IES20180242A2 - Broad spectrum antimicrobial agents thiamphenicol synthesis method - Google Patents
Broad spectrum antimicrobial agents thiamphenicol synthesis method Download PDFInfo
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- IES20180242A2 IES20180242A2 IES2018/0242A IES20180242A IES20180242A2 IE S20180242 A2 IES20180242 A2 IE S20180242A2 IE S20180242 A IES20180242 A IE S20180242A IE S20180242 A2 IES20180242 A2 IE S20180242A2
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- thiamphenicol
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- synthesis method
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- 229960003053 thiamphenicol Drugs 0.000 title abstract description 17
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 title abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract description 12
- 239000004599 antimicrobial Substances 0.000 title abstract description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 abstract description 12
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 abstract description 12
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 abstract description 6
- 229940043279 diisopropylamine Drugs 0.000 abstract description 6
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 abstract description 6
- 229910052939 potassium sulfate Inorganic materials 0.000 abstract description 6
- 235000011151 potassium sulphates Nutrition 0.000 abstract description 6
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 abstract description 5
- 230000018044 dehydration Effects 0.000 abstract description 5
- 238000006297 dehydration reaction Methods 0.000 abstract description 5
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000843 powder Substances 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 5
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 abstract description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 abstract description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229940095564 anhydrous calcium sulfate Drugs 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229960005091 chloramphenicol Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- -1 chloramphenicol methyl sulfone derivatives Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention discloses broad spectrum antimicrobial agents thiamphenicol synthesis method,comprises the following steps: 1-p-dimethoxysulfonylpheny1-2-dichloroacetamido-1,3-propanediol and potassium sulfate solution were added to the reaction vessel, controlled the stirring speed, controlled the temperature of the solution, added n-bromoacetamide, added acetylacetone solution in batches, continued to react; then added cobalt chloride powder, controlled the temperature of the solution, continued to react, added sodium bromide solution, until the solution was stratified, separated the reservoir, washed with cyclopropane solution, recrystallized in diisopropylamine solution, dehydrated with dehydration, got the finished product thiamphenicol.
Description
TRUE COPY i I Q ,3 AS Bro d spectrum antimicrobial agents thiamphenicol 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 Broad spectrum antimicrobial agents thiamphenicol synthesis method.
GENERAL BACKGROUND Thiamphenicol belongs to chloramphenicol methyl sulfone derivatives and is a synthetic broad-spectrum antimicrobial. Antibacterial spectrum and antibacterial effect are basically similar to chloramphenicol. It enters into the bacterial cells mainly through the dispersion, reversibly binds to the SOS subunit of the bacterial ribosome, blocks the growth of peptide chain, inhibits the role of transpeptidase, inhibits the formation of peptide chains, and prevents the synthesis of protein, thus makes antibacterial effect. Thiamphenicol still has a strong immunosuppressive effect, 6 times stronger than chloramphenicol, and can inhibit the synthesis of immunoglobulin and production of antibody. Most of the existing synthesis methods using dichloroacetylate, hydrogen peroxide, and acetic anhydride as raw materials for the synthesis of thiamphenicol. The reaction raw material hydrogen peroxide is an explosive strong oxidant. In a sealed container with an appropriate temperature, a gas phase explosion will occur. Hydrogen peroxide has a strong corrosive. These factors show that hydrogen peroxide as a reaction material will greatly increase the risk factor in the synthesis process, it also endangers the health of production staffs. The reaction raw material acetic anhydride is flammable, corrosive and irritating and can cause burns to human body; it is also harmful to the environment, and can pollute water.
After inhalation, it can stimulate the respiratory tract, causing cough, chest pain and difficulty breathing; its vapors are irritating to the eye, directly contacst to the skin and the eye can cause burns. The analysis of these factors shows that: acetic anhydride as a raw material causes great environmental pollution, the synthesis process is harmful to the health of production operators, which is not conducive to safe production. The above analysis shows that this synthetic method has many shortcomings, so 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 broad spectrum antimicrobial agents thiamphenicol synthesis method, comprises the following steps: A: 1—p-dimethoxysulfonylphenyldichloroacetarnido-1,3-propanediol and potassium sulfate solution were added to the reaction vessel, controlled the stirring speed at 210-230 rpm, controlled the temperature of the solution at 20-26 °C, added n-bromoacetamide, in 20-40 min, added acetylacetone solution in batches, continued to react for 50-80 min; B: then added cobalt chloride powder, controlled the temperature of the solution at 28-32 °C, continued to react for 2-3 h, added sodium bromide solution, until the solution was stratified, separated the reservoir, washed with cyclopropane solution for -50 min, recrystallized in diisopropylamine solution, dehydrated with dehydration, got the finished product thiamphenicol.
Preferably, potassium sulfate solution has a mass fraction of 15-22%.
Preferably, acetylacetone solution has mass fraction of 30-36%.
Preferably, sodium bromide solution has mass fraction of 10-16%.
Preferably, cyclopropane solution has mass fraction of 50-55%.
Preferably, diisopropylamine solution has a mass fraction of 60-66%.
Throughout the reaction process can be the following reaction formula: SCH3 -SCI-13 ‘ H_~,CO\'|§//OCH3 S02 1 C5§‘l5O~_a 9 CQCI-_» 1‘ C3l“l.:BYN0 ———p CH NHCOCHCI /CH\ ,NHCOCHCl2 HO/ \C/ 2 Ho c’ HCHQOH I-1CH20H Compared with the synthesis method disclosed in the background art, the invention provides broad spectrum antimicrobial agents thiamphenicol synthesis method, it is unnecessary to use hydrogen peroxide and acetic anhydride as reactants, avoids the risk of gas exlpsion generated by hydrogen peroxide in a sealed container, avoids to cause harm to the health of production operators, and decreases the risk factor of the synthesis process. It also avoids the vulnerability characteristics of flammable, corrosive of acetic anhydride, which have potential risks to damage to the production operators, which is conducive to safety production, reduces the pollution of the environment, reduces pollution control costs to the late response. 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.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Embodiment l Broad spectrum antimicrobial agents thiamphenicol synthesis method, comprises the following steps: A: 21nol 1-p-dimethoxysulfonylphenyldichloroacetarnido-1,3-propanediol and 800 ml potassium sulfate solution with a mass fraction of l5% were added to the reaction vessel, controlled the stirring speed at 210 rpm, controlled the temperature of the solution at 20 °C, added 4mol n-bromoacetamide, in 20 min, added 4mol acetylacetone solution with a mass fraction of 30% in 2 times, continued to react for 50 min; B: then added 4mol cobalt chloride powder, controlled the temperature of the solution at 28 °C, continued to react for 2 h, added 1.3 L sodium bromide solution with a mass fraction of 10%, until the solution was stratified, separated the reservoir, washed with cyclopropane solution with a mass fraction of 50% for 30 min, recrystallized in diisopropylamine solution with a mass fraction of 60%, dehydrated with anhydrous calcium sulfate dehydration, got the finished product thiamphenicol 699. l84g, yield of98.2%.
Embodiment 2 Broad spectrum antimicrobial agents thiamphenicol synthesis method, comprises the following steps: A: 2mol l—p—dimethoxysulfonylphenyl—2-dichloroacetamido—l,3—propanediol and 800 ml potassium sulfate solution with a mass fraction of 18% were added to the reaction vessel, controlled the stirring speed at 220 rpm, controlled the temperature of the solution at 23 "C, added 5mol n—bromoacetamide, in 30 min, added Smol acetylacetone solution with a mass fraction of 33% in 3 times, continued to react for 70 min; B: then added 5mol cobalt chloride powder, controlled the temperature of the solution at 30 °C, continued to react for 2.5 h, added 1.3 L sodium bromide solution with a mass fraction of 13%, until the solution was stratified, separated the reservoir, washed with cyclopropane solution with a mass fraction of 53% for 40 min, recrystallized in diisopropylamine solution with a mass fiaction of 63%, dehydrated with anhydrous calcium sulfate dehydration, got the finished product thiamphenicol 701.32g, yield of98.5%.
Embodiment 3 Broad spectrum antimicrobial agents thiamphenicol synthesis method, comprises the following steps: A: 2mol l-p-dimethoxysulfonylphenyldichloroacetamido-l,3-propanediol and 800 ml potassium sulfate solution with a mass fraction of 22% were added to the reaction vessel, controlled the stirring speed at 230 rpm, controlled the temperature of the solution at 26 °C, added 6mol n-bromoacetamide, in 40 min, added 6mol acetylacetone solution with a mass fraction of 36% in 4 times, continued to react for 80 min; B: then added 6mol cobalt chloride powder, controlled the temperature of the solution at 32 "C, continued to react for 3 h, added 1.3 L sodium bromide solution with a mass fraction of 16%, until the solution was stratified, separated the reservoir, washed with cyclopropane solution with a mass fraction of 55% for 50 min, recrystallized in diisopropylamine solution with a mass fraction of 66%, dehydrated with anhydrous calcium sulfate dehydration, got the finished product thiamphenicol 702.744g, yield of 98.7%.
The embodiments of the present invention are merely preferred embodiments of the presentinventkny butthe range ofthe presentinventkniis notlinnted flns,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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES20180242A IES20180242U1 (en) | 2018-08-16 | 2018-08-16 | Broad spectrum antimicrobial agents thiamphenicol synthesis method |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| APAPPLICATIONREFUSEDUNDERSECTION31 | |||
| IES20180242A IES20180242U1 (en) | 2018-08-16 | 2018-08-16 | Broad spectrum antimicrobial agents thiamphenicol synthesis method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES20180242A2 true IES20180242A2 (en) | 2020-02-19 |
| IES20180242U1 IES20180242U1 (en) | 2020-02-19 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES20180242A IES20180242U1 (en) | 2018-08-16 | 2018-08-16 | Broad spectrum antimicrobial agents thiamphenicol synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IES20180242U1 (en) |
-
2018
- 2018-08-16 IE IES20180242A patent/IES20180242U1/en not_active Application Discontinuation
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