IES20180251A2 - Nicotinamide-n-oxide drug intermediates synthesis method - Google Patents
Nicotinamide-n-oxide drug intermediates synthesis methodInfo
- Publication number
- IES20180251A2 IES20180251A2 IES20180251A2 IE S20180251 A2 IES20180251 A2 IE S20180251A2 IE S20180251 A2 IES20180251 A2 IE S20180251A2
- Authority
- IE
- Ireland
- Prior art keywords
- solution
- added
- nicotinamide
- synthesis method
- oxide
- Prior art date
Links
- USSFUVKEHXDAPM-UHFFFAOYSA-N Nicotinamide N-oxide Chemical compound NC(=O)C1=CC=C[N+]([O-])=C1 USSFUVKEHXDAPM-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 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 15
- 229940079593 drug Drugs 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 16
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims abstract description 16
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims abstract description 14
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 7
- YACLQRRMGMJLJV-UHFFFAOYSA-N chloroprene Chemical compound ClC(=C)C=C YACLQRRMGMJLJV-UHFFFAOYSA-N 0.000 claims abstract description 7
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 claims abstract description 7
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims abstract description 6
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 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
- 235000002867 manganese chloride Nutrition 0.000 claims abstract description 6
- 239000011565 manganese chloride Substances 0.000 claims abstract description 6
- 229940099607 manganese chloride Drugs 0.000 claims abstract description 6
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims abstract description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 6
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 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 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- -1 compound nicotinamide-N-oxide Chemical class 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- PBYZMCDFOULPGH-UHFFFAOYSA-N tungstate Chemical compound [O-][W]([O-])(=O)=O PBYZMCDFOULPGH-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention discloses drug intermediates nicotinamide-N-oxide drug intermediates synthesis method, comprises the following steps: 3-methylpyridine and potassium chloride solution were added to the reaction vessel, controlled the stirring speed, controlled the temperature of the solution, added diethyl fumarate solution and 1,3 -propanediamine solution, added N-chloroacetamide in batches, continued to react; then added manganese chloride powder, controlled the stirring speed, continued to react, added sodium sulfate solution, until the solution was stratified, separated the reservoir, washed with potassium bromide solution, washed with chlorobutadiene solution, recrystallized in ethylene glycol monomethyl ether solution, dehydrated with dehydration, got the finished product nicotinamide-N-oxide.
Description
Nicotinamide-N-oxide drug intermediates 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 nicotinamide-N-oxide drug intermediates synthesis method.
GENERAL BACKGROUND Nicotinamide—N-oxide is mainly used for the study of the mechanism of nicotinic acid—related granulocyte differentiation, for example human promyelocytic leukemia cells (HL—60), nicotinainide-N—oxide can reduce the expression of c-myc in HL-60 cell lines. Most of the existing synthesis methods use 3-cyanopyridine, hydrogen peroxide and sodium reaction raw materials to tungstate as compound nicotinamide-N-oxide. This synthesis method uses the reaction material 3-cyanopyridine which is combustible and irritating, which will irritate eyes, skin, mucous membranes and upper respiratory tract; inhibit the central nervous system, and can cause permanent corneal opacity. These factors will jeopardize the health of the production operators, not conducive to safe production. Reaction raw material hydrogen peroxide has a strong corrosive, inhalation of its vapor or fog will irritate respiratory tract strongly. Directly contacts to the eye with the liquid can cause irreversible damage or even blindness. In a sealed container with appropriate temperature, it will produce gas explosion. Therefore, the use of hydrogen peroxide as the reaction raw material will bring great risks to the production operation and is not conducive to safe production. Reactive raw material sodium tungstate can cause skin irritation, respiratory irritation symptoms, will stimulate the eyes, greatly harm the health of the production staffs. All of these factors indicate that there are many shortcomings in this synthetic approach, so it is necessary to propose a new synthetic method.
SUMMARY Based on the technical problems of the background technology, the purpose of the present invention is to provide nicotinamide-N-oxide drug intermediates synthesis method, comprises the following steps: A: 3-methylpyridine and potassium chloride solution were added to the reaction vessel, controlled the stirring speed at 150-180 rpm, controlled the temperature of the solution at 40-45 "C, added diethyl fumarate solution and 1,3-propanediamine solution, in 30-50 min, added N-chloroacetamide in batches, continued to react for 80-100 min; B: then added manganese chloride powder, controlled the stirring speed at 230-250 rpm, continued to react for 3-5 h, added sodium sulfate solution, until the solution was stratified, separated the reservoir, washed with potassium bromide solution for 30-50 min, washed with chlorobutadiene solution for 20-40 min, recrystallized in ethylene glycol monomethyl ether solution, dehydrated with dehydration, got the finished product nicotinamide-N-oxide.
Preferably, potassium chloride solution has a mass fraction of 10- 14%.
Preferably, diethyl fumarate solution has mass fraction of 20-25%.
Preferably, 1,3-propanediamine solution has mass fraction of 30-3 6%.
Preferably, sodium sulfate solution has mass fraction of 10-16%.
Preferably, potassium bromide solution has a mass fraction of 15-21%.
Preferably, chlorobutadiene solution has mass fraction of 40-46%.
Preferably, ethylene glycol monomethyl ether solution has a mass fraction of 60-66%.
Throughout the reaction process can be the following reaction formula: CH-. 1 ~' V E '- CSH|3()4 + H|0N;x *2‘ -Ir “—"*' l .. \\ ’/ .‘\ N/,/ /1 Compared with the synthesis method disclosed in the background art, the invention provides nicotinamide-N-oxide drug intermediates synthesis method, it is unnecessary to use 3-cyanopyridine, hydrogen peroxide and sodium tungstate as the reaction of raw materials, thus avoids risk of the combustible 3-cyanopyridine to safety production, also avoids risks of a strong corrosive hydrogen peroxide on the /cow:-I2 health of production staffs, as well as the corrosion damage of the reaction equipment, which is conducive to reduce the risk coefficient; also it avoids the impact of reaction of raw material sodium tungren to the health of the production operators, ultimately conducive to safe production. It also reduces intermediate links reaction, decreases the reaction time and improves 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.
DESCRIPTION OF THE DRAWINGS Figure 1 is the infrared analysis spectrum of finished product nicotinamide-N—oxide.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Embodiment 1 Nicotinamide-N—oxide drug intermediates synthesis method, comprises the following steps: A: 2mol 3-methylpyridine and 900 ml potassium chloride solution with a mass fraction of 10% were added to the reaction vessel, controlled the stirring speed at 150 rpm, controlled the temperature of the solution at 40 "C, added 4mol diethyl fuinarate solution with a mass fraction of 20% and 4mol 1,3 -propanediamine solution with a mass fraction of 30%, in 30 min, added 4mol N-Chloroacetamide in 2 times, continued to react for 80 min; B: then added 2mol manganese chloride powder, controlled the stirring speed at 230 rpm, continued to react for 3 h, added 1.2 L sodium sulfate solution with a mass fraction of 10%, until the solution was stratified, separated the reservoir, washed with potassium bromide solution with a mass fraction of 15% for 30 min, washed with chlorobutadiene solution with a mass fraction of 40% for 20 min, recrystallized in ethylene glycol monomethyl ether solution with a mass fraction of 60%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product nicotinamide-N—oxide 270.756g, yield of 98. 1%.
Embodiment 2 Nicotinamide-N—oxide drug intermediates synthesis method, comprises the following steps: A: 2mol 3-methylpyridine and 900 ml potassium chloride solution with a mass fraction of 12% were added to the reaction vessel, controlled the stirring speed at 160 rpm, controlled the temperature of the solution at 43 °C, added Smol diethyl fumarate solution with a mass fraction of 23% and 5mol 1,3-propanediamine solution with a mass fraction of 33%, in 40 min, added Smol N-Chloroacetamide in 3 times, continued to react for 90 min; B: then added 3mol manganese chloride powder, controlled the stirring speed at 240 rpm, continued to react for 4 h, added 1.2 L sodium sulfate solution with a mass fraction of 13%, until the solution was stratified, separated the reservoir, washed with potassium bromide solution with a mass fiaction of 18% for 40 min, washed with chlorobutadiene solution with a mass fraction of 43% for 30 min, recrystallized in ethylene glycol monomethyl ether solution with a mass fraction of 63%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product nicotinamide-N-oxide 271.308g, yield of 98.3%.
Embodiment 3 Nicotinamide-N—oxide drug intermediates synthesis method, comprises the following steps: A: 2mol 3-methylpyridine and 900 ml potassium chloride solution with a mass fraction of 14% were added to the reaction vessel, controlled the stirring speed at 180 rpm, controlled the temperature of the solution at 45 "C, added 6mol diethyl fumarate solution with a mass fraction of 25% and 6mol 1,3 -propanediamine solution with a mass fraction of 36%, in 50 min, added 6mol N-Chloroacetamide in 4 times, continued to react for 100 min; B: then added 4mol manganese chloride powder, controlled the stirring speed at 250 rpm, continued to react for 5 h, added 1.2 L sodium sulfate solution with a mass fraction of 16%, until the solution was stratified, separated the reservoir, washed with potassium bromide solution with a mass fraction of 21% for 50 min, washed with chlorobutadiene solution with a mass fraction of 46% for 40 min, recrystallized in ethylene glycol monomethyl ether solution with a mass fraction of 66%, dehydrated with anhydrous magnesium sulfate dehydration, got the finished product nicotinamide-N-oxide 272.136g, yield of 98.6%.
Figure 1 is the infiared analysis spectrum of finished product nicotinamide—N—oxide.
The infrared analysis of data is shown in Table 1.
Table 1 Infrared analysis Serial Peak position Transmittance Half width Peak difference number (cm'l) (%) (cm'l) (%) 1 497 39 35 31 2 563 26 54 49 3 654 22 27 64 4 735 22 14 45 756 38 27 30 6 806 55 14 3 1 7 874 59 13 31 8 926 40 16 54 9 101 1 30 10 68 1102 42 17 44 1 '1 g 1 141 61 12 8 12 1 155 62 20 9 13 1227 10 28 66 14 1267 65 3 1 10 1388 10 33 63 16 1431 21 19 54 17 1476 38 15 45 18 1560 32 16 48 19 1626 24 38 42 1682 9 50 60 21 3140 12 242 33 22 3383 12 209 44 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 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. Nicotinamide-N—oxide drug intermediates synthesis method, comprises the following steps: A: 3-methylpyridine and potassium chloride solution were added to the reaction vessel, controlled the stirring speed at 150-180 rpm, controlled the temperature of the solution at 40-45 °C, added diethyl fumarate solution and 1,3-propanediamine solution, in 30-50 min, added N-Chloroacetamide in batches, continued to react for 80-100 min; B: then added manganese chloride powder, controlled the stirring speed at 230-250 rpm, continued to react for 3-5 h, added sodium sulfate solution, until the solution was stratified, separated the reservoir, washed with potassium bromide solution for 30-50 min, washed with chlorobutadiene solution for 20-40 min, recrystallized in ethylene glycol monomethyl ether solution, dehydrated with dehydration, got the finished product nicotinamide-N-oxide.
2. Nicotinamide-N-oxide drug intermediates synthesis method according to claim 1 wherein potassium chloride solution has a mass fraction of 10-14%.
3. Nicotinamide-N-oxide drug intermediates synthesis method according to claim 1 wherein diethyl fumarate solution has mass fraction of 20-25%.
4. Nicotinamide—N-oxide drug intermediates synthesis method according to claim 1 wherein 1,3-propanediamine solution has mass fraction of 30-36%.
5. Nicotinamide—N—oxide drug intermediates synthesis method according to claim 1 wherein sodium sulfate solution has mass fraction of 10-16%.
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS6034939A (en) | Manufacture of diaryl compound | |
| AU596824B2 (en) | Dichloroaniline derivatives | |
| US4355043A (en) | Novel derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membrane | |
| US3113949A (en) | Substituted pyrazole sulfonamides | |
| JPS60155141A (en) | Poly-substituted naphthalene compound, manufacture and medicinal and cosmetic composition | |
| JPS61260091A (en) | Novel erythromycin a/fatty acid ester, its production and pharmaceutical and cosmetic composition containing the same | |
| CA1103674A (en) | .alpha.-(3-AZETIDINYL)-.alpha.-PHENYL ACETONITRILE AND ACETAMIDES | |
| IES20180251A2 (en) | Nicotinamide-n-oxide drug intermediates synthesis method | |
| AU2018101172A4 (en) | Nicotinamide-N-oxide drug intermediates synthesis method | |
| AU2018101173A4 (en) | 2-hydroxyquinoxaline drug intermediates synthesis method | |
| US3018222A (en) | Central stimulant and appetite depressant composition | |
| IES87060B2 (en) | Butyraldehyde oxime drug itermediates synthesis method | |
| KR870001240B1 (en) | Method for preparing N-methyl-D-glucamine salt | |
| PT93844A (en) | PROCESS FOR THE PREPARATION OF PHENETHANOLAMINE DERIVATIVES | |
| AU2018101182A4 (en) | Rubber cross-linking agent cyclohexanone peroxide synthesis method | |
| CN116554078B (en) | Compound with anti-lung cancer activity and preparation method and application thereof | |
| AU2018101146A4 (en) | Benzoyl peroxide organic intermediates synthesis method | |
| AU2018101181A4 (en) | Dibenzyl sulfoxide organic intermediates synthesis method | |
| KR930000113B1 (en) | Process for preparing azonia spironotropanol ester | |
| AU2018101147A4 (en) | Methylchloroperoxybenzoic acid drug intermediates synthesis method | |
| Wang et al. | Synthesis and structure of a dimeric hydroxobridged erbium (III) complex, di-μ-hydroxo-bis [(1, 4, 7, 10, 13, 16-hexaazacyclooctadecane) erbium (III)] tetra (trifloromethanesulfonate) | |
| EP0278728A2 (en) | 1-(4-Amino-3,5-dichlorophenyl)-2-(substituted amino)ethanol derivatives and their use in the treatment of respiratory disease | |
| NO744713L (en) | ||
| AU2018101180A4 (en) | Broad spectrum antimicrobial agents thiamphenicol synthesis method | |
| Khankari et al. | Crystal structure of nedocromil sodium heptahemihydrate and its comparison with that of nedocromil sodium trihydrate |