IES86981B2 - Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis - Google Patents
Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis Download PDFInfo
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- IES86981B2 IES86981B2 IES20180114A IES20180114A IES86981B2 IE S86981 B2 IES86981 B2 IE S86981B2 IE S20180114 A IES20180114 A IE S20180114A IE S20180114 A IES20180114 A IE S20180114A IE S86981 B2 IES86981 B2 IE S86981B2
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- nitrobenzoic acid
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- QAYNSPOKTRVZRC-UHFFFAOYSA-N 99-60-5 Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1Cl QAYNSPOKTRVZRC-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims abstract description 9
- 239000000543 intermediate Substances 0.000 title claims abstract description 9
- IYLLULUTZPKQBW-UHFFFAOYSA-N Acrinol Chemical compound CC(O)C(O)=O.C1=C(N)C=CC2=C(N)C3=CC(OCC)=CC=C3N=C21 IYLLULUTZPKQBW-UHFFFAOYSA-N 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007787 solid Substances 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 8
- 238000001308 synthesis method Methods 0.000 claims abstract description 7
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 229960001047 methyl salicylate Drugs 0.000 claims abstract description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 abstract description 6
- HKJYVRJHDIPMQB-UHFFFAOYSA-N propan-1-olate;titanium(4+) Chemical compound CCCO[Ti](OCCC)(OCCC)OCCC HKJYVRJHDIPMQB-UHFFFAOYSA-N 0.000 abstract description 5
- ODYOOXCNJGTOOL-UHFFFAOYSA-N 3-chloro-5-nitro-2-propan-2-ylphenol Chemical compound ClC1=C(C(=CC(=C1)[N+](=O)[O-])O)C(C)C ODYOOXCNJGTOOL-UHFFFAOYSA-N 0.000 abstract description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 abstract 3
- 239000000047 product Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 3
- 229960001860 salicylate Drugs 0.000 description 3
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis method, comprises the following steps: 3 mol 2-chloro-4-nitro-6-hydroxy-isopropylbenzene and 4-6 mol N-methylmorpholine were added to the reaction vessel, raised the temperature of the solution to 40-46C, controlled the stirring speed at 170-190 rpm, kept for 50-70 min, added 6 mol tetra-n-propyl titanate, raised the solution temperature to 50-55 `C, refluxed for 90-110min, reduced the solution temperature to 10-15 C, after the solid precipitated, filter it, and the solid washed with allylamine solution, adjust the pH to 3-4 with the oxalic acid solution, lowered the temperature to 5-8'C, after the crystals precipitated, filtrated it, washed with methyl salicylate solution, dehydrated with dehydration, got finished product 2- chloro-4-nitrobenzoic acid.
Description
HELD OF THE INVENTION ς Ί he pi esent invention relates to nvanol medicine intermediates
2-chloio-4-mtrobenzoic acid synthesis method
GENERAL BACKGROUND
2-chIoro-4-mtrobenzoic acid used as a pharmaceutical intermediate for the production of drugs nvanol. as a mediator of nvanol, it can also be used as a pieservative antiseptic However, most of the existing synthetic methods are derived from p-mtrotoluene by chlorination, oxidation, it is complicated and the final yield is not veiy 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 I' has important economic significance
SUMMARY i he pin pose of the present invention is to provide rtvanol medicine intermediates
2- chloio-4-nitrobenzoic acid synthesis method, comprises the following steps (i) 3 mol 2-chloiO-4-nitro-6-hydroxy-isopropylbenzene and 4-6 mol
N-methylmorpholme were added to the reaction vessel, raised the temperature of the solution to 40-46’C, controlled the stirring speed at 170-190 rpm, kept for 50-70 nnn, added 6 mol tetra-n-propyl titanate, raised the solution temperature to 50-55 iefluxed foi 90-110mm. ieduced the solution temperature to 10-15 V, after the solid piecipitated, filter it, and the solid washed with ailylamine solution, adjust the pH to
3- 4 with the oxalic acid solution, lowered the temperature to 5-8 C, after the crystals precipitated, filtrated it, washed with methyl salicylate solution, dehydrated with dehydration, got finished product 2- chloro-4-mtrobenzoic acid, wherein, the N-methylmorphohne solution has a mass fraction of 80-85% as described m step (i), the mass fraction of the ailylamine solution in step (1) is 70 to 76%, the mass fraction of the oxalic acid solution in step (i) is 30 to 35%, the mass fraction of the methyl xalicxlatc solution clescubed in step (i) is 90-96%. and the dehydrating agent described in step (i) is any one of anhvdious calcium sulfate and anhydrous potassium carbonate
Throughout the reaction process can be the following reaction formula 'ch c 0011
MO- NO;
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 lire following examples with reference to specific embodiments of the present invention aie further illustrated nvanol medicine intermediates 2-ch!oro-4-nitrobenzoic acid synthesis method
I ς Embodiment 1 mol 2-chloro-4-mtro-6-hydroxy-isopropylbenzene and 4 mol
N-methylmorphohne with a mass fraction of 80% were added to the reaction vessel, raised the temperatuie of the solution to 40 °C, controlled the stirring speed at 170 rpm, kept foi 50 mm, added 6 mol tetra-n-propyl titanate, raised the temperature of the 20 solution to 50 C, refluxed for 90 min, reduced the solution temperature to 10 C. after the solid precipitated, filter, solid was washed with allylamine solution with a mass fraction 70%, adjusted the pH to 3 with oxalic acid solution with a mass fraction of 30%, reduced temperature to 5 °C. precipitated crystals, filtered, washed with salicylate solution with a mass fraction of 90%, dehydrated with anhydrous sulfuric 25 acid calcium dehydration agent, the finished product 2 - chloro - 4 - nitrobenzoic acid ίΆ 82g. the \ lekl of V1 o
Embodiment 2 mol 2-chloro-4-mtro-6-hydiOxy-isopropylbenzene and 5 lll0| ς \-incthy Imorpbohne with a mass fraction of 82% were added to the reaction vessel, laised the temperature of the solution to 43 °C, controlled the stirring speed at 180 rpm. kept for 60 mm, added 6 mol tetra-n-propyl titanate, raised the temperature of the solution to 52 C. refluxed fbi 100 min, reduced the solution temperature to 12'0. after the solid piecipitated, filter, solid was washed with allylamme solution with a mass |o fi action 73%, adjusted the pH to 3 5 with oxalic acid solution with a mass fraction of I2°o, reduced temperature to 6 °C, precipitated crystals, filtered, washed with salicylate solution with a mass fraction of 93%, dehydrated with anhydrous potassium carbonate dehydration agent, the finished product 2 - chloro - 4 - nitrobenzoic acid 173 86g. the yield of 93%
IEmbodiment 3 mol 2-chloro-4-nitro-6-hydroxy-isopropylbenzene and 6 mol X-methylmorpholine with a mass fraction of 85% were added to the reaction vessel, laised the temperature of the solution to 46 °C, controlled the stirring speed at 190 rpm. 2() kept for 70 nun, added 6 mol tetra-n-propyl titanate, raised the temperature of the solution to 55 '0, refluxed for 110 min, reduced the solution temperature to 15 C, after the solid precipitated, filter, solid was washed with allylanune solution with a mass fraction 76%. adjusted the pH to 4 with oxalic acid solution with a mass fraction of 35%, ieduced temperature to 8 °C, precipitated crystals, filtered, washed with 2^ salicylate solution with a mass fraction of 96%, dehydrated with anhydrous sulfuric acid calcium dehydration agent, the finished product 2 - chloro - 4 - nitrobenzoic acid 385 (>2g. the yield of 96%
Claims (2)
1 Rixanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis method, lompiises the following steps (Ο 3 mol 2-cliloro-4-nitro-6-hydroxy-isopropylbenzene and 4-6 mol \-nieth\ Imorpholine were added to the reaction vessel, raised the temperature of the solution to 40-4(1 f . conhollcd the stirring speed at 170-190 rpm, kept for 5(1-70 min added (> mol letra-n-propyl titanate, raised the solution temperature to 50-55 I. refluxed for 90-1 lOnun, reduced the solution temperature to 10-15 '0, after the solid piecipitated. filter it, and the solid washed with allylanune solution, adjust the pH to 10 1-4 with the oxalic acid solution, lowered the temperature to 5-8 J C, after the crystals precipitated, filtrated it. washed with methyl salicylate solution, dehydrated with dehydration, got finished product 2- chloro-4-nitrobenzoic acid, wherein, the X-methylnioi pho line solution has a mass fraction of 80-85% as described in step (1), the mass fiaction of the allylanune solution in step (i) is 70 to 76%, the mass fraction 1 ς of the oxalic acid solution m step (i) is 30 to 35%
2. Rtvanol medicine intermediates 2-chloro-4-mtiobenzoic acid synthesis method according to claim 1 wherein the mass fraction of the methyl salicylate solution de'.ciibed in step (1) is 90-96% I Ritanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis method according to claim I wherein the dehydrating agent described in step (i) is any one of anhydious calcium sulfate and anhydrous potassium carbonate
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES20180114A IES86981B2 (en) | 2018-04-03 | 2018-04-03 | Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES20180114A IES86981B2 (en) | 2018-04-03 | 2018-04-03 | Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES20180114A2 IES20180114A2 (en) | 2019-05-01 |
| IES86981B2 true IES86981B2 (en) | 2019-05-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES20180114A IES86981B2 (en) | 2018-04-03 | 2018-04-03 | Rivanol medicine intermediates 2-chloro-4-nitrobenzoic acid synthesis |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IES86981B2 (en) |
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2018
- 2018-04-03 IE IES20180114A patent/IES86981B2/en unknown
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| IES20180114A2 (en) | 2019-05-01 |
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