CN102746250B - The preparation method of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide - Google Patents
The preparation method of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide Download PDFInfo
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- CN102746250B CN102746250B CN201210256215.0A CN201210256215A CN102746250B CN 102746250 B CN102746250 B CN 102746250B CN 201210256215 A CN201210256215 A CN 201210256215A CN 102746250 B CN102746250 B CN 102746250B
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- morpholinyl
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- -1 fluoro-4-morpholinyl Chemical group 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 16
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 14
- ABCGRFHYOYXEJV-UHFFFAOYSA-N 4-methylisoindole-1,3-dione Chemical compound CC1=CC=CC2=C1C(=O)NC2=O ABCGRFHYOYXEJV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000007098 aminolysis reaction Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 abstract description 12
- 229960003907 linezolid Drugs 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 238000007605 air drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to medicinal chemistry art, be specifically related to the preparation method of a kind of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, its preparation method is: by (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, methylamine solution and solvent at room temperature join in there-necked flask, direct backflow aminolysis 2 ~ 16h, obtained product, wherein solvent is methyl alcohol, acetonitrile, Virahol, N, dinethylformamide, 1, 4-dioxane, one or more mixing in acetone or propyl carbinol.Grasp its reaction conditions, the preparation condition of Linezolid can have been controlled better, thus can be reduced it produced in Linezolid preparation process, improve the yield of Linezolid.
Description
The invention belongs to medicinal chemistry art, be specifically related to the impurity produced in a kind of Linezolid preparation process---the preparation method of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide.
Background technology
Disclose the preparation method of Linezolid in patent CN1130379A, wherein the final step of a kind of preparation method is such as formula I.Verify by experiment, the reaction of this step can produce a kind of impurity, and its chemical formula is such as formula II, and name is called N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide.This impurity can be mixed in the finished product, therefore studies its preparation method, understands its reaction conditions, has important realistic meaning to the quality product controlling Linezolid.
Summary of the invention
The invention reside in the preparation method providing a kind of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, to control quality and the productive rate of Linezolid product.
The present invention has prepared N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, chemical formula such as formula II,
Its preparation method is: by (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, methylamine solution and solvent at room temperature join in there-necked flask, direct backflow aminolysis 2 ~ 16h, obtained product, wherein solvent is methyl alcohol, acetonitrile, Virahol, N, one or more mixing in dinethylformamide, Isosorbide-5-Nitrae-dioxane, acetone or propyl carbinol.
Wherein, the preferred reaction times is 2 ~ 8h.
(S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] mol ratio of methyl phthalimide and methylamine solution is preferably 1:5 ~ 20, wherein methylamine solution is in solid content, and methylamine solution is aqueous methylamine solution or methylethylolamine solution.
(S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] ratio of methyl phthalimide and solvent is preferably 1g:3 ~ 15ml.
Beneficial effect of the present invention is:
N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] the methyl]-2-methylamino--benzamide prepared, for the major impurity in Linezolid preparation process, grasp the reaction conditions of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, the preparation condition of Linezolid can be controlled better, thus N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide can be reduced produce in Linezolid preparation process, improve the yield of Linezolid.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrum of embodiment 1 gained Linezolid impurity.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
By 18.390g (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, the methylethylolamine solution of 74ml40%, 80ml methyl alcohol and 110ml Virahol join in 500ml there-necked flask, stirs into suspension; Heating, back flow reaction 6h, obtains yellow clear solution; 50 DEG C remove solvent under reduced pressure, obtain lurid solid; Add 300ml acetone and 300ml purified water, stir 10min; Filter, collect filter cake, and forced air drying at 50 DEG C, obtain white solid 8.296g, yield is 42.05%.This test, by the control to agents useful for same and reflux time, makes the yield of N-in reaction product [[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide improve.
Hydrogen spectrum (solvent is dimethyl sulfoxide (DMSO)) data of obtained N-[[3-(3-fluoro-4-morpholinyl-4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide are as follows:
1H-NMR(DMSO-d
6，600MHz)2.70(d，3H，-CH
3)，2.96(t，4H，-CH
2NCH
2-)，3.52～3.62(m，2H，-CH
2NH-)，3.73(t，4H，-CH
2OCH
2-)3.98(dd，1H，4-H)，4.08(t，1H，4-H)，4.80(m，1H，5-H)，7.07(t，1H，-NH-)，7.26(dd，1H，-NHCH
3)，7.40(dd，1H，-Ar)，7.44～7.53(m，4H，-Ar)，8.25(dd，1H，-Ar)，8.64(t，1H，-Ar)。
Embodiment 2
By 22.463g (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, the aqueous methylamine solution of 50ml40% and 250ml acetone joins in 1000ml there-necked flask, stirs into suspension; Heating, back flow reaction 6h, obtains yellow clear solution; 50 DEG C remove solvent under reduced pressure, obtain yellow solid; Add 200ml acetone and 200ml purified water, stir 10min; Filter, collect filter cake, and forced air drying at 50 DEG C, obtain white solid 16.000g, yield is 66.39%.
Embodiment 3
By 16.963g (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, the methylethylolamine solution of 74ml40%, 70ml Virahol and 100ml methyl alcohol joins in 500ml there-necked flask, stirs into suspension; Heating, back flow reaction 6h, obtains yellow clear solution; 50 DEG C remove solvent under reduced pressure, obtain lurid solid; Add 200ml acetone and 200ml purified water, stir 10min; Filter, collect filter cake, and forced air drying at 50 DEG C, obtain white solid 5.510g, yield is 40.96%.
Embodiment 4
By 25.013g (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, the aqueous methylamine solution of 50ml40% and 370ml propyl carbinol join in 1000ml there-necked flask, stirs into suspension; Heating, back flow reaction 6h, obtains yellow clear solution; 50 DEG C remove solvent under reduced pressure, obtain yellow solid; Add 300ml acetone and 300ml purified water, stir 10min; Filter, collect filter cake, and forced air drying at 50 DEG C, obtain white solid 9.124g, yield is 46.00%.
Embodiment 5
By 20.150g (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, the methylethylolamine solution of 80ml40%, 50mlN, dinethylformamide and 100ml methyl alcohol join in 500ml there-necked flask, stir into suspension; Heating, back flow reaction 6h, obtains yellow clear solution; Remove solvent under reduced pressure, obtain lurid solid; Add 300ml acetone and 300ml purified water, stir 10min; Filter, collect filter cake, and forced air drying at 50 DEG C, obtain white solid 7.250g, yield is 45.37%.
Claims (4)
1. the preparation method of N-[[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, it is characterized in that: by (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] methyl phthalimide, methylamine solution and solvent at room temperature join in there-necked flask, direct backflow aminolysis 2 ~ 16h, obtained product, wherein solvent is methyl alcohol, acetonitrile, Virahol, N, dinethylformamide, 1, 4-dioxane, one or more mixing in acetone or propyl carbinol.
2. the preparation method of N-according to claim 1 [[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, is characterized in that: the time of described backflow aminolysis is 2 ~ 8h.
3. the preparation method of N-according to claim 1 [[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, is characterized in that: described (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] mol ratio of methyl phthalimide and methylamine solution is 1:5 ~ 20.
4. the preparation method of N-according to claim 1 [[3-(the fluoro-4-morpholinyl of 3--4-base-phenyl)-2-oxazole ketone group-5-base] methyl]-2-methylamino--benzamide, is characterized in that: described (S)-N-[3-[the fluoro-4-morpholinyl of 3-] phenyl]-2-oxo-5-oxazolidinyl] ratio of methyl phthalimide and solvent is 1g:3 ~ 15ml.
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|---|---|---|---|---|
| CN1288462A (en) * | 1998-01-23 | 2001-03-21 | 法玛西雅厄普约翰美国公司 | Oxazolidinone combinatorial libraries, compositions and method of prepn. |
| US20060173047A1 (en) * | 2001-02-09 | 2006-08-03 | Bayer Aktiengesellschaft | Substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1, 3-oxazolines and their use as anticoagulant and antithrombotics |
| CN101772496A (en) * | 2007-06-20 | 2010-07-07 | 拜耳先灵制药股份公司 | Substituted oxazolidinones and the use thereof |
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Patent Citations (3)
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|---|---|---|---|---|
| CN1288462A (en) * | 1998-01-23 | 2001-03-21 | 法玛西雅厄普约翰美国公司 | Oxazolidinone combinatorial libraries, compositions and method of prepn. |
| US20060173047A1 (en) * | 2001-02-09 | 2006-08-03 | Bayer Aktiengesellschaft | Substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1, 3-oxazolines and their use as anticoagulant and antithrombotics |
| CN101772496A (en) * | 2007-06-20 | 2010-07-07 | 拜耳先灵制药股份公司 | Substituted oxazolidinones and the use thereof |
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| Title |
|---|
| A new and concise synthetic route to enantiopure Linezolid from (S)-epichlorohydrin;T Rajesh等;《Der Pharma Chemica》;20111231;第3卷(第5期);全文 * |
| Development and Validation of a liquid chromatographic method for simultaneous determination of Linezolid and its related substances and Degradation impurities in bulk drug;K.Jaya Prasanti等;《Journal of Pharmacy Research》;20120531;第5卷(第5期);全文 * |
| New Antibacterial Tetrahydro-4(2H)-thiopyran and Thiomorpholine S-Oxide and S,S-Dioxide Phenyloxazolidinones;Upinder Singh等;《Bioorganic & Medicinal Chemistry Letters》;20031231;第13卷;全文 * |
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Address after: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee after: Ruiyang Pharmaceutical Co., Ltd Address before: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |