IES86973B2 - Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method - Google Patents
Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method Download PDFInfo
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- IES86973B2 IES86973B2 IES20180079A IES20180079A IES86973B2 IE S86973 B2 IES86973 B2 IE S86973B2 IE S20180079 A IES20180079 A IE S20180079A IE S20180079 A IES20180079 A IE S20180079A IE S86973 B2 IES86973 B2 IE S86973B2
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- IE
- Ireland
- Prior art keywords
- solution
- dicarboxylic acid
- washed
- mass fraction
- methyl ether
- Prior art date
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000000543 intermediate Substances 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 229940079593 drug Drugs 0.000 title claims abstract 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 24
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 8
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical compound CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 claims abstract description 8
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 claims abstract description 8
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 8
- 235000010333 potassium nitrate Nutrition 0.000 claims abstract description 8
- 239000004323 potassium nitrate Substances 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 7
- BFXIRLJNNHSRRI-UHFFFAOYSA-N 2-ethyl-6-propan-2-ylpyridine-3,5-diol Chemical compound C(C)(C)C1=NC(=C(C=C1O)O)CC BFXIRLJNNHSRRI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 description 2
- 101000950981 Bacillus subtilis (strain 168) Catabolic NAD-specific glutamate dehydrogenase RocG Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000016901 Glutamate dehydrogenase Human genes 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method, comprises the following steps: 2 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 5-7 mol ethylene glycol methyl ether were added to the reaction vessel, controlled the stirring rate at 190-230 rpm, raised the temperature to 60-67 V, added 3-4mol bismuth trichloride, kept for 40-60 min, reduced the temperature of the solution to 5-9 V, precipitated the solid, filtrated, washed with potassium nitrate solution for 3-7 times, combined the filtrate and washing solution, controlled the stirring speed at 110-130 rpm, adjusted the pH to 2-3 by oxalic acid solution, washed with N-benzylmethylamine solution, washed with benzyl methyl ether solution, recrystallized in propyl phenyl ketone solution, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine.
Description
FIELD OF THE INVENTION
The present invention relates to medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method.
GENERAL BACKGROUND
2,6-dicarboxylic acid pyridine is mainly used as a competitive inhibitor of bovine glutamate dehydrogenase, it can also be used for the preparation of lanthanum and transition metal ligand complex, however, most of the existing synthetic methods are using 2,6-dicarboxylic acid pyridine as the reactant, it is complicated and the final yield is not very high. Therefore, it is necessary to propose a new synthetic method for further improving the quality and yield of the product and reducing the byproduct content, it has important economic significance.
SUMMARY
The purpose of the present invention is to provide medicine intermediates
2,6-dicarboxylic acid pyridine synthesis method, comprises the following steps:
(i) 2 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 5-7 mol ethylene glycol methyl ether were added to the reaction vessel, controlled the stirring rate at 190-230 rpm, raised the temperature to 60-67 °C, added 3-4mol bismuth trichloride, kept for 40-60 min, reduced the temperature of the solution to 5-9 °C, precipitated the solid, filtrated, washed with potassium nitrate solution for 3-7 times, combined the filtrate and washing solution, controlled the stirring speed at 110-130 rpm, adjusted the pH to
2-3 by oxalic acid solution, washed with N-benzylmethylamine solution, washed with benzyl methyl ether solution, recrystallized in propyl phenyl ketone solution, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine; wherein, the ethylene glycol methyl ether solution in step (i) has a mass fraction of 70 to 80%, the mass fraction of the potassium nitrate solution in step (i) is 30 to 40%, the mass fraction of the oxalic acid solution described in step (i) is 20 to 28%, the N-benzyl methylamine solution mass in step (i) has a fraction of 70-78%, the mass fraction of benzyl methyl ether solution in step (i) is 80-86%, the mass fraction of the propyl phenyl ketone solution described in step (i) is 92-97%.
Throughout the reaction process can be the following reaction formula:
ch3
Advantage of the present invention is that: reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The following examples with reference to specific embodiments of the present invention are further illustrated:
medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method.
Embodiment 1 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 5 mol ethylene glycol methyl ether with a mass fraction of 70 %were added to the reaction vessel > controlled the stirring rate at 190 rpm, raised the temperature to 60 °C, added 3mol bismuth trichloride, kept for 40 min, reduced the temperature of the solution to 5 °C, precipitated the solid, filtrated, washed with potassium nitrate solution with a mass fraction of 30 % for 3 times, combined the filtrate and washing solution, controlled the stirring speed at 110 rpm, adjusted the pH to 2 by oxalic acid solution with a mass fraction of 20 %, washed with N-benzylmethylamine solution with a mass fraction of 70%, washed with benzyl methyl ether solution with a mass fraction of 80%, recrystallized in propyl phenyl ketone solution with a mass fraction of 92%, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine 303.94g, yield of 91%.
Embodiment 2 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 6 mol ethylene glycol methyl ether with a mass fraction of 75 %were added to the reaction vessel, controlled 5 the stirring rate at 210 rpm, raised the temperature to 63 °C, added 3.5mol bismuth trichloride, kept for 50 min, reduced the temperature of the solution to 7 °C, precipitated the solid, filtrated, washed with potassium nitrate solution with a mass fraction of 35 % for 5 times, combined the filtrate and washing solution, controlled the stirring speed at 120 rpm, adjusted the pH to 2.5 by oxalic acid solution with a mass 10 fraction of 25 %, washed with N-benzylmethylamine solution with a mass fraction of 73%, washed with benzyl methyl ether solution with a mass fraction of 83%, recrystallized in propyl phenyl ketone solution with a mass fraction of 94%, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine 310.62g, yield of 93%.
Embodiment 3 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 7 mol ethylene glycol methyl ether with a mass fraction of 80 %were added to the reaction vessel, controlled the stirring rate at 230 rpm, raised the temperature to 67 °C, added 4mol bismuth 20 trichloride, kept for 60 min, reduced the temperature of the solution to 9 °C, precipitated the solid, filtrated, washed with potassium nitrate solution with a mass fraction of 40 % for 7 times, combined the filtrate and washing solution, controlled the stirring speed at 130 rpm, adjusted the pH to 3 by oxalic acid solution with a mass fraction of 28%, washed with N-benzylmethylamine solution with a mass fraction of 25 78%, washed with benzyl methyl ether solution with a mass fraction of 86%, recrystallized in propyl phenyl ketone solution with a mass fraction of 97%, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine 320.64g, yield of 96%.
Claims (3)
1. Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method, comprises the following steps: (i) 2 mol 2-isopropyl-3,5-dihydroxy-6-ethylpyridine and 5-7 mol ethylene glycol methyl ether were added to the reaction vessel· controlled the stirring rate at 190-230 rpm, raised the temperature to 60-67 °C, added 3-4mol bismuth trichloride, kept for 40-60 min, reduced the temperature of the solution to 5-9 °C, precipitated the solid, filtrated, washed with potassium nitrate solution for 3-7 times, combined the filtrate and washing solution, controlled the stirring speed at 110-130 rpm, adjusted the pH to 2. -3 by oxalic acid solution, washed with N-benzylmethylamine solution, washed with benzyl methyl ether solution, recrystallized in propyl phenyl ketone solution, precipitated the crystals, got the finished product 2,6-dicarboxylic acid pyridine; wherein, the ethylene glycol methyl ether solution in step (i) has a mass fraction of 70 to 80%, the mass fraction of the potassium nitrate solution in step (i) is 30 to 40%, the mass fraction of the oxalic acid solution described in step (i) is 20 to 28%, the N-benzyl methylamine solution mass in step (i) has a fraction of 70-78%.
2. Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method according to claim 1 wherein the mass fraction of benzyl methyl ether solution in step (i) is 80-86%.
3. Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method according to claim 1 wherein the mass fraction of the propyl phenyl ketone solution described in step (i) is 92-97%.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710207918.7A CN108239023A (en) | 2017-04-02 | 2017-04-02 | A kind of synthetic method of medicine intermediate 2,6- dioctyl phthalate pyridines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES20180079A2 IES20180079A2 (en) | 2019-04-03 |
| IES86973B2 true IES86973B2 (en) | 2019-05-01 |
Family
ID=58744620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES20180079A IES86973B2 (en) | 2017-04-02 | 2018-03-27 | Medicine intermediates 2,6-dicarboxylic acid pyridine synthesis method |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN108239023A (en) |
| AU (1) | AU2018100413A4 (en) |
| GB (1) | GB201705844D0 (en) |
| IE (1) | IES86973B2 (en) |
-
2017
- 2017-04-02 CN CN201710207918.7A patent/CN108239023A/en active Pending
- 2017-04-11 GB GBGB1705844.7A patent/GB201705844D0/en not_active Ceased
-
2018
- 2018-03-27 IE IES20180079A patent/IES86973B2/en unknown
- 2018-03-31 AU AU2018100413A patent/AU2018100413A4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| IES20180079A2 (en) | 2019-04-03 |
| GB201705844D0 (en) | 2017-05-24 |
| AU2018100413A4 (en) | 2018-05-10 |
| CN108239023A (en) | 2018-07-03 |
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