IES20180280A2 - Methylchloroperoxybenzoic acid drug intermediates synthesis method - Google Patents
Methylchloroperoxybenzoic acid drug intermediates synthesis method Download PDFInfo
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- IES20180280A2 IES20180280A2 IES2018/0280A IES20180280A IES20180280A2 IE S20180280 A2 IES20180280 A2 IE S20180280A2 IE S20180280 A IES20180280 A IE S20180280A IE S20180280 A2 IES20180280 A2 IE S20180280A2
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- methylchloroperoxybenzoic
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- mass fraction
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- SAZIXRNDDOLEGS-UHFFFAOYSA-N CC=1C(=C(C(=O)OO)C=CC=1)Cl Chemical compound CC=1C(=C(C(=O)OO)C=CC=1)Cl SAZIXRNDDOLEGS-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 239000000543 intermediate Substances 0.000 title claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 55
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 16
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims abstract description 16
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims abstract description 16
- RZKSECIXORKHQS-UHFFFAOYSA-N Heptan-3-ol Chemical compound CCCCC(O)CC RZKSECIXORKHQS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 13
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 claims abstract description 12
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011780 sodium chloride Substances 0.000 claims abstract description 8
- 235000010344 sodium nitrate Nutrition 0.000 claims abstract description 8
- 239000004317 sodium nitrate Substances 0.000 claims abstract description 8
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims abstract description 7
- FBSIKJFOVXUNMI-UHFFFAOYSA-N 2-(3-chlorophenyl)acetamide Chemical compound NC(=O)CC1=CC=CC(Cl)=C1 FBSIKJFOVXUNMI-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
- 239000000843 powder Substances 0.000 claims abstract description 6
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 7
- 230000007797 corrosion Effects 0.000 description 4
- 238000005260 corrosion Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 231100000206 health hazard Toxicity 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 229910001868 water Inorganic materials 0.000 description 1
Abstract
The present invention discloses methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: m-chlorophenylacetamide and sodium nitrate solution were added to the reaction vessel, controlled the stirring speed, controlled the temperature of the solution, added methyl n-butyl ether solution and 1,4-butanediol solution, added n-bromoacetamide in batches, continued to react; then added aqueous solution and zinc fluoride powder, controlled the stirring speed, continued to react, washed with sodium chloride solution, washed with 3-heptanol solution, recrystallized in nitroethane solution, dehydrated with dehydration, got the finished product methylchloroperoxybenzoic acid.
Description
Methylchloroperoxybenzoic acid 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 drug intermediates methylchloroperoxybenzoic acid drug intermediates synthesis method.
GENERAL BACKGROUND Methylchloroperoxybenzoic acid is mainly used as synthetic agent for pharmaceuticals, pesticides and other fine chemical products; it is used for cyclization, Baeyer~Villiger reaction, N-oxidation, S-oxidation, etc. Most of the existing synthesis methods are in the reaction vessel, adding magnesium sulfate, sodium hydroxide, water, hydrogen peroxide, dioxane and ice cube, reducing the temperature to 5 °C, stirring, adding m-chlorobenzoyl chloride, then adding ice cube, maintaining the temperature below 25 "C, adding sulfuric acid, standing, filtering, evaporating the filtrate to get the solvent, and getting methylchloroperoxybenzoic acid. This synthesis method requires the use of sodium hydroxide, hydrogen peroxide, sulfuric acid as the reaction material. Sodium hydroxide has a strong irritation and corrosion, its dust or smoke can irritate eyes and respiratory tract, directly contacts to Na0H, skin and eye with can get burns. Therefore, the use of sodium hydroxide as a reaction raw material will endanger the health of production operators, which is not conducive to safety production. Hydrogen peroxide belongs to an explosive strong oxidizing agent, and can react with the combustibles to release of a lot of heat and oxygen which can cause fire explosion. Hydrogen peroxide has a strong corrosive, inhalation of its vapor or fog can irritate strongly the respiratory tract. These will increase the risk factor in the reaction process, which are not conducive to safety production. Sulfuric acid is a highly corrosive solution, it requires a higher corrosion resistance to the production equipment, resulting in increasing equipment manufacturing costs, which is not conducive to reducing the project costs; and the strong corrosion of sulfuric acid solution, will be a health hazard of the production operators. The analysis of these factors shows that there are many shortcomings in this synthetic method, so it is necessary to propose a new synthetic method.
CONTENTS OF THE INVENTION Methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: A: m-chlorophenylacetamide and sodium nitrate solution were added to the reaction vessel, controlled the stirring speed at 230-260 rpm, controlled the temperature of the solution at 10-16 "C, added methyl n-butyl ether solution and 1,4-butanediol solution, in 20-40 min, added n-bromoacetamide in batches, continued to react for 60-90 min; B: then added aqueous solution and zinc fluoride powder, controlled the stirring speed at 310-330 rpm, continued to react for 3-4 h, washed with sodium chloride solution for 30-50 min, washed with 3-heptanol solution for 20-40 min, recrystallized in nitroethane solution, dehydrated with dehydration, got the finished product methylchloroperoxybenzoic acid.
Preferably, sodium nitrate solution has a mass fraction of 10-16%.
Preferably, methyl n-butyl ether solution has mass fraction of 15-22%.
Preferably, 1,4-butanediol solution has mass fraction of 20-26%.
Preferably, sodium chloride solution has mass fraction of 5~11%.
Preferably, 3-heptanol solution has a mass fraction of 30-3 7%.
Preferably, nitroethane solution has a mass fraction of 60-65%.
Throughout the reaction process can be the following reaction formula: O NH ‘\\\,C/ 2 O 0 ,. CSHDC, ., Crimoz + C21"14B1'NO I13‘) 2.nI==;, Ci Compared with the synthesis method disclosed in the background art, the invention provides methylchloroperoxybenzoic acid drug intermediates synthesis method, does not need to use sodium hydroxide, hydrogen peroxide, sulfuric acid as the reaction of raw materials, avoids a strong stimulus and corrosive sodium hydroxide as a reactant, which will endanger the health of the production operators, thus it is conducive to safety production. It avoids the explosive strong oxidant hydrogen peroxide as a reactant, reduces the risk coefficient of the reaction process; it also avoids the strong corrosive sulfuric acid as a reactant, reduces the corrosion resistance requirement for production equipment, decreases equipment manufacturing costs, and also reduces the health hazards to the production operators. It also reduces intermediate links reaction, decreases the reaction time and improves the reaction yield, at the same time.
DESCRIPTION OF THE DRAWINGS Figure l is the infrared analysis spectrum of finished product methylchloroperoxybenzoic acid.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Embodiment 1 Methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: A: Zmol m-chlorophenylacetamide and 900 ml sodium nitrate solution with a mass fraction of 10% were added to the reaction vessel, controlled the stirring speed at 230 rpm, controlled the temperature of the solution at l0 °C, added 4mol methyl n—butyl ether solution with a mass fraction of 15% and 411101 1,4-butanediol solution // \ with a mass fraction of 20%, in 20 min, added 4mol mbromoacetamide in 2 times, continued to react for 60 min; B: then added 4mol aqueous solution and 2mol zinc fluoride powder, controlled the stirring speed at 310 rpm, continued to react for 3 h, washed with sodium chloride solution with a mass fraction of 5% for 30 min, washed with 3-heptanol solution with a mass fraction of 30% for 20 min, recrystallized in nitroethane solution with a mass fraction of 60%, dehydrated with anhydrous sodium sulfate dehydration, got the finished product rnethylchloroperoxybenzoic acid 337.808g, yield of 98.2%.
Embodiment 2 Methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: A: Zmol m-chlorophenylacetamide and 900 ml sodium nitrate solution with a mass fraction of 13% were added to the reaction vessel, controlled the stirring speed at 240 rpm, controlled the temperature of the solution at 13 °C, added Smol methyl n—butyl ether solution with a mass fraction of 19% and Smol 1,4-butanediol solution with a mass fraction of 23%, in 30 min, added Smol n-bromoacetamide in 3 times, continued to react for 70 min; B: then added Smol aqueous solution and 3mol zinc fluoride powder, controlled the stirring speed at 320 rpm, continued to react for 3.5 h, washed with sodium chloride solution with a mass fraction of 8% for 40 min, washed with 3-heptanol solution with a mass fraction of 34% for 30 min, recrystallized in nitroethane solution with a mass fraction of 63%, dehydrated with anhydrous sodium sulfate dehydration, got the finished product methylchloroperoxybenzoic acid 338.840g, yield of 98.5%.
Embodiment 3 Methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: A: 2mol m-chlorophenylacetamide and 900 ml sodium nitrate solution with a mass fraction of 16% were added to the reaction vessel, controlled the stirring speed at 260 rpm, controlled the temperature of the solution at 16 “C, added 6mol methyl n-butyl ether solution with a mass fiaction of 22% and 6mol 1,4-butanediol solution with a mass fraction of 26%, in 40 min, added 6mol n-bromoacetamide in 4 times, continued to react for 60 min; B: then added 6mol aqueous solution and 4mol zinc fluoride powder, controlled the stirring speed at 330 rpm, continued to react for 4 h, washed with sodium chloride solution with a mass fraction of 11% for 50 min, washed with 3—heptanol solution with a mass fraction of 37% for 40 min, recrystallized in nitroethane solution with a mass fraction of 65%, dehydrated with anhydrous sodium sulfate dehydration, got the finished product methylchloroperoxybenzoic acid 339.528g, yield of 98.7%.
Figure 1 is the infrared analysis spectrum of finished product methylchloroperoxybenzoic acid.
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) cm 1 671 68 9 23 2 721 44 12 49 3 752 28 14 61 4 853 67 16 18 900 54 15 1 7 6 918 62 33 9 7 1077 67 23 13 8 1143 59 21 23 9 1264 20 20 45 l0 1304 16 4] 52 ll l4l9 34 47 9 l2 M79 64 66 10 13 l577 32 19 39 M A 1599 50 19 20 l5 1697 9 56 62 16 2555 44 400 7 17 3089 33 393 19 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. Methylchloroperoxybenzoic acid drug intermediates synthesis method, comprises the following steps: A: m-chlorophenylacetamide and sodium nitrate solution were added to the reaction vessel, controlled the stirring speed at 230-260 rpm, controlled the temperature of the solution at 10-16 "C, added methyl n-butyl ether solution and 1,4-butanediol solution, in 20-40 min, added n-bromoacetamide in batches, continued to react for 60-90 min; B: then added aqueous solution and zinc fluoride powder, controlled the stirring speed at 310-330 rpm, continued to react for 3-4 h, washed with sodium chloride solution for 30-50 min, washed with 3—heptanol solution for 20-40 min, recrystallized in nitroethane solution, dehydrated with dehydration, got the finished product methylchloroperoxybenzoic acid.
2. Methylchloroperoxybenzoic acid drug intermediates synthesis method according to claim 1 wherein sodium nitrate solution has a mass fraction of 10-16%.
3. Methylchloroperoxybenzoic acid drug intermediates synthesis method according to claim 1 wherein methyl n-butyl ether solution has mass fraction of 15-22%.
4. Methylchloroperoxybenzoic acid drug intermediates synthesis method according to claim 1 wherein 1,4-butanediol solution has mass fraction of 20-26%.
5. Methylchloroperoxybenzoic acid drug intermediates synthesis method according to claim 1 wherein sodium chloride solution has mass fraction of 5-11%.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNCHINA17/09/20172017108366626 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IES20180280A2 true IES20180280A2 (en) | 2020-10-14 |
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