CN113861060A - Synthetic method of sphingosine kinase agonist - Google Patents
Synthetic method of sphingosine kinase agonist Download PDFInfo
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- CN113861060A CN113861060A CN202111307864.4A CN202111307864A CN113861060A CN 113861060 A CN113861060 A CN 113861060A CN 202111307864 A CN202111307864 A CN 202111307864A CN 113861060 A CN113861060 A CN 113861060A
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- octanoyl chloride
- intermediate iii
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- 239000000556 agonist Substances 0.000 title claims abstract description 18
- 108010035597 sphingosine kinase Proteins 0.000 title claims abstract description 13
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 claims abstract description 19
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- CGYVFCHCRBGGJG-UHFFFAOYSA-N n-(1,3-dihydroxypropan-2-yl)-2-hexyl-3-oxodecanamide Chemical compound CCCCCCCC(=O)C(C(=O)NC(CO)CO)CCCCCC CGYVFCHCRBGGJG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000001308 synthesis method Methods 0.000 claims description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract description 2
- 230000006866 deterioration Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- -1 amino hydrogen Chemical compound 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 2
- 229940106189 ceramide Drugs 0.000 description 2
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010061363 Skeletal injury Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of sphingosine kinase agonist K6PC-5, belonging to the technical field of organic synthesis, and the synthetic method comprises the following specific steps: (1) using octanoyl chloride (compound II) as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III; (2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5. The synthetic method is simple to operate, economical and efficient, and can be used for large-scale production, the one-pot method avoids the intermediate III from being excessively exposed to the air after being formed, the possibility of deterioration of the intermediate III is reduced, and the whole operation is safe, reliable, rapid and efficient.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a one-pot synthesis method of sphingosine kinase agonist K6 PC-5.
Background
Sphingosine kinases (sphingases) are key rate-limiting enzymes and intracellular signal transduction enzymes for maintaining intracellular sphingolipid balance, have the functions of maintaining the balance of sphingosine-1-phosphate, ceramide and sphingosine, and participate in regulating various physiological functions of cell proliferation and apoptosis, vasoconstriction and remodeling, inflammation and metabolism and the like. K6PC-5 is a novel unnatural ceramide having an agonistic effect on sphingosine kinase 1, and is effective in enhancing sphingosine-1-phosphate production, controlling keratinocyte proliferation and differentiation, fibroblast proliferation and collagen synthesis, treating skin wound, improving wrinkle and inhibiting skin aging. In addition, it has been reported that K6PC-5, as a sphingosine kinase agonist, has a certain effect on the anti-glucocorticoid-related bone injury, the inhibition of Ebola virus infection in endothelial cells, and the anti-tumor effect.
Disclosure of Invention
Aiming at the blank existing in the prior art, the invention provides a one-pot synthesis method of sphingosine kinase agonist K6 PC-5. The synthesis method disclosed by the invention is efficient and high in yield, and is suitable for large-scale industrial production.
The technical scheme adopted by the invention is as follows:
a synthetic method of sphingosine kinase agonist K6PC-5 is carried out according to the following steps:
the method comprises the following specific steps:
(1) using octanoyl chloride (compound II) as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III;
(2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5.
In the step (1), the mol ratio of octanoyl chloride to triethylamine is 1: 1-1.2; preferably, the molar ratio of octanoyl chloride to triethylamine is 1: 1.1.
In the step (1), the volume consumption of the dichloromethane is 4-6 times of that of the octanoyl chloride; preferably, the amount of dichloromethane used is 5 times the volume of octanoyl chloride.
In the step (1), the reaction conditions are as follows: reacting for 3-4h at room temperature; preferably, the reaction is carried out at 25 ℃ for 4 h.
In the step (2), the mol ratio of serinol to octanoyl chloride is 0.55-0.65: 1; preferably, the molar ratio of serinol to octanoyl chloride is 0.6: 1.
In the step (2), the reaction conditions are as follows: reacting for 8-12h at room temperature; the reaction is preferably carried out at 25 ℃ for 10 h.
The beneficial technical effects of the invention are as follows:
the method provided by the invention provides a synthetic method which is simple to operate, economic and efficient and can be used for large-scale production for K6PC-5, the intermediate III has poor stability under conventional conditions and is easy to react with water and nucleophilic reagents to deteriorate, so that the purity and yield of the product are influenced, the intermediate III is prevented from being excessively exposed in the air after being formed by using a one-pot method, the possibility of deterioration of the intermediate III is reduced, and the whole operation is safe, reliable, rapid and efficient. This method has been applied to scale-up production.
Drawings
FIG. 1 shows the NMR spectrum of agonist K6PC-5 prepared in example 1 of the present invention.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1:
a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 350L of dichloromethane and 48kg of triethylamine (475mol) are added into a reaction kettle, 70kg of octanoyl chloride (432mol) is dripped under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the octanoyl chloride (432mol) is dripped and stirred for 4 hours at 25 ℃.
(2) Adding 24kg of serinol (263mol) into the reaction kettle in batches, keeping the reaction kettle at 25 ℃ for stirring for 10 hours after the addition is finished, adding 1mol/L of dilute hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 100L of saturated saline solution, concentrating to obtain a crude product, adding 70L of acetone, stirring for dissolving, slowly adding 140L of water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 42.5kg of a product (I), namely the agonist K6 PC-5.
The nmr hydrogen spectrum of the obtained product is shown in fig. 1, and it can be seen from fig. 1 that the single hydrogen double peak with chemical shift of 6.89ppm corresponds to the amino hydrogen on the amide bond, the single hydrogen multiple peak near 3.93ppm corresponds to the methine group connected to the amino group on the serinol fragment, the multiple peak of four hydrogen at 3.75-3.86ppm corresponds to two methylene groups connected to the hydroxyl group on the serinol fragment, the single hydrogen triple peak at 3.40ppm corresponds to the methine group in the middle of two carbonyl groups, the broad peak of two hydrogen at 2.60ppm corresponds to two hydroxyl hydrogen on the serinol fragment, the double hydrogen triple peak at 2.55ppm corresponds to the methylene group adjacent to the carbonyl group, the two double hydrogen multiple peaks at 1.8ppm and 1.6ppm correspond to two methylene groups with two alkyl chains separated by one carbon from the carbonyl group, the broad peak of 16 hydrogen at 1.27ppm corresponds to the other methylene groups on two alkyl chains, and the hexahydro peak at 0.88ppm corresponds to two terminal methyl groups on two alkyl chains.
Example 2:
a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 28L of dichloromethane and 4.36kg of triethylamine (43.2mol) are added into a reaction kettle, 7kg of octanoyl chloride (43.2mol) is added dropwise under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the dropwise addition is finished and the stirring is carried out for 3 hours at 20 ℃.
(2) Adding 2.16kg serinol (23.8mol) into the reaction kettle in batches, keeping the reaction kettle at 20 ℃ for stirring for 8 hours after the addition is finished, adding 1mol/L diluted hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 10L saturated saline solution, concentrating to obtain a crude product, adding 7L acetone, stirring for dissolving, slowly adding 14L water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 4.05kg of a product (I), namely the agonist K6 PC-5.
Example 3:
a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 42L of dichloromethane and 5.23kg of triethylamine (51.8mol) are added into a reaction kettle, 7kg of octanoyl chloride (43.2mol) is added dropwise under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the dropwise addition is kept at 28 ℃ and stirred for 5 hours.
(2) Adding 2.55kg serinol (28.1mol) into the reaction kettle in batches, keeping the reaction kettle at 28 ℃ for stirring for 12 hours after the addition is finished, adding 1mol/L dilute hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 10L saturated saline solution, concentrating to obtain a crude product, adding 7L acetone, stirring for dissolving, slowly adding 14L water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 4.12kg of a product (I), namely the agonist K6 PC-5.
Claims (10)
1. A synthetic method of sphingosine kinase agonist K6PC-5 is characterized by comprising the following steps:
the method comprises the following specific steps:
(1) using octanoyl chloride as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III;
(2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5.
2. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of octanoyl chloride to triethylamine is 1: 1-1.2.
3. The synthesis method according to claim 2, wherein the molar ratio of octanoyl chloride to triethylamine is 1: 1.1.
4. The synthesis method according to claim 1, wherein in the step (1), the volume of the dichloromethane is 4-6 times that of the octanoyl chloride.
5. The method of claim 4, wherein the amount of dichloromethane used is 5 times the volume of octanoyl chloride.
6. The synthesis method according to claim 1, wherein in the step (1), the reaction conditions are as follows: reacting for 3-4h at room temperature.
7. The synthesis method according to claim 6, characterized in that the reaction conditions are: the reaction was carried out at 25 ℃ for 4 h.
8. The method of claim 1, wherein in step (2), the molar ratio of serinol to octanoyl chloride is 0.55-0.65: 1.
9. The method of claim 8, wherein the molar ratio of serinol to octanoyl chloride is 0.6: 1.
10. The synthesis method according to claim 1, wherein in the step (2), the reaction conditions are as follows: the reaction is carried out at room temperature for 8-12h, preferably at 25 ℃ for 10 h.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2828265A1 (en) * | 1978-06-28 | 1980-01-17 | Bayer Ag | Improving tolerance to anilide herbicides of crop plants - by treating with amide to as to improve selectivity of the herbicide |
| WO2001038289A1 (en) * | 1999-11-25 | 2001-05-31 | Neste Chemicals Oy | Method for acetoacetylation of nucleophilic compounds |
| US20060094790A1 (en) * | 2004-11-03 | 2006-05-04 | Park Byeong-Deog | Use of sphingosine kinase activator as skin disease treating agent and method for treating skin diseases using the same |
| WO2006049404A1 (en) * | 2004-11-03 | 2006-05-11 | Neopharm Co., Ltd. | Sphingosine kinase activator and skin disease treating agent comprising the same |
| US20200390671A1 (en) * | 2019-06-12 | 2020-12-17 | Neopharm Co., Ltd. | Cosmetic Composition for Inhibiting Sebum Hypersecretion |
| US20200392089A1 (en) * | 2019-06-12 | 2020-12-17 | Neopharm Co., Ltd. | Novel Amide Compounds and Use Thereof |
-
2021
- 2021-11-05 CN CN202111307864.4A patent/CN113861060B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2828265A1 (en) * | 1978-06-28 | 1980-01-17 | Bayer Ag | Improving tolerance to anilide herbicides of crop plants - by treating with amide to as to improve selectivity of the herbicide |
| WO2001038289A1 (en) * | 1999-11-25 | 2001-05-31 | Neste Chemicals Oy | Method for acetoacetylation of nucleophilic compounds |
| US20060094790A1 (en) * | 2004-11-03 | 2006-05-04 | Park Byeong-Deog | Use of sphingosine kinase activator as skin disease treating agent and method for treating skin diseases using the same |
| WO2006049404A1 (en) * | 2004-11-03 | 2006-05-11 | Neopharm Co., Ltd. | Sphingosine kinase activator and skin disease treating agent comprising the same |
| US20200390671A1 (en) * | 2019-06-12 | 2020-12-17 | Neopharm Co., Ltd. | Cosmetic Composition for Inhibiting Sebum Hypersecretion |
| US20200392089A1 (en) * | 2019-06-12 | 2020-12-17 | Neopharm Co., Ltd. | Novel Amide Compounds and Use Thereof |
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