CN112724096A - Preparation method of S-4-phenyl-2-oxazolidinone - Google Patents
Preparation method of S-4-phenyl-2-oxazolidinone Download PDFInfo
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- CN112724096A CN112724096A CN202110192333.9A CN202110192333A CN112724096A CN 112724096 A CN112724096 A CN 112724096A CN 202110192333 A CN202110192333 A CN 202110192333A CN 112724096 A CN112724096 A CN 112724096A
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- oxazolidinone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 11
- 239000011591 potassium Substances 0.000 claims abstract description 11
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- -1 inorganic base potassium carbonate Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 abstract description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 239000002360 explosive Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of S-4-phenyl-2-oxazolidinone, which comprises the following steps: reducing the compound 8 by potassium borohydride under an acidic condition to obtain a compound 9, and then cyclizing the compound 9 and diethyl carbonate under an alkaline condition to obtain a compound 10, namely the(s) -4-phenyl-2-oxazolidinone. The preparation method disclosed by the invention has the advantages that the raw materials are easy to obtain, the reaction conditions are mild, the steps are simple, flammable and explosive reagents are not used, the preparation method is suitable for large-scale industrial production, and the safety is high; and the reaction yield is higher and the cost is lower. Has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of synthesis of chemical intermediates of organic synthesis, and particularly relates to a preparation method of S-4-phenyl-2-oxazolidinone.
Background
The S-4-phenyl-2-oxazolidinone is a common organic medical intermediate, such as a key material of a lipid-lowering drug namely ezetimibe, and can also be used for synthesizing a pesticide intermediate and auxiliary macromolecules.
The currently disclosed preparation method of S-4-phenyl-2-oxazolidinone requires three steps for synthesis, and the synthetic route is as follows:
in the method, the synthesis steps are more, the reaction in the first step is violent, the control is not suitable, the yield of the final product is low, and the large-scale production cannot be realized.
In view of the good market prospects of S-4-phenyl-2-oxazolidinone, there is a need to develop new preparation methods for S-4-phenyl-2-oxazolidinone.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of S-4-phenyl-2-oxazolidinone aiming at the defects in the prior art, and the preparation method is mild in reaction conditions, simple in steps and capable of obtaining by one-step reduction.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of S-4-phenyl-2-oxazolidinone comprises the following specific processes:
a. reducing the compound 8 and a reducing agent potassium borohydride or sodium borohydride under an acidic condition to obtain a compound 9;
wherein compound 8 has the following structural formula:
wherein compound 9 has the following structural formula:
b. and cyclizing the compound 9 and diethyl carbonate under an alkaline condition to obtain the S-4-phenyl-2-oxazolidinone.
The molar ratio of the compound 8 to the reducing agent in the step a is 1: 2.0-2.6.
The acidic condition is an inorganic acid solution condition, and the alkaline condition is an inorganic alkali solution condition.
The inorganic acid is sulfuric acid, and the inorganic base is potassium carbonate.
The molar ratio of the compound 8 to the inorganic acid in the step a is 1:0.8-1.
The synthesis reaction of the step a is specifically as follows:
uniformly adding 10 batches of potassium borohydride and a compound 8 into a tetrahydrofuran system, wherein the mass ratio of the compound 8 to the tetrahydrofuran is 1:4.2, and slowly dropwise adding sulfuric acid at the temperature of 27-30 ℃, wherein the molar ratio of the compound 8 to the sulfuric acid is 1: 0.8-1.2; after the addition is finished, the system is kept at the temperature of 30-40 ℃ for 4h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding a sodium hydroxide aqueous solution with the mass concentration of 20% into the system, wherein the mass ratio of the compound 8 to the sodium hydroxide aqueous solution is 1:2.5, refluxing the system at 90-100 ℃ for 2h, stirring for reaction for 30min, naturally cooling to 65-70 ℃, standing for layering; the organic phase was collected, dried and concentrated under reduced pressure to give intermediate compound 9.
The synthesis reaction of the step b is specifically as follows:
adding potassium carbonate and a compound 9 into a toluene solvent system, wherein the mass ratio of the compound 9 to toluene is 1: 8, heating to 60-70 ℃ and stirring; the control system is that diethyl carbonate is slowly dripped at 70-75 ℃, wherein the molar ratio of the compound 9 to the diethyl carbonate is 1: 1, stirring and reacting for 1.5h under heat preservation after dripping is finished, distilling at normal pressure after heat preservation is finished, and cooling the system to below 40 ℃ after distillation is finished; adding a cyclization agent inorganic base potassium carbonate into a nitrogen replacement system in 5 batches under the protection of nitrogen, stirring and heating after the addition is finished, keeping the temperature at 90-100 ℃, refluxing for 30min, and cooling to below 40 ℃; wherein the molar ratio of compound 9 to potassium carbonate is 1: 0.2; acetic acid is dropwise added, and the mass ratio of the compound 9 to the acetic acid is 1: 0.15, and then dropwise adding water, wherein the mass ratio of the compound 9 to the water is 1: 3.3; cooling the system to below 10 ℃ after the addition, stirring for 1h, and filtering to obtain white solid S-4-phenyl-2-oxazolidinone.
The synthetic route is as follows:
the positive progress effects of the invention are as follows: the S-4-phenyl-2-oxazolidinone prepared by the invention has high reaction yield (about 83%), simple preparation method, easily obtained used raw materials, mild reaction conditions, simple steps, one-step reduction, easy operation, environmental friendliness, suitability for large-scale industrial production, high safety and wide application prospect.
Detailed Description
The following provides a detailed description of the preferred embodiments of the present invention.
Example 1
A process for the preparation of compound 9, wherein the reducing agent is potassium borohydride:
evenly dividing 10 batches of potassium borohydride (9.3 g) and a compound 8 (10 g) and putting the mixture into a tetrahydrofuran (42 g) system, and slowly dropwise adding sulfuric acid (8.0 g) at the temperature of 27 ℃; after the addition is finished, the system is kept at the temperature of 30 ℃ for 3h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding 25g of sodium hydroxide aqueous solution with the mass concentration of 20% into the system, refluxing the system at 100 ℃ for 2h, stirring for 30min, naturally cooling to 70 ℃, standing and layering; the organic phase was collected, dried and concentrated under reduced pressure to give the intermediate compound 9 in 85% yield.
Example 2
Preparation of compound 9, wherein the reducing agent is potassium borohydride:
evenly dividing 10 batches of potassium borohydride (93 g) and compound 8 (100 g) into tetrahydrofuran (420 g) of the system, and slowly dropwise adding sulfuric acid (80.0 g) at the temperature of the system being 30 ℃; after the addition is finished, the system is kept at the temperature of 35 ℃ for 3h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding 250g of sodium hydroxide aqueous solution with the mass concentration of 20% into the system, refluxing the system at 95 ℃ for 2h, stirring for 30min, naturally cooling to 70 ℃, standing and layering; the organic phase was collected, dried and concentrated under reduced pressure to give the intermediate compound 9 in 85% yield.
Example 3
Preparation of compound 9, wherein the reducing agent is potassium borohydride:
evenly dividing 10 batches of potassium borohydride (80 g) and compound 8 (100 g) into tetrahydrofuran (420 g) of the system, and slowly dropwise adding sulfuric acid (80.0 g) at the temperature of 27 ℃; after the addition is finished, the system is kept at 40 ℃ for 3h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding 250g of sodium hydroxide aqueous solution with the mass concentration of 20% into the system, refluxing the system at 90 ℃ for 2h, stirring for 30min, naturally cooling to 65 ℃, standing and layering; the organic phase was collected, dried and concentrated under reduced pressure to give intermediate compound 9 in 80% yield.
Example 4
Preparation of compound 9, wherein the reducing agent is sodium borohydride:
sodium borohydride (6.6 g) and a compound (8) (10 g) are alternately put into tetrahydrofuran (42 g) of a system, and sulfuric acid (9.6 g) is slowly added dropwise at the temperature of the system being 30 ℃; after the addition is finished, the system is kept at 40 ℃ for 3h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding 25g of sodium hydroxide aqueous solution with the mass concentration of 20% into the system, refluxing the system at 100 ℃ for 2h, stirring for 30min, naturally cooling to 65 ℃, standing and layering; the organic phase was collected, dried and concentrated under reduced pressure to give the intermediate compound 9 in 85% yield.
Example 5
Preparation of compound 9, wherein the reducing agent is sodium borohydride:
sodium borohydride (66 g) and a compound (8) (100 g) are alternately put into tetrahydrofuran (420 g) of a system, and sulfuric acid (80 g) is slowly added dropwise when the temperature of the system is 28 ℃; after the addition, the system is kept at the temperature of 30-40 ℃ for 3h, and the reaction is finished; cooling the system, dropwise adding 250g of sodium hydroxide aqueous solution with the mass concentration of 20% into the system, refluxing the system at 100 ℃ for 2h, stirring for 30min, naturally cooling to 70 ℃, standing and layering; the organic phase was collected, dried and concentrated under reduced pressure to give the intermediate compound 9 in 85% yield.
Example 6
Preparation of compound 10:
potassium carbonate (8.22 g) and compound 9 (10 g) were added to toluene (80 g) as a solvent, and the mixture was heated to 70 ℃ and stirred; slowly dripping 8.6g of diethyl carbonate at 75 ℃ in the system, preserving the temperature and stirring for reaction for 1.5h after dripping, carrying out normal pressure distillation after preserving the temperature, allowing an azeotrope of toluene and water to flow out when the internal temperature is 95 ℃, and cooling the system to below 40 ℃ after distillation; after replacing the system with nitrogen, adding potassium carbonate (2 g) in batches under the protection of nitrogen, stirring and heating after the addition is finished; refluxing at 100 deg.C for 30min, and cooling to below 40 deg.C; acetic acid (1.5 g) and water (33 g) were added dropwise; after the addition, the temperature of the system is reduced to below 10 ℃, the mixture is stirred for 1h, and the S-4-phenyl-2-oxazolidinone compound 10 is obtained after filtration, with the yield of 83 percent.
Example 7
Preparation of compound 10:
potassium carbonate (82.2 g) and compound 9 (100 g) were added to toluene (800 g) as a solvent, and the mixture was heated to 60 ℃ and stirred; slowly dripping 86g of diethyl carbonate at the temperature of 70 ℃ in the system, preserving the temperature, stirring and reacting for 1.5h after dripping, distilling at normal pressure after preserving the temperature, wherein an azeotrope of toluene and water flows out when the internal temperature is 95 ℃, and cooling the system to below 40 ℃ after distilling; after replacing the system with nitrogen, adding potassium carbonate (20 g) in batches under the protection of nitrogen, stirring and heating after the addition is finished; keeping the temperature at 90 ℃ for refluxing for 30min, and then cooling to below 40 ℃; dropwise adding acetic acid (15 g) and water (330 g); after the addition, the temperature of the system is reduced to below 10 ℃, the mixture is stirred for 1h, and the S-4-phenyl-2-oxazolidinone compound 10 is obtained after filtration, with the yield of 83 percent.
Claims (7)
1. A preparation method of S-4-phenyl-2-oxazolidinone is characterized by comprising the following specific processes:
a. reducing the compound 8 and a reducing agent potassium borohydride or sodium borohydride under an acidic condition to obtain a compound 9;
wherein compound 8 has the following structural formula:
wherein compound 9 has the following structural formula:
b. and cyclizing the compound 9 and diethyl carbonate under an alkaline condition to obtain the S-4-phenyl-2-oxazolidinone.
2. A process for the preparation of S-4-phenyl-2-oxazolidinone as defined in claim 1, wherein: the molar ratio of the compound 8 to the reducing agent in the step a is 1: 2.0-2.6.
3. A process for the preparation of S-4-phenyl-2-oxazolidinone as defined in claim 1 or 2, wherein: the acidic condition is an inorganic acid solution condition, and the alkaline condition is an inorganic alkali solution condition.
4. A process for the preparation of S-4-phenyl-2-oxazolidinone as defined in claim 3, wherein: the inorganic acid is sulfuric acid, and the inorganic base is potassium carbonate.
5. A process for the preparation of S-4-phenyl-2-oxazolidinone as claimed in claim 1 or 4, wherein: the molar ratio of the compound 8 to the inorganic acid in the step a is 1: 0.8-1.2.
6. A process for the preparation of S-4-phenyl-2-oxazolidinone as defined in claim 5, wherein: the synthesis reaction of the step a is specifically as follows:
uniformly adding 10 batches of potassium borohydride and a compound 8 into a tetrahydrofuran system, wherein the mass ratio of the compound 8 to the tetrahydrofuran is 1:4.2, and slowly dropwise adding sulfuric acid at the temperature of 27-30 ℃, wherein the molar ratio of the compound 8 to the sulfuric acid is 1: 0.8-1.2; after the addition is finished, the system is kept at the temperature of 30-40 ℃ for 4h, and the reaction is finished; cooling the system to 10 ℃, dropwise adding a sodium hydroxide aqueous solution with the mass concentration of 20% into the system, wherein the mass ratio of the compound 8 to the sodium hydroxide aqueous solution is 1:2.5, refluxing the system at 90-100 ℃ for 2h, stirring for reaction for 30min, naturally cooling to 65-70 ℃, standing for layering; the organic phase was collected, dried and concentrated under reduced pressure to give intermediate compound 9.
7. A process for the preparation of S-4-phenyl-2-oxazolidinone as defined in claim 6, wherein: the synthesis reaction of the step b is specifically as follows:
adding potassium carbonate and a compound 9 into a toluene solvent system, wherein the mass ratio of the compound 9 to toluene is 1: 8, heating to 60-70 ℃ and stirring; the control system is that diethyl carbonate is slowly dripped at 70-75 ℃, wherein the molar ratio of the compound 9 to the diethyl carbonate is 1: 1, stirring and reacting for 1.5h under heat preservation after dripping is finished, distilling at normal pressure after heat preservation is finished, and cooling the system to below 40 ℃ after distillation is finished; adding a cyclization agent inorganic base potassium carbonate into a nitrogen replacement system in 5 batches under the protection of nitrogen, stirring and heating after the addition is finished, keeping the temperature at 90-100 ℃, refluxing for 30min, and cooling to below 40 ℃; wherein the molar ratio of compound 9 to potassium carbonate is 1: 0.2; acetic acid is dropwise added, and the mass ratio of the compound 9 to the acetic acid is 1: 0.15, and then dropwise adding water, wherein the mass ratio of the compound 9 to the water is 1: 3.3; cooling the system to below 10 ℃ after the addition, stirring for 1h, and filtering to obtain white solid S-4-phenyl-2-oxazolidinone.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151258A (en) * | 2014-08-26 | 2014-11-19 | 江苏万年长药业有限公司 | Method and apparatus for recycling tetrahydrofuran solvent during reduction reaction of L-phenylglycinol |
| CN104744390A (en) * | 2015-03-19 | 2015-07-01 | 南京师范大学 | Preparation method of ezetimibe internmediate ketone |
| US20150336943A1 (en) * | 2013-01-07 | 2015-11-26 | Pierre Fabre Medicament | Novel benzodioxane-piperidine derivatives and their therapeutic applications for treating neuropsychiatric disorders |
| CN108484419A (en) * | 2018-05-04 | 2018-09-04 | 江苏万年长药业有限公司 | The improved method of hydrolysis process in a kind of L- benzene glycinol preparation process |
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2021
- 2021-02-20 CN CN202110192333.9A patent/CN112724096A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150336943A1 (en) * | 2013-01-07 | 2015-11-26 | Pierre Fabre Medicament | Novel benzodioxane-piperidine derivatives and their therapeutic applications for treating neuropsychiatric disorders |
| CN104151258A (en) * | 2014-08-26 | 2014-11-19 | 江苏万年长药业有限公司 | Method and apparatus for recycling tetrahydrofuran solvent during reduction reaction of L-phenylglycinol |
| CN104744390A (en) * | 2015-03-19 | 2015-07-01 | 南京师范大学 | Preparation method of ezetimibe internmediate ketone |
| CN108484419A (en) * | 2018-05-04 | 2018-09-04 | 江苏万年长药业有限公司 | The improved method of hydrolysis process in a kind of L- benzene glycinol preparation process |
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| Title |
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| ATSUSHI ABIKO ET AL.: "An Improved, Convenient Procedure for Reduction of Amino Acids to Aminoalcohols：Use of NaBH4-H2SO4" * |
| DANIELE ZAMPIERI ET AL.: "Computer-assis ted de sign, synthesis , binding and cytotoxicity assessmen ts of new 1-(4-(aryl(methyl ) amino)butyl)-heterocyclic sigma 1 ligands" * |
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Application publication date: 20210430 |