CN113861060B - Synthesis method of sphingosine kinase agonist - Google Patents
Synthesis method of sphingosine kinase agonist Download PDFInfo
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- CN113861060B CN113861060B CN202111307864.4A CN202111307864A CN113861060B CN 113861060 B CN113861060 B CN 113861060B CN 202111307864 A CN202111307864 A CN 202111307864A CN 113861060 B CN113861060 B CN 113861060B
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- k6pc
- octanoyl chloride
- intermediate iii
- agonist
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- 239000000556 agonist Substances 0.000 title claims abstract description 18
- 108010035597 sphingosine kinase Proteins 0.000 title claims abstract description 14
- 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
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 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
- 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 18
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 claims abstract description 18
- 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 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000010189 synthetic method Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000005580 one pot 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 10
- 239000001257 hydrogen Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 150000002431 hydrogen Chemical class 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
- 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
- -1 amino hydrogen Chemical compound 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 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
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 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
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 206010061363 Skeletal injury Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect 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
- 230000001276 controlling effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 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
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 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
- 238000005406 washing Methods 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- 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 synthesis method of a sphingosine kinase agonist K6PC-5, which belongs to the technical field of organic synthesis, and comprises the following specific steps: (1) Octanoyl chloride (compound II) is used as a raw material, and reacts in dichloromethane under the action of triethylamine to obtain an intermediate III; (2) Intermediate III is reacted with serinol to give compound I, the agonist K6PC-5. The synthesis method provided by the invention is simple to operate, economical and efficient, and can be used for large-scale production, and the use of a one-pot method avoids excessive exposure to air after the intermediate III is formed, reduces the possibility of deterioration of the intermediate III, and ensures that 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 a sphingosine kinase agonist K6PC-5.
Background
Sphingosine kinases (sphingosine kinases, sphKs) 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 are involved in regulating various physiological functions such as cell proliferation and apoptosis, vasoconstriction and remodeling, inflammation and metabolism. K6PC-5 is a novel non-natural ceramide with agonism to sphingosine kinase 1, which can effectively enhance the generation of sphingosine-1-phosphate, control the proliferation and differentiation of keratinocytes, the proliferation of fibroblasts and the synthesis of collagen, thereby treating skin wounds, improving wrinkles and inhibiting skin aging. In addition, K6PC-5 has been reported to have a certain effect as a sphingosine kinase agonist in inhibiting Ebola virus infection in endothelial cells against glucocorticoid-related bone injury and in resisting tumors.
Disclosure of Invention
The invention aims at solving the blank existing in the prior art and provides a one-pot synthesis method of a sphingosine kinase agonist K6PC-5. The synthesis method of the invention has high efficiency and high yield, and is suitable for large-scale industrial production.
The technical scheme adopted by the invention is as follows:
a synthesis method of a sphingosine kinase agonist K6PC-5 is carried out according to the following flow:
the method comprises the following specific steps:
(1) Octanoyl chloride (compound II) is used as a raw material, and reacts in dichloromethane under the action of triethylamine to obtain an intermediate III;
(2) Intermediate III is reacted with serinol to give compound I, the agonist K6PC-5.
In the step (1), the molar 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 usage of dichloromethane is 4-6 times of octanoyl chloride; preferably, the volume amount of dichloromethane is 5 times that 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 4h.
In the step (2), the molar ratio of the serinol to the 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; preferably at 25℃for 10h.
The beneficial technical effects of the invention are as follows:
the method provides a synthetic method for K6PC-5, which is simple to operate, economical and efficient, can be used for large-scale production, is poor in stability of the intermediate III under the conventional condition, is easy to react with water and nucleophilic reagent to deteriorate, affects the purity and yield of products, avoids excessive exposure to air after the intermediate III is formed, reduces the possibility of deterioration, and ensures that the whole operation is safe, reliable, rapid and efficient. This method has been applied to scale-up production.
Drawings
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the agonist K6PC-5 prepared in example 1 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the drawings and examples.
Example 1:
a synthesis method of a sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 350L of dichloromethane and 48kg of triethylamine (475 mol) were added to the reaction vessel, 70kg of octanoyl chloride (432 mol) was added dropwise under the protection of nitrogen, and the mixture was stirred at 25℃for 4 hours to obtain a reaction solution containing an intermediate III.
(2) Adding 24kg of serinol (263 mol) into the reaction kettle in batches, stirring for 10 hours at 25 ℃ after the addition, adding 1mol/L of diluted hydrochloric acid, regulating the pH to 3-5 after the reaction, standing for layering, removing the water phase, washing the organic phase once by 100L of saturated saline water, 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 the product (I), namely the agonist K6PC-5.
As shown in FIG. 1, the nuclear magnetic resonance hydrogen spectrum of the obtained product is shown in FIG. 1, wherein the chemical shift of the single hydrogen double peak corresponds to the amino hydrogen on the amide bond, the single hydrogen multiple peak near 3.93ppm corresponds to the methine connected with the amino group on the serinol segment, the four hydrogen multiple peaks at 3.75-3.86ppm correspond to the two methylene groups connected with the hydroxyl group on the serinol segment, the single hydrogen triple peak at 3.40ppm corresponds to the methine in the middle of the two carbonyl groups, the two hydrogen triple peak at 2.60ppm corresponds to the two hydroxyl hydrogen on the serinol segment, the dihydro triple peak at 2.55ppm corresponds to the methylene group adjacent to the alkyl chain and the carbonyl group, the two dihydro multiple peaks at 1.8ppm and 1.6ppm correspond to the two methylene groups separated by one carbon from the two alkyl chains, the 16 hydrogen triple peak at 1.27ppm corresponds to the other methylene groups on the two alkyl chains, and the hexahydro peak at 0.88ppm corresponds to the two methyl groups at the three ends on the two alkyl chains.
Example 2:
a synthesis method of a sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 28L of methylene chloride, 4.36kg of triethylamine (43.2 mol) and 7kg of octanoyl chloride (43.2 mol) were added dropwise under the protection of nitrogen, and the mixture was stirred at 20℃for 3 hours to obtain a reaction solution containing an intermediate III.
(2) 2.16kg of serinol (23.8 mol) is added into the reaction kettle in batches, stirring is carried out for 8 hours at 20 ℃ after the addition, 1mol/L of diluted hydrochloric acid is added after the reaction is finished, the pH is regulated to 3-5, the reaction kettle is kept stand for layering, the water phase is removed, the organic phase is washed once by 10L of saturated saline water, the concentration is carried out to obtain a crude product, 7L of acetone is added, stirring and dissolving are carried out, 14L of water is slowly added, crystallization is carried out at the temperature of 0-5 ℃, filtering and drying are carried out, and 4.05kg of the product (I) is obtained, namely the agonist K6PC-5.
Example 3:
a synthesis method of a sphingosine kinase agonist K6PC-5 comprises the following specific steps:
(1) 42L of methylene chloride, 5.23kg of triethylamine (51.8 mol) and 7kg of octanoyl chloride (43.2 mol) were added dropwise under nitrogen protection, and the mixture was stirred at 28℃for 5 hours to obtain a reaction solution containing intermediate III.
(2) 2.55kg of serinol (28.1 mol) is added into the reaction kettle in batches, the mixture is stirred for 12 hours at the temperature of 28 ℃ after the addition, 1mol/L of diluted hydrochloric acid is added after the reaction is finished, the pH is regulated to 3-5, the mixture is kept stand for layering, the water phase is removed, the organic phase is washed once by 10L of saturated saline water, the mixture is concentrated to obtain a crude product, 7L of acetone is added, the mixture is stirred and dissolved, 14L of water is slowly added, the temperature is controlled to be 0-5 ℃ for crystallization, the mixture is filtered and dried to obtain 4.12kg of the product (I), namely the agonist K6PC-5.
Claims (9)
1. A synthesis method of a sphingosine kinase agonist K6PC-5, which is characterized by comprising the following steps of:
the method comprises the following specific steps:
(1) Octanoyl chloride is used as a raw material, and reacts in dichloromethane under the action of triethylamine to obtain an intermediate III;
(2) Reacting the intermediate III with serinol to obtain a compound I, namely the agonist K6PC-5;
in the step (1), the molar ratio of octanoyl chloride to triethylamine is 1:1-1.2;
in the step (2), the molar ratio of the serinol to the octanoyl chloride is 0.55-0.65:1.
2. The method of claim 1, wherein the molar ratio of octanoyl chloride to triethylamine is 1:1.1.
3. The process according to claim 1, wherein in step (1), the volume amount of dichloromethane is 4 to 6 times that of octanoyl chloride.
4. A synthetic method according to claim 3, characterized in that the volume amount of dichloromethane is 5 times that of octanoyl chloride.
5. The synthetic method of claim 1 wherein in step (1), the reaction conditions are: the reaction is carried out for 3 to 4 hours at room temperature.
6. The synthetic method according to claim 5, wherein the reaction conditions are: the reaction was carried out at 25℃for 4h.
7. The synthesis according to claim 1, wherein the molar ratio of serinol to octanoyl chloride is 0.6:1.
8. The synthetic method of claim 1 wherein in step (2), the reaction conditions are: the reaction is carried out for 8 to 12 hours at room temperature.
9. The synthetic method of claim 8 wherein the reaction conditions are: the reaction was carried out at 25℃for 10 hours.
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Citations (3)
| 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 |
| WO2006049404A1 (en) * | 2004-11-03 | 2006-05-11 | Neopharm Co., Ltd. | Sphingosine kinase activator and skin disease treating agent comprising the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100607438B1 (en) * | 2004-11-03 | 2006-08-02 | (주)네오팜 | Skin disease treating agent containing sphingosine kinase activator |
| KR102043291B1 (en) * | 2019-06-12 | 2019-11-12 | (주)네오팜 | Cosmetic composition for inhibiting of sebum hypersecretion |
| KR102043294B1 (en) * | 2019-06-12 | 2019-11-12 | (주)네오팜 | Novel amide compounds and use thereof |
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Patent Citations (3)
| 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 |
| WO2006049404A1 (en) * | 2004-11-03 | 2006-05-11 | Neopharm Co., Ltd. | Sphingosine kinase activator and skin disease treating agent comprising the same |
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