexane, normal heptane or water.
8. purposes according to claim 4, it is characterised in that: the pressure for being passed through hydrogen reaction is 0.1-2.0MPa.
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| DK0681868T3 (en) * | 1994-05-13 | 2003-11-24 | Kataleuna Gmbh Catalysts | Carbon-containing catalyst carriers and processes for their preparation |
| CN101767022B (en) * | 2008-12-29 | 2012-07-25 | 中国科学院大连化学物理研究所 | Catalyst with non-oxide as carrier and application thereof |
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