CN112500361B - Preparation method of (S) -4-phenyl-2-oxazolidinone - Google Patents
Preparation method of (S) -4-phenyl-2-oxazolidinone Download PDFInfo
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- CN112500361B CN112500361B CN202011572054.7A CN202011572054A CN112500361B CN 112500361 B CN112500361 B CN 112500361B CN 202011572054 A CN202011572054 A CN 202011572054A CN 112500361 B CN112500361 B CN 112500361B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 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 title description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 18
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 18
- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 9
- 229910000085 borane Inorganic materials 0.000 claims abstract description 9
- 229920001021 polysulfide Polymers 0.000 claims abstract description 9
- 239000005077 polysulfide Substances 0.000 claims abstract description 9
- 150000008117 polysulfides Polymers 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 10
- FSRZPRRAZVZKFE-UHFFFAOYSA-N tert-butyl n-(2-hydroxy-2-phenylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC(O)C1=CC=CC=C1 FSRZPRRAZVZKFE-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- OJOFMLDBXPDXLQ-VIFPVBQESA-N (4s)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-VIFPVBQESA-N 0.000 claims description 3
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 claims description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical group [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- LVIJIGQKFDZTNC-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidine-2-thione Chemical compound C1OC(=S)N[C@H]1C1=CC=CC=C1 LVIJIGQKFDZTNC-MRVPVSSYSA-N 0.000 claims 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 231100000433 cytotoxic Toxicity 0.000 abstract description 3
- 230000001472 cytotoxic effect Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
-
- 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
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- 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 for synthesizing (S) -4-phenyl-2-oxazolidone, belonging to the technical field of organic synthesis. N-Boc-L-phenylglycine is reduced by a borane reagent to obtain N-Boc-L-phenylglycine alcohol, and then the N-Boc-L-phenylglycine alcohol is subjected to ring closure reaction under the action of a catalyst to obtain (S) -4-phenyl-2-oxazolidone. The product can be reacted with sulfur powder and ammonium sulfide or ammonium polysulfide to obtain (S) -4-phenyl oxazolidine-2-thioketone. The method avoids the use of cytotoxic reagents or solvents, has the advantages of easily available raw materials, simple and convenient operation and the like, accords with green chemistry, and has potential industrial amplification prospect.
Description
Technical Field
The invention relates to a preparation method of (S) -4-phenyl-2-oxazolidone, belonging to the technical field of organic synthesis.
Background
The (S) -4-phenyl-2-oxazolidinone and CAS 99395-88-7 mainly act on asymmetric chiral organic amine reaction, are widely applied to the field of medicine, are important medical intermediates, and have good chiral induction effects in asymmetric alkylation, aldol condensation and conjugate addition in the aspect of organic synthesis. Meanwhile, the structural compound has biological activities of sterilization, disinsection and spasmolysis, can be used as an anti-inflammatory analgesic active pharmacophore, has important application in the fields of pesticides, medicines, dyes, metal rust removal and the like, and has a certain development prospect. Meanwhile, the sulfur atom in the (S) -4-phenyl oxazolidine-2-thioketone which is a further derivative has good lipophilicity in terms of biological membranes and can reach the inside of cells quickly.
The synthesis literature of (S) -4-phenyl-2-oxazolidinone is relatively more reported, however (S) -4-phenyl oxazolidinone-2-thione is mainly prepared by heating L-phenylglycine alcohol, carbon disulfide and hydrogen peroxide under alkaline conditions to react to obtain the product. The hydrogen peroxide is strongly released in the process of adding the hydrogen peroxide into the system, and simultaneously the reaction uses carbon disulfide with cytotoxicity, which is volatile and has strong toxicity, thereby being unfavorable for the large-scale production.
Therefore, it is necessary to conduct intensive research on the synthesis process of (S) -4-phenyl-2-oxazolidinone and its derivative (S) -4-phenyl-oxazolidinone-2-thioketone, avoid using carbon disulfide or expensive Lawson reagent, and provide a reaction route which is more economical, mild in reaction, safe and stable, advocates green chemistry, so as to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method for synthesizing (S) -4-phenyl-2-oxazolidone. N-Boc-L-phenylglycine is reduced by a borane reagent to obtain N-Boc-L-phenylglycine alcohol, and then the N-Boc-L-phenylglycine alcohol is subjected to ring closure reaction under the action of a catalyst to obtain (S) -4-phenyl-2-oxazolidone. (S) -4-phenyl-2-oxazolidinone is reacted with sulfur powder and ammonium sulfide or ammonium polysulfide to obtain (S) -4-phenyl-2-oxazolidinone. The method avoids the use of cytotoxic reagents or solvents, has the advantages of easily available raw materials, simple and convenient operation and the like, accords with green chemistry, and has potential industrial amplification prospect.
The preparation method of the (S) -4-phenyl-2-oxazolidone comprises the following steps:
adding N-Boc-L-phenylglycine into an organic solvent, adding a borane reagent for reduction, adding sulfolane and a catalyst after the reaction is finished, and heating for reaction to obtain (S) -4-benzyl-2-oxazolidone;
further, in the above technical scheme, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran, preferably tetrahydrofuran.
Further, in the above technical scheme, the borane reagent is selected from borane-tetrahydrofuran (BH 3 THF, 1.0M) or borane-dimethyl sulfide (BH 3 -Me 2 S, 10M), preferably BH 3 -THF; the reaction temperature is selected from 0-25 ℃.
Further, in the above technical scheme, the molar ratio of the N-Boc-L-phenylglycine to the borane reagent is 1:2-4.5.
Further, in the above technical scheme, the catalyst in the second step is selected from potassium tert-butoxide or sodium tert-butoxide.
Further, in the technical scheme, in the second step, the molar ratio of the N-Boc-L-phenylglycinol to the catalyst is 1:1.0-2.0, and the reaction is carried out at room temperature. When the reaction is carried out under reduced pressure distillation conditions, the same reaction effect can be achieved by using 0.05 to 0.15 equivalent of the catalyst (relative to N-Boc-L-phenylglycinol).
The invention further provides a preparation method of the (S) -4-phenyloxazolidine-2-thioketone, which comprises the following steps:
by adopting the preparation method, the (S) -4-phenyl-2-oxazolidone is obtained, and then the (S) -4-benzyl-2-oxazolidone is mixed with sulfur powder and ammonium sulfide or ammonium polysulfide for reaction to obtain the (S) -4-phenyl-2-oxazolidone.
Further, in the above technical scheme, the sulfur powder is selected from high-purity sulfur or sulfur riser, wherein the sulfur riser reacts with an aqueous solution of ammonium sulfide or a combination of high-purity sulfur and ammonium polysulfide.
Further, in the above technical scheme, the molar ratio of (S) -4-benzyl-2-oxazolidinone, sulfur powder, ammonium sulfide or ammonium polysulfide is 1:1-1.15:1-1.25, and the reaction temperature is 40-50 ℃.
Advantageous effects of the invention
The method has mild reaction, and after borane is reduced, the oxazolidinone is directly generated by ring closure under the condition of a catalyst, so that the operation is simpler, more convenient and more efficient. Then changing the C=O group into the C=S group under the conditions of sulfur powder, ammonium sulfide and the like. The whole process avoids using inflammable and explosive or cytotoxic reagents such as lithium aluminum hydride or carbon disulfide and Lawsen reagent, accords with the development of green chemistry, and is suitable for industrial scale-up production. The synthesis yield of the (S) -4-phenyl oxazolidine-2-thioketone is up to more than 70%, and the purity is up to more than 99.0%.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Mixing 50g (0.199 mol) of N-Boc-L-phenylglycine with 100mL of tetrahydrofuran under the protection of nitrogen, cooling to 0 ℃ and dropwise adding (BH) at 0-20 ℃ under the control of the temperature 3 -THF, 1.0M) 600mL, after the addition was completed, stirring was continued for 2 hours until TLC detected complete reaction of starting materials. Cooling the reaction solution to about-10 ℃, slowly dropwise adding methanol, quenching the reaction, when no bubble overflows, heating to room temperature, continuously stirring for 1 hour, then distilling under reduced pressure to generate trimethyl borate and tetrahydrofuran solvent, distilling until no liquid flows, adding heptane/MTBE (6/1, 185 mL), pulping to obtain 45.0g of N-Boc-L-phenylglycinol, and performing HPLC:97.6 percent and the yield is 95.3 percent. 1 HNMR(400MHz,CDCl 3 ):7.43-7.01(m,5H),5.25(s,1H),4.76-4.72(m,1H),4.01-3.65(m,2H),2.08(s,1H),1.42(s,9H)。
45.0g (0.190 mol) of N-Boc-L-phenylglycinol and 300mL of tetrahydrofuran were mixed under nitrogen atmosphere and separated23.0g of potassium tert-butoxide (0.205 mol) was added in portions and reacted at 25-30℃for 10 hours, and the completion of the reaction was detected by sampling TLC. After evaporating the solvent, ethyl acetate and a water layer were added, saturated brine was used for washing, the organic phase was concentrated to a non-flowing liquid, 100g of ethyl acetate was added for heating to reflux, 50mL of isopropyl ether was added dropwise, and the mixture was recrystallized to give 27.1g of (S) -4-phenyl-2-oxazolidinone, HPLC:99.6% and yield 87.7%. 1 HNMR(400MHz,CDCl 3 ):7.43-7.33(m,5H),6.12(s,1H),4.99-4.94(m,1H),4.76-4.17(m,1H),4.20-4.16(m,1H)。
Example 2
Mixing 50g (0.199 mol) of N-Boc-L-phenylglycine with 200mL of 2-methyltetrahydrofuran under the protection of nitrogen, cooling to 0 ℃ and dropwise adding (BH) at 0-20 ℃ under the control of the temperature 3 -Me 2 S, 10M) 60mL, stirring was continued for 2 hours until TLC detected complete reaction of starting material. The reaction solution is cooled to about minus 10 ℃, methanol is slowly added dropwise, the quenching reaction is carried out, when no bubble overflows, the reaction solution is heated to room temperature and is continuously stirred for 1 hour, then trimethyl borate, dimethyl sulfide and 2-methyltetrahydrofuran solvent are generated by reduced pressure distillation, the reaction solution is distilled to no fluid, heptane/MTBE (6/1, 205 mL) is added, and pulping is carried out to obtain 45.4g of N-Boc-L-phenylglycinol, HPLC:95.8% and 96.1% yield.
45g (0.190 mol) of N-Boc-L-phenylglycinol and 200mL of 2-methyltetrahydrofuran are mixed under the protection of nitrogen, 23.1g of sodium tert-butoxide (0.240 mol) is added in portions, the mixture is reacted for 3 hours at 25-30 ℃, and the reaction is detected to be complete by sampling TLC. After evaporating the solvent, ethyl acetate and a water layer were added, saturated brine was used for washing, the organic phase was concentrated to a non-flowing liquid, 100g of ethyl acetate was added for heating to reflux, 50mL of isopropyl ether was added dropwise, and 26.1g of (S) -4-phenyl-2-oxazolidinone was obtained by recrystallization, HPLC:99.6% and yield 84.2%.
Example 3
Mixing 50g (0.199 mol) of N-Boc-L-phenylglycine with 100mL of tetrahydrofuran under the protection of nitrogen, cooling to 0 ℃ and dropwise adding (BH) at 0-20 ℃ under the control of the temperature 3 -THF, 1.0M) 600mL, after the addition was completed, stirring was continued for 2 hours until TLC detected complete reaction of starting materials. Cooling the reaction solution to about-10 ℃, slowly dropwise adding methanol, quenching the reaction, when no bubble overflows, heating to room temperature, continuously stirring for 1 hour, then distilling under reduced pressure to generate trimethyl borate and tetrahydrofuran solvent, distilling until no liquid flows, adding heptane/MTBE (6/1, 185 mL), pulping to obtain 45.0g of N-Boc-L-phenylglycinol, and performing HPLC:97.6 percent and the yield is 95.3 percent.
In a reaction flask equipped with a distillation apparatus, 45.0g (0.190 mol) of N-Boc-L-phenylglycinol and 150mL of sulfolane were added, and after stirring uniformly, 3.3g of potassium tert-butoxide (29.4 mmol) was further added, followed by heating to 90-100℃until no more tert-butanol was distilled off (about 1.2 hours), and the reaction was completed by sampling TLC. Ethyl acetate and water were added and the layers were separated, the organic layer was washed three times with water, saturated brine, the organic phase was concentrated to no-flow, 100g of ethyl acetate was added and warmed to reflux, 50mL of isopropyl ether was added dropwise, and recrystallized to give (S) -4-phenyl-2-oxazolidinone 28.5g, hplc:99.3% and 92.1% yield.
Example 4
Under the protection of nitrogen, 25g (0.153 mol) of (S) -4-phenyl-2-oxazolidone and 5.2g (0.161 mol) of high-purity sulfur are put into a reaction bottle, 87.8g (0.161 mol) of 30% ammonium polysulfide aqueous solution is dripped at room temperature, after the dripping is finished, the temperature is raised to 40-50 ℃ for reaction for 8 hours, and the sampling raw material is less than 0.5%. The reaction mixture was cooled to room temperature and then filtered, water and MTBE were added to the filtrate, the layers were separated, the aqueous phase was extracted once more with MTBE, MTBE was combined, concentrated and recrystallized by adding n-heptane/ethyl acetate (6/1) at elevated temperature, filtered and dried to give (S) -4-phenyl-2-oxazolethione 25.2g, HPLC:99.2% and 91.6% yield. 1 HNMR(400MHz,CDCl 3 ):8.17(s,1H),7.43-7.33(m,5H),5.13-5.09(m,1H),4.99-4.94(m,1H),4.38-4.34(m,1H)。
Example 5
Under the protection of nitrogen, 25g (0.153 mol) of (S) -4-phenyl-2-oxazolidone solution and 5.3g (0.164 mol) of sublimate are put into a reaction bottle, 21.1g (0.164 mol) of 53% ammonium sulfide aqueous solution is added dropwise at room temperature, after the addition, the temperature is raised to 40-50 ℃ for reaction for 15 hours, and the sampling raw material is less than 0.5%. The reaction mixture was cooled to room temperature, water and MTBE were added after filtration, the layers were separated, the aqueous phase was extracted once more with MTBE, MTBE was combined, concentrated and recrystallized by adding n-heptane/ethyl acetate (6/1) at elevated temperature, filtered and dried to give (S) -4-phenyl-2-oxazolidinone 24.4g, HPLC:99.1% and 88.7% yield.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (8)
1. A preparation method of (S) -4-phenyloxazolidine-2-thioketone is characterized by comprising the following steps: the first step, adding N-Boc-L-phenylglycine into an organic solvent, and adding a borane reagent for reduction to obtain an intermediate N-Boc-L phenylglycine; secondly, reacting an intermediate L-phenylglycine alcohol in the presence of a catalyst to obtain (S) -4-benzyl-2-oxazolidone; the catalyst is selected from potassium tert-butoxide or sodium tert-butoxide; and thirdly, mixing the (S) -4-benzyl-2-oxazolidinone with sulfur powder and ammonium sulfide or ammonium polysulfide for reaction to obtain the (S) -4-phenyloxazolidinone-2-thione, wherein the reaction temperature of the step is 40-50 ℃.
2. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: in the first step, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is selected from 0-25 ℃.
3. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: the borane reagent is selected from borane tetrahydrofuran or borane dimethyl sulfide.
4. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: in the first step, the molar ratio of the N-Boc-L-phenylglycine to the borane reagent is 1:2-4.5.
5. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: in the second step, the molar ratio of N-Boc-L-phenylglycinol to the catalyst is 1:1.0-2.0, the reaction temperature is room temperature.
6. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: in the second step, the molar ratio of N-Boc-L-phenylglycinol to the catalyst is 1:0.05-0.15, and the reaction adopts reduced pressure distillation.
7. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: the sulfur powder is selected from high purity sulfur or sublimed sulfur, wherein the sublimed sulfur reacts with an aqueous ammonium sulfide solution or high purity sulfur reacts with ammonium polysulfide.
8. The process for the preparation of (S) -4-phenyloxazolidine-2-thione according to claim 1, wherein: the molar ratio of the (S) -4-benzyl-2-oxazolidinone, sulfur powder, ammonium sulfide or ammonium polysulfide is 1:1-1.15:1-1.25.
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