IES87069B2 - Drug intermediates n-methylpyridin-2-one synthesis method - Google Patents
Drug intermediates n-methylpyridin-2-one synthesis method Download PDFInfo
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- IES87069B2 IES87069B2 IES20180259A IES87069B2 IE S87069 B2 IES87069 B2 IE S87069B2 IE S20180259 A IES20180259 A IE S20180259A IE S87069 B2 IES87069 B2 IE S87069B2
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- methylpyridin
- synthesis method
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000000543 intermediate Substances 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 239000000243 solution Substances 0.000 claims abstract description 52
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 16
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000001103 potassium chloride Substances 0.000 claims abstract description 8
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims abstract description 8
- 235000011152 sodium sulphate Nutrition 0.000 claims abstract description 8
- 239000008096 xylene Substances 0.000 claims abstract description 8
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 claims abstract description 6
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007864 aqueous solution 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
- IHUHXSNGMLUYES-UHFFFAOYSA-J osmium(iv) chloride Chemical compound Cl[Os](Cl)(Cl)Cl IHUHXSNGMLUYES-UHFFFAOYSA-J 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 6
- -1 potassium ferricyanide Chemical compound 0.000 description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- HZONRRHNQILCNO-UHFFFAOYSA-N 1-methyl-2h-pyridine Chemical compound CN1CC=CC=C1 HZONRRHNQILCNO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010042344 Subcutaneous emphysema Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses drug intermediates N-methylpyridin-2-one synthesis method, comprises the following steps: 6-methoxypyridine, potassium chloride solution, heptane solution are added to the reaction vessel, controls the temperature of the solution, the aqueous solution and aluminum isopropoxide are added, controls the stirring speed, continues to reacts; then osmium chloride powder is added, controls the temperature, continues to react, and then reduces the temperature, put it aside, the solution layers, separated from the oil, washed several times with sodium sulfate solution, washed several times with xylene solution, recrystallized in cyclohexene solution, dehydrated with dehydration, gets the finished product N-methyl pyridin-2-one.
Description
Drag intermediates N-methyIpyridin-2-one synthesis method
FIELD OF THE INVENTION
The present invention relates to a method for preparing a pharmaceutical intermediate which belongs to the field of organic synthesis, more particularly, relates to drug intermediates N-methylpyridin~2-one synthesis method.
GENERAL BACKGROUND
N-methylpyridin-2-one is mainly used as a synthesis intermediate for pharmaceuticals. Most of the existing synthesis methods requires the use of dimethyl sulfate, potassium ferricyanide and sodium hydroxide as raw materials. This synthesis method using dimethyl sulfate, potassium ferricyanide as the reaction material, dimethyl sulfate is of high toxicity, the function is similar to mustard gas, acute toxicity is similar to phosgene, 15 times more than chlorine, it has a strong stimulating effect on respiratory.' tract, it has a strong corrosive effect on skin, it can cause conjunctival hyperemia, edema, corneal epithelial shedding, trachea, bronchial epithelial cell necrosis, perforation leads to mediastinoscopy or subcutaneous emphysema. In addition, it can also damage the liver, kidney and myocardium, skin contact can cause burns, blisters and deep necrosis. Potassium cyanide inhalation, ingestion or absorption through the skin is harmful to the body, which can cause kidney damage, it can produce hydrogen cyanide under heating or acid. Therefore the use of dimethyl sulfate, potassium ferricyanide as synthesis of raw materials will lead to increased risk factor in the synthesis process, the health of synthesis operators get greater impact, it is not conducive to safe production, therefore, it is necessary to propose a new synthesis method.
SUMMARY
Based on the technical problems of the background technology, the purpose of the present invention is to provide drug intermediates N-methylpyridin-2-one synthesis method, comprises the following steps:
A: 6-methoxypyridine, potassium chloride solution, heptane solution are added to the reaction vessel, controls the temperature of the solution to 10-15 ”C, the aqueous solution and aluminum isopropoxide are added, controls the stirring speed at 350-370 rpm, continues to react for 90-120 min;
B: then osmium chloride powder is added, controls the temperature at 20-26 °C, continues to react for 2-3 h, and then reduces the temperature to 3-8 °C, put it aside for 30-50 min, the solution layers, separated from the oil, washed several times with sodium sulfate solution, washed several times with xylene solution, recrystallized in cyclohexene solution, dehydrated with dehydration, gets the finished product N-methyl pyridin-2-one.
Preferably, the potassium chloride solution has a mass fraction of 16-22%.
Preferably, the mass fraction of the heptane solution is 20-26%.
Preferably, the sodium sulfate solution has a mass fraction of 10-15%.
Preferably, the xylene solution has a mass fraction of 70-77%.
Preferably, the mass fraction of cyclohexene solution is 80-86%.
Throughout the reaction process can be the following reaction formula:
Compared with the synthesis method disclosed in the background art, the invention provides drug intermediates N-methylpyridin-2-one synthesis method, it is unnecessary to use dimethyl sulfate, potassium ferricyanide as reaction material, avoiding the damage of high toxicity dimethyl sulfate to synthesis operators, as well avoiding the risk of potassium ferricyanide producing hydrogen cyanide when heated or acid, reducing the risk factor of synthesis process, reducing the health hazards on synthesis operators, it is conducive to safe production, reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield, at the same time, the present invention provides a new synthetic route which has laid a good foundation for further enhancing the yield of the reaction.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The following examples with reference to specific embodiments of the pi esent invention are further illustrated:
Embodiment I
Drug intermediates N-inethylpyridin-2-one synthesis method, comprises the following steps:
A: 2 mol 6-methoxypyridine, 700ml potassium chloride solution with a mass fraction of 16%. 1.2L heptane solution with a mass fraction of 20% are added to the reaction vessel, controls the temperature of the solution to 10 C. the aqueous solution and 4 mol aluminum isopropoxide are added,, controls the stirring speed at J 50 ipm, 10 continues to react for 90 min;
B: then 4 mol osmium chloride powder is added, controls the temperature at 20 C, continues to react for 2 h, and then reduces the temperature to 3 C, put. it aside foi 30 min, the solution layers, separated from the oil, washed 3 times with sodium sulfate solution with a mass fraction of 10%, washed 6 times with xylene solution with a mass 15 fraction of 70%. recrystallized in cyclohexene solution with a mass fraction of 8O ./o, dehydrated with anhydrous sodium sulfate dehydration, gets the finished pioduct N-methyl pyridin-2-one 214.294g, yield 98.3%.
Embodiment 2
Drug intermediates N-methylpyridin-2-one synthesis method, comprises the following steps:
A: 2 mol 6-methoxypyridine, 700ml potassium chloride solution with a mass fraction of 19%, 1.2L heptane solution with a mass fraction of 23% are added to the reaction vessel, controls the temperature of the solution to 12.5 C, the aqueous solution and 5 mol aluminum isopropoxide are added, , controls the stirring speed at 25 360 rpm, continues to react for 115 min;
B: then 5 mol osmium chloride powder is added, controls the temperature at 23 C, continues to react for 2.5 h, and then reduces the temperature to 5.5 C, put it aside foi 40 min, the solution layers, separated from the oil, washed 4 times with sodium sulfate solution with a mass fraction of 12.5%, washed 7 times with xylene solution with a 30 mass fraction of 73.5%, recrystallized in cyclohexene solution with a mass fraction of
83%, dehydrated with anhydrous sodium sulfate dehydration, gets the finished product N-methyl pyridin-2-one 214.948g, yield 98.6%.
Embodiment 3
Drug intermediates N-methylpyridin-2-one synthesis method, comprises the following steps:
A: 2 mol 6-methoxypyridine, 700ml potassium chloride solution with a mass fraction of 22%, 1.2L heptane solution with a mass fraction of 26% are added to the reaction vessel, controls the temperature of the solution to 15 °C, the aqueous solution and 6 mol aluminum isopropoxide are added,, controls the stirring speed at 370 rprn, 10 continues to react for 120min;
B: then 6 mol osmium chloride powder is added, controls the temperature at 26 °C, continues to react for 3 h, and then reduces the temperature to 8 °C, put it aside for 50 min, the solution layers, separated from the oil, washed 5 times with sodium sulfate solution with a mass fraction of 15%, washed 8 times with xylene solution with a mass 15 fraction of 77%, recrystallized in cyclohexene solution with a mass fraction of 86%, dehydrated with anhydrous sodium sulfate dehydration, gets the finished product N-methyl pyridin-2-one 216.038g, yield 99.1%.
The embodiments of the present invention are merely preferred embodiments of the present invention, but. the range of the present invention is not limited this, and 20 any person who is familiar with those skilled in the arts, within the technical range of the present invention. It is intended that the technical solution and its inventive concept be replaced or modified equivalently with reference to the range of the invention.
Claims (5)
1. Drug intermediates N-methylpyridin-2-one synthesis method, comprises the following steps: A: 6-methoxypyridine, potassium chloride solution, heptane solution are added to the reaction vessel, controls the temperature of the solution to 10-15 °C, the aqueous solution and aluminum isopropoxide are added, , controls the stirring speed at 350-370 rpm, continues to react for 90-120 min; B: then osmium chloride powder is added, controls the temperature at 20-26 °C, continues to react for 2-3 h, and then reduces the temperature to 3-8 °C, put it aside for 30-50 min, the solution layers, separated from the oil, washed several times with sodium sulfate solution, washed several times with xylene solution, recrystallized in cyclohexene solution, dehydrated with dehydration, gets the finished product N-methyi pyridin-2-one.
2. Drag intermediates N-methylpyridin-2-one synthesis method according to claim 1 wherein the potassium chloride solution has a mass fraction of 16-22%.
3. Drug intermediates N-methylpyridin-2-one synthesis method according to claim 1 wherein the mass fraction of the mass fraction of the heptane solution is 20-26%.
4. Drug intermediates N-methylpyridin-2-one synthesis method according to claim I wherein the sodium sulfate solution has a mass fraction of 10-15%.
5. Drug intermediates N-methylpyridin-2-one synthesis method according to claim 1 wherein the xylene solution has a mass fraction of 70-77%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES20180259 IES20180259A2 (en) | 2018-08-23 | 2018-08-23 | Drug intermediates n-methylpyridin-2-one synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES20180259 IES20180259A2 (en) | 2018-08-23 | 2018-08-23 | Drug intermediates n-methylpyridin-2-one synthesis method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES87069B2 true IES87069B2 (en) | 2019-11-27 |
| IES20180259A2 IES20180259A2 (en) | 2019-11-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES20180259 IES20180259A2 (en) | 2018-08-23 | 2018-08-23 | Drug intermediates n-methylpyridin-2-one synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IES20180259A2 (en) |
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2018
- 2018-08-23 IE IES20180259 patent/IES20180259A2/en unknown
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| Publication number | Publication date |
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| IES20180259A2 (en) | 2019-11-27 |
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